MERTENIL

Mertenil®

Effect on the kidneys

Proteinuria, predominantly of tubular origin, was observed in patients taking Mertenil® in high doses, especially at a dose of 40 mg, but in most cases it was intermittent or short-term. It has been shown that such proteinuria does not indicate the onset of acute or progression of existing kidney disease. The incidence of serious renal dysfunction is increased when taking rosuvastatin 40 mg. It is recommended to monitor renal function parameters during therapy with Mertenil® .

Musculoskeletal system

When using Mertenil in all doses, especially when taking the drug in a dose of more than 20 mg, myalgia, myopathy and, in rare cases, rhabdomyolysis were detected. Rhabdomyolysis has occurred very rarely with concomitant use of ezetimibe and HMG-CoA reductase inhibitors. In this case, pharmacological interaction between the drugs cannot be excluded, so Mertenil® and ezetimibe should be used together with caution.

The incidence of rhabdomyolysis increases when taking rosuvastatin at a dose of 40 mg.

Determination of CPK

Determination of CPK activity should not be carried out after intense physical activity that causes an increase in CPK, as this may complicate the interpretation of the results. If the CK level increases before the start of therapy to more than 5 times the ULN, a repeat measurement should be taken after 5-7 days. If repeated measurements confirm the initial CPK value (5 times higher than the ULN), Mertenil therapy should not be started.

Before starting therapy

Mertenil®, like other HMG-CoA reductase inhibitors, should be prescribed with extreme caution to patients with existing risk factors for myopathy/rhabdomyolysis. These factors include:

- renal failure;

- hypothyroidism (for a dose of 40 mg);

- own or family history of muscle diseases (for a dose of 40 mg);

- a history of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates (for a dose of 40 mg);

- alcohol abuse (for a dose of 40 mg);

— age over 65 years;

- conditions accompanied by an increase in the concentration of the drug in the blood plasma (for a dose of 40 mg);

- simultaneous use of fibrates (for a dose of 40 mg).

In such patients, the balance of risk and possible benefit of therapy should be assessed and clinical monitoring should be carried out throughout the entire course of therapy.

During therapy

In such patients, it is imperative to monitor CPK activity. Treatment should be discontinued if CPK levels are more than 5 times the ULN or if muscle symptoms are severe and cause daily discomfort throughout the day (even if CPK activity is 5 times less than the ULN). If symptoms disappear and CPK activity returns to normal, re-prescribing Mertenil or prescribing an alternative HMG-CoA reductase inhibitor in lower doses should be considered with careful monitoring of the patient. Regular monitoring of CK activity in patients in the absence of symptoms of rhabdomyolysis is impractical.

However, an increase in the incidence of myositis and myopathy was detected in patients taking other HMG-CoA reductase inhibitors together with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses, antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Therefore, simultaneous use of rosuvastatin and gemfibrozil is not recommended. The risk/benefit ratio should be carefully assessed when co-using rosuvastatin with fibrates or nicotinic acid in lipid-lowering doses (more than 1 g). Concomitant use of rosuvastatin at a dose of 40 mg and fibrates is contraindicated.

Mertenil® should not be prescribed to patients with acute, severe illness suggestive of myopathy or with the possible development of secondary renal failure (for example, sepsis, arterial hypertension, surgery, trauma, metabolic syndrome, seizures, endocrine disorders, electrolyte disturbances).

Effect on the liver

Like other HMG-CoA reductase inhibitors, Mertenil® should be prescribed with extreme caution to patients who abuse alcohol or have a history of liver disease.

Secondary hypercholesterolemia

In patients with secondary hypercholesterolemia due to hypothyroidism, nephrotic syndrome, therapy for the underlying disease should be carried out before starting treatment with Mertenil.

Ethnic groups

Pharmacokinetic studies revealed an increase in systemic concentrations of rosuvastatin among patients of Asian origin compared to data obtained among Caucasian patients.

Protease inhibitors

Concomitant use of rosuvastatin with protease inhibitors is not recommended.

Lactose

The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Impact on the ability to drive vehicles and operate machinery

Studies have not been conducted to study the effect of Mertenil on the ability to drive a vehicle and use technical equipment. However, based on the pharmacodynamic properties of the drug, it can be assumed that Mertenil® should not have such an effect. However, when driving a vehicle or other machinery, it is necessary to take into account that dizziness may occur during treatment.

Lipid-lowering drug. Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a cholesterol precursor. The main target of action of rosuvastatin is the liver, where cholesterol (C) synthesis and LDL catabolism occur.

Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, increasing the uptake and catabolism of LDL.

It also inhibits the synthesis of VLDL-C in liver cells, thereby reducing the total content of LDL and VLDL. Rosuvastatin reduces the elevated content of LDL-C, total cholesterol and triglycerides (TG), increases the content of HDL-C, and also reduces the content of apolipoprotein B (ApoB), non-HDL-C (the content of total cholesterol minus the content of HDL cholesterol, VLDL-C, TG -VLDL) and increases the level of apolipoprotein AI (ApoA-I). Rosuvastatin reduces the ratio of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C and ApoB/ApoA-I.

The therapeutic effect can be achieved within one week after the start of treatment; after 2 weeks, 90% of the maximum possible effect is achieved. Typically, the maximum possible therapeutic effect is achieved after 4 weeks and is maintained with further use of the drug.

Clinical effectiveness

Rosuvastatin is effective in the treatment of adult patients with hypercholesterolemia with or without symptoms of hypertriglyceridemia, regardless of their race, gender or age, as well as in the treatment of a special category of patients with diabetes mellitus or a hereditary form of familial hypercholesterolemia. Rosuvastatin is effective for the treatment of patients with Fredrickson type IIa and IIb hypercholesterolemia (average initial LDL-C level of about 4.8 mmol/l). In 80% of patients receiving rosuvastatin at a dose of 10 mg, the target LDL-C levels established by the European Society for Research on Atherosclerosis (less than 3 mmol/l) were achieved.

In patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses from 20 to 80 mg according to a forced dose titration scheme, all doses taken had a significant effect on changes in parameters characterizing lipid content and on achieving the goals of therapy. As a result of dose titration to 40 mg/day (12 weeks of therapy), the LDL-C content decreased by 53%. In 33% of patients, LDL-C values (less than 3 mmol/l) were achieved, corresponding to the target standards of the European Society for Research on Atherosclerosis guidelines.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average reduction in LDL-C was 22%. In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dL who received rosuvastatin at a dose of 5 mg to 40 mg 1 time / day for 6 weeks, the concentration of TG in the blood plasma significantly decreased.

An additive effect is observed in combination with fenofibrate in terms of TG content and with nicotinic acid (more than 1 g/day) in terms of HDL-C content.

Studies on the effect of rosuvastatin on reducing the number of complications caused by lipid disorders, such as coronary artery disease, have not yet been completed.

In patients with a low risk of coronary artery disease (defined as a Framingham risk of less than 10% over a period of more than 10 years), with an average LDL-C level of 4 mmol/l (154.5 mg/dl), rosuvastatin at a dose of 40 mg/day significantly slowed down the increase in the maximum value characterizing thickening of the carotid artery wall in 12 segments, compared with placebo, at a rate of -0.0145 mm/year (95% confidence interval (CI): -0.0196 to -0.0093, with p <0.0001). The 40 mg dose should be prescribed only to patients with severe hypercholesterolemia and a high risk of developing cardiovascular disease.

Pharmacokinetics

Suction

Cmax of rosuvastatin in blood plasma is achieved 5 hours after oral administration of the appropriate dose. Absolute bioavailability is approximately 20%.

Systemic exposure of rosuvastatin increases in proportion to the dose. There are no changes in pharmacokinetic parameters when taking the drug several times a day.

Distribution

Rosuvastatin is absorbed predominantly by the liver, which is the main site of cholesterol synthesis and clearance of LDL-C metabolism. Vd of rosuvastatin is approximately 134 l. 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism

Subject to limited metabolism (approximately 10%). Rosuvastatin is a fairly non-core substrate for metabolism by enzymes of the cytochrome P450 system. CYP2C9 is the main isoenzyme involved in metabolism, while the isoenzymes CYP2C19, CYP3A4 and CYP2D6 are involved in metabolism to a lesser extent. The main metabolite is N-desmethyl, which is 50% less active than rosuvastatin. Lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest is provided by its metabolites.

Removal

Approximately 90% of the administered dose of rosuvastatin is excreted unchanged from the body through the intestines (including absorbed and unabsorbed rosuvastatin), and the remainder is excreted unchanged by the kidneys. T1/2 is 19 hours, does not change with increasing dose of the drug. The geometric mean plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As is the case with other HMG-CoA reductase inhibitors, the process of “hepatic” uptake of rosuvastatin involves a membrane carrier of cholesterol across membranes, the transport protein C of organic anions. This transporter plays an important role in the elimination of rosuvastatin by the liver.

Pharmacokinetics in special clinical situations

Age and gender do not have a clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Comparative pharmacokinetic studies showed a two-fold increase in the mean AUC and Tmax in patients of Asian origin (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with values in Caucasians. In Indians, an approximately 1.3-fold increase in the average value of AUC and Cmax was observed. At the same time, an analysis of pharmacokinetics indicators for the entire study population did not reveal clinically significant differences in the pharmacokinetics of the drug among representatives of the Caucasian, Negroid races, and Latin Americans.

In patients with mild to moderate renal failure, plasma concentrations of rosuvastatin or N-desmethyl metabolite do not change significantly. In patients with severe renal failure (creatinine clearance less than 30 ml/min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration of N-desmethyl metabolite is 9 times higher compared to healthy volunteers. Plasma concentrations of rosuvastatin in hemodialysis patients were approximately 50% higher than in healthy volunteers.

In patients with varying degrees of liver failure (7 points and below on the Child-Pugh scale), an increase in T1/2 of rosuvastatin was not detected. However, in 2 patients (Child-Pugh scores 8 and 9), T1/2 prolongation was noted to be approximately 2 times greater than that of patients with lower Child-Pugh scores. There is no experience with the use of rosuvastatin in patients with liver failure more than 9 points on the Child-Pugh scale.

Arterial hypertension (AH) remains one of the most common pathologies in the population, contributing to the structure of disability and mortality from cardiovascular diseases (CVD) [18]. The course of hypertension is influenced by both external and internal factors. Hypertension is often associated with metabolic disorders: obesity, including abdominal obesity, impaired glucose tolerance, dyslipidemia, etc. [6]. According to the literature [13], dyslipidemia with increased levels of atherogenic lipid fractions is more common in hypertension.

A number of studies [11, 14] conducted in recent years have confirmed the prognostic value of arterial stiffness in different groups of patients. The spectrum of vascular disorders in hypertension is wider and includes non-atheromatous restructuring of the arteries, accompanied by a violation of their damping function with changes in left ventricular afterload and coronary perfusion. Currently, the concept of endothelial dysfunction (ED), which regulates the balance of processes such as maintaining vascular tone and permeability, hemostasis and local inflammation, including in hypertension, is being considered. Apparently, DE in combination with existing risk factors for the development of CVD contribute to its development and progression. In addition, a number of researchers [2, 7, 17, 28] believe that decreased endothelial function acts as a prognostic factor for unfavorable outcome in CVD. Cardiovascular complications (CVC) are not only the result of various interrelated processes called atherosclerosis, arteriosclerosis, DE, but also, as numerous studies have shown, the result of structural and functional restructuring of the heart, which can also worsen the prognosis of the underlying disease [4, 12, 15, 29].

Despite the fact that progress has now been made in studying the cardiovascular system in a number of pathological conditions, studies of these processes in women with dyslipidemia, suffering from hypertension at various periods of her “hormonal” life, are few in number and are extremely fragmented and often contradictory. At the same time, the study of these issues is of undoubted scientific and practical interest, as it allows us to develop recommendations aimed at improving the quality of examination of women with hypertension during the premenopausal period (PMP) in order to prevent cardiovascular complications in subsequent periods of a woman’s life - in menopause and postmenopause.

A decrease in estrogen levels in women in primary care leads to the development of metabolic disorders. Estrogens have a protective effect on lipid metabolism. Most authors point to the beneficial effect of estrogens on the content of cholesterol (C) and lipoproteins in the blood plasma - a decrease in the fraction of low-density lipoproteins (LDL) and an increase in high-density lipoproteins (HDL) (N.A. Gratsiansky, 1994; Walsh et al., 1991; Samsioe, 1993; Chow, 1995). Thanks to estrogens, the processes of cholesterol uptake and degradation in the vascular wall are inhibited (Hough, Zilversmit, 1986; Haarbo et al., 1991; Wagner et al., 1991; Clarkson et al., 1994). Due to estrogens, the production of very low density lipoproteins (VLDL) increases, which is accompanied by an increase in the level of triglycerides (TG) in the blood, and the LDL content decreases by increasing the number of liver receptors for LDL, which leads to increased catabolism. Estrogens inhibit the activity of hepatic triglyceride lipase, causing an increase in HDL levels due to a delay in their clearance [1, 23].

Antihypertensive therapy significantly reduces the risk of disease and death from cardiovascular complications [3, 9]. However, most studies concerning the problems of hypertension in middle-aged and older women cover mainly primary care [10, 16], paying much less attention to the premenopausal period. There is very little data that allows us to develop standards for the diagnosis and treatment of hypertension in women with dyslipidemia in this period. The information available in the literature on the course of hypertension in perimenopause and PMP is ambiguous regarding the relationship with the level of sex hormones in the blood and dyslipidemia, while there is a consensus on the increased manifestations of hypertension in women at this age.

Currently, the doctor has at his disposal a large number of pharmacological agents that, during long-term treatment, cause a decrease in blood pressure (BP), reverse development of left ventricular hypertrophy, and peripheral artery DE [20, 24]. It seems to us that it is justified to try in this situation to use mertenil and diroton, which affect the level of blood pressure, the process of remodeling of the vascular bed and left chambers of the heart, and DE.

Material and methods

The study included 52 women with stage II hypertension in primary care at the age of 45.0±3.5 years with changes in the rhythm and nature of menstruation, a decrease in estradiol levels (average 0.34±0. 04 pg/ml) and an increase in the level of follicle-stimulating hormone (FSH) in the blood serum (average 17.84±1.15 IU/ml). Lipid metabolism indicators were as follows: total cholesterol level - 5.43±1.50 mmol/l, LDL cholesterol - 4.1±1.8 mmol/l, HDL cholesterol - 1.31±1.60 mmol/l, TG - 1.71±1.50 mmol/l, atherogenic coefficient - 4.1±1.4.

The duration of hypertension disease averaged 4.8±2.2 years. The average level of systolic blood pressure (SBP) was 148±8 mm Hg, diastolic blood pressure (DBP) was 98±6 mm Hg. The study did not include patients with coronary heart disease, chronic heart failure, diabetes mellitus, or renovascular pathology.

The studied parameters were studied before treatment, during treatment and after 4-6 months of treatment. Additionally, the women kept diaries in which they recorded blood pressure and heart rate (HR) in the morning and evening.

The patients were divided into two groups. Patients of group 1 (n=22) received monotherapy with lisinopril (Diroton) at a dose of 10 mg for 6 months. Patients of group 2 (n=30) received combination therapy with lisinopril (Diroton) at a dose of 10 mg and rosuvastatin (Mertenil) at a dose of 10 mg/day for 4 months. A decrease in DBP by 10% or 10 mmHg was taken as a criterion for the effectiveness of antihypertensive therapy. and SBP by 15 mm Hg. from the initial level. The target blood pressure during therapy was considered to be less than 140/90 mmHg.

To assess the structural and functional state of the vascular bed before and after treatment, duplex scanning of the common carotid arteries (CAA) was performed using an Acuson 128 XP/10 device. When scanning the CCA, the intima-media thickness was measured at a distance of 1 cm proximal to the bifurcation along the posterior wall. Blood pressure on the brachial artery (BA) was measured twice according to the standard method; the average SBP and DBP and pulse pressure from two measurements were taken into account. In M-mode with synchronous ECG recording, the lumen of the CCA was measured in systole and diastole. For comparison between groups, a mean value equal to half the sum of the systolic and diastolic diameters was used. To assess the elasticity of the CCA, the elongation coefficient (CR) and the stiffness index (SI) were used. CR was calculated using the formula: CR = 2·ΔD/ΔPD/D{10-3 kPa}, where D is the diameter of the artery, ΔD is the change in artery diameter during the cardiac cycle, ΔPD is the change in pulse arterial pressure. IL was calculated using the formula: IL = log(SBP/DBP) / (ΔD /D), where D is the artery diameter, ΔD is the change in artery diameter during the cardiac cycle.

From the hemodynamic parameters of intravascular blood flow, the maximum systolic blood flow velocity (cm/s) and resistance index (units) were analyzed.

Statistical processing of data was carried out using the Statistica 6.0 program. Differences were considered statistically significant at p<0.05.

Results and discussion

In patients of both groups, a good antihypertensive effect was obtained after 2 weeks and was maintained for 6 months (Table 1).

A comparative analysis of the parameters of the structural and functional state of the vascular bed is presented in Table. 2.

In a comparative analysis of the diameter of the CCA after treatment, normalization of their average diameter was observed in group 2 (p <0.05). The speed of blood flow in the CCA in group 2 also turned out to be higher after treatment (p <0.05). The resistance index was lower in patients of group 2 who received combination therapy (p <0.001). The elastic properties of the carotid artery wall improved after treatment, the stiffness index decreased after treatment in patients of group 2 (p <0.001). Thus, the data obtained convincingly indicate the positive effect of combination therapy with diroton and mertenil on improving the elasticity of the CCA wall and reducing its stiffness in patients with hypertension with dyslipidemia in primary care hospitals with reduced estradiol levels.

Large arteries perform two main functions in the body: transport and damping. Changes in the vascular wall in hypertension lead to disruption of the damping function of blood vessels, contributing to an increase in pulse pressure and cardiac afterload [8]. The elasticity of the vascular wall is determined by the elastin fibers of the intercellular matrix, and the strength and rigidity are determined by collagen fibers [19, 21]. An increase in blood pressure during hypertension in women with dyslipidemia in a primary care setting with estrogen deficiency causes a change in their ratio with an increase in the total concentration in the vascular wall. As a result, it becomes stiffer and requires higher pressure than before to function properly. A cyclic process is completed, potentiating further progression of the disease. According to the Hagen-Poiseuille formula, a small increase in the radius of the vessel leads to a significant decrease in blood flow, which implies a decrease in the speed in it, and a small speed provides optimal conditions for the delivery of procoagulant factors to the interested area of the vascular wall and promotes the development of intermolecular interaction, aggregation and adhesion of formed elements and, thus, to the progression of atherosclerosis [12, 15, 22, 25]. In our study, we observed an expansion of the lumen of the CCA before treatment and a decrease in blood flow velocity in the carotid arteries associated with the expansion of the lumen of the vessel without hemodynamically significant stenoses, which indicates more pronounced structural and functional changes in the wall in the form of more pronounced arteriosclerosis. Under the influence of combination therapy, an improvement in the elasticity of the CCA wall and a decrease in its rigidity was observed.

According to modern data, DE occupies one of the most important places in the development and progression of CVD.

The endothelium provides regulation of vascular tone, the processes of hypertrophy and proliferation of smooth muscle cells, modulation of blood coagulation and fibrinolysis, as well as the process of inflammation. The main causes of endothelial damage are risk factors for the development of atherosclerosis: arterial hypertension, smoking and elevated levels of LDL in the blood plasma. It is known that modified LDL, subjected to slight oxidation, plays a critical role in the development of DE and the initiation of the atherosclerotic process. Modified LDL induces inflammatory cells to synthesize chemokines with subsequent stimulation of LDL peroxidation processes by activated monocytes and macrophages. Modified lipoproteins and cytokines reduce the formation of endothelial NO synthase. Fully oxidized LDL has pronounced pro-inflammatory and pro-atherogenic properties: they stimulate the synthesis of adhesion molecules, chemokines, growth factors, increase the proliferation of smooth muscle cells, collagen degradation and increase the coagulation capacity of the blood.

Damage to target organs, primarily the vascular bed with the development of arteriosclerosis, suggests a decrease in the vasomotor function of the endothelium in women with hypertension with dyslipidemia in PMP with hypoestrogenemia.

As can be seen from the data presented in table. 3,

When performing a test with post-occlusion reactive hyperemia, patients suffering from hypertension with dyslipidemia in the primary hospital are characterized by an increase in the increase in the diameter of the VA, more pronounced in group 2, in which the percentage of VA dilatation was higher after treatment (p <0.001). It should be noted that when conducting a test of reactive hyperemia against the background of a decrease in the vasomotor function of the VA endothelium, in 48.7% of cases an inertial type of vasomotor reaction was detected, which is characterized by the absence of a reaction within 2 minutes from the start of the test, which may indicate preclinical (initial) ) signs of atherosclerosis. After treatment with diroton, the inertial type of vasomotor reaction was detected only in 24.7% of cases in group 2 and in 31.3% in group 1.

In addition, when assessing the intraluminal diameters of elastic and muscular vessels, it was revealed that in patients the carotid artery was dilated relative to the size of the VA (p <0.001). It seems that arteries with a predominance of elastin structures are exposed to hemodynamic factors to a greater extent than arteries with smooth muscle and collagen fibers, and the identified direct correlation between the level of SBP and an increase in the diameter of the lumen of the carotid artery in patients with hypertension and hypoestrogenism (r = 0.56; p=0.001) may indicate that the leading place in the expansion of CCA as a sign of remodeling and preclinical atherosclerotic lesions of the vascular wall is occupied by the level of SBP, apparently due to a more pronounced variability of this indicator against the background of disturbed hormonal levels. The identified inverse correlation between the shear stress on the endothelium of the CCA and the thickness of the intima-media complex before treatment (r = –0.65; p = 0.001), as well as the diameter of the CCA (r = –0.57; p = 0.001) may indicate that that the expansion of the lumen reduces the shear stress on the endothelium, and this can, by influencing the mechanisms of nitric oxide production, stimulate the constriction of the muscle cells of the media, increasing the tone and thickness of the vascular wall. In addition, the patients had a low dilating response of the endothelium during the reactive hyperemia test, which was apparently associated with deeper organic changes in the smooth muscle cells of the vascular wall. This may be due to an increase in the mass of smooth muscle cells against the background of estrogen deficiency, which increases the degree of vasoconstriction in response to neurohormones, leads to an increase in peripheral vascular resistance and contributes to the stabilization and worsening of hypertension [28]. Thickening of the vascular wall, leukocyte infiltration, and mechanical damage due to excess blood pressure trigger the process of apoptosis of endothelial cells and predispose to the development and progression of atherosclerosis [4, 5, 11]. In addition, with a progressive decrease in the level of estradiol, the level of fibrinogen increases, which is characterized by an increase in blood viscosity, hypercoagulation, increased platelet aggregation and damage to erythrocytes [15], which also affects the condition of the vascular bed and contributes to the aggravation of atherosclerotic changes in the vascular wall.

Damage to target organs and, above all, their vascular bed with the development of arteriosclerosis, the manifestations of which we found in women with hypertension with dyslipidemia in the PMP, suggests a decrease in the vasomotor function of the endothelium in patients with hypertension with estrogen deficiency. According to modern data, one of the most important places in the development and progression of CVD is occupied by DE, which regulates the balance of processes such as maintaining the tone and structure of blood vessels, hemostasis, local inflammation and permeability of the vascular wall.

Angiotensin-converting enzyme inhibitors can improve endothelial function and inhibit atherogenesis. The clinical trial TREND (Trial on Reversing ENDotelial Dysfunction) confirmed the data of numerous experimental studies on the presence of endothelium-modulating and anti-atherosclerotic properties in this group of drugs. With DE, remodeling of the vascular wall is possible due to estrogen deficiency, which has a negative effect on the vascular wall. In addition, the endothelium of the vessel is constantly under pressure load and is damaged due to high blood pressure, and NO, which the endothelium secretes to expand the lumen of blood vessels, is not released in the required quantity, the stiffness of the vessel increases, elasticity is lost, vasodilation decreases, oxygen delivery decreases, and can develop ischemia.

One of the pleiotropic effects of statins is the improvement of endothelial function. It is known that the vasodilatory effect and prevention of pathological vasospasm under the influence of acetylcholine administration develop within 24 hours after taking a single dose of statins [26]. Vasodilation occurs due to increased production of nitric oxide due to increased expression of NO synthase. In addition, there is a decrease in the concentration of the vasoconstrictor factor endothelin-1. It has been established that in addition to an increase in NO concentration under the influence of statins, there is an improvement in the bioavailability of NO produced by the endothelium [27].

Thus, when examining women with hypertension and dyslipidemia in the primary care hospital, it is necessary to take into account blood lipid composition and disturbances in the status of sex hormones as independent risk factors for the progression of hypertension. Women with hypertension in primary care, dyslipidemia, and an imbalance of sex hormones should be allocated to a separate group of dispensary observation. The rapid progression of vascular wall remodeling with the development of arteriosclerosis and DE, characteristic of these patients, as well as the combination of such independent risk factors as high blood pressure, imbalance of sex hormones, which determine the transition of adaptive remodeling to maladaptive with the development of hemodynamic disorders and chronic heart failure, requires involvement in observation not only a cardiologist, but also a gynecologist-endocrinologist to determine the management tactics for patients in this category.

We noted an improvement in endothelial function and VA distensibility in both groups, more pronounced during combination therapy with diroton and mertenil. The data presented in the article are important for the practicing physician, as they allow one to predict the course of hypertension and changes in the structural and functional state of the vascular bed in this and the next periods of a woman’s life.

Instructions for use MERTENIL®

The incidence of rhabdomyolysis increases when taking rosuvastatin at a dose of 40 mg.

Determination of CPK activity should not be carried out after intense physical activity that causes an increase in CPK, as this may complicate the interpretation of the results. If the CK level increases before the start of therapy to more than 5 times the ULN, a repeat measurement should be taken after 5-7 days. If repeated measurement confirms the initial CPK value (5 times higher than ULN), therapy with Mertenil® should not be started.

Mertenil®, like other HMG-CoA reductase inhibitors, should be prescribed with extreme caution to patients with existing risk factors for myopathy/rhabdomyolysis. These factors include:

renal failure;
hypothyroidism (for a dose of 40 mg);
own or family history of muscle diseases;
a history of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates;
alcohol abuse;
age over 70 years;
conditions accompanied by an increase in the concentration of the drug in the blood plasma;
simultaneous use of fibrates.

In such patients, the balance of risk and possible benefit of therapy should be assessed and clinical monitoring should be carried out throughout the entire course of therapy. Treatment should not be started if there is a significant increase in the initial CK level (5 times higher than ULN).

It is recommended that patients be informed to immediately notify their physician if they experience unexpected muscle pain, muscle weakness, or cramps, especially when accompanied by malaise or fever. In such patients, it is imperative to monitor CPK activity. Treatment should be discontinued if CPK levels are more than 5 times the ULN or if muscle symptoms are severe and cause daily discomfort throughout the day (even if CPK activity is 5 times less than the ULN). If symptoms disappear and CPK activity returns to normal, re-prescribing Mertenil® or prescribing an alternative HMG-CoA reductase inhibitor in lower doses should be considered with careful monitoring of the patient. Regular monitoring of CK activity in patients in the absence of symptoms of rhabdomyolysis is impractical.

Very rare cases of immune-mediated necrotizing myopathy, clinically manifested by persistent proximal muscle weakness and increased serum CPK activity, have been reported during treatment or after discontinuation of treatment with statins, including rosuvastatin. Additional studies of the muscular and nervous system, serological studies, and therapy with immunosuppressive drugs may be required.

However, an increase in the incidence of myositis and myopathy was detected in patients taking other HMG-CoA reductase inhibitors together with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses, antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Therefore, simultaneous use of rosuvastatin and gemfibrozil is not recommended. The risk/benefit ratio should be carefully assessed when co-administering rosuvastatin with fibrates or nicotinic acid in lipid-lowering doses (more than 1 g). Concomitant use of rosuvastatin at a dose of 40 mg and fibrates is contraindicated.

Like other HMG-CoA reductase inhibitors, Mertenil® should be prescribed with extreme caution to patients who abuse alcohol or have a history of liver disease.

It is recommended to measure liver function parameters before and 3 months after the start of treatment. If the activity of hepatic transaminases in the blood serum is 3 times higher than the ULN, you should stop taking the drug Mertenil® or reduce the dose taken. The frequency of severe liver dysfunction (associated mainly with increased activity of liver transaminases) increases when taking 40 mg of the drug. In patients with secondary hypercholesterolemia due to hypothyroidism, nephrotic syndrome, treatment of the underlying disease should be carried out before starting treatment with Mertenil®.

Pharmacokinetic studies revealed an increase in the systemic concentration of rosuvastatin among patients of the Mongoloid race compared to data obtained among patients of the Caucasian race.

During co-administration of rosuvastatin and various HIV protease inhibitors with ritonavir, an increase in the systemic exposure of rosuvastatin is observed. In patients with HIV taking HIV protease inhibitors, both the benefit of lowering blood lipid concentrations while taking rosuvastatin should be carefully assessed, and the possible increase in rosuvastatin plasma concentrations should be taken into account at the beginning of treatment and during the period of increasing the dose of the drug. Concomitant use with HIV protease inhibitors is not recommended without dosage adjustment of rosuvastatin.

Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, nonproductive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

There is evidence that statins, as a class of drugs, cause increases in blood glucose concentrations and, in some patients at high risk of developing diabetes in the future, may cause a level of hyperglycemia at which standard diabetes treatment is indicated. However, this risk is outweighed by the reduced risk of vascular complications, so there is no reason to stop statin treatment. In patients at risk of hyperglycemia (fasting glucose concentration from 5.6 to 6.9 mmol/l, BMI >30 kg/m2, elevated triglyceride concentrations, arterial hypertension), clinical and biochemical parameters should be monitored in accordance with national recommendations.

The drug contains lactose, so it should not be used in patients with lapp lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Use in pediatrics

It is known that the effect of rosuvastatin on height, body weight, BMI and the development of secondary sexual characteristics according to the Tanner scale in children and adolescents aged 10 to 17 years was assessed for only one year.

Impact on the ability to drive vehicles and machinery

Studies have not been conducted to study the effect of the drug Mertenil® on the ability to drive vehicles and operate machinery. However, based on the pharmacodynamic properties of the drug, it can be assumed that Mertenil® should not have such an effect. However, when driving vehicles or other mechanisms, it is necessary to take into account that dizziness may occur during treatment.