RU2294741C1 - Method for treating patients with ischemic cardiac disease, stable stenocardia in combination with arterial hypertension - Google Patents

Abstract

FIELD: medicine, cardiology.

SUBSTANCE: at the background of conventional therapy with β-blockers, inhibitors of angiotensin converting enzyme, antiaggregants and/or antagonists of calcium it is necessary to introduce monocinque at the dosage of 20 mg once or twice daily in combination with melatonin at the dosage of 3-6 mg once daily nocturnally. The innovation provides normalization of global systolic and diastolic myocardial function due to optimal combination of medicinal preparations introduced at declared schemes and dosages.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex, 9 tbl

Description

The present invention relates to medicine and relates to a method for the treatment of patients with coronary heart disease (NBS), stable angina pectoris (SS) in combination with arterial hypertension (AH).

Among cardiovascular diseases, the most adverse consequences are associated with coronary heart disease, which includes a wide range of clinical forms - from asymptomatic myocardial ischemia and angina pectoris to postinfarction cardiosclerosis.

Angina pectoris is its most frequent manifestation.

Currently, treatment of stable angina pectoris is traditionally based on three basic principles of antianginal drugs: β-blockers, calcium antagonists and nitrates [1, 2, 3]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are used as antihypertensive agents.

However, modern antianginal therapy does not always lead to the desired lasting effect. The individual selection of drugs often causes difficulties, despite the wide selection of antianginal and antihypertensive drugs. This is due to the restriction of contraindications, intolerance, lack of sensitivity to the selected drug, etc. This necessitates the search for new approaches in the treatment of IHD.

At present, nitro drugs related to mononitrates are used to prevent angina pectoris in patients with coronary artery disease and improve their quality of life.

Monochinque (isosorbide-5-mononitrate) - the latest generation nitrate is an antianginal drug, a peripheral vasodilator with a predominant effect on venous vessels [4, 5]. The mechanism of vasodilating and antianginal action of monochinqua consists of myotropic and neurotropic components. Monochinque is indicated for the prevention and long-term therapy of angina pectoris, rehabilitation treatment after myocardial infarction, and treatment of chronic heart failure [6].

However, monochinqua monotherapy in some patients does not achieve an improvement in global systolic and diastomic myocardial function and there is no night-time decrease in blood pressure. In addition, the short duration of action of monocinque, up to 12 hours, makes it necessary to use it as part of combination therapy, but in this case the desired clinical effect is not always achieved. For example, it has been proven that the combination of atenolol with isosorbide mononitrate, as well as the combination of atenolol, isosorbide mononitrate and nifedinin do not exceed the effectiveness of atenolol monotherapy [7].

The fact of different individual sensitivity of patients to prescribed drugs at different hours of the day is also known, which is associated with the biological rhythms (BR) of each patient. Biological rhythm is a self-sustaining (autonomous) process of periodically alternating the state of an organism and fluctuations in the intensity of physiological processes and reactions.

One of the treatment methods that allow taking into account the patient's daily and seasonal biological rhythms in order to increase the body's sensitivity to pharmacological effects is chronotherapy [8]. The principle of chronotherapy is that the patient receives the drug in accordance with its biorhythms [9]. This method requires preliminary clinical and pharmacological studies within a few days.

In recent years, there has been an increase in information about the importance of melatonin in the regulation of a wide range of physiological processes. Melatonin is the pineal gland neuropeptide, is N-acetyl-5-methoxytryptamine and is the biochemical key of the biological clock located in the suprachiasmatic nuclei of the hypothalamus. It has a wide spectrum of biological activity: antioxidant, antistress, sedative, immunomodulatory, vasodilator functions. It has a regulatory effect on the calcium channels of cell membranes, stimulates the production of prostanglandin E, which determines its vasodilating effect [10].

In clinical conditions, its antihypertensive effect in monotherapy has been proven and its effect is deepened when combined with angiotensin-converting enzyme inhibitors such as cantoprilim, a cozaar angiotensin receptor blocker [11]. However, the main goal in this case was to increase the antihypertensive effect in people not suffering from coronary heart disease.

The anti-ischemic and antianginal effects of melatonin in angina pectoris are not known.

The objective of the present invention is to increase the effectiveness of standard antianginal and antihypertensive drugs in the treatment of patients with coronary heart disease, stable angina pectoris in combination with arterial hypertension.

To this end, the effect of melatonin in combination with monochinque was studied in the traditional therapy of treatment of patients with coronary artery disease, stable angina pectoris in combination with hypertension on the dynamics of the main morphofunctional and hemodynamic parameters.

In accordance with the invention, a method is described for treating patients with coronary heart disease, stable angina pectoris in combination with arterial hypertension by administering β-adrenergic blocking agents, angiotensin converting enzyme inhibitors, antiplatelet agents and / or calcium antagonists to the patient, while monochinque is prescribed to the patient against standard therapy of the above diseases a dose of 20 mg 1-2 times a day and melatonin at a dose of 3-6 mg once a day at night.

In the case of the appointment of monochinque 1-2 times a day, it is taken in the morning and in the evening.

Under the influence of monocinque treatment in combination with melatonin, against the background of standard therapy, a significant, significant improvement in the global contractile function of the myocardium is noted, a normal degree of nighttime decrease in blood pressure is noted, the clinical effect occurs on the fourth day.

The invention is illustrated by the following examples.

Example 1

The study of two randomized groups of patients with coronary artery disease, stable angina pectoris (CCH) of the II-III functional classes (FC) in combination with hypertension (GB).

The first group of patients was 24 people. Among them were 13 men and 11 women aged 44 to 67 years, the average age was 57.9 ± 1.6 years. The duration of the disease ranged from 1 to 14 years (an average of 8.2 ± 1.2 years). CCH II FC was diagnosed in 11, CCH III FC in 13 patients. In 10 patients with IHD, heart failure (HF) I FC was complicated (according to NYHA classification), in 5 patients - CH II FC, in 9 patients there were no signs of HF. Two patients suffered from stage I GB, 10 - stage II GB, 12 - stage III GB. Postinfarction cardiosclerosis was diagnosed in 7 patients, one suffered from diabetes mellitus.

Patients of this group received traditional treatment (TL), including a drug from the IZS-5-MN group (monochinque - manufacturer "Berlin-Chemie AG", Germany - at a dose of 20 mg twice a day) - 24 people, β-blockers (atenolol at a dose of 25 mg twice a day) - 17, calcium antagonists (verapamil at a dose of 40 mg three times a day) - 7, angiotensin converting enzyme inhibitors (enap at a dose of 5 mg twice a day) - 15, antiplatelet agents (dose of aspirin 125 mg once in the evening) - 16 people.

The second group of patients was 19 people. Among them were 11 men and 8 women aged 49 to 69 years, the average age was 59.3 ± 1.8 years. The duration of the disease in this group ranged from 3 to 18 years (average 10.2 ± 1.9 years). CCH II FC was diagnosed in 10, CCH III FC in 9 patients. In 8 patients with coronary heart disease, HF I FC was complicated (according to NYHA classification), in 7 - HF II FC, in 4 patients there were no signs of HF. Three patients suffered from stage I GB, 11 - stage II GB, 5 - stage III GB. Postinfarction cardiosclerosis was diagnosed in 3 patients.

Patients of the second group received complex treatment (CL), including monochinqua at a dose of 20 mg 1-2 times a day - 19 people, β-blockers (atenolol at a dose of 25 mg twice a day) - 10, calcium antagonists (verapamil at a dose of 40 mg three times a day) - 9, angiotensin-converting enzyme inhibitors (enap at a dose of 5 mg 2 times a day) - 7, antiplatelet agents (aspirin at a dose of 125 mg once in the evening) - 7 people. All patients received melatonin (manufacturer "Nature's Bountry", USA) in a dose of 3 to 6 mg once a day at 22 hours.

The duration of treatment of patients in both groups was 14 days.

Before and after treatment, all patients underwent clinical and instrumental examination with the inclusion of Holter monitoring of the electrocardiogram (XM ECG), daily monitoring of blood pressure (BPM) and echocardiography. In addition, daily dynamic monitoring of the subjects was carried out, during which the number of anginal pains (CAB), their duration (PAB) and the number of tablets of nitroglycerin (KTH) taken to stop these pains were recorded, and a 6-minute walking test (6MTX) )

The study of central hemodynamics was carried out on an ultrasound scanner of the expert class Vivid 7 (USA). The indicators of systolic function of the left ventricle (LV) were analyzed: the final systolic and diastolic sizes of the left ventricle, the final systolic and diastolic volumes of the left ventricle, and the ejection fraction according to the Simpson method. The stroke and minute volumes of the heart (UO and MOS), the fraction of shortening of myocardial fibers and the rate of shortening of circular myocardial fibers (CV CVM) were determined. Total peripheral vascular resistance was calculated using the Frank-Poiseuille formula.

The LV diastolic function was also evaluated by the rate of early diastolic filling (peak E, cm / s) and the speed of slow filling (peak F, cm / s), as well as the ratio of peak E / peak A and isovolumetric relaxation time.

XM ECG was performed on a MT-101 Schiller portable device (Switzerland). Cardiac signals were recorded in modified leads Y, V5, V6 and analyzed on a computer analyzer of the same company. Determined the average, minimum and maximum values of the number of heartbeats (heart rate) during the day. Heart rhythm disturbances were revealed: the type of arrhythmia, the time of occurrence of extrasystoles, the number of episodes of ST segment depression during the day.

The number of episodes of depression (QED) of the ST segment, the amplitude of horizontal depression (AGD), the amplitude of oblique depression (AKND) and the total duration of episodes of depression (SPED) of the ST segment, as well as the number of episodes of ST segment elevation were determined. For episodes of subendocardial ischemia, the appearance of a horizontal or oblique depression of the ST segment by more than 100 μV (1 mm) with respect to the contour, or oblique slow depression of the ST segment by more than 150 μV (1 mm) was considered characteristic; for subepicardial ischemia - ST elevation of more than 1 mm.

Smad was performed non-invasively using a portable device "BR-102 Schiller" (Switzerland). Monitoring began at 8-9 a.m. and continued for 24 hours. Blood pressure (BP) was recorded every 15 minutes during wakefulness and every 30 minutes at night. During the study, patients kept self-observation diaries, in which episodes of physical and emotional activity, medication, sleep time, and periods of poor health were indicated.

According to the results MMAD was determined daily average, daytime and nighttime systolic (SBP) and diastolic (DBP) blood pressure variability (standard deviation) BP (STD BP), pulse pressure (PAP), mean arterial blood pressure (BP _avg), double product ( DP). The time index (IW) was also calculated, and the daytime and nighttime IW SBP and IW DBP were evaluated. The value of the morning rise (BP) of blood pressure was determined from 4 to 10 hours, the degree of night-time decrease (SNA) of SBP and DBP, on the basis of which the daily BP profile was estimated.

(6MTX) was performed in accordance with the standard protocol, according to which patients are encouraged to walk along the measured corridor at their own pace, trying to cover the maximum distance for 6 minutes.

As a result, the patient's tolerance to physical activity, the functional class of heart failure were determined.

All research results before and after the course of therapy were subjected to mathematical statistical analysis. Differences were considered significant at a significance level of P <0.05. For statistical testing of the hypotheses of materiality of differences in the average of independent samples with the same and different variances, the corresponding two-sampled parametric student criterion (t) was used. In a number of cases (with correlation coefficient values <0.7), a paired two sample t-test for averages was used to compare dependent (related) samples. All calculations were carried out on a personal computer using the Microsoft Excel program.

Analyzing the dynamics of clinical indicators with two alternative treatment methods, it was found that the appointment of melatonin in complex treatment with monochinqua leads to a persistent clinical effect (SLE) on 4.2 ± 0.6 days, and in the group of patients who received TL with monochinqua without melatonin, SLE advancing only on 6.1 ± 0.8 grids (Table 1).

Both treatment methods led to a significant decrease in indicators such as CAB, PAB and CTN. With CL, a more pronounced clinical effect was observed. The 6MTX test in both groups was indicative. A comparative analysis of the results of the two methods of therapy reliably confirms the higher efficiency of the second method of treatment (complex treatment of monochinqua with melatonin), which we used in the treatment of these categories of patients. This is confirmed by comparing the dynamics of the indicators KAB (P _(KL-TL) = 0.01) and KTN (P _(KL-TL) <0.01) (Table 1).

A comparative analysis of the dynamics of the main morphofunctional and hemodynamic parameters with two alternative methods of treatment showed that with traditional treatment with monochinqua, of all the main indicators characterizing systolic function of the heart, only the indicator (SECM) increased significantly. Whereas in CR with melatonin, clearly significant positive changes in almost all indicators were obtained, except for UO, which also did not change in TL. This may indicate a predominant effect of CL with monochinque and melatonin on the global contractile function of the myocardium (Table 2).

The favorable effect of TL with monochinqua on LV diastolic function was manifested by a significant increase in the rate of early diastolic filling (P _TL = 0.05) and the peak E / peak A ratio (P _TL = 0.04). There was a tendency to a decrease in the time of isovolumetric relaxation (P _TL = 0.06). The effectiveness of complex treatment with monochinqua and melatonin was also confirmed by a significant increase in peak E (P _KL = 0.009) and E / A ratio (P _KL = 0.002) (Table 2).

A comparative analysis of two treatment methods (TL with monochinque and CL with monochinque and melatonin) in relation to the dynamics of indicators of LV systolic and diastolic functions indicate the presence of significant differences in the results of such indicators as CSF, BWW, CSR, FU, SUTsVM and peak E (P _{( CL-TL)} = 0.02; 0.05; 0.04; 0.05; 0.04 and 0.04, respectively) (Table 2). This confirms the more favorable effect of CL with monochinqua and melatonin on LV systolic and diastolic functions.

According to the XM ECG, a positive anti-ischemic effect was established both in case of TL and CL, however, when CL with monochinqua and melatonin, all indicators improved more reliably, including the amplitude of oblique depression (AKND) of the ST segment (P _CL = 0.01) , which with TL with monochinqua decreased insignificantly (P _TL = 0.20) (Table 3). Therefore, with CL a more pronounced anti-ischemic effect was obtained.

A comparative analysis of the dynamics of the main indicators of XM ECG indicates a high reliability of differences in the indicators of QED ST and SPED ST after the treatment courses by two alternative methods (P _(KL-TL) = 0.003 and P _(KL-TL) = 0.001, respectively).

When analyzing the dynamics of the main indicators of ABPM, a positive effect of both treatment methods on the dynamics of average daily and average daily blood pressure indicators was obtained. However, in CL with monochinqua and melatonin, a more pronounced hypotensive effect was obtained. The high efficiency of CL with monochinqua and melatonin is most clearly observed in the analysis of night-time indicators of ABPM, in particular, GARDEN, DBP, SNA GARDEN and SNA DBP (Table 4).

Studying the variability of blood pressure, data were obtained on the positive effects of both treatments in the daytime. At night, the variability of blood pressure significantly decreased only under the influence of CL with monochinque and melatonin.

Comparative analysis of the dynamics of the main indicators of daily blood pressure monitoring indicates high reliability of differences DBP values _cf. AD and PD after the course of treatment with two alternative methods (P _(CL-TL) = 0.01, P _(CL-TL) = 0.01 and P _(KL-TL) = 0.02, respectively). This indicates a higher efficiency of CL monochinque with melatonin in comparison with TL with the inclusion of monochinque.

Analysis of the daily parameters of SBP indicates a significant difference only in the variability of SBP and DBP after treatment courses (P _(KL-TL) = 0.05 and P _(KL-TL) = 0.0001, respectively), which confirms a more pronounced effect of KL on the variability of blood pressure in the daytime.

Comparing the dynamics of the nighttime indicators of ABPM, a significant difference was found between the SBP and the DBP (P _(CL-TL) = 0.02 and P _(CL-TL) = 0.004, respectively), which indicates a more pronounced hypotensive effect of CL with monochinqua and melatonin at night Times of Day.

SNA SBP and DBP significantly increased only in CR with monochinqua and melatonin (P = 0.003 and P = 0.03, respectively). In addition, a high reliability of differences in the values of SNA CAD and SNA DBP was found in the treatment with two alternative methods (P _(CL-TL) <0.001 and P _(CL-TL) <0.001, respectively), which confirms the normalizing effect on the daily profile of blood pressure only in CL with monochinqua with melatonin.

According to the results of cosinor analysis, before and after complex treatment of monochinqua with melatonin, the presence of regular circadian rhythms of SBP, heart rate, and DP was established. Moreover, after CL with monochinqua with melatonin, the acrophases of heart rate and DP shifted from evening to daytime, and the daily rhythms of DBP and PAD were restored. It should be noted that after TL with the inclusion monocinque acrophase DBP and ABP _cf. significantly shifted in the early morning hours. Significant changes in the acrophase MAP, heart rate, PAD and DP were not observed. This suggests that CL monochinqua with melatonin has a more significant normalizing effect on the daily chronostructure of blood pressure and heart rate.

The beneficial effect of melatonin is apparently due to its pronounced antioxidant activity, vasodilating effect, sedative, antistress and biorhythmological properties.

After complex treatment of monochinqua with melatonin against the background of TL, there was a significant positive dynamics in the daily profile of blood pressure in most patients (Table 5).

Table 5
BPM indices before and after complex treatment of monochinqua with melatonin against the background of traditional therapy Indicators Before treatment (n = 19) After treatment (n = 19) R M ± m σ M ± m σ Daily values of indicators Heart rate, str / min 78.4 ± 1.4 5.9 70.5 ± 0.9 4.1 <0.001 *** GARDEN, mmHg 158.3 ± 5.0 21.9 135.7 ± 4.6 20.1 0.002 ** DBP, mmHg 93.6 ± 2.9 12.7 81.9 ± 2.2 9.8 0.003 ** ADSR, mmHg 115.1 ± 1.9 8.3 99.8 ± 1.6 6.9 <0.001 *** PAD, mmHg 64.7 ± 6.9 29.9 53.8 ± 6.0 26.0 0.24 DP, conv. units 123.7 ± 4.0 17.4 95.5 ± 3.2 14.1 <0.001 *** Daily Values GARDEN, mmHg 164.8 ± 4.5 19.6 142.8 ± 5.4 23.6 0.004 ** DBP, mmHg 97.8 ± 2.5 10.9 87.1 ± 3.0 13,2 0.009 ** IV garden,% 80.5 ± 4.5 19.5 66.4 ± 3.8 16,4 0.02 * IV DAD,% 69.1 ± 4.8 21.1 51.6 ± 5.1 22.1 0.02 * Night values of indicators GARDEN, mmHg 151.2 ± 4.0 17.6 123.2 ± 4.1 17.9 <0.001 *** DBP, mmHg 90.8 ± 2.4 10,4 77.3 ± 2.6 11.1 <0.001 *** IV garden,% 83.7 ± 4.2 18.1 71.9 ± 4.3 18.5 0.06 IV DAD,% 65.9 ± 7.2 31,4 43.6 ± 6.0 26.3 0.02 * OUP GARDEN, mm Hg 41.7 ± 3.2 14.0 28.2 ± 4.7 20.3 0.02 * VUP DAD, mmHg 25.4 ± 2.4 10,2 17.6 ± 2.5 11.0 0.03 * SNA GARDEN,% 8.1 ± 1.1 4.7 13.4 ± 0.9 3.9 0.003 ** SNS DAD,% 7.0 ± 1.0 4.3 11.0 ± 1.1 4.8 0.03 *

Example 2

The second group of patients suffering from coronary heart disease, CCH II-III FC in combination with GB and receiving traditional therapy in combination with monochinqua and melatonin, amounted to 19 people. The treatment of monochinqua with melatonin was quite effective with the onset of a persistent clinical effect on average 4.2 ± 0.6 days. The efficacy of CL was indicated by reliable favorable changes in clinical indicators (Table 6).

Table 6
The dynamics of clinical indicators under the influence of complex treatment of monochinqua with melatonin Indicators Before treatment (n = 19) After treatment (n = 19) R M ± m σ M ± m σ KAB per day 4.3 ± 0.4 1,6 0.2 ± 0.1 0.4 <0.001 *** PUB, min 8.8 ± 1.8 4.6 0.9 ± 4.6 0.4 <0.001 *** KTH per day, pcs 2.7 ± 0.3 1,5 0.2 ± 0.1 0.4 <0.001 *** 6MTX, m 400.0 ± 12.5 54.7 471.6 ± 9.7 42,2 <0.001 *** Here and in the following tables:
n is the number of examined patients;
M - average values of the studied indicators;
m is the error of the mean value;
σ is the standard deviation;
P is the significance level of the difference in means (M) before and after treatment;
*) - significance of differences, with * (Р≤0.05), ** (Р≤0.01) and *** (Р≤0.001).

The improvement of clinical symptoms was manifested by a significant significant decrease in the CAB from 4.3 ± 0.4 to 0.2 ± 0.1 times per day (P <0.001) and their duration (PAB) from 8.8 ± 1.8 to 0.9 ± 0.1 minutes (P <0.001). The daily number of nitroglycerin tablets used to relieve angina attacks from 2.7 ± 0.3 to 0.2 ± 0.1 (P <0.001).

The test with a 6-minute walk showed a significant increase in the results from 400.0 ± 12.5 to 471.6 ± 9.7 m (P <0.001) (Table 6).

The effect of the complex treatment of monochinqua with melatonin on morphofunctional and hemodynamic parameters is presented in table 7.

The analysis of the dynamics of indicators characterizing the morphofunctional state of the heart according to the Echo of the CG testified to a significant decrease in the CRC and CSR of the left ventricle from 5.25 ± 0.04 to 5.11 ± 0.05 cm (P = 0.01) and from 3, 75 ± 0.03 to 3.47 ± 0.03 cm (P <0.001), respectively (Table 7). BWW and CSR of the left ventricle also significantly decreased from 131.1 ± 2.4 to 122.9 ± 2.0 ml (P = 0.01) and from 58.4 ± 0.8 to 51.5 ± 1.3 ml ( P <0.001), respectively. A decrease in the final sizes and volumes of the left ventricle led to a significant increase in PV and FU from 55.3 ± 0.9 to 58.0 ± 1.1% (S = 0.006) and from 28.6 ± 0.7 to 31.9 ± 0.5% (P = 0.001), respectively. STMSVM significantly increased from 0.36 ± 0.02 to 0.41 ± 0.01 cm / s (P = 0.003). The positive dynamics of the described indicators indicates the beneficial effect of the complex treatment of monochinqua with melatonin on the global systolic function of the left ventricle, and on the improvement of myocardial contractility.

It should be noted that the MA and MI practically did not change (Table 7). In this case, the values of MOS and SI significantly decreased from 5.69 ± 0.19 to 5.03 ± 0.16 l / min (P = 0.01) and from 2.99 ± 0.11 to 2.65 ± 0, 09 l / min / m ² (P = 0.02), respectively, mainly due to the establishment of heart rate. OPSS and OPSS at KL decreased insignificantly.

Echocardiography revealed violations of local LV myocardial contractility in the form of hypokinesia (moderate, severe). Prior to treatment, hypokinesia sites were identified in six patients. After CL, as a result of improved coronary circulation, there were fewer areas of impaired local contractility (in 3 patients).

Table 7
Morphofunctional and hemodynamic parameters in patients with heart failure before and after complex treatment of monochinqua with melatonin against the background of TL Indicators Before treatment (n = 19) After treatment (n = 19) R M ± m σ M ± m σ KDR, cm 5.25 ± 0.04 0.17 5.11 ± 0.05 0.15 0.01 ** DAC, cm 3.75 ± 0.03 0.14 3.47 ± 0.03 0.11 <0.001 *** BWW, ml 131.1 ± 2.4 10.5 122.9 ± 2.0 8.5 0.01 ** CSR, ml 58.4 ± 0.8 3.6 51.5 ± 1.3 5.7 <0.001 *** PV,% 55.3 ± 0.9 3,7 58.0 ± 1.1 4.7 0.006 ** FU,% 28.6 ± 0.7 2,8 31.9 ± 0.5 2,4 0.001 *** SUTsVM, cm / s 0.36 ± 0.02 0.06 0.41 ± 0.01 0.04 0.003 ** UO, ml 72.7 ± 2.3 10.0 71.4 ± 2.0 8.5 0.65 UI, ml / m ² 40.07 ± 2.08 9.07 40.85 ± 1.85 8.04 0.78 MOS, l / min 5.69 ± 0.19 0.82 5.03 ± 0.16 0.69 0.01 ** SI, l / min / m ² 2.99 ± 0.11 0.47 2.65 ± 0.09 0.38 0.02 * OPSS, dyne / s / cm ^-5 1652.7 ± 66.2 288.4 1621.2 ± 64.9 282.7 0.58 OSS, dyne / s / cm ^-5 / m ² 870.9 ± 36.8 160,5 853.8 ± 35.7 155.5 0.57 Diastolic function Peak E, m / s 0.46 ± 0.02 0.08 0.50 ± 0.02 0,07 0.06 Peak A, m / s 0.72 ± 0.03 0.15 0.68 ± 0.03 0.15 0.44 E / A 0.68 ± 0.05 0.21 0.78 ± 0.05 0.22 0.02 * VIR, ms 98.8 ± 2.1 9.1 95.2 ± 1.8 7.6 0.18

Prior to the course of treatment, a model of diastolic dysfunction of the first type was identified. The effect of complex treatment with monochinqua and melatonin on LV diastolic function showed a tendency to increase the speed of early diastolic filling (peak E) from 0.46 ± 0.02 to 0.50 ± 0.02 m / s (P = 0.06) and an unreliable decrease in the speed of slow filling (peak A) from 0.72 ± 0.03 to 0.68 ± 0.03 m / s (P = 0.44) (Table 7). The ratio of peak E / peak A significantly increased from 0.68 ± 0.05 to 0.78 ± 0.05 m / s (P = 0.02). The isovolumetric relaxation time (VIR) significantly decreased from 98.8 ± 2.1 to 95.2 ± 1.8 ms (P = 0.18). Thus, CL monocinque with melatonin against the background of traditional therapy favorably affects the processes of myocardial relaxation.

The results of the XM ECG under the influence of complex therapy of monochinqua with melatonin against the background of traditional treatment

According to the XM ECG in patients of this group, various changes of the ischemic type were revealed. Of these, 12 patients (63.2%) had horizontal ST segment depression below the isoline by 1.0-2.5 mm (1.77 ± 0.16 mm); in 7 patients (36.8%), an obliquely downward shift of the ST segment was observed below the contour by 1.0-3.0 mm (1.88 ± 0.15 mm).

When analyzing the time of occurrence of myocardial ischemia, it was found that the majority (65%) of ischemic episodes occurred in the night and early morning hours, and the smaller part (35%) - in the daytime and during the active activity of patients. In addition, in patients with high arterial hypertension, myocardial ischemia occurred more often at night, which, obviously, is associated with a disturbance in the circadian rhythm of blood pressure as arterial hypertension increases.

Combined treatment of monochinqua with melatonin led to a significant decrease in the number of daily episodes of myocardial ischemia and normalization of the ST segment, which indicates the anti-ischemic effect of the therapy (Table 8). According to the results of the XM ECG, a significant significant decrease in the number of episodes of depression of the ST segment (QED ST) from 4.9 ± 0.5 to 0.8 ± 0.1 (P <0.001), as well as their total duration (SPED ST) per day, was found from 14.8 ± 1.7 to 1.2 ± 0.2 minutes (P <0.001). The ST segment elevation episodes (STE ST) were not registered in this group of patients either before or after treatment.

Analyzing the dynamics of the amplitude of the ST segment shift under the influence of CR, a significant decrease in the amplitude of horizontal ST depression (AGD ST) and the amplitude of oblique depression of the ST segment (AKND ST) from 1.77 ± 0.18 to 0.62 ± 0.11 mm (P <0.001) and from 1.88 ± 0.21 to 0.98 ± 0.23 mm (P = 0.01).

According to the results of the study, no favorable antiarrhythmic effect of CL of monochinque with melatonin was found. The data obtained indicate that the number of ventricular extrasystoles (VE) and supraventricular extrasystoles (SVE) significantly decreased from 57.2 ± 2.4 to 52.1 ± 2.4 (P = 0.14) and from 58.9 ± 3. 3 to 49.8 ± 4.3 (P = 0.10), respectively (Table 8).

Table 8
The effectiveness of complex treatment of monochinqua with melatonin on the background of TL in relation to indicators of ECM XM Indicators Before treatment (n = 19) After treatment (n = 19) R M ± m σ M ± m σ QED ST 4.9 ± 0.5 2.1 0.8 ± 0.1 0.4 <0.001 *** KEE ST - - - - - SPED ST per day, min 14.8 ± 1.7 7.5 1.2 ± 0.2 1,0 <0.001 *** AGD ST, mm 1.77 ± 0.18 0.62 0.62 ± 0.11 0.36 <0.001 *** AKND ST, mm 1.88 ± 0.21 0.55 0.98 ± 0.23 0.62 0.01 ** Renewable energy 57.2 ± 2.4 10,4 52.1 ± 2.4 10.5 0.14 SVE 58.9 ± 3.3 14.6 49.8 ± 4.3 18.7 0.10

The dynamics of hemodynamic parameters was manifested by a significant decrease in the daily SBP from 158.3 ± 5.0 to 135.7 ± 4.6 mm Hg. (P = 0.002), DBP from 93.6 ± 2.9 to 81.9 ± 2.2 mm Hg (P = 0.003) and blood pressure from 115.1 ± 1.9 to 99.8 ± 1.6 mm Hg (P <0.001). An unreliable decrease in PAD under the influence of CR from 64.7 ± 6.9 to 53.8 ± 6.0 mm Hg was established. (P = 0.24). In addition, there was a significant decrease in heart rate from 78.4 ± 1.4 to 70.5 ± 0.9 beats per minute and DP from 123.7 ± 4.0 to 95.5 ± 3.2 (P <0.001), which indicates a decrease in myocardial energy costs.

The day and night values of the GARDEN parameters after the course of CL monochinwe with melatonin significantly decreased from 164.8 ± 4.5 to 142.8 ± 5.4 (P = 0.004) and from 151.2 ± 4.0 to 123.2 ± 4 , 1 mmHg (P <0.001), respectively. There is also a significant decrease in daily DBP values from 97.8 ± 2.5 to 87.1 ± 3.0 mm Hg. (P = 0.009) and DBP values at night from 90.8 ± 2.4 to 77.3 ± 2.6 mm Hg (P <0.001).

IV DBP significantly decreased day and night from 69.1 ± 4.8 to 51.6 ± 5.1% and from 65.9 ± 7.2 to 43.6 ± 6.0%, respectively (P = 0.02) . This indicates a decrease in the pressure load exerted by increased blood pressure on the target organs (heart, kidneys, brain, etc.).

VUP GARDEN and VUP DAD decreased significantly from 41.7 ± 3.2 to 28.2 ± 4.7 mm Hg. (P = 0.02) and from 25.4 ± 2.4 to 17.6 ± 2.5 mm Hg (P = 0.03), respectively.

SNS GARDEN and SNS DBP initially averaged 8.1 ± 1.1 and 7.0 ± 1.0%, respectively (non-dippers), and after complex treatment - 13.4 ± 0.9% (P = 0.003) and 11.0 ± 1.1% (P = 0.03) (dippers).

Variability (STD) of blood pressure before and after complex treatment with melatonin was determined on the basis of generally accepted statistical processing of the corresponding standard deviations from mean blood pressure values (Table 9).

Studying the variability of blood pressure in the daytime and at night before and after treatment, respectively, it was found that in the daytime, STD SBP and STD DBP significantly decreased from 22.3 ± 1.8 to 15.1 ± 1.2 mm Hg. (P = 0.003) and from 17.5 ± 0.4 to 14.5 ± 0.4 mm Hg (P <0.001), respectively. At night, the variability indices of STD SBP and STD DBP also significantly decreased from 16.1 ± 1.4 to 12.7 ± 1.0 mm Hg. (P = 0.05) and from 13.1 ± 0.7 to 11.1 ± 0.7 mm Hg (P = 0.05), respectively.

Thus, melatonin in combination with monochinqua against the background of the traditional treatment of patients with coronary artery disease, CCH II-III FC in combination with hypertension has a pronounced antianginal and anti-ischemic effect. In addition, CL monochinqua with melatonin has a beneficial effect on myocardial contractility and left ventricular diastolic function. According to the ABPM, a positive dynamics was revealed in the form of a significant decrease in the average daily, average daily and average daily indicators of blood pressure and pressure load indicators. Data were also obtained on the restoration of the normal daily blood pressure profile (a sufficient decrease in blood pressure at night) and a significant decrease in its variability.

The above results indicate that with the lack of effectiveness of standard antianginal and antihypertensive drugs, the inclusion of melatonin in combination with monochinque in the traditional therapy of patients with coronary artery disease, SS in combination with hypertension can be recommended.

Information sources

1. Moiseev B.C., Belousov Yu.B., Karpov Yu.A. et al. Place of mononitrates in the treatment of coronary heart disease. Cardiology, 2000, No. 7, pp. 85-96.

2. Olbinskaya LI, Morozova TE, Modern aspects of pharmacotherapy of coronary heart disease, Physician, 2003, No. 6, pp. 14-19.

3. Abrams J., Beneficial actions of nitrates in cardiovascular disease, Am.J. Cardiol., 1996, v. 77, p.31-37.

4. Parker I.O., IS-5-MN Study Group: Eccentric dosing with isosorbide-5-mononit-rate in angina pectoris, Am. J. Cardiol., 1993, v. 72, p. 871-876.

5. Belousov Yu.B., Isosorbide-5-mononitrate: clinical pharmacology. New Medical Journal, 1997, No. 3, pp. 3-6.

6. Vidal is a specialist. Handbook "Cardiology", Moscow: AstraPharmService, 2004, p. 624.

7. Akhras F., Jackson G., Efficacy of nifedipine and mononitrate in combination with atenolol in stable angina. Lancet, 1991, v. 338, p. 1036-1039.

8. Zaslavskaya P.M., Chronopharmacology and chronotherapy, Chronobiology and chronomedicine, M .: Triada-X., 2000, pp. 179-211.

9. RF patent 2072337, A 61 K 31/00, 02/10/1997.

10. Malinovskaya NK, Anisimov VN, Basic ideas about the role of melatonin in the human body, Melatonin in norm and pathology, M .: Medpraktika Publishing House, 2004, pp. 72-84.

11. RF patent 2134108, A 61 K 31/405, 08/10/1999.

Claims (2)

1. A method of treating patients with coronary heart disease, stable angina pectoris in combination with arterial hypertension by administering β-blockers, angiotensin-converting enzyme inhibitors, antiplatelet agents and / or calcium antagonists to the patient, while monochinque is prescribed to the patient with a dose of 20 mg 1 against standard therapy -2 times a day in combination with melatonin at a dose of 3-6 mg once a day at night. 2. The method according to claim 1, characterized in that in the case of the appointment of monochinqua 2 times a day, it is taken in the morning and evening.