RU2359686C2 - Way of correction of endothelial dysfunction - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to cardiology, and can be used for correction of endothelial dysfunction. For this purpose against a diet, the dosed out exercise stresses and smoking termination, a biologically active additive "Timarin" in a dose of 5 ml 2 times a day to meal by a course 21 day is in addition entered.

EFFECT: reduction of terms of correction of endothelial dysfunction, and also improvement of function of an intercellular matrix, at the expense of nitrogen oxide level augmentation and depression of level of a complex matrix metalloproteinase-9/tissue inhibidor-1.

5 tbl, 4 ex, 2 cl

Description

The invention relates to medicine and can be used to correct endothelial dysfunction in patients suffering from various diseases and pathological conditions, the basis of the pathogenesis of which is endothelial dysfunction and dysfunction of the intercellular matrix.

Recent studies have convincingly shown the important role of endothelium in the development of cardiovascular disease (CVD). Endothelium is a highly specialized and metabolically active monolayer of cells lining the inner surface of blood vessels, heart valves, and some body cavities. Endotheliocytes respond to changes in the physical, chemical and humoral environment, producing biologically active substances that determine the function of smooth muscle cells (MMC), supporting intimal non-adhesion, regulating cell proliferation, and inflammatory and immune mechanisms in the vascular wall [Ageev F.T. et al. Endothelial dysfunction and heart failure // Cons med. - 2001. - No. 3. - S. 61].

From modern positions, the key link in the pathogenesis of atherosclerosis is considered to be endothelial dysfunction (ED), which is manifested by a violation of the delicate balance between the main functions of the endothelium: vasodilation and vasoconstriction, inhibition and promotion of proliferation, antithrombotic and prothrombotic, antioxidant and prooxidant. Some researchers believe that ED initiates the development of atherosclerosis, essential hypertension. This is facilitated by such modifiable CVD risk factors as smoking, hypokinesia, salt loading, various intoxications (including alcohol), disorders of carbohydrate, lipid, protein metabolism, infection, meteofactors, etc. The effect of age and hormonal adjustment during menopause is also great.

In the parameters of the physiological norm, in response to changes in the effect of “deformation of the endothelial shift”, rises and decreases in blood pressure in arterioles are leveled due to the finely balanced synthesis of vasodilators and vasoconstrictors. As a result, the blood flow velocity throughout the vessel remains stable, which improves the metabolism of organs and tissues [Ostroumova OD, Dubinskaya R.E. Endothelial dysfunction in cardiovascular diseases. Based on the materials of the XIII European Conference on Arterial Hypertension // Cardiology. - 2005. - No. 2. - S. 59-62].

Endothelial vasodilators such as nitric oxide (NO), prostacyclin, adrenomedullin, C-type natriuretic peptide, bradykinin and endothelial hyperpolarization factor have already been identified. They are opposed by the effects of endothelial vasoconstrictors: endothelin, angiotensin II (AT II), thromboxane

A ₂ , endoperoxides and superoxide anion.

It is known that NO contributes to the normalization of the functional state of the cell wall, as well as the coagulation potential of blood and microcirculation. It has been established that NO is involved in the regulation of lipid peroxidation: in physiological concentrations, NO acts as an antioxidant that inhibits the development of radical oxidative reactions. In addition, NO regulates the activity of genes expressing compounds that promote the adhesion of monocytes and leukocytes. The synthesis of vasoactive mediators is interconnected with the neurohumoral reninangiotensinaldosterone system (RAAS), which also regulates the proliferative activity of MMC vessels, cardiomyocytes, fibroblasts. The main effectors of RAAS are AT II and aldosterone, to which receptors on cell membranes of various tissues, including endothelium and MMC, are sensitive. The increased content in the blood and tissues of AT II and aldosterone along with hyperinsulinemia through the mechanism of synthesis of growth factors stimulates the processes of remodeling (pathological aging) of the cardiovascular system [Parshina S.S. Modern views on the biological effects of nitric oxide and its role in the development of cardiovascular pathology // Cardiovascular therapy and prevention. - 2006. - No. 5. - S.88-94].

Thus, endothelium and RAAS from morphofunctional positions represents a single whole, especially in the regulation of vascular tone. ED mechanisms are largely associated with changes in NO activity, a decrease in its synthesis, or an increase in its decay. But, in addition, such mechanisms as oxidative stress, imbalance in the RAAS, as well as substances produced by endothelial cells (cytokines, endotheliums and prostaglandins) participate in the development of ED.

In turn, proinflammatory cytokines (TNF-α, IL-1) stimulate macrophage activation and secretion of matrix metalloproteinases (MMPs). MMPs belong to the family of proteolytic enzymes that break down the main components of the extracellular matrix. The main source of MMP products are activated macrophages. Recently, much attention has been paid to the role of MMP in the pathogenesis of atherosclerosis and coronary heart disease. The relationship between the development of endothelial dysfunction and a violation of the structure and functional properties of both the matrix and matrix-cell relationships was revealed. Violations of the state of the extracellular matrix lead to a change in the structure and function of blood vessels, contribute to a decrease in the elasticity of the vascular wall, a change in the response to the vasodilating effect of nitric oxide, thereby accelerating the progression of the atherosclerotic process. The increased content of MMP leads to the destruction of intimal collagen, including collagen fibers of the atherosclerotic plaque tire, leading to its weakening, rupture and, as a result, to destabilization of IHD.

Methods of correction of endothelial dysfunction primarily include the appointment of a diet, increase physical activity and stop smoking [Galenko A.S., Shulenin S.N. Methods of non-pharmacological and pharmacological correction of endothelial dysfunction // PHARMindeks-Practician. - 2006. - No. 10. - C.2-10].

Great attention is currently drawn to the study of medical methods for the correction of ED [Kolomoets N.M. Endothelial dysfunction and its clinical significance // Military Medical Journal. - 2001. - No. 5. - S. 29-35; Galenko A.S., Shulenin S.N. Methods of non-pharmacological and pharmacological correction of endothelial dysfunction // PHARMindeks-Practician. - 2006. - No. 10. - C.2-10].

The modulators of endothelial dysfunction include a highly selective 3rd generation β-blocker. Clinical studies have proven the vasodilating effect of the drug by stimulating the activity of NO synthase in endothelial cells, increasing NO production, as well as reducing systemic oxidative stress.

Inhibitors of the angiotensin-converting enzyme (ACE inhibitor) improve endothelial function by reducing the vasoconstrictor reactions of the coronary arteries by 10-20% and inhibit the processes of atherogenesis. The beneficial effect of ACE inhibitors is associated with an increase in the level of bradykinin, which stimulates the formation of NO. Another mechanism of the action of ACE inhibitors on endothelial function is the blockade of the formation of AT II, which is an inducer of oxidative stress.

Antioxidants (ascorbic acid, etc.) improve the response of the brachial artery to reactive hyperemia in patients with coronary heart disease, arterial hypertension, heart failure, and smokers [Steinberg D. Antioxidants and atherosclerosis. A currant assessment // Circulation. - 1991 .-- Vol.84. - P.1420-1425]. Alpha-tocopherol (vitamin E) also improves the tonus-regulating function of the endothelium, especially in patients with post-infarction cardiosclerosis, with hypercholesterolemia, in smokers. Free peroxide radicals inactivate NO synthase. This effect, apparently, is the basis of the positive effect of antioxidants on microcirculation [Rimm T.V. et.al. Vitamin E consumption and the risk of coronary heart in men // N. Engl. J. Med. -1993. - Vol. 328. - P.1450-1456].

However, data on the effect on the endothelial function of drugs with antioxidant activity are quite contradictory [Galenko A.S., Shulenin S.N. Methods of non-pharmacological and pharmacological correction of endothelial dysfunction // PHARMindeks-Practician. - 2006. - No. 10. - C.2-10]. Numerous observations on the use of well-known antioxidants (vitamins A, C, E) did not give the expected positive result without the use of additional drug treatment. Duvall W.L. in his work cites data on the very low therapeutic efficacy of vitamins A, C and E used in the treatment of coronary artery disease [Duvall W.L. Endothelial dysfunction and antioxidants // Mt. Sinai J. Med. - 2005. - Vol. 72, No. 2. - P.71-80].

As the closest analogue to the claimed method of ED correction according to the achieved technical result, a correction method is selected that includes a combination of non-pharmacological methods, such as diet, dosed physical activity, smoking cessation and the use of pharmacological agents such as statins [Appendix to the journal “Cardiovascular Therapy” and prevention. " - 2004. - No. 2. - S.13].

HMG-CoA reductase inhibitors (statins) improve endothelial function by increasing the activity of endothelial NO synthase (e-NOS), reduce the expression of caveolin-1 in endothelial cells, resulting in increased NO production. It was established that in the treatment with statins, their effect on endothelial function appears earlier than the lipid-lowering effect. Modern studies provide data on the effect of statins on the increase in the number of endotheliocyte precursor cells, which contributes to the regeneration of endothelium and neovascularization in ischemic zones. The stabilization and regression of atherosclerosis under the influence of statins is the result of the correction of endothelial dysfunction, which usually occurs after 2-6 months of complex treatment. The mechanism of action of statins on endothelial function has been little studied. Perhaps its effect is associated with a decrease in blood cholesterol [Shevchenko OV et al. Statins. HMG-CoA reductase inhibitors. - Moscow. Reafarm Publishing House - 2003. - P.23-36].

The versatility of the action of statins allows you to use them as a kind of metabolic corrector.

However, taking statins may be accompanied by adverse reactions in the form of abdominal pain, constipation, diarrhea, increased liver enzymes, etc. [Appendix to the journal “Cardiovascular Therapy and Prevention”. - 2004. - No. 2. - S.15-16].

Thus, the correction of endothelial dysfunction today is a new and promising direction in the development of cardiology. Promising is the creation and use of combined tools that could solve the problems of correction of endothelial dysfunction.

The technical result of the invention is to shorten the correction time for endothelial dysfunction, as well as to improve the function of the intercellular matrix, which is expressed in an increase in the level of nitric oxide (NO) and a decrease in the level of the complex matrix metalloproteinase-9 / tissue inhibitor-1 (MMP-9 / TIMP-1).

The technical result is achieved by the fact that in the known method for the correction of endothelial dysfunction, including diet, dosed physical activity, smoking cessation and the use of a metabolic corrector, according to the invention, a biologically active food supplement “Timarin” at a dose of 5 ml 2 times a day is used before meals in monthly courses for 21 days.

Patients with various forms of coronary heart disease, in addition, are prescribed an angiotensin-converting enzyme inhibitor and / or β-blocker and / or statin.

Dietary supplement "Timarin" is a source of antioxidants and vitamin C and is an ethanol extract of the sea urchin, the active principle of which is echinochrome A, and additionally, "Timarin" contains ascorbic acid [Sanitary and epidemiological conclusion No. 77.99.03.935. B.0001380604, TU 9350-50 064-02698170-2004; manufacturing organization Pacific Institute of Bioorganic Chemistry FEB RAS]. In addition to echinochrome A, phospholipids, free amino acids and peptides, carbohydrates, selenium, macro- and microelements are determined in the extract.

When using the proposed method, a reduction in the correction time of endothelial dysfunction in patients is achieved by 2-4 times (up to 3 weeks instead of 6-12 weeks when using the prototype method) and improving the function of the intercellular matrix (within 3 weeks instead of 6-12 weeks when using the method prototype).

We examined 30 patients with coronary heart disease (14 men and 16 women; average age 53.7 years). The diagnosis of coronary heart disease was confirmed clinically (stable angina pectoris 1-2 functional class (FC), data echocardiography, bicycle ergometry and coronary angiography.

Patients of the main group received standard coronary artery disease therapy (diet therapy, dosed physical activity, smoking cessation was recommended, as well as drug therapy - beta-blockers and / or angiotensin-converting enzyme inhibitors according to indications) and additionally received Timarin dietary supplement orally 5 ml 2 once a day on an empty stomach for 3 weeks.

Before and after taking Timarin, the level of NO metabolites and the level of the MMP-9 / TIMP-1 complex were studied in all patients.

Patients noted the good tolerance of the biologically active supplement "Timarin", complications, allergic reactions, individual intolerance was not noted.

The comparison group — 30 patients with coronary artery disease — received similar standard therapy with atorvastatin (trade name Liprimar) at a dose of 20 mg per day for 12 weeks.

The results of the study are shown in table 1.

Table 1 The dynamics of the studied indicators Healthy faces Main group Comparison group Before taking Timarin After taking Timarin Before taking Liprimar After taking Liprimar Metabolite level
NO, μmol / L 47.0 ± 0.43 39.9 ± 0.77 43.7 ± 0.82 35.5 ± 0.65 40.1 ± 0.65 Complex level
MMP-9 / TIMP-1, ng / ml 2.77 ± 0.12 7.76 ± 0.57 5.66 ± 0.49 7.19 ± 0.16 5.77 ± 0.14

As can be seen from table 1, taking Liprimar for 12 weeks and Timarin for 3 weeks contributed to an increase in the level of NO metabolites in the main group and the comparison group. It is noteworthy that in the main group, against the background of prolonged standard therapy of coronary heart disease with additional Timarin, an increase in NO production to 43.7 ± 0.82 μmol / L is noted, which exceeds the initial values and is higher than the comparison group. Moreover, these results were obtained after 3 weeks of supplementing with standard therapy with Timarin, while in the comparison group, an increase in NO to 40.1 ± 0.65 μmol / L occurs 12 weeks after the start of therapy with Liprimar.

Both in the main and in the comparison groups, endothelial dysfunction is combined with impaired function of the intercellular matrix - this is evidenced by an increase in the level of the MMP-9 / TIMP-1 complex to 7.76 ± 0.57 ng / ml and 7.19 ± 0.16 ng / ml, respectively (p <0.05).

Correction by Liprimar for 12 weeks and Timarin for 3 weeks leads to stabilization of the condition and to an improvement in the function of the intercellular matrix in the form of a decrease in the level of the MMP-9 / TIMP-1 complex to 5.66 ± 0.49 ng / ml and 5 , 77 ± 0.14 ng / ml, respectively, which is significantly different from the initially elevated level. Considering that dysfunction of the extracellular matrix leads to a decrease in the elasticity of the vascular wall, a change in the response to the vasodilating effect of nitric oxide, the use of Timarin improves and, in some cases, the restoration of the vasodilating function of the endothelium due to the improvement of matrix-cell interactions, which increases the synthesis and bioavailability endogenous NO.

We also examined patients with hypercholesterolemia without the clinical manifestations of coronary artery disease, but there was a violation of endothelial dysfunction and the function of the intercellular matrix. In this case, patients are recommended diet, dosed physical activity, smoking cessation and dietary supplement "Timarin" in a dose of 5 ml 2 times a day orally on an empty stomach for 3 weeks. The result of the correction of ED is illustrated in example 1.

Examples 2-4 illustrate the correction of ED in patients with various forms of ischemic heart disease.

Example 1. Patient D., 55 years old. During the next medical examination revealed hyperlipidemia: total cholesterol 7.2 mmol / l; triglycerides 1.32 mmol / L; HDL 0.9 mmol / L; LDL 3.5 mmol / L; VLDL 2.8 mmol / L, which according to the WHO classification corresponds to the IIb phenotype. The examination did not reveal an increase in blood pressure, but the woman has the following risk factors for CVD: smoking 1 pack of cigarettes a day for 15-20 years, burdened by heredity in CVD (my father suffered from hypertension for many years and suffered myocardial infarction at the age of 51) .

All of the above suggests a low risk of death from diseases associated with atherosclerosis, and does not require the appointment of drug therapy for dyslipidemia.

An additional laboratory examination revealed a low content of NO metabolites in the blood serum and the level of the MMP-9 / TIMP-1 complex exceeding twice the normal level.

The patient was recommended diet, dosed physical activity, smoking cessation and taking dietary supplement "Timarin" in a dose of 5 ml 2 times a day orally on an empty stomach for 3 weeks. The results are presented in table 2.

table 2 The dynamics of the studied indicators Indicators Before taking Timarin After taking Timarin The level of metabolites NO, µmol / l 36.7 42,2 The level of the complex MMP-9 / TIMP-1, ng / ml 5.41 4.76

The results obtained in the course of the study indicate that, despite the absence of clinical manifestations of coronary heart disease, a woman has endothelial dysfunction, manifested by a decrease in NO production, as well as a dysfunction of the intercellular matrix, which contributes to a change in the response of the endothelium to the vasodilating effect of nitric oxide, thereby exacerbating endothelial dysfunction and contributing to the progression of atherosclerosis. Three-week therapy with Timarin corrects an imbalance in the endothelium system - the intercellular matrix.

Example 2. Patient P., 41 years old, suffers from hypertension for about 2 years with a maximum increase in blood pressure to 160/100 mm Hg, there is hypercholesterolemia (total cholesterol 6.2 mmol / L, LDL 3.7 mmol / L) . Bad habits - smoking 1/2 pack of cigarettes a day for about 10 years. There is a burdened heredity in cardiovascular pathology: mother - hypertension, myocardial infarction at the age of 60 years.

The patient is recommended diet therapy, regular exercise, smoking cessation, as well as treatment with the drug Lisinopril (an angiotensin-converting enzyme inhibitor) at a dose of 5 mg 2 times a day.

Given that against the background of standard therapy the desired result was not achieved, the patient was additionally prescribed Timarin in a dose of 5 ml 2 times a day orally on an empty stomach for 3 weeks.

The results are presented in table 3.

Table 3 The dynamics of the studied indicators Indicators Before taking Timarin After taking Timarin The level of metabolites NO, µmol / l 37.3 41.5 The level of the complex MMP-9 / TIMP-1, ng / ml 6.92 4.48

According to the data given in table 2, we can talk about an increase in the synthesis of nitric oxide and a decrease in the activity of the MMP-9 / TIMP-1 complex after taking Timarin, which may indicate an improvement in vascular tone and help slow down vascular remodeling, which causes the development and progression of atherosclerosis.

Example 3. Patient Sh., 65 years old, suffers from hypertension for about 15 years, in 1996 suffered a large focal anterior myocardial infarction, in September 2005 - repeated myocardial infarction in the scar zone. There is hypercholesterolemia (total cholesterol 5.9 mmol / L, LDL 3.89 mmol / L). Burdened heredity for paternal hypertension.

The patient is recommended diet therapy, regular physical activity, as well as treatment with Metoprolol (β-blocker) at a dose of 25 mg 2 times a day and Timarin is additionally prescribed at a dose of 5 ml 2 times a day orally on an empty stomach for 3 weeks due to insufficient the effect of previous therapy. The results are presented in table 4.

Table 4 The dynamics of the studied indicators Indicators Before taking Timarin After taking Timarin The level of metabolites NO, µmol / l 35,4 39.1 The level of the complex MMP-9 / TIMP-1, ng / ml 6.96 2.27

As a result of the treatment, a significant decrease in the level of the MMP-9 / TIMP-1 complex and an increase in the level of endogenous NO were obtained, which suggests a decrease in the imbalance in the system of some regulatory substances that determine the overall functioning of the circulatory system.

Example 4. Patient G., 48 years old, suffers from coronary heart disease for about 5 years (stable angina pectoris II FC), atherosclerosis of the aorta, coronary arteries, post-infarction cardiosclerosis (myocardial infarction of lower localization). Over the past 2 years, arterial hypertension with blood pressure rises up to 160/90 mm Hg Smokes up to 10 cigarettes per day; heredity in IHD is not burdened. During the examination, there is hypercholesterolemia (total cholesterol 6.2 mmol / L, LDL 4.1 mmol / L, HDL 0.8 mmol / L). For several years, receives a β-blocker (egilok 25 mg 2 times a day) and statin Liprimar 20 mg per day. Due to the insufficient effect of the previous therapy, the patient is recommended to take Timarin dietary supplement in a dose of 5 ml 2 times a day orally on an empty stomach for 3 weeks. The results are presented in table 5.

Table 5 The dynamics of the studied indicators Indicators Before taking Timarin After taking Timarin The level of NO metabolites, µmol / l 44.8 48.9 The level of the complex MMP-9 / TIMP-1, ng / ml 4.39 3.05

The data obtained indicate a normalization of the level of nitric oxide synthesis and a significant decrease in the level of the MMP-9 / TIMP-1 complex against the background of additional administration of Timarin, while normalization of the level of total cholesterol (4.39 mmol / L) due to a decrease in LDL to 2 was obtained. 7 mmol / L in comparison with the initial values and an increase in HDL level from 0.8 mmol / L to 1.04 mmol / L.

Claims (2)

1. A method for the correction of endothelial dysfunction, including diet, dosed physical activity and smoking cessation, characterized in that it is additionally administered the dietary supplement "Timarin" at a dose of 5 ml 2 times a day before meals for 21 days. 2. The method according to claim 1, characterized in that patients with various forms of coronary heart disease are additionally administered an angiotensin converting enzyme inhibitor, and / or β-blocker, and / or statin.