RU2597161C2 - Agent with immunomodulating properties for prevention of atherosclerosis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to an agent with immunomodulating properties for prevention of atherosclerosis. Above agent contains 21 wt% of dried garlic powder, 21 wt% of dried Rhaponticum carthamoides powder, 21 wt% of powder of dried green tea leaves, 24 wt% of milk sugar (lactose), 7.8 wt% of stearic acid and 5.2 wt% of medical polyvinylpyrrolidone.

EFFECT: invention has immunomodulatory action, which manifests itself in depolarisation of macrophages, hypolipidemic action, antioxidant activity and thrombolytic action.

1 cl, 2 dwg, 2 tbl

Description

The invention relates to medicine and can be used as a prophylactic agent with immunomodulating and antiatherosclerotic properties.

In medical practice, a wide range of drugs is used for the treatment and prevention of atherosclerosis and other cardiovascular diseases, but recently, medical workers are increasingly turning to drugs of natural origin.

Closest to the invention is an anti-atherosclerotic agent made on the basis of garlic powder freeze-drying, stearic acid, low molecular weight polyvinylpyrrolidone medical and auxiliary substances for the preparation of tablets - aerosil, water-soluble methylcellulose (Orekhov A.N., Dobrotvorsky AE. Agent for prophylaxis. Federation No. 2082427 of June 27, 1997). The disadvantage of the drug is the insufficient manifestation of immunomodulating properties due to the use of one active component (powdered garlic), which reduces the effectiveness of the prevention and treatment of atherosclerosis.

The preparation of combined preparations based on phytonutrients opens up additional possibilities in their use in clinical practice.

The technical result that can be achieved by carrying out the invention is the creation of an effective pharmacological agent of natural origin with pronounced immunomodulating properties for antisclerotic therapy, which are ensured by the action of three active components: powder (granulate) of dried garlic (Allium sativum L.), powder of dried safflower (Rhaponticum carthamoides L.) and dried green tea leaf powder (Camellia sinensis L.). The drug also has an immunomodulatory effect, manifested in the depolarization of macrophages, lipid-lowering effect, antioxidant activity, thrombolytic properties.

The technical result is achieved due to the fact that the composition of the immunomodulating agent for the treatment of atherosclerotic diseases includes: sulfur compounds of garlic Allium sativum L. (allinin and allicin) at least 0.5% by weight of the drug, the sum of ecdysteroids of the safflower-like Rhaponticum carthamoides L. levzea (20 -hydroxyecdysone and inocosterone) - at least 1% by weight of the drug, the amount of gallocatechins of Camellia sinensis L. green tea (epicatech, epigallocatechin, epicatechin gallate, epigallocatechin gallate) - at least 10% by weight of the drug. The combination of these substances leads to a pronounced synergistic effect.

In the analyzed patent information sources, no information was found on the use of pharmacological agents with immunomodulating and anti-atherosclerotic properties, which are made on the basis of dried garlic powder, dried safflower-like powder and dried green tea leaf powder, which allows us to conclude that this technical solution meets the criteria for its protection .

The composition with immunomodulating properties for the prevention of atherosclerosis includes dried garlic powder (granulate), safflower-like dried levzea powder, dried green tea leaf powder, milk sugar (lactose), stearic acid, low molecular weight polyvinylpyrrolidone medical in the following ratio, wt. %:

dried garlic powder - 21.0;

powder of dried safflower levzea - 21.0;

powder of dried green tea leaf - 21.0;

milk sugar (lactose) - 24.0;

stearic acid - 7.8;

low molecular weight polyvinylpyrrolidone medical - 5.2.

The drug is made in the form of tablets as follows.

Example. Take 210 g of dried garlic powder, 210 g of dried safflower-like Levzea powder, 210 g of dried green tea leaf powder and mix with the other components to obtain a tablettable mass, while milk sugar (lactose) (GOST R 54664-2011) take 240 g, acids stearin (GOST 9419-78) - 78 g, low molecular weight polyvinylpyrrolidone medical (FS 42-1194-78) - 52 g.

The mass is tabletted in the usual way and 10-20 tablets are packed in blister strip packaging from a polyvinyl chloride film according to GOST 25250-82 and a printed aluminum foil varnished according to GOST 745-79.

The color of the tablets is creamy with a greenish tint, the smell and taste are specific.

Shelf life - no more than 24 months in a dry room at a temperature not exceeding + 30 ° C in a hermetically sealed package.

One 1.2 g tablet contains 250 mg of dried garlic powder, 250 mg of dried safflower-like powder, 250 mg of dried green tea leaf powder.

For the effective prevention of atherosclerosis and the manifestation of immunomodulating properties, the drug should be taken 1 tablet 2 times a day in the morning and in the evening, with an interval between meals of no more than 12 hours, ideally during meals. The tablets should be swallowed without chewing, drinking plenty of fluids.

The drug is contraindicated in gallstone disease, individual intolerance to garlic and leuzea.

The biological properties of the drug are to reduce blood cholesterol and triglycerides with hyperlipidemia, resorption of acute blood clots, prevent the development of atherosclerosis, strengthen the walls of blood vessels, reduce atherosclerotic plaques, the risk of heart attack and stroke, mass and individual prevention of acute respiratory viral infections, including increasing the body's defense system, normalizing immunity indicators.

Description of experimental data

The authors of the patent developed a unique approach to the creation of anti-atherosclerotic drugs. This approach is based on the use of a culture of cells isolated from aorta or human blood (macrophages) as a test system. Various substances are added to the primary culture of such cells. The anti-atherosclerotic activity of these substances is judged by the suppression of the main manifestations of atherosclerosis at the cellular level: the accumulation of intracellular lipids, proliferative activity, the synthesis of connective tissue matrix (aortic cells) or the secretion of pro-inflammatory cytokines (macrophages).

Atherogenesis is known to be a hidden inflammatory process, the regulators of which are tissue macrophages, which are highly active as a result of changes in peripheral blood monocytes (macrophages) under the influence of various endogenous pathological stimuli already in the early stages of the disease [Libby P et al., 2009, Kzhyshkovska Yu.G. et al. 2012]. A method for evaluating the functional analysis of macrophage activity was developed on the basis of data on the secretion of tumor necrosis factor-alpha (TNF-alpha) and CC chemokine 18 (CCL18). Promising experimental data were obtained that confirmed the hypothesis about the possibility of using macrophages as a model for diagnosis and test systems.

This technique can be used in the ex-vivo variant, when not the pharmacological substances themselves are added to the cell culture, but the blood serum taken from the patient after oral administration of the drug. Using this approach allows us to evaluate the antiatherosclerotic activity of not only drugs, but also natural plant components. Moreover, the results obtained are easily interpreted. Studies on cells are as close as possible to the situation in the body, since cultured human cells are used that interact with blood components, which very accurately mimics the situation in vivo.

Studies of the authors of the application revealed the anti-atherosclerotic properties of many substances, which allowed us to develop and create a series of functional food products and dietary supplements that have anti-atherosclerotic therapeutic potential. One of the products in this series is a TYPE based on garlic, leuzea and green tea.

The results of previous biotesting work, which is a scientific and technical methodological groundwork on the subject of the patent, are published in the international peer-reviewed publication: Sobenin I, Andrianova I, Ionova V, Karagodin V, Orekhov A. Anti-aggregatory and fibrinolytic effects of time-released garlic powder tablets. Applied Technologies and Innovations 2012 7 (2): 40-45.

In the study, the atherogenicity of the blood serum of patients with atherosclerosis was studied after a single dose of various drugs, including TIP and its ingredients. Blood was taken before and after a single dose of drugs. Sera obtained from blood samples were added to the primary culture of macrophage monocytes.

To assess the anti-inflammatory properties of TIP, the secretion of pro-inflammatory molecules in cultured human macrophages was measured. The criterion for evaluating anti-inflammatory efficacy was a pronounced (at least 15%) significant decrease in atherogenicity (expression of pro-inflammatory cytokines) when patients received TIP or its ingredients.

Thus, the anti-inflammatory effectiveness of TYPs is approximately 88% of the effectiveness of diclofenac, one of the most powerful non-steroidal anti-inflammatory drugs used in modern medicine. The effect of TYPE, as can be seen from the data in the table, is synergistic with respect to the effects of its components.

Evaluation of the antioxidant efficacy of the TYPE preparation was carried out in in vitro experiments. To quantify the antioxidant effects of TIP, a method was used based on a comparison of the effect of glutathione with the activity of TIP. The essence of the method is that red blood cells of donated blood undergo hemolysis under the influence of hydrogen peroxide. Then the experiment is repeated in the presence of glutathione taken in physiological concentration. The protective effect of glutathione is taken as 100%. Then, the protective effect of TIP was determined and its antioxidant potential was expressed in “glutathione” units, which turned out to be comparable with the action of glutathione.

As the experiments showed, the three-component composition should include: Allium sativum L garlic, safflower Rhaponticum carthamoides L and green tea Camellia sinensis L.

The content in the experimental samples of the components of the active principle, determining their health properties, was:

- sulfur compounds of garlic Allium sativum L. (allinin and allicin) at least 0.5% by weight of the functional food ingredient;

- the sum of ecdysteroids of the leuzea safflower Rhaponticum carthamoides L. (20-hydroxyecdysone and inocosterone) - at least 1% by weight of the functional food ingredient;

- the sum of gallocatechins of green tea Camellia sinensis L. (epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate) - at least 10% by weight of the functional food ingredient.

The TIP formulation, which included plants in the optimal combination, is presented in table 2.

Post-marketing studies have revealed the clinical efficacy of TYPE, which reduces the incidence of cardiovascular disease, acute respiratory viral infections and other diseases. In terms of anti-atherosclerotic efficacy, TIP is not inferior to well-known drugs that cause regression of atherosclerosis, such as statins and calcium antagonists. A direct correlation was found between the ability of TIPs to cause regression of atherosclerosis in patients and inhibition of lipid accumulation in cultured cells in an ex vivo model.

In particular, the following data were obtained on the preventive and clinical efficacy of the TYPE preparation:

- In a double-blind, placebo-controlled study, the effect of TIP on the dynamics of atherosclerotic changes was evaluated in 211 men aged 40-74 years. The progression of atherosclerosis was evaluated by the change in the thickness of the intimalomedial layer (IMS) of the carotid arteries and the state of the walls of the vessels. The thickness of the IC was evaluated by high-resolution ultrasonography in the B-mode. The initial thickness of the IC was 0.935 ± 0.009 mm. In the group of men taking TIP (1200 mg per day), a decrease in the thickness of the IMS was observed (-0.028 ± 0.008 mm per year), while in the placebo group, moderate progression of atherosclerotic lesions was observed, which amounted to 0.014 ± 0.009 mm per year (p = 0.002). A significant decrease in the thickness of IMS was observed in 53.3% of men taking the TYPE, and in 25.5% in the placebo group (p <0.05). In contrast, a significant increase in the thickness of IMS was observed only in 19.0% of men taking the TYPE, and in 52.8% of the placebo group (p <0.05). When including the blood serum of patients, it was shown that it has pronounced atherogenic properties, that is, it causes an average 1.6-fold increase in cholesterol in cultured macrophages. In men taking the TYPE, serum atherogenicity decreased on average by 45% from the baseline, while in the placebo group, no significant changes in serum atherogenicity were observed. The results of the study confirm that prolonged use of TIP leads to the development of a direct anti-atherosclerotic effect, combined with a pronounced suppression of the atherogenic properties of blood serum (Fig. 1).

- In a double-blind, placebo-controlled study, the effect of TIP on serum lipids was studied in moderate hyperlipidemia in 42 patients aged 35-70 years. The first group of patients took TYPE at a dose of 1200 mg / day, the second group took placebo 1 tablet 2 times a day, for 84 days. As a result of this study, it was shown that TIP compared to placebo reduces total cholesterol by 11%, low-density lipoprotein cholesterol by 15%, increases high-density lipoprotein cholesterol by 13%. Accordingly, TIP can be recommended for correction of lipid content in patients with moderate hyperlipidemia.

- In a double-blind, placebo-controlled study, the effect of TIP on hemostatic and fibrinolysis systems in patients with cerebral atherosclerosis complicated by chronic cerebrovascular pathology was studied. The study was carried out in two stages in cross-groups. Each stage consisted of a preparatory period and a period of drug exposure. At the first stage, the first group of patients (n = 15) took TYPE at a dose of 1200 mg / day; the second group (n = 14) is a placebo. In the second stage, the first group of patients (n = 15) took a placebo; the second group (n = 14) - TYPE in the same mode. It was found that TIP significantly suppresses ADP-induced aggregation of blood platelets in vitro and ex vivo. At the same time, TIP reduces the blood fibrinogen content and normalizes the initially reduced indicators of fibrinolytic activity and fibrinolysis index. Therefore, TIP, due to its ability to suppress platelet hyperactivity, reduce fibrinogen level, normalize blood fibrinolytic potential and dissolve acute blood clots, can be recommended along with other antithrombotic agents for the prevention and treatment of cerebral atherosclerosis complicated by chronic cerebrovascular insufficiency.

- In an open epidemiological study among healthy working residents of Moscow, it was found that taking TYPE during the year led to a decrease in total cholesterol by an average of 9%, triglycerides by 18%, while HDL cholesterol increased 11% of the initial level. At the same time, in men who received TYPs during the year, the estimated 10-year risk of coronary heart disease decreased by 16% from the initial value and became significantly lower than the value typical for men of the corresponding age. The estimated 4-year risk of myocardial infarction decreased by 5% and became equal to the value characteristic of men of the corresponding age in Western European countries.

- In an absentee open epidemiological monitoring conducted among elderly residents of Moscow, it was found that taking TYPE during the year leads to a significant (3.5-fold) decrease in cardiovascular mortality, which can be primarily associated with anti-aggregation and antithrombotic action of biologically active components of TIP (Fig. 2).

- In an open study, the effect of taking TYPE for 5 months on the incidence of acute respiratory infections in 172 students was studied. The control group consisted of 468 students. It was found that the use of TIP in children did not cause adverse reactions from the gastrointestinal tract. In the second month of treatment, the incidence of acute respiratory viral infections in children taking the TYPE decreased from 28.4% to 9.3%, compared with the level before treatment, and was 2.6 times lower than in the control group. The incidence of acute respiratory viral infections in the group of children taking the TYPE was 2.4 times lower on average throughout the study period than in the control group. Within a month after discontinuation of the drug, the incidence of acute respiratory viral infections in the group of children taking the TYPE remained low.

- In an absentee open three-year epidemiological observation conducted among adult residents of Moscow, it was found that the continuous use of TYPE during the year leads to a significant (average 2.3 times) decrease in the incidence of SARS and influenza, and with annual seasonal epidemic outbreaks incidence is reduced by 4-5 times.

Claims (1)

An agent with immunomodulatory properties for the prevention of atherosclerosis containing dried garlic powder, stearic acid, low molecular weight polyvinylpyrrolidone medical, characterized in that it additionally contains dried safflower-like levzea powder, dried green tea leaf powder, milk sugar in the following ratio, wt. %:
dried garlic powder - 21.0;
powder of dried safflower levzea - 21.0;
powder of dried green tea leaf - 21.0;
milk sugar (lactose) - 24.0;
stearic acid - 7.8;
low molecular weight polyvinylpyrrolidone medical - 5.2.