Composition containing angiotensin II receptor blocker and application of composition in medicine for dilating heart disease

Abstract

The invention relates to the technical field of medicine, in particular to a composition containing an angiotensin II receptor blocker and application of the composition in heart disease dilation medicine. The composition comprises an angiotensin converting enzyme inhibitor and an angiotensin II receptor blocker, and a small dose of ACEI and a large dose of ARB are combined to be used for dilating the heart disease. The traditional Chinese medicine composition has excellent effects in the aspects of reducing the left ventricular end diastolic anterior-posterior diameter or left-right diameter, plasma brain natriuretic peptide precursor (NT-pro BNP) plasma level, pulmonary arterial pressure and left ventricular ejection fraction, does not influence the normal levels of physiological indexes such as blood potassium, serum creatinine, urea nitrogen, alanine aminotransferase (ALT) and asparaginic acid aminotransferase (AST), and can be used for preparing a medicine for treating the left ventricular end diastole. The medicine can be applied to heart disease dilation medicines.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and particularly relates to a composition containing an angiotensin II receptor blocker and its application in drugs for dilated cardiomyopathy. Background Art

[0002] Cardiomyopathy refers to heart diseases other than congenital heart disease, pulmonary heart disease, hypertensive heart disease, coronary heart disease, valvular heart disease, and hyperthyroid heart disease, etc., mainly manifested as a group of heart diseases with myocardial lesions. Cardiomyopathy refers to a type of cardiomyopathy with impaired myocardial function. Dilated cardiomyopathy and restrictive cardiomyopathy are the most common among the six types of cardiomyopathy internationally.

[0003] In clinical practice, the most common cardiomyopathy and the one with the highest incidence is dilated cardiomyopathy (DCM), which is characterized by the enlargement of one or both cardiac chambers and impaired myocardial systolic function, with the main feature of congestive heart failure (CHF). Dilated cardiomyopathy is the third leading cause of heart failure, and malignant arrhythmia and sudden cardiac death are the final clinical manifestations, and it is the primary cause of heart transplantation.

[0004] In recent years, the incidence of dilated cardiomyopathy in China has shown a gradually increasing trend. Multiple factors such as genes, autoimmunity, infection, cellular immunity, and alcoholism can cause myocardial injury, and death can occur at any stage of DCM because its development shows a progressive aggravation trend, with difficult treatment and poor prognosis bringing a serious disease burden to individuals, families, and society.

[0005] Angiotensin-converting enzyme inhibitors (ACEI) can inhibit the renin-angiotensin-aldosterone system (RAAS), slow down the degradation of bradykinin, and strongly dilate peripheral arteries and veins; at the same time, it reduces water and sodium retention, decreases the preload and afterload of the heart, and increases the non-emissive heart rate, which can promote the improvement of heart failure, delay the deterioration of renal function, and reverse ventricular remodeling, and has an obvious therapeutic effect on refractory heart failure. Literature research reports at home and abroad show that most scholars apply angiotensin-converting enzyme inhibitors (ACEI) combined with β-blockers in drugs for dilated cardiomyopathy, and there are few reports on the application of low-dose angiotensin-converting enzyme inhibitors (ACEI) combined with high-dose angiotensin II receptor blockers (ARB) in drugs for dilated cardiomyopathy. Summary of the Invention

[0006] For the above reasons, the present application provides a composition containing an angiotensin II receptor blocker, which uses a small dose of angiotensin-converting enzyme inhibitor (ACEI) in combination with a large dose of angiotensin II receptor blocker (ARB) for dilated cardiomyopathy drugs, improves cardiac function, reduces the anteroposterior diameter or left-right diameter at the end of left ventricular diastole, plasma level of N-terminal pro-brain natriuretic peptide (NT-proBNP), pulmonary artery pressure, increases left ventricular ejection fraction, and does not affect the normal levels of physiological indicators such as blood potassium, serum creatinine, blood urea nitrogen, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

[0007] To achieve the above object, the present application provides a composition containing an angiotensin II receptor blocker, comprising an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker.

[0008] Further, the angiotensin-converting enzyme inhibitor is benazepril hydrochloride or perindopril.

[0009] Further, the dosage of benazepril hydrochloride, the angiotensin-converting enzyme inhibitor, is 5 - 10 mg / d.

[0010] Further, the dosage of perindopril, the angiotensin-converting enzyme inhibitor, is 2 - 4 mg / d.

[0011] Further, the angiotensin II receptor blocker is irbesartan or valsartan.

[0012] Further, the dosage of irbesartan, the angiotensin II receptor blocker, is 300 - 750 mg / night.

[0013] Further, the dosage of valsartan, the angiotensin II receptor blocker, is 160 - 480 mg / night.

[0014] The present application also provides an application of a composition containing an angiotensin II receptor blocker in dilated cardiomyopathy drugs.

[0015] In summary, the present application has the following beneficial effects:

[0016] The composition containing an angiotensin II receptor blocker provided by the present application has excellent effects in improving cardiac function, reducing the anteroposterior diameter or left-right diameter at the end of left ventricular diastole, plasma level of N-terminal pro-brain natriuretic peptide (NT-pro BNP), pulmonary artery pressure, and increasing left ventricular ejection fraction, and there is no increase in physiological indicators such as blood potassium, serum creatinine, blood urea nitrogen, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Detailed implementation manners

[0017] Next, in combination with the embodiments of the present application, the technical solutions in the embodiments of the present application will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0018] In addition: Benazepril hydrochloride was purchased from Novartis Pharma AG (China); Irbesartan was purchased from Sanofi Winthrop Industrie; Metoprolol succinate was purchased from AstraZeneca Pharmaceuticals Co., Ltd.; Conventional treatment included: bed rest, low-flow oxygen inhalation, diuretic and digitalis drug treatment.

[0019] Example 1

[0020] The administration dose of Benazepril hydrochloride was 5 mg / d combined with Irbesartan 300 mg / night, in combination with conventional treatment.

[0021] Control Example 1

[0022] The initial administration dose of Metoprolol succinate was 11.875 mg / d, orally, with an additional 23.75 mg / d added every week until the dose reached 47.5 mg / d, in combination with conventional treatment.

[0023] Performance Test

[0024] The schemes of Example 1 and Control Example 1 were verified. 195 patients admitted to the inpatient and outpatient departments of Xijing Hospital, the First Affiliated Hospital of the Fourth Military Medical University and the Second People's Hospital of Gansu Province were selected as the research objects. The patients were divided into Example 1 (110 cases) and Control Example 1 (85 cases) according to their tolerance to high-dose drugs. In Example 1, there were 81 males and 29 females; the average age was 54.31 ± 14.28 years; there were 15 cases with cardiac function grade II, 74 cases with grade III, and 21 cases with grade IV. In Control Example 1, there were 52 males and 33 females; the average age was 56.35 ± 11.83 years; there were 14 cases with cardiac function grade II, 60 cases with grade III, and 11 cases with grade IV. They were diagnosed with dilated cardiomyopathy according to the diagnostic criteria of WHO / ISEC. The cardiac function classification (using the New York Heart Association cardiac function classification standard), anteroposterior or left-right diameter of the left ventricular end-diastolic, left ventricular ejection fraction, NT-pro BNP, pulmonary artery pressure, blood potassium, serum creatinine, urea nitrogen, AST, and ALT were measured at 1 month, 3 months, 6 months, and 1 year respectively. After examination, the two groups of patients were comparable in terms of cardiac function classification, anteroposterior or left-right diameter of the left ventricular end-diastolic, left ventricular ejection fraction, NT-pro BNP, and age. The specific test results are shown in Tables 1-8.

[0025] (1) Comparison of changes in cardiac function classification between the two groups

[0026] Table 1: Changes in the effective rates of cardiac function in two groups

[0027] Group 1 month 3 months 6 months 1 year Example 1 40.91 93.64 100.00 100.00 Control Example 1 48.24 48.24 74.12 75.29

[0028] As can be seen from Table 1, the effective rate of cardiac function remission in Example 1 has been higher than that in Control Example 1 since the 3rd month. The effective rate of remission in Example 1 has been 100.00% since the 6th month, indicating that the synergistic effect of Example 1 in cardiac function remission is significant, and the effect is better than that of Control Example 1.

[0029] (2) Comparison of the anteroposterior or left-right diameters of the left ventricular end-diastolic diameter between the two groups

[0030] Table 2: Changes in the anteroposterior or left-right diameters of the left ventricular end-diastolic diameter before and after the implementation of the two groups of regimens

[0031] Group Before implementation 1 month 3 months 6 months 1 year Example 1 74.55±9.59 68.65±10.19 64.87±10.02 62.46±10.44 61.08±10.87 Control Example 1 72.27±7.47 69.68±7.46 68.64±7.66 68.27±7.42 66.69±7.51

[0032] As can be seen from Table 2, before the implementation of the two groups of regimens, the average value of the anteroposterior or left-right diameter of the left ventricular end-diastolic diameter in Example 1 was 74.55±9.59, and the average value of the anteroposterior or left-right diameter of the left ventricular end-diastolic diameter in Control Example 1 was 72.27±7.47, with no significant difference. There were significant differences in the changes of the anteroposterior or left-right diameter of the left ventricular end-diastolic diameter between Control Example 1 and Example 1 at 3 months, 6 months, and 1 year. The change in the anteroposterior or left-right diameter of the left ventricular end-diastolic diameter in Example 1 was significantly higher than that in Control Example 1, indicating that after 3 months, Example 1 was superior to Control Example 1 in shortening the anteroposterior or left-right diameter of the left ventricular end-diastolic diameter, indicating that Example 1 had an obvious advantage in improving ventricular remodeling.

[0033] (3) Comparison of the left ventricular ejection fraction between the two groups

[0034] Table 3: Changes in the left ventricular ejection fraction before and after the implementation of the two groups of regimens

[0035] Group Before implementation 1 month 3 months 6 months 1 year Example 1 33.34±8.73 38.91±9.18 41.31±10.06 45.23±10.11 50.60±11.09 Control Example 1 33.88±9.60 36.62±11.26 38.24±10.74 37.16±11.14 37.35±11.10

[0036] As can be seen from Table 3, before the implementation of the two groups of regimens, the average left ventricular ejection fraction in Example 1 was 33.34±8.73, and the average in Control Example 1 was 33.88±9.60, with no significant difference between the two groups. The left ventricular ejection fraction in Example 1 was significantly higher than that in Control Example 1 at 3 months, 6 months, and 1 year, indicating that after 3 months, Example 1 was superior to Control Example 1 in increasing the left ventricular ejection fraction. It shows that Example 1 has an obvious advantage in improving ventricular remodeling.

[0037] (4) Comparison of NT-pro BNP between the two groups

[0038] Table 4: Changes in NT-pro BNP before and after the implementation of the two groups of regimens

[0039] Group Before implementation 1 month 3 months 6 months 1 year Example 1 393.24 292.74 357.49 182.41 136.46 Control Example 1 267.10 238.00 153.79 174.35 207.16

[0040] As can be seen from Table 4, the average value of NT-pro BNP in Example 1 after 1 year was significantly lower than that in Control Example 1, and the change in NT-pro BNP before and after the implementation of Example 1 was significantly higher than that in Control Example 1, indicating that the effect of Example 1 was better than that of Control Example 1 in reducing the NT-proBNP level.

[0041] (V) Comparison of Pulmonary Artery Pressure between Two Groups

[0042] Table 5: Changes in Pulmonary Artery Pressure before and after the Implementation of Two Groups of Schemes

[0043] Group Before implementation 1 month 3 months 6 months 1 year Example 1 24.97±3.46 25.42±4.52 25.52±3.45 24.16±2.92 24.50±2.82 Control Example 1 25.62±3.14 25.11±3.11 25.58±3.01 25.06±2.96 26.94±2.56

[0044] As can be seen from Table 5, the average pulmonary artery pressures of Example 1 and Control Example 1 before the implementation of the two groups of schemes were 24.97 ± 3.46 and 25.62 ± 3.14 respectively. The test results showed that there was no significant difference in the pulmonary artery pressures of the two groups before the implementation of the two groups of schemes. At 1 month and 3 months, there was no significant difference in the pulmonary artery pressure levels of the two groups. At 6 months and 1 year, there were significant differences in the pulmonary artery pressure levels of the two groups, indicating that after 6 months, the pulmonary artery pressure of Example 1 was lower than that of Control Example 1, further indicating that the effect of Example 1 was better than that of Control Example 1.

[0045] (VI) Comparison of Blood Potassium between Two Groups

[0046] Table 6: Changes in Blood Potassium before and after the Implementation of Two Groups of Schemes

[0047] Group Before implementation 1 month 3 months 6 months 1 year Example 1 3.93±0.36 4.17±0.42 4.14±0.40 4.07±0.39 4.11±0.42 Control Example 1 4.00±0.37 3.99±0.33 4.12±0.37 4.07±0.37 4.07±0.38

[0048] As can be seen from Table 6, the blood potassium level of Example 1 fluctuated between 4.07 - 4.17 mmol / L, and the blood potassium level of Control Example 1 fluctuated between 3.99 - 4.12 mmol / L. The normal value of blood potassium was 3.50 - 5.5 mmol / L, indicating that no adverse reaction of increased blood potassium level occurred in Example 1.

[0049] (VII) Comparison of Renal Function between Two Groups

[0050] Table 7: Changes in Renal Function before and after the Implementation of Two Groups of Schemes

[0051]

[0052] As can be seen from Table 7, the serum creatinine level in Example 1 fluctuated between 92.00 - 97.90 μmol / L, and that in Control Example 1 fluctuated between 75.45 - 79.44 μmol / L. The normal value range of serum creatinine is 53 - 115 μmol / L, indicating that the serum creatinine level in Control Example 1 is lower than that in Example 1, but the serum creatinine levels of both groups are within the normal range. The urea nitrogen level in Example 1 was 6.29 - 6.82 mmol / L, and that in Control Example 1 was 6.09 - 6.46 mmol / L. The normal range of urea nitrogen is 3.10 - 8.00 mmol / L, indicating that there is no difference in the urea nitrogen levels of the two groups at 1 month, 3 months, 6 months, and 1 year later, and both are within the normal range, further indicating that applying the scheme of Example 1 will not cause abnormal renal function.

[0053] (VIII) Comparison of liver function between the two groups

[0054] Table 8: Changes in liver function before and after the implementation of the two groups of schemes

[0055]

[0056]

[0057] As can be seen from Table 8, the AST level in Example 1 fluctuated between 20.91 - 25.59 IU / L, and that in Control Example 1 fluctuated between 20.80 - 23.27 IU / L. The normal value of AST is 15 - 40 IU / L, and the AST levels of both groups are within the normal range. The ALT level in Example 1 was 21.35 - 23.27 IU / L, and that in Control Example 1 was 21.04 - 24.57 IU / L. The normal value range of ALT is 9 - 50 IU / L, indicating that there is no difference in the ALT levels of the two groups, and the ALT levels of both groups are within the normal range, further indicating that applying the scheme of Example 1 will not cause abnormal liver function.

[0058] In summary, Example 1 is superior to Control Example 1 in improving cardiac function, reducing the anteroposterior diameter or left - right diameter at the end of left ventricular diastole, NT - proBNP plasma level, pulmonary artery pressure, and increasing left ventricular ejection fraction, and no increase in blood potassium, serum creatinine, urea nitrogen, AST, or ALT is observed.

[0059] The above content is only an example and explanation of the concept of this application. Those skilled in the art of this technology can make various modifications or supplements to the specific embodiments described or use similar methods for substitution, as long as they do not deviate from the concept of the invention or exceed the scope defined by this claim book, they should all fall within the protection scope of this application.

Claims

1. A composition containing an angiotensin II receptor blocker, characterized in that, It includes an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker.

2. The composition containing an angiotensin II receptor blocker according to claim 1, characterized in that, The angiotensin-converting enzyme inhibitor is benazepril hydrochloride or perindopril.

3. The composition containing an angiotensin II receptor blocker according to claim 2, wherein, The dosage of the angiotensin-converting enzyme inhibitor benazepril hydrochloride is 5 - 10 mg / d.

4. A composition comprising an angiotensin II receptor blocker according to claim 2, characterized in that, The dosage of the angiotensin-converting enzyme inhibitor perindopril is 2 - 4 mg / d.

5. A composition comprising an angiotensin II receptor blocker according to claim 1, characterized in that, The angiotensin II receptor blocker is irbesartan or valsartan.

6. The composition containing an angiotensin II receptor blocker according to claim 5, wherein, The dosage of the angiotensin II receptor blocker irbesartan is 300 - 750 mg / night.

7. A composition containing an angiotensin II receptor blocker according to claim 5, characterized in that, The dosage of the angiotensin II receptor blocker valsartan is 160 - 480 mg / night.

8. Use of a composition containing an angiotensin II receptor blocker according to any one of claims 1 - 7 in the medicine for dilated cardiomyopathy.

Images