Application of composition in preparation of medicine for treating unstable angina pectoris

Abstract

The invention belongs to the technical field of medicine application, and relates to application of a composition in preparation of a medicine for treating unstable angina pectoris, the composition and combined use of the composition and nicodil are used for improving the attack frequency of the unstable angina pectoris and the lasting time of the unstable angina pectoris, reducing the levels of LDL-C, TC and TG in serum, and improving the treatment effect of the unstable angina pectoris. According to the present invention, the application of the preparation of the unstable angina pectoris treatment drug can be provided, such that the HDL-C level in the serum can be increased, the BNP level and the LVEDD level in the plasma can be reduced, and the LVEF level can be increased; the composition disclosed by the invention and the combination of the composition and nicodil can improve the attack frequency of unstable angina pectoris, shorten the symptom duration and improve the effective rate of treatment.

Description

Technical Field

[0001] The invention belongs to the technical field of drug application, and relates to application of a composition in preparing a drug for treating unstable angina pectoris. Background Art

[0002] Coronary atherosclerotic heart disease seriously threatens human health, leading to a gradual increase in the incidence of coronary heart disease. Unstable angina pectoris (UAP) is a syndrome with paroxysmal chest pain or chest discomfort as clinical manifestations caused by acute temporary ischemia and hypoxia of myocardial cells. Especially for elderly people with unstable angina pectoris, the incidence is high and the risk of sudden death is extremely high. Previous studies have shown that heart failure is closely related to the activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system. The activation of these systems can lead to hemodynamic changes in patients, aggravate myocardial remodeling, and cause the patient's heart function to deteriorate continuously. Therefore, it is very important to adopt timely and effective treatment methods.

[0003] At present, the commonly used treatment methods for unstable angina pectoris include drug therapy. In drug therapy, the commonly used Western medicines are: nitrate drugs, long-term use may produce drug resistance, and some patients may experience side effects such as headaches and facial flushing; beta-blockers, which may cause bradycardia, hypotension, etc., and are contraindicated for patients with severe bradycardia and atrioventricular block; calcium ion antagonists, which may cause side effects such as headaches, dizziness, and facial flushing, and should be used with caution for patients with heart failure; antiplatelet drugs, long-term use may increase the risk of bleeding, such as gastrointestinal bleeding, cerebral hemorrhage, etc.; lipid-regulating drugs, which may cause side effects such as abnormal liver function and muscle pain, and should be used with caution for patients with severe liver disease.

[0004] In traditional Chinese medicine, unstable angina is usually classified as "sudden heart pain". Traditional Chinese medicine believes that its pathogenesis is related to the blockage of heart blood and paralysis. It is a clinical syndrome caused by insufficient blood supply to the coronary arteries, acute and temporary myocardial ischemia and hypoxia, with paroxysmal chest pain or chest discomfort as the main manifestation. The treatment ideas of traditional Chinese medicine mainly include promoting blood circulation and removing blood stasis, replenishing qi and nourishing yin, regulating qi and relieving pain, etc., aiming to relieve symptoms by improving the state of insufficient blood supply to the heart and regulating the balance of qi and blood.

[0005] Limited by the drawbacks of Western medicine treatment, such as large adverse reactions, many contraindications, and a small scope of application; indeed, in this clinical practice context, traditional Chinese medicine has extremely prominent advantages in the prevention and treatment of unstable angina pectoris, providing room for the use of traditional Chinese medicine in the treatment of unstable angina pectoris. Summary of the invention

[0006] In view of the technical problems existing in the above-mentioned background technology, the present invention provides an application of a composition in preparing a drug for treating unstable angina pectoris.

[0007] The present invention uses the composition in the preparation of a drug for treating unstable angina pectoris, thereby improving the effective rate of treatment by improving the frequency of unstable angina pectoris attacks and shortening the duration of symptoms.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is:

[0009] Application of the composition in preparing medicine for treating unstable angina pectoris.

[0010] The composition is used in preparing a drug for treating unstable angina pectoris by improving the attack frequency and duration of unstable angina pectoris.

[0011] The composition is used in preparing a drug for treating unstable angina pectoris by reducing the levels of LDL-C, TC and TG in serum and increasing the level of HDL-C in serum.

[0012] The composition is used in preparing a drug for treating unstable angina pectoris by reducing plasma BNP level and LVEDD level and increasing LVEF level.

[0013] Furthermore, the composition includes coptis chinensis, tuckahoe, immature bitter orange, sophora flavescens, artemisia annua, ginseng, ophiopogon japonicus and licorice; the mass ratio of coptis chinensis, tuckahoe, immature bitter orange, sophora flavescens, artemisia annua, ginseng, ophiopogon japonicus and licorice is 1: (0.625-0.771): (0.428-0.6): (0.571-0.781): (0.571-0.745): (0.428-0.6): (0.743-0.875): (0.468-0.5).

[0014] Furthermore, the composition also contains Pinellia ternata, Radix Dichroae and Lotus Seed Heart; the mass ratio of Pinellia ternata to Coptis chinensis is 0.745:1; the mass ratio of Radix Dichroae to Coptis chinensis is 0.745:1; the mass ratio of Lotus Seed Heart to Coptis chinensis is 0.135:1.

[0015] It is further specified that the composition is prepared by combining the following raw materials in the following mass ratio: the mass ratio of Coptidis Root, Pinellia Rhizome, Poria, Immature Citrus Aurantium, Radix Dichroae, Lotus Seed Pith, Sophora Flavescentis, Artemisia Annua, Ginseng, Ophiopogon japonicus and Licorice is 1:0.748:0.748:0.5:0.748:0.126:0.748:0.748:0.5:0.748:0.5.

[0016] It is further defined that the dosage of the composition is 1.92 g each time, three times a day.

[0017] Use of the composition combined with Nicorandil in the preparation of a drug for treating unstable angina pectoris.

[0018] It is further defined that the dosage of Nicorandil is 2.5 mg each time, three times a day, and the dosage of the composition is 1.92 g each time, three times a day.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. The present invention has found through clinical studies that the composition of the present invention has a certain effect on improving the electrocardiogram of patients with unstable angina pectoris and reducing the duration and severity of unstable angina pectoris attacks in patients, with a total effective rate of 95.9%. This shows that the composition of the present invention can be used in the preparation of drugs for treating unstable angina pectoris by improving the number of attacks and duration of symptoms of unstable angina pectoris.

[0021] 2. The present invention has found through clinical studies that the composition of the present invention can reduce serum low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and triglyceride (TG) levels, and increase serum high-density lipoprotein cholesterol (HDL-C) levels; plasma BNP levels are reduced, LVEF is increased after treatment, and LVEDD is reduced. This shows that the composition of the present invention has a significant effect on patients with unstable angina pectoris, can improve patients' blood lipid metabolism disorders, reduce BNP levels, and improve cardiac function.

[0022] 3. The present invention has found through research that the combination of Nicorandil and the combination has a certain effect on improving the electrocardiogram of patients and reducing the duration and severity of angina attacks in patients, with a total effective rate of 98.0%. This shows that the combination of Nicorandil and the combination has a synergistic effect, and has a more obvious therapeutic effect on patients with unstable angina pectoris, and can effectively improve the patient's blood lipid metabolism disorder, reduce the BNP level, and promote cardiac function.

[0023] 4. Use of nicorandil combined with a composition can effectively reduce the dosage of nicorandil, thereby reducing cardiovascular system symptoms such as palpitations, fatigue, facial flushing, lower limb edema, etc. that may be caused by the use of nicorandil alone. DETAILED DESCRIPTION

[0024] The technical solution protected by the present invention is described in detail below. It should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments described here. It should be noted that, unless otherwise specified, the drugs, reagents, instruments, etc. used in the following embodiments are all conventional commercial products in the industry.

[0025] The present invention proposes an application of a composition in the preparation of a drug for treating unstable angina pectoris. According to an embodiment of the present invention, the composition comprises coptis root, tuckahoe, immature bitter orange, sophora flavescens, artemisia annua, ginseng, ophiopogon japonicus and liquorice; in the composition, the mass ratio of coptis root, tuckahoe, immature bitter orange, sophora flavescens, artemisia annua, ginseng, ophiopogon japonicus and liquorice is 1: (0.625-0.771): (0.428-0.6): (0.571-0.781): (0.571-0.745): (0.428-0.6): (0.743-0.875): (0.468-0.5).

[0026] In order to further enhance the efficacy and achieve the purpose of monarch, minister, assistant and envoy between the Chinese medicinal components, the above composition can also be added with Banxia, ​​Changshan and Lianzixin. Banxia can dry dampness and resolve phlegm, reduce adverse reactions and stop vomiting, eliminate lumps and resolve knots, and relieve various symptoms caused by phlegm and dampness; Changshan has the effect of vomiting phlegm and helps to clear the phlegm in the body, and Lianzixin removes heat evil in the body and enhances heart function. In the prescription, Coptis chinensis, Banxia, ​​Poria cocos, and Zhishi can clear heart heat, calm the heart and calm palpitations; Changshan, Sophora flavescens, Lianzixin, and Artemisia annua can clear heat and resolve phlegm; Ginseng and Ophiopogon japonicus can nourish qi and yin; Licorice is sweet and flat, and harmonizes all medicines. In order to ensure the optimal dosage, the mass ratio of Banxia to Coptis chinensis is 0.745:1, the mass ratio of Changshan to Coptis chinensis is 0.745:1, and the mass ratio of Lianzixin to Coptis chinensis is 0.135:1.

[0027] The composition of the present application is implemented according to the compatibility in the following table, and see Table 1 below for details.

[0028] Table 1 Compatibility of the composition of the present invention

[0029]

[0030]

[0031] The preparation process of the composition of the present invention is as follows:

[0032] (1) cleaning, slicing, and drying the raw materials for later use;

[0033] (2) taking coptis root, immature bitter orange, radix chebulae, lotus seed core and sophora flavescens, adding 60% ethanol, and reflux extraction twice, the first time adding 8 times the amount of ethanol of the raw material, reflux extraction for 2 hours, the second time adding 6 times the amount of ethanol of the raw material, reflux extraction for 1.5 hours, combining the two extracts, filtering, taking the filtrate and recovering ethanol under reduced pressure at 0.04 MPa and 75° C., and continuing to concentrate to a thick paste with a relative density of 1.36 to 1.38 at 60° C., drying at 80° C. to form a dry paste, and discarding the residue;

[0034] (3) Take ginseng, Poria cocos and Pinellia ternata, add 70% ethanol, and reflux extract twice. The first time, add 10 times the amount of ethanol of the raw material, reflux extract for 2.5 hours, and the second time, add 8 times the amount of ethanol of the raw material, reflux extract for 2 hours. Combine the two extracts, filter, and collect the filtrate in another container for later use;

[0035] (4) The residue obtained in step (3) is combined with Ophiopogon japonicus, Artemisia annua, and Glycyrrhiza uralensis, and decocted twice with water, with 10 times the amount of the raw material added in the first decoction and 8 times the amount of the raw material added in the second decoction, each time for 1 hour, the decoction is combined, filtered, and the filtrate is concentrated to a clear paste with a relative density of 1.05 to 1.06 at 80° C., 95% ethanol is added to make the alcohol concentration reach 70%, mixed, and allowed to stand for 24 hours to precipitate, the supernatant is collected, filtered, and the filtrate is combined with the filtrate collected in another device in step (3), and ethanol is recovered under reduced pressure at 0.04 MPa and 75° C., and the mixture is further concentrated to a thick paste with a relative density of 1.36 to 1.38 at 60° C., and dried at 80° C. to obtain a dry paste;

[0036] (5) The two dry pastes obtained in step (2) and step (4) are combined and crushed into fine powder to obtain the composition of the present invention.

[0037] During implementation, the composition is in the form of tablets, capsules, granules or pills. The formulations and process steps of different dosage forms are the same as those in Example 1, and different dosage forms are prepared by adding excipients corresponding to the dosage form and following the conventional preparation methods of each dosage form.

[0038] The following capsule dosage forms (0.48 g per capsule) were prepared by combining the compositions of Examples 1 and 2 of the present invention to verify the effects of the composition, nicorandil and the combination of the composition on blood lipid metabolism, brain natriuretic peptide (BNP), cardiac function, vascular endothelial function and oxidative stress indicators in patients with unstable angina pectoris, and illustrate the therapeutic effects of the composition, nicorandil and the combination of the composition on patients with unstable angina pectoris.

[0039] 1. Model and Method

[0040] 1.1 Patient Information

[0041] A total of 196 patients with unstable angina pectoris were selected, including 124 males and 72 females, aged 65 to 75 years old, with an average age of (71.3±3.0) years old. They were divided into a control group and an observation group according to the random number table method, and the treatment implementers, evaluators and recorders were separated.

[0042] Control group: 30 males and 19 females, aged 64 to 75 years old, with an average age of (71.2±2.6) years old;

[0043] Observation group 1: 30 males and 19 females, aged 65 to 75 years old, with an average age of (70.6±2.9) years old;

[0044] Observation group 2: 32 males and 17 females, aged 65 to 75 years old, with an average age of (71.8±2.2) years old;

[0045] Observation group 3: 32 males and 17 females, aged 65 to 75 years old, with an average age of (71.3±2.5) years old.

[0046] There was no significant difference in the general information of the four groups of patients, and they were comparable (P>0.05).

[0047] 1.2 Inclusion and Exclusion Criteria

[0048] Inclusion criteria: The diagnosis of unstable angina pectoris must comply with the diagnostic criteria for coronary heart disease established by the World Health Organization in 1979. All patients must have ① a clear diagnosis of changes in the nature of stable angina pectoris, i.e., frequent attacks, severe severity, and prolonged duration of angina pectoris; ② attacks of angina pectoris during rest; and ③ angina pectoris that has occurred recently within the past month and can be induced by even mild physical activity. If one or more of the three items is present, accompanied by ST-T changes on the electrocardiogram, the diagnosis can be established. If there is a history of stable angina pectoris, myocardial infarction, abnormal coronary angiography, and positive exercise test, even if there are no ST-T changes on the electrocardiogram, the diagnosis can be established if there are typical symptoms of unstable angina pectoris.

[0049] Exclusion criteria: ① Patients with acute myocardial infarction (AMI) and other myocardial injury diseases such as cardiogenic shock within 3 months; ② Patients with liver and kidney dysfunction and tumor diseases; patients with peripheral vascular disease, cerebrovascular disease and diabetic vascular complications; ③ Patients with uncontrolled severe heart failure, malignant hypertension, and stroke; ④ Patients with trauma, surgery, bleeding, or infection within 1 month; ⑤ Patients with allergies or intolerance to therapeutic drugs.

[0050] All patients participating in the above study were informed truthfully and signed written informed consent.

[0051] 1.3 Treatment methods

[0052] All three groups of patients received conventional treatment, including a low-salt, low-fat diet and appropriate exercise.

[0053] Control group: aspirin was used to prevent platelet aggregation, atorvastatin was used to reduce lipid, and Nicorandil (Xi'an Hanfeng Pharmaceutical Co., Ltd.) was used for vasodilation. The dosage of Nicorandil was 5 mg each time, three times a day.

[0054] Observation group 1: Based on the control group, the combination of the composition of Example 2 and Nicorandil (Xi'an Hanfeng Pharmaceutical Co., Ltd.) was given for treatment. The composition was taken orally 4 capsules each time (1.92 g in total), 3 times a day, and the dosage of Nicorandil was 2.5 mg each time, 3 times a day.

[0055] Observation group 2: On the basis of the control group, the patients were given the composition of Example 2 alone for treatment, with 4 capsules of the composition (1.92 g in total) taken orally each time, 3 times a day;

[0056] Observation group 3: On the basis of the control group, the patients were given the composition of Example 1 alone for treatment. Four capsules of the composition (1.92 g in total) were taken orally 3 times a day.

[0057] All four groups were treated for 8 consecutive weeks.

[0058] 1.4 Evaluation Indicators

[0059] (1) Clinical observation indicators: ① The number of angina attacks; ② The duration of angina attacks; ③ The dynamic changes of the electrocardiogram.

[0060] (2) Serum low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels in the two groups before and after treatment.

[0061] (3) Left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP), and left ventricular end-diastolic diameter (LVEDD) in the two groups before and after treatment.

[0062] 1.5 Data Analysis and Processing

[0063] All data were statistically processed using SPSS 25.0 software for t-test, χ 2 test.

[0064] 2. Test results

[0065] 2.1 Comparison of efficacy

[0066] After treatment, the total effective rate was 98% in observation group 1, 95.9% in observation group 2, and 93.9% in observation group 3. The total effective rates were all higher than 91.8% in the control group, as shown in Table 2.

[0067] Table 2 Comparison of efficacy [n (%)]

[0068] Group n Significant effect efficient invalid Total effective rate (%) Observation Group 1 49 24(49.0) 24(49.0) 1(2.0) 98.0 Observation Group 2 49 12(24.5) 35(71.4) 2(4.1) 95.9 Observation Group 3 49 13(26.6) 33(67.3) 3(6.1) 93.9 Control group 49 22(44.9) 23(46.9) 4(8.2) 91.8

[0069] 2.2. Improvement of electrocardiogram

[0070] The total effective rate of electrocardiogram improvement in observation group 1, observation group 2 and observation group 3 was higher than that in the control group, as shown in Table 3.

[0071] Table 3 Comparative example of electrocardiogram improvement [n (%)]

[0072]

[0073]

[0074] 2.3 Comparison of blood lipid metabolism

[0075] There was no significant difference in blood lipid metabolism indicators before treatment (P>0.05); and for observation group 1, observation group 2 and observation group 3, serum LDL-C, TC and TG levels were significantly reduced, while serum HDL-C level was significantly increased after treatment, which were better than those in the control group, as shown in Table 4.

[0076] Table 4 Comparison of blood lipid metabolism (x±s, n=49, mmol / L)

[0077]

[0078] 2.4. Plasma BNP levels and changes in cardiac function

[0079] Left ventricular ejection fraction (LVEF) refers to the proportion of blood volume pumped out of the heart cavity during contraction of the left ventricle. When LVEF is less than 50%, it may indicate a decline in left ventricular function and the risk of heart failure or heart insufficiency. Left ventricular end-diastolic diameter (LVEDD) is the inner diameter of the left ventricle at the end of diastole. After treatment, the index data of observation group 1, observation group 2 and observation group 3 were more advantageous, as shown in Table 5.

[0080] Table 5 Comparison of plasma BNP levels and cardiac function changes (x±s, n=49)

[0081]

[0082]

[0083] From the results in Table 5, it can be seen that after treatment, the BNP and blood lipid levels in observation group 1, observation group 2 and observation group 3 were all lower than those in the control group, which indicates that the combined use of nicorandil and the composition, or the use of the composition alone, can reduce the risk stratification of patients with unstable angina pectoris and improve their prognosis. After treatment, the total effective rate of the efficacy of observation group 1 for patients with unstable angina pectoris was 98%, the total effective rate of the efficacy of observation group 2 for patients with unstable angina pectoris was 95.9%, and the total effective rate of the efficacy of observation group 3 for patients with unstable angina pectoris was 93.9%, all of which were better than the control group. This shows that the composition can improve the clinical efficacy of patients with unstable angina pectoris; in addition, the combination of the composition and nicorandil can further improve the clinical efficacy of patients with unstable angina pectoris, while reducing the dosage of nicorandil, and effectively reducing the adverse cardiovascular symptoms such as palpitations, fatigue, facial flushing, and lower limb edema that may be caused by nicorandil.

[0084] The coptis root in the composition of the present invention plays a role in improving myocardial blood supply and microcirculation for ischemic myocardium. Matrine in Sophora flavescens can dilate coronary blood vessels and improve myocardial oxygen supply. Fructus aurantii can enhance myocardial contractility, improve myocardial pumping, and increase coronary blood flow. The combination of the medicines plays a role in resisting myocardial arteriosclerosis, improving myocardial metabolism, reducing lipids and anti-inflammatory, improving cardiac function, thereby shortening the course of treatment for the patient, and it is found that the liver and kidney functions of the patient are not damaged. It shows that the composition has good clinical effect and safety, and also provides a certain theoretical basis for the application of Chinese patent medicines.

[0085] The above model test shows that: in terms of clinical efficacy, observation group 1, observation group 2 and observation group 3 all have a certain effect on the improvement of electrocardiogram, and the total effective rates of the three groups are 81.6%, 79.6% and 77.5% respectively. It shows that the combination alone, or Nicorandil combined with the combination, has a significant effect on improving the electrocardiogram of patients; in terms of the duration and severity of angina pectoris, observation group 1, observation group 2 and observation group 3 also have a certain effect on the improvement of angina pectoris symptoms, and the total effective rates of the three groups are 98.0%, 95.9% and 93.9% respectively. It shows that the combination alone, or Nicorandil combined with the combination, has a significant effect on improving the number and duration of angina pectoris attacks in patients.

[0086] The above clinical effects were verified by the combination of the compositions of Example 1 and Example 2. The clinical efficacy of the combinations of the compositions of the remaining examples was also verified, and all showed the same or similar effects as the compositions of Example 1 or Example 2. Each composition was used alone, or each composition was used in combination with Nicorandil, and had a significant effect on improving the electrocardiogram of patients and improving the number and duration of angina attacks in patients.

[0087] In summary, the combination alone can significantly improve the therapeutic effect of unstable angina pectoris in patients; Nicorandil combined with the combination has a significant synergistic effect on the therapeutic effect of unstable angina pectoris, and is worthy of clinical promotion and application.

[0088] Obviously, the above embodiments are only examples for clear explanation, and are not intended to limit the implementation methods. For ordinary technicians in the relevant field, other different forms of changes or modifications made on the basis of the technical ideas and technical solutions of the present invention all fall within the protection scope of the present invention.

Claims

1. Use of the composition in preparing a drug for treating unstable angina pectoris.

2. Use of the composition in preparing a drug for treating unstable angina pectoris by improving the frequency and duration of unstable angina pectoris attacks.

3. The composition is used in the preparation of a drug for treating unstable angina pectoris by reducing the levels of LDL-C, TC and TG in serum and increasing the level of HDL-C in serum.

4. Use of the composition in preparing a drug for treating unstable angina pectoris by reducing plasma BNP level and LVEDD level and increasing LVEF level.

5. The use according to any one of claims 1 to 4, characterized in that: The composition includes coptis root, tuckahoe, immature bitter orange, sophora flavescens, artemisia annua, ginseng, ophiopogon japonicus and liquorice; the mass ratio of coptis root, tuckahoe, immature bitter orange, sophora flavescens, artemisia annua, ginseng, ophiopogon japonicus and liquorice is 1: (0.625-0.771): (0.428-0.6): (0.571-0.781): (0.571-0.745): (0.428-0.6): (0.743-0.875): (0.468-0.5).

6. The use according to claim 5, characterized in that: The composition also includes Pinellia ternata, Radix Dichroae and Lotus Seed Heart; the mass ratio of Pinellia ternata to Coptis chinensis is 0.745:1; the mass ratio of Radix Dichroae to Coptis chinensis is 0.745:1; the mass ratio of Lotus Seed Heart to Coptis chinensis is 0.135:

1.

7. The use according to claim 6, characterized in that: The composition is prepared by combining the following raw materials in the following mass ratio: the mass ratio of coptis root, pinellia tuber, tuckahoe, immature bitter orange, radix chebulae, lotus seed core, sophora flavescens, artemisia annua, ginseng, ophiopogon japonicus and liquorice is 1:0.748:0.748:0.5:0.748:0.126:0.748:0.748:0.5:0.748:0.

5.

8. The use according to any one of claims 1 to 4, characterized in that: The dosage of the composition is 1.92 g each time, three times a day.

9. Use of the combination of the composition and nicorandil in the preparation of a drug for treating unstable angina pectoris.

10. The use according to claim 9, characterized in that: The dosage of Nicorandil is 2.5 mg, three times a day, the dosage of the composition is 1.92 g each time, three times a day.

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