WO2013176564A1 - Produit à base de terpénoïdes pour la prophylaxie et le traitement de l'athérosclérose et l'atténuation du syndrome métabolique - Google Patents

Produit à base de terpénoïdes pour la prophylaxie et le traitement de l'athérosclérose et l'atténuation du syndrome métabolique Download PDF

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WO2013176564A1
WO2013176564A1 PCT/RU2012/000420 RU2012000420W WO2013176564A1 WO 2013176564 A1 WO2013176564 A1 WO 2013176564A1 RU 2012000420 W RU2012000420 W RU 2012000420W WO 2013176564 A1 WO2013176564 A1 WO 2013176564A1
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terpenoid
agent
cholesterol
metabolic syndrome
atherosclerosis
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PCT/RU2012/000420
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Russian (ru)
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Людмила Анатольевна ЛАЦЕРУС
Анатолий Федорович ПИНИГИН
Фания Иршатовна МАГАНОВА
Нина Максимовна ПИНИГИНА
Валерий Геннадьевич МАКАРОВ
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Общество С Ограниченной Ответственностью "Инитиум-Фарм"
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Priority to PCT/RU2012/000420 priority Critical patent/WO2013176564A1/fr
Publication of WO2013176564A1 publication Critical patent/WO2013176564A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the field of medicine and the pharmaceutical industry, and in particular a terpenoid agent for the prevention and / or treatment of atherosclerosis and correction of the metabolic syndrome, the use of the pharmaceutical substance Abisil for the prevention and / or treatment of atherosclerosis and correction of the metabolic syndrome and the use of the pharmaceutical substance Abisil for the manufacture terpenoid agents for the prevention and / or treatment of atherosclerosis and the correction of metabolic syndrome.
  • the proposed terpenoidal agent has an anti-atherosclerotic effect, characterized by a decrease in blood total lipids, total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL), stimulation of cholesterol and bile acid excretion with bile, a decrease in the degree of damage to aortic intima, and prevention of aortic atherosclerosis and myocardial infarction , as well as the corrective effect in metabolic syndrome, characterized by normalization of blood pressure tions, triglycerides and blood glucose levels.
  • LDL low-density lipoprotein cholesterol
  • the proposed terpenoid agent can be used in diseases such as peripheral vascular atherosclerosis, arterial hypertension, coronary heart disease, type 2 diabetes and a number of other diseases caused by atherosclerosis, as well as in the correction of lipid and carbohydrate metabolism in metabolic syndrome.
  • agents that violate the stability of the cellular structures of the endothelium the following are considered: chemical injuries (hypercholesterolemia and homocystinemia), mechanical stress (hypertension), immune (organ transplantation), etc.
  • the development and course of the atherosclerotic process is determined by the ability of the cells of the arterial wall to maintain the integrity of the endothelium, for which many complex and interconnected metabolic processes stopping destructive changes are initiated. It has been established that with atherosclerosis, the release of chemokines by almost any cells is enhanced. This occurs under the influence of cytokines, lymphokines, bacterial lipopolysaccharides and viral infections of various etiologies (Arabidze G.G., Tebloev K.I. Atherosclerosis and risk factors - M: Litterra, 2008.- 240 s).
  • hypocholesterolemic formulations (patent RU N ° 2164408, 2001; patent RU Jfe2192856, 2002; RU patent Ns2394587, 2009; US patent N ° 4231938, 1980), carbohydrate metabolism-normalizing agents (RU patent N ° 2158590, 2000; RU patent N ° 2185826, 2001) or blood coagulation factors (RU patent Ns2129001, 1999).
  • statins or inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase HMG-CoA reductase
  • fluvastatin lovastatin, pravastatin, atorvastatin, rosuvastatin and anion exchange resins (sequestrants of bile acids - cholestyramine or colestipol); nicotinic acid and its derivatives; fibrates (derivatives of fibroic acid - bezafibrate, gemfibrozil, fenofibrate); bisphenol derivative - probucol; Omega-3 polyunsaturated fatty acids and a specific inhibitor of cholesterol absorption from the intestine - ezetimibe (patent RU jY ° 4137322, 1979; patent RU N ° 2011383, 1994; patent RU M> 2372921, 2009; patent RU N ° 2372923,
  • cholestyramine is contraindicated in obstruction of the biliary tract, nicotinic acid in case of impaired liver function, exacerbation of peptic ulcer, diabetes mellitus, gout, statins in acute liver diseases, pregnancy and lactation, infections, injuries, fibrates in pregnancy.
  • bile acid sequestrants often cause constipation, flatulence, anorexia, heartburn, dysphagia, hiccups, diarrhea, sometimes peptic ulcer, bowel obstruction, pancreatitis, bleeding due to vitamin K deficiency, weight gain.
  • nicotinic acid redness and itching of the skin, gastrointestinal disorders, hyperglycemia, hepatotoxicity.
  • myositis may develop with a significant increase in the content of creatine kinase in the blood and muscle tissue, as well as the appearance of insomnia, generalized, eczematous skin lesions, gastrointestinal disorders, hypersensitivity with the development of anaphylaxis and angioedema.
  • Gemfibrozil can contribute to the formation of gallstones.
  • MS metabolic syndrome
  • Another possible way to achieve this goal is to use drugs with a multifunctional effect.
  • Compounds of natural origin plant compositions, fungi, microorganisms
  • Plant compositions, fungi, microorganisms can meet this criterion.
  • statins - HMG-CoA reductase inhibitors the positive effects of which are determined not only by a direct effect on cholesterol synthesis, but also by its pleiotropic properties such as improved endothelial function, anti-inflammatory effect, and decreased LDL oxidation processes, suppression of thrombosis, antiproliferative and other actions.
  • statins One of the known drugs from the group of natural statins is lovastatin isolated from microorganisms belonging to the genus Aspergillus (US patent No. 4231938, 1980).
  • statins that have the necessary anti-atherogenic multifunctionality and are capable of correcting the metabolic syndrome, numerous toxic effects are noted, which causes contraindications to the appointment, and also require a long period of use for several years to achieve a therapeutic effect, which, moreover, is not sufficient.
  • terpenoids isoprenoids
  • terpenes and their derivatives the number of which currently totals more than 23,000 (isolated and chemically described), a wide variety of types of biological effects are recorded b
  • the pharmaceutical substance Abisil was used in the form of a dosage form (20% solution in oil) for local and external use, for which antimicrobial, anti-inflammatory, analgesic, wound healing and immunomodulating activities were identified and described [Patent RU 54945, 02.27.1996; Patent RU K ° 2198653, 02.20.2003; Patent RU JYQ2338547, 20.1 1.2008; The register of medicines of the Russian Federation, 2008, T.1: 14, 85], as well as antitumor and angiogenesis-inhibiting effects [PCT / RU 2008/000147. Published WO 2009/1 13902, September 17, 2009].
  • the present invention seeks to overcome the disadvantages of the state of the art.
  • the first aspect of the present invention provides a terpenoid agent for the prevention and / or treatment of atherosclerosis and correction of metabolic syndrome, containing from 10 to 20 mass. %, preferably 15 wt. % by weight of the pharmaceutical substance Abisil and a pharmaceutically acceptable vegetable oil.
  • vegetable oil includes sunflower oil, olive oil or soybean oil.
  • the terpenoid agent is formulated for oral administration, preferably in the form of a solution or gelatin capsules.
  • the proposed terpenoidal agent has an anti-atherosclerotic effect, characterized by a decrease in blood total lipids, total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL), stimulation of cholesterol and bile acid excretion with bile, a decrease in the degree of damage to aortic intima, and prevention of aortic atherosclerosis and myocardial infarction as well as corrective action for metabolic syndrome, characterized by normalization of blood pressure, triglycerides and glucose in the blood.
  • LDL low-density lipoprotein cholesterol
  • a second aspect of the present invention provides the use of the pharmaceutical substance Abisil for the prevention and / or treatment of atherosclerosis and the correction of metabolic syndrome.
  • the pharmaceutical substance Abisil is used in the form of from 10 to 20 mass. % solution, preferably 15 wt. % solution in pharmaceutically acceptable vegetable oil.
  • vegetable oil includes sunflower oil, olive oil or soybean oil.
  • the proposed solution is administered orally, preferably in the form of gelatin capsules.
  • the proposed solution has an anti-atherosclerotic effect, characterized by a decrease in blood total lipids, total cholesterol, triglycerides and cholesterol low density lipoproteins (LDL), stimulating the excretion of cholesterol and bile acids with bile, reducing the degree of damage to aortic intima, preventing the development of aortic atherosclerosis and the occurrence of myocardial infarction as well as the corrective effect in metabolic syndrome, characterized by the normalization of blood pressure, level three litseridov and blood glucose.
  • LDL cholesterol low density lipoproteins
  • a third aspect of the present invention provides for the use of
  • Abisil pharmaceutical substance for the manufacture of a terpenoid agent for the prevention and / or treatment of atherosclerosis and the correction of metabolic syndrome
  • the terpenoid agent contains from 10 to 20 mass. % by weight of the agent, preferably 15 wt. % by weight of the pharmaceutical substance Abisil and a pharmaceutically acceptable vegetable oil.
  • vegetable oil includes sunflower oil, olive oil or soybean oil.
  • the terpenoid agent is formulated for oral administration, preferably in the form of a solution or gelatin capsules.
  • the proposed terpenoidal agent has an anti-atherosclerotic effect, characterized by a decrease in blood total lipids, total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL), stimulation of cholesterol and bile acid excretion with bile, a decrease in the degree of damage to aortic intima, and prevention of aortic atherosclerosis and myocardial infarction , as well as the corrective effect in metabolic syndrome, characterized by normalization of blood pressure tions, triglycerides and blood glucose levels.
  • LDL low-density lipoprotein cholesterol
  • the aim of the present invention is to obtain a medicinal product that has an effective effect in the prevention and / or treatment of atherosclerosis against the background of destructive processes in the vascular wall, as well as in the development of metabolic syndrome.
  • the goal is achieved by means of a terpenoid based on the pharmaceutical substance Abisil, containing from 10 to 20 mass. % of the pharmaceutical substance Abisil by weight of the drug in a pharmaceutically acceptable vegetable oil.
  • the use of the proposed terpenoid drug is of great clinical importance, since with appropriate therapy it is possible to eliminate or reduce the main manifestations of these pathologies, especially since the metabolic syndrome predisposes to the development of atherosclerosis, arterial hypertension and type 2 diabetes mellitus - the main causes of morbidity and mortality in the world .
  • the claimed pharmaceutical substance Abisil and a terpenoid preparation made on its basis for oral use (15% oil solution in capsules) differs from the above funds in that it includes natural fir terpenoids of the genus Fir (Abies) taken in a certain mass ratio, which allows to reduce the amount of pharmaceutical Abisil substances for oral use without reducing its therapeutic efficacy, by dissolving this substance in oil (sunflower, olive or soybean) to 15% concentration and and making capsules.
  • composition of the claimed terpenoid agent (15% oil solution in capsules, for oral use) includes the starting components of the pharmaceutical substance Abisil in a mass fraction of%, namely: monoterpenoids (35 - 38%); sesquitepenoids (3 - 6%); neutral diterpenoids (1 1 - 15%); diterpenic acids (23 - 28%); triterpene acids (8 - 16%); unsaturated and saturated fatty acids (0, 1 - 0.3%); phenolic compounds (0, 1 - 0.2%) with a content of boronyl acetate of at least 10.0% of the total composition of terpenes dissolved in sunflower oil.
  • the pharmaceutical substance Abisil may be contained in an amount of from 10 to 20 masses. %, most preferably 15 wt. % by weight of the product.
  • the proposed amount of the pharmaceutical substance Abisil had specific activity and did not exert a general toxic effect on the body. animals. Even a single intragastric administration of the substance Abisil, at a dose of 10,000 mg / kg (100 times the therapeutic dose) to white mice weighing 20-22 grams, did not cause significant functional and structural changes in the organs and tissues of animals.
  • a pharmaceutically acceptable vegetable oil can be used as a pharmaceutically acceptable carrier, for example
  • sunflower oil olive oil or soybean oil.
  • Vegetable oil is also used as a solvent for the preparation of the proposed terpenoid agent of the desired concentration, because
  • the pharmaceutical substance Abisil represented by fir terpenoids of the genus Abies, is by nature a lipophilic formation and is therefore preferably soluble in vegetable fatty oils.
  • the amount of the pharmaceutical substance Abisil obtained in example 1, which allows to achieve the maximum therapeutic effect in the treatment and / or prevention of atherosclerosis with the correction of the concomitant metabolic syndrome, as part of the terpenoid agent used, should correspond to 15% of its concentration in a solution of sunflower (olive or soybean) oil.
  • the terpenoid agent can be formulated for oral administration, preferably in the form of a solution or gelatin capsules.
  • the claimed terpenoid agent is preferably used orally in a gelatin capsule or in the form of a 15% solution in oil, at a dose of 4-40 mg / kg body weight.
  • the proposed terpenoid agent has an antiatherosclerotic effect, characterized by a decrease in blood levels lipids, total cholesterol, low density lipoproteins and triglycerides, stimulating the secretion of bile cholesterol and bile acids, reducing the degree of damage to the aortic intima, preventing the development of aortic atherocalcinosis and the occurrence of myocardial infarction.
  • the preferred embodiment of the invention is the use of a terpenoid agent in the prevention and treatment of atherosclerosis, when administered orally at a dose of 10 ⁇ 0 mg / kg, since the most pronounced antiatherosclerotic effect was observed in rabbits atherosclerosis model at this dose.
  • the proposed terpenoid agent has a corrective effect in the metabolic syndrome, characterized by the normalization of blood pressure, the level of triglycerides and glucose in the blood.
  • a preferred embodiment of the invention is the use of a terpenoid agent for the correction of arterial hypertension, lipid and carbohydrate metabolism disorders when administered orally at a dose of 4-12 mg / kg, detected by modeling the metabolic syndrome in spontaneously hypertensive SHR rats.
  • Example 1 The preparation and composition of the terpenoid pharmaceutical substance Abisil
  • the initial raw material for the manufacture of the proposed pharmaceutical substance Abisil is the contents of capsules (nodules) located between the bark and bast of various representatives of the genus Fir (Abies), which is obtained by direct puncture and collection in light-proof bottles.
  • the capsule extract obtained in this way is a thick liquid from yellow to milky white with a specific odor and contains the entire complex of natural, naturally balanced terpenoids.
  • this natural terpenoid composition should contain a provoked (in terms of yield and synthesis) composition for bioprotection against stress factors and be enriched with monoterpene compounds. Stress factors can be environmental (temperature fluctuations, damage by microorganisms, smoke, etc.) or specially provoked (short-term tapping of trunks).
  • the capsule extract thus obtained was filtered at room temperature. His physico-chemical analysis showed:
  • IKS 3400, 2900, 1740, 1690-1700, 1450, 1390, 1270, 1250, 1040, 900 words 800 words cm "1.
  • PMR 0.82; 1, 67; 4.71; 5.77 ppm (C 6 D 6 ). Elemental analysis data:
  • a purified capsule extract is taken, placed in a flask in a water bath with an attached Klevenger apparatus, a finger cooler, and a graduated separation pipette with a drain by crane. Stripping is continued for 12 hours.
  • the volatile fraction collected in this way is an essential oil consisting of monoterpenic compounds: tricyclene, limonene, ⁇ -pinene, santene, camphene, etc.
  • the terpenoid pharmaceutical substance Abisil is obtained with
  • an oral terpenoid agent (15% oil solution in capsules), capable of exerting antiatherosclerotic therapeutic and / or prophylactic effects with simultaneous relief of the concomitant metabolic syndrome, it is characterized by the fact that it contains capsule terpenes of plants of the Pinaceae family, provoked by the release and synthesis, fir (Abies), enriched with identical monoterpenoids and includes the following components, wt.%:
  • Example 2 Obtaining a terpenoid agent (15% oil solution in capsules) for oral administration
  • solvents to a concentration of 5-40 mass. % by weight of the product.
  • solvents used pharmaceutically acceptable vegetable oils for example sunflower oil, olive oil or soybean oil, and various alcohols.
  • Mixing the substance with solvents is carried out at room temperature to avoid evaporation of volatile fractions and inactivation of the target product.
  • this composition can be used as a solution or in the form of capsules for oral administration.
  • the obtained terpenoid agent is characterized by the following physical constants: density 0.85-2.50; refractive index 1, 50-1, 52; saponification number 100-130; acid number 70-90; an ether number of 10-60 and a monoterpenoid-bornyl acetate content of at least 10.0% of the total number of terpenoids.
  • Abisil is an oral dosage form - 15% oil solution in capsules, with a new spectrum of pharmacological action and new possibilities for stopping pathological processes, in particular, with the development of atherosclerosis and metabolic syndrome.
  • Example H The study of the antiatherosclerotic effect of a terpenoid agent The study of the anti-atherosclerotic effect of the claimed terpenoid agent (15% oil solution, for oral use) was carried out in accordance with the “Methodological guidelines for the study of the lipid-lowering and anti-atherosclerotic effects of pharmacological substances” using generally accepted methods for determining changes in lipid and carbohydrate metabolism [Experimental (preclinical) manual the study of new pharmacological substances. M .: 2005: 452-461; Medical laboratory technology. St. Moscow: Intermedica, 2002, 600 s].
  • an atherosclerosis model was used, which was reproduced in rabbits by daily intragastric administration of cholesterol (manufacturer XIAMEN, China) at a dose of 0.3 g / kg.
  • vitamin D 2 ergocalciferol, manufactured by Nycomed, MerckKGaG, Germany
  • adrenaline was administered to rabbits twice every 15 days (producer of FSUE Moscow Endocrine Plant, Russia) at a dose of 0.04 mg / kg .
  • the inventive terpenoid agent (15% oil solution, for oral use) was used in doses of 10 mg / kg, 20 mg / kg and 40 mg / kg based on the active substances of the substance of this drug.
  • As a comparison drug used the well-known lipid-lowering agent used in the treatment of atherosclerosis - lovastatin at a dose of 0.7 mg / kg.
  • the animals were administered a terpenoid agent and lovastatin intragastrically through an atraumatic probe, once a day, on an empty stomach, for 60 days.
  • Intact and control (model of atherosclerosis without treatment) animals were given as a placebo sunflower oil GOST 1 129-73 in a volume of 1 ml.
  • lipid metabolism indicators were determined: total lipids (OL), phospholipids (FL), total cholesterol (OXC), triglycerides (TG), ⁇ -cholesterol - cholesterol of high density lipoproteins (HDL) and calculated indicators - cholesterol of low density lipoproteins (LDL), as well as lecithin-cholesterol index (LHI).
  • Blood biochemical parameters were determined on an A-25 biochemical analyzer using reagents from BioSystems, Parma, Olveks, SPINREACT in serum without traces of hemolysis. The procedure was carried out on an empty stomach, after 12 hours of fasting, in the morning at 9.00 hours. These indicators were evaluated five times during the experiment, at each blood sampling (on 0, 15, 30, 45, and 60 days).
  • CXI EFA / OXC, where: FA - total bile acids, mg%;
  • the aorta, its thoracic and abdominal sections were completely isolated. A longitudinal section of the aorta was opened, washed physical. solution, analyzed the area of damage to the aorta. Each aorta was photographed and planimetric atheromatous changes. Expected% of the lesion area. Measurements were performed using VideoTest software - Size 5.0. In addition, a macroscopic examination of the heart, coronary, carotid and pulmonary arteries, small arteries of the liver and spleen was performed.
  • Fragments of the aorta and liver were fixed in a 10% solution of neutral formalin for 24 hours, then the material underwent standard processing in alcohols increasing concentration (70-95%), xylene and paraffin for the manufacture of histological and immunohistochemical preparations with a thickness of serial paraffin sections 5-7 microns.
  • sections were stained with hematoxylin and eosin.
  • sections with a thickness of 7-10 ⁇ m were cut on a freezing microtome and stained with Sudan IV.
  • a morphological study of histological preparations and preparations stained by the immunohistochemical method was carried out using a Leica DM LS light-optical microscope with a magnification of 200 and 400.
  • ** - differences are statistically significant compared with control animals according to student criterion, at p ⁇ 0.05.
  • the level of total lipids in the group of intact animals remained within the physiological norm .
  • a sharp increase in the concentration of total lipids in the blood serum of experimental animals was observed: after 30 days, 2 times, after 45 days 3 times, by the end of the study, the level of total lipids was 3.2 times higher in comparison with the initial data.
  • the studied terpenoid agent restrained the growth of total lipids and by the 60th day their level was on average 2 times lower than the control, in the minimum dosage the difference was 2.2, in the maximum - 1, 7 times, which may indicate a tendency to inverse dose dependence.
  • the comparison drug lovastatin kept the level of total lipids within the physiological norm throughout the study and from day 45 had a statistically significant difference compared with the control group.
  • the level of total cholesterol in intact animals throughout the study did not change and fit into the range of physiological norms.
  • control animals and animals of the experimental groups treated with the atherogenic complex starting from the 15th day of the study, a marked increase in the level of total cholesterol was observed. It was maximally expressed in animals that did not receive treatment by the 45th day of the study, having a value 1 1 times higher than this indicator in the intact group in the same time period.
  • the level of total cholesterol was 7 times higher.
  • the cholesterol level had a maximum increase by the 45th day, with a slight tendency to decrease by the 60th study day.
  • the studied terpenoid agent showed an inverse dose dependence with respect to the level of OXC: it turned out to be ineffective in its maximum dosage, and the minimum studied dose showed a more pronounced decrease in OXC by the final day than when using the drug comparing lovastatin.
  • LDL (HDL-C) - (TG / 2.2). Normally, this indicator should not increase more than 3.87 mmol / l - the level of "risk".
  • the dynamics of LDL is consistent with the dynamics of total cholesterol.
  • the level of LDL in intact animals throughout the study did not change and fit into the range of physiological norms.
  • a marked increase in the level of LDL was observed. The most pronounced increase in this indicator was observed in animals that did not receive treatment, and by the 60th day the excess compared to intact animals was 15.5 times.
  • the studied terpenoid agent inhibited the growth of the studied parameter, which was more pronounced in the minimum dosage and by the 60th day was a decrease in LDL by 2.8 times compared with the control group of animals and the drug compared to lovastatin was superior in effect.
  • the lecithin-cholesterol index is calculated as: phospholipids / OXS. Normally, this index should not fall below 0.9-1, 2. In all studied groups, the lecithin-cholesterol index, starting from day 0 of the study, had threshold values and decreased during the experiment. Neither the reference drug nor the tested terpenoid agent had a statistically significant therapeutic effect on this indicator. However, a terpenoid drug in the minimum dosage tended to normalize LHI, the index of which was 60.03 days 1, 03 ⁇ 0.35.
  • the tested terpenoid drug in all the studied doses, was effective against dyslipidemia, it positively influenced the level of total lipids, total cholesterol, LDL and triglycerides, with respect to other indicators of lipid metabolism, the positive effect was expressed only as a tendency.
  • a dose of 10 mg / kg terpenoid agent had a positive effect on the level of total lipids, LDL, total cholesterol, triglycerides, phospholipids, and in terms of total cholesterol, LDL, phospholipids and lecithin-cholesterol index, the effect exceeded the effect of the comparison drug lovastatin.
  • lovastatin comparison drug against the background of pathology led to increased excretion of cholic acid, deoxycholic, while the excretion of cholesterol and bile acids increased by 22% and 43%, respectively, compared with the control group, and the cholesterol-cholesterol index increased by 17%.
  • the terpenoid agent significantly increased the excretion of bile, as well as bile acids and cholesterol, both in comparison with intact animals and with control animals.
  • a dose of 20 mg / kg of terpenoid agent increased the excretion of cholesterol by 1 1% and bile acids by 14% compared with the control group.
  • a terpenoid agent in the group of animals that received the minimum dose of a terpenoid agent, there was no atherocalcinosis of the aorta and cases of myocardial infarction.
  • a terpenoid agent at a dose of 10 mg / kg was found to be the most effective, which prevented the development of atherocalcinosis of the aorta and myocardial infarction.
  • the usual arrangement of hepatocyte beams with uniformly stained cytoplasm was recorded in the hepatic lobules. Necrosis and signs of metabolic damage were absent. Slight lymphoid infiltration of the portal tracts was observed. The data obtained allow us to conclude that there are no pathological effects of drugs on liver function.
  • the detected changes in the liver tissue are associated with the functional tension of the organ in response to an increase in the concentration of lipids in the blood.
  • a terpenoid agent had a positive effect on inhibiting the growth of atherogenic lipoproteins - it prevented an increase in total lipids, total cholesterol, LDL and triglycerides.
  • the test agent prevented the development of atherocalcinosis, reduced the area of damage to the aorta and damage to the aortic valve, thereby reducing the severity of atherosclerotic changes and the likelihood of myocardial infarction.
  • the terpenoid agent has a choleretic effect, as well as the ability to stimulate the release of cholesterol and bile acids with bile, which is most likely one of its mechanisms of action, which is reflected in its effect on the blood lipid spectrum.
  • Modeling of metabolic syndrome was carried out using the diet "cafeteria diet” on rats - males of the breed SHR (spontaneously - hypertensive).
  • the diet used is most recognized for the induction of a metabolic syndrome in animals close to human [Sampey B. P. et al. Obesity, 201 1, 19 (6), 1 109-1 1 17].
  • the products included in the nutritional composition (white bread, chocolate, potato chips, chocolate chip cookies, cheese crackers) were mixed with standard food and fed to the cage of experimental animals.
  • the diet contained 25-35% fat and 25-30% easily digestible carbohydrates. Induction of the metabolic syndrome using the “cafeteria diet” continued for 8 weeks.
  • the developed pathology was accompanied by arterial hypertension, glucose tolerance, impaired lipid metabolism with an increase in triglycerides and was recorded from 5 weeks.
  • the intragastric administration of the studied terpenoid agent (15% oil solution, for oral administration) was carried out at a dose of 4 mg / kg, 8 mg / kg, 12 mg / kg and 24 mg / kg based on the active substances of the drug substance.
  • Metformin [US Pat. No. 3,174,901], recommended by the WHO in the treatment of MS, at a dose of 200 mg / kg in a 1% solution of starch suspension was used as a comparison drug.
  • the administration of the studied drugs was carried out according to the treatment regimen, once a day, during the last 3 weeks in a volume of 1 ml.
  • GOST-1 129-73 sunflower oil was used as a placebo.
  • Glucose was measured using a OneTouch Horizjn glucometer from Lifescan USA. To do this, a puncture was made along the tail vein of the animal, the device was brought up with an inserted test strip, the device automatically took 1, 5 ⁇ l of blood.
  • the method for determining glucose is electrochemical, based on the biosensor glucose - oxidase principle. Linear measuring range 1, 1 - 33.3 mmol / L.
  • GTT glucose tolerance test
  • Blood pressure was measured at 6, 7 and 8 weeks of the experiment. To do this, an injection cuff with an integrated sensor was applied to the proximal section of the tail, and an ultrasonic pressure measurement sensor was slightly lower. The time of the most calm state of the animal, when it was in fixing house without movement. After fixing the cuff and sensors in a personal computer (PC), the LabChart 7 program window opened. Air was injected into the cuff after pressing the “Start / stop” button in the rat blood pressure measurement system (AD Instruments, Australia). The device is certified according to the rules of Good Laboratory Practice (GLP). Graphs for measuring blood pressure were displayed on a PC screen. Each animal was measured for 5-7 minutes. During this time, the device recorded blood pressure 5-7 times.
  • GLP Good Laboratory Practice
  • the baseline for assessing blood pressure was values obtained from animals kept on a standard diet of vivarium at 0 week. Changes in blood pressure were performed at 6 and 8 weeks of the experiment. The data are shown in table 4.
  • the comparison drug metformin at a dose of 200 mg / kg did not have a positive effect on lipid metabolism.
  • the studied terpenoid agent in doses of 12 mg / kg, 8 mg / kg and 4 mg / kg contributed to a statistically significant decrease in the concentration of TG in relation to control animals.
  • chenodeoxycholic acid is the primary bile acid that is formed in the liver from cholesterol
  • deoxycholic acid is formed from primary bile acids in the intestine under the influence of enzymes of microorganisms of the intestinal microflora.
  • An increase in the amount of deoxycholic and chenodeoxycholic acids can reduce the ability of the liver to produce cholesterol, prevent cholesterol reabsorption, and also increase cholesterol solubility.
  • This effect can be associated with both the direct effect of the studied terpenoid drug on liver metabolism and the effect on the binding of lipoproteins and cholesterol to receptors. It can be concluded that the studied terpenoid agent has a positive effect on the synthetic function of the liver.
  • the examples 1-4 show that the proposed terpenoid agent, in a therapeutically effective dose, when administered orally to animals with simulated signs of atherosclerosis and metabolic syndrome, leads to a decrease in blood levels of total lipids, total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL) and glucose, has a choleretic effect, stimulates the secretion of bile cholesterol and bile acids, lowers blood pressure, reduces the degree of damage to the intima of the aorta and its ateroc lecinosis, prevents the development of myocardial infarction.
  • LDL low density lipoprotein cholesterol
  • the proposed terpenoid agent with the most well-known drugs such as lovastatin and metformin, which are widely used in the treatment of atherosclerosis and metabolic syndrome
  • the terpenoid agent (15% solution in oil) revealed significant advantages, as in the specificity activity and to achieve a higher therapeutic effect.
  • a wide range of identified pharmacological activity of the proposed terpenoid drug makes it possible to reduce the number of administered lipid-lowering, hypoglycemic, antihypertensive, anti-inflammatory, immunomodulatory and other drugs used in the complex treatment of atherosclerosis or metabolic syndrome, which also reduces the frequency of adverse reactions.
  • terpenoid drug for a pharmaceutical substance a wide range of pharmacologically significant activities was previously identified: antimicrobial, anti-inflammatory, wound healing, analgesic, immunomodulating, antitumor and angiogenesis-inhibiting.

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Abstract

L'invention concerne un produit à base de terpénoïdes pour la prophylaxie et/ou le traitement de l'athérosclérose et l'atténuation du syndrome métabolique, l'utilisation de la substance pharmaceutique Abicil pour la prophylaxie et/ou le traitement de l'athérosclérose et l'atténuation du syndrome métabolique et l'utilisation de la substance pharmaceutique Abicil pour la fabrication d'un produit à base de terpénoïdes pour la prophylaxie et/ou le traitement de l'athérosclérose et l'atténuation du syndrome métabolique. L'invention porte sur un produit à base de terpénoïdes qui possède une action dirigée contre l'athérosclérose caractérisé par la baisse dans le sang des lipides totaux, du cholestérol total, des triglycérides et du lipocholestérol à lipoprotéines de basse densité par la stimulation de la sécrétion avec la bile du cholestérol et des acides biliaires, une atténuation des lésions subies par l'intima de l'aorte, l'empêchement du développement de l'athéro-calcinose de l'aorte et le développement d'un infarctus du myocarde, ainsi qu'un effet correcteur lors du syndrome X caractérisé par la normalisation des indicateurs de pression artérielle, de niveau de triglycérides et de glucose dans le sang, et peut s'utiliser lors de maladies telles que l'athérosclérose des vaisseaux périphériques, l'hypertension artérielle, la cardiopathie ischémique, le diabète de type 2 et toute une série d'autres maladies influencées par l'athérosclérose ainsi que pour la correction des troubles du métabolisme lipidique et carbonique lors du syndrome métabolique.
PCT/RU2012/000420 2012-05-25 2012-05-25 Produit à base de terpénoïdes pour la prophylaxie et le traitement de l'athérosclérose et l'atténuation du syndrome métabolique WO2013176564A1 (fr)

Priority Applications (1)

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PCT/RU2012/000420 WO2013176564A1 (fr) 2012-05-25 2012-05-25 Produit à base de terpénoïdes pour la prophylaxie et le traitement de l'athérosclérose et l'atténuation du syndrome métabolique

Applications Claiming Priority (1)

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PCT/RU2012/000420 WO2013176564A1 (fr) 2012-05-25 2012-05-25 Produit à base de terpénoïdes pour la prophylaxie et le traitement de l'athérosclérose et l'atténuation du syndrome métabolique

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WO2013176564A1 true WO2013176564A1 (fr) 2013-11-28

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2054945C1 (ru) * 1995-06-28 1996-02-27 Нина Максимовна Пинигина Средство "абисил-1", обладающее противовоспалительной, антибактериальной и ранозаживляющей активностью
RU2216337C2 (ru) * 2002-02-04 2003-11-20 Научно-исследовательский институт кардиологии Томского научного центра СО РАМН Кардиопротекторное средство
RU2244928C2 (ru) * 2003-02-19 2005-01-20 Пинигина Нина Максимовна Эндогенная фармацевтическая композиция, полученная на основе целенаправленной активации гуморальных медиаторов нервных окончаний коры головного мозга
EP2275112A1 (fr) * 2008-03-14 2011-01-19 Obschestvo S Ogranichennoy Otvetstvennostyu "Initium-Pharm" Composition pharmacologique antitumorale à base de terpénoïdes 'abissiline' possédant une action inhibitrice d'angiogenèse

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2054945C1 (ru) * 1995-06-28 1996-02-27 Нина Максимовна Пинигина Средство "абисил-1", обладающее противовоспалительной, антибактериальной и ранозаживляющей активностью
RU2216337C2 (ru) * 2002-02-04 2003-11-20 Научно-исследовательский институт кардиологии Томского научного центра СО РАМН Кардиопротекторное средство
RU2244928C2 (ru) * 2003-02-19 2005-01-20 Пинигина Нина Максимовна Эндогенная фармацевтическая композиция, полученная на основе целенаправленной активации гуморальных медиаторов нервных окончаний коры головного мозга
EP2275112A1 (fr) * 2008-03-14 2011-01-19 Obschestvo S Ogranichennoy Otvetstvennostyu "Initium-Pharm" Composition pharmacologique antitumorale à base de terpénoïdes 'abissiline' possédant une action inhibitrice d'angiogenèse

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