Traditional Chinese medicine composition for treating qi deficiency and blood stasis type coronary heart disease angina pectoris and application thereof

Abstract

The invention provides a traditional Chinese medicine composition for treating qi deficiency and blood stasis type coronary heart disease angina pectoris. The traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 210 to 290 parts of radix salviae miltiorrhizae, 310 to 390 parts of flos chrysanthemi indici, 210 to 290 parts of radix codonopsis, 210 to 290 parts of fructus trichosanthis, 30 to 70 parts of flos caryophylli, 80 to 120 parts of vinegar-processed rhizoma corydalis, 210 to 290 parts of radix astragali seu hedysari, 210 to 290 parts of rhizoma chuanxiong and 30 to 70 parts of radix notoginseng. The invention further provides application of the traditional Chinese medicine composition. The traditional Chinese medicine decoction has the advantages that clinical and animal experiments prove that the traditional Chinese medicine decoction has a better effect on treating qi deficiency and blood stagnation type coronary heart disease angina pectoris, has the effects of tonifying qi and activating blood, regulating qi and relieving pain, and warming yang and reducing phlegm, and is worthy of popularization.

Description

[Technical field]

[0001] The invention relates to the technical field of traditional Chinese medicines, in particular to a traditional Chinese medicine composition for treating angina pectoris of coronary heart disease of qi deficiency and blood stasis type and application thereof. [Background technology]

[0002] Common symptoms of coronary heart disease angina pectoris (CHD-AP) include chest discomfort, chest pain, shortness of breath, etc. If the disease is prolonged, it may be complicated by myocardial infarction, affecting the patient's quality of life. At present, Western medicine treats CHD-AP by anticoagulation, lipid-lowering, plaque stabilization, etc. to relieve angina symptoms, but Western medicine treatment has certain limitations and obvious adverse reactions. Traditional Chinese medicine classifies CHD-AP as "true heart pain" and "chest pain", and believes that its occurrence is mostly related to improper diet, cold invasion, aging and physical weakness, emotional disorders and other factors. Heart meridian obstruction is the main pathogenesis, and treatment should be based on dredging collaterals to relieve pain and promoting blood circulation and removing blood stasis.

[0003] The document "Exploring the Effect of Yiqi Huoxue Tongmai Decoction in the Treatment of Angina Pectoris in Coronary Heart Disease" discloses "Analysis of the Clinical Efficacy of Yiqi Huoxue Tongmai Decoction in the Treatment of Angina Pectoris in Coronary Heart Disease": Both groups received conventional treatment, and the control group was given isosorbide mononitrate tablets + enteric-coated aspirin tablets + atorvastatin calcium tablets + metoprolol tartrate tablets on the basis of conventional treatment. Oral isosorbide mononitrate tablets, oral, 10-20 mg / time, 2-3 times / d, severe cases can use 40 mg, 2-3 times / d; enteric-coated aspirin tablets, oral, 75-160 mg / time, 1 time / d; atorvastatin calcium tablets, starting dose is 10 mg, 1 time / d, and the dose adjustment interval should be 4 weeks or longer. The maximum dose of this product is 80 mg / time, 1 time / d; metoprolol tartrate tablets, oral, 25 mg / time, 2 times / d, for a total of 2 months of treatment. The treatment group was treated with traditional Chinese medicine, Yiqi Huoxue Tongmai Decoction, 30g of Astragalus, 12g of Xiebai, 12g of Guizhi, 12g of Angelica, 12g of Chuanxiong, 12g of Peach Kernel, 12g of Safflower, 12g of Qingpi, 20g each of Danshen and Chishao, 15g of Quangualou, and 6g of Zhigancao. The decoction was boiled with water until 300mL, and taken warm twice a day, morning and evening. The treatment lasted for 2 months.

[0004] Chinese patent document CN200410065180.8 discloses "a Chinese medicine composition for treating heart and chest pain of blood stasis and qi stagnation type, and angina pectoris of coronary heart disease and its preparation method", which is composed of the following raw materials by weight: 180g of salvia miltiorrhiza, 180g of notoginseng, and 360g of tribulus terrestris. The results confirm that the Chinese medicine composition provided by the present invention can simultaneously treat infertility, threatened abortion, miscarriage and miscarriage, and has the characteristics of low treatment cost, good efficacy, high cure rate, low recurrence rate, and small toxic and side effects, and has the effect of improving endometrial receptivity. Chinese patent document CN200510017256.4 discloses "a Chinese medicine compound for treating coronary heart disease and angina pectoris", which is composed of the following raw materials by weight: the compound is mainly composed of saffron, storax, safflower, supplemented with chuanxiong, salvia miltiorrhiza, notoginseng, and added with cinnabar, borneol, astragalus, schisandra, jujube seed, jujube, mint ice and other ingredients. The results confirmed that the present invention can effectively treat coronary heart disease and angina pectoris, and has strong adaptability to patient groups.

[0005] At present, there is no report on the Chinese medicine composition for treating angina pectoris of coronary heart disease of qi deficiency and blood stasis type and its application. [Summary of the invention]

[0006] The purpose of the present invention is to provide a Chinese medicine composition for treating angina pectoris of coronary heart disease of qi deficiency and blood stasis type in view of the deficiencies in the prior art.

[0007] Another object of the present invention is to provide a use of the above-mentioned Chinese medicine composition.

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

[0009] In a first aspect, the present invention provides a traditional Chinese medicine composition for treating angina pectoris of coronary heart disease of qi deficiency and blood stasis type, which is prepared from the following raw materials in parts by weight: 210-290 parts of salvia miltiorrhiza, 310-390 parts of wild chrysanthemum, 210-290 parts of codonopsis pilosula, 210-290 parts of trichosanthes, 30-70 parts of cloves, 80-120 parts of vinegar-processed corydalis, 210-290 parts of astragalus, 210-290 parts of ligusticum chuanxiong, and 30-70 parts of panax notoginseng.

[0010] Preferably, the traditional Chinese medicine composition is made of the following raw materials in parts by weight: 230-270 parts of Salvia miltiorrhiza, 330-370 parts of Chrysanthemum indica, 230-270 parts of Codonopsis pilosula, 230-270 parts of Trichosanthes kirilowii, 40-60 parts of Cloves, 90-110 parts of vinegar-processed Corydalis yanhusuo, 230-270 parts of Astragalus, 230-270 parts of Chuanxiong, and 40-60 parts of Panax notoginseng.

[0011] More preferably, the Chinese medicine composition is made of the following raw materials in parts by weight: 250 parts of Salvia miltiorrhiza, 350 parts of Chrysanthemum indica, 250 parts of Codonopsis pilosula, 250 parts of Trichosanthes kirilowii, 50 parts of Cloves, 100 parts of Vinegar-processed Corydalis yanhusuo, 250 parts of Astragalus, 250 parts of Chuanxiong, and 50 parts of Panax notoginseng.

[0012] The dosage form of the Chinese medicine composition is decoction, granules, tablets, capsules, oral liquid, mixture or syrup.

[0013] Preferably, the dosage form of the Chinese medicine composition is a decoction.

[0014] Preferably, the preparation method of the drug is: decocting twice with water, adding 6 times the amount of water for the first time and decocting for 1.5 hours, adding 4 times the amount of water for the second time and decocting for 1.5 hours, filtering the decoction, combining, standing for 8-10 hours, taking the supernatant and concentrating it to 950ml, adding 3g of benzoic acid and 200g of sucrose, stirring well, filtering, adding water to the filtrate to make 1000ml, stirring well, and packaging, 200ml per bottle.

[0015] In a second aspect, the present invention provides use of any of the above-described traditional Chinese medicine compositions in the preparation of a drug for treating angina pectoris caused by coronary heart disease.

[0016] Preferably, the angina pectoris caused by coronary heart disease is angina pectoris caused by qi deficiency and blood stasis type.

[0017] The present invention has the advantages that:

[0018] 1. The Chinese medicine composition of the present invention conforms to the compatibility of "monarch, minister, assistant and messenger". In the prescription, Trichosanthes is the monarch, which can dispel phlegm and resolve stagnation, regulate qi and relieve chest tightness; Codonopsis and Astragalus are used to invigorate the middle and replenish qi, nourish blood and produce body fluid, and treat palpitations and shortness of breath caused by qi and blood deficiency; Salvia miltiorrhiza and Chuanxiong are used to invigorate blood circulation and nourish blood, promote qi circulation and relieve pain, and treat pain caused by blood stasis, and are all ministerial drugs; Panax notoginseng is used to disperse blood stasis and relieve pain, and it can dissolve blood stasis without hurting the body, and it can treat chest pain caused by blood stasis, and it can also be used to invigorate the body and strengthen the body, and can treat various symptoms of fatigue and weakness; Corydalis is pungent and warm to promote qi circulation, promote blood circulation and relieve pain, and is good at promoting qi stagnation in the blood, and the two are used together to enhance the effect of promoting blood circulation and removing blood stasis; Clove is pungent and warm to promote qi circulation, and treats cold pain in the heart and abdomen; Wild chrysanthemum is pungent and slightly cold, enters the heart meridian and clears the heart heat, and is all adjuvant drugs. The whole prescription plays the effects of invigorating qi and promoting blood circulation, regulating qi and relieving pain, and warming yang and resolving phlegm.

Brief Description of the Drawings

[0019] Figure 1 (a, b) shows the changes in angina scores during treatment period in the two groups of patients;

[0020] Figure 2 (a, b) shows the comparison of the frequency of angina attacks between the two groups after treatment;

[0021] Figure 3 (a, b) shows the comparison of the average duration of angina pectoris between the two groups after treatment;

[0022] Figure 4 To compare the efficacy of angina pectoris between the two groups after treatment;

[0023] Figure 5 (a, b) shows the comparison of TCM syndrome scores between the two groups after treatment;

[0024] Figure 6 To compare the efficacy of TCM symptoms between the two groups after treatment;

[0025] Figure 7 (a, b, c, d) shows the comparison of blood lipids between the two groups after treatment;

[0026] Figure 8 (a, b, c, d, e) shows the comparison of Seattle angina scores between the two groups after treatment;

[0027] Fig. 9 This is the effect of Gualou Guanxin mixture on the body weight of mice in each group;

[0028] Fig.10 This is the effect of Gualou Guanxin mixture on blood lipids of mice in each group;

[0029] Figure 11 (a, b) shows the effects of Trichosanthes Guanxin mixture on the aortic sinus of each group of mice. [Specific implementation method]

[0030] The specific implementation modes provided by the present invention are described in detail below.

[0031] Example 1 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (I)

[0032] 250 parts of Salvia miltiorrhiza, 350 parts of Chrysanthemum indici, 250 parts of Codonopsis pilosula, 250 parts of Trichosanthes, 50 parts of Cloves, 100 parts of Vinegar-processed Corydalis, 250 parts of Astragalus, 250 parts of Chuanxiong, and 50 parts of Notoginseng.

[0033] Example 2 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (II)

[0034] 250 parts of Salvia miltiorrhiza, 330 parts of Chrysanthemum indici, 270 parts of Codonopsis pilosula, 210 parts of Trichosanthes, 70 parts of Cloves, 100 parts of Vinegar-processed Corydalis, 230 parts of Astragalus, 270 parts of Chuanxiong, and 30 parts of Panax notoginseng.

[0035] Example 3 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (III)

[0036] 230 parts of Salvia miltiorrhiza, 370 parts of Chrysanthemum indici, 210 parts of Codonopsis pilosula, 290 parts of Trichosanthes, 50 parts of Cloves, 90 parts of Vinegar-processed Corydalis, 210 parts of Astragalus, 270 parts of Chuanxiong, and 70 parts of Notoginseng.

[0037] Example 4 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (IV)

[0038] 270 parts of Salvia miltiorrhiza, 310 parts of Chrysanthemum indici, 290 parts of Codonopsis pilosula, 250 parts of Trichosanthes, 40 parts of Cloves, 110 parts of Vinegar-processed Corydalis, 210 parts of Astragalus, 290 parts of Chuanxiong, and 50 parts of Notoginseng.

[0039] Example 5 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (V)

[0040] 210 parts of Salvia miltiorrhiza, 390 parts of Chrysanthemum indici, 250 parts of Codonopsis pilosula, 230 parts of Trichosanthes, 60 parts of Cloves, 80 parts of Vinegar-processed Corydalis, 290 parts of Astragalus, 250 parts of Chuanxiong, and 40 parts of Notoginseng.

[0041] Example 6 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (VI)

[0042] 290 parts of Salvia miltiorrhiza, 350 parts of Chrysanthemum indici, 230 parts of Codonopsis pilosula, 270 parts of Trichosanthes, 30 parts of Cloves, 120 parts of Vinegar-processed Corydalis, 250 parts of Astragalus, 230 parts of Chuanxiong, and 60 parts of Notoginseng.

[0043] Example 7 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (VII)

[0044] 250 parts of Salvia miltiorrhiza, 370 parts of Chrysanthemum indici, 210 parts of Codonopsis pilosula, 290 parts of Trichosanthes, 50 parts of Cloves, 90 parts of Vinegar-processed Corydalis, 210 parts of Astragalus, 270 parts of Chuanxiong, and 70 parts of Notoginseng.

[0045] Example 8 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (VIII)

[0046] 230 parts of Salvia miltiorrhiza, 310 parts of Chrysanthemum indici, 290 parts of Codonopsis pilosula, 250 parts of Trichosanthes, 40 parts of Cloves, 110 parts of vinegar-processed Corydalis yanhusuo, 210 parts of Astragalus, 290 parts of Chuanxiong, and 50 parts of Notoginseng.

[0047] Example 9 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (IX)

[0048] 270 parts of Salvia miltiorrhiza, 390 parts of Chrysanthemum indici, 250 parts of Codonopsis pilosula, 230 parts of Trichosanthes, 60 parts of Cloves, 80 parts of Vinegar-processed Corydalis, 290 parts of Astragalus, 250 parts of Chuanxiong, and 40 parts of Notoginseng.

[0049] Example 10 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (X)

[0050] 210 parts of Salvia miltiorrhiza, 350 parts of Chrysanthemum indici, 230 parts of Codonopsis pilosula, 270 parts of Trichosanthes, 30 parts of Cloves, 120 parts of vinegar-processed Corydalis yanhusuo, 250 parts of Astragalus, 230 parts of Chuanxiong, and 60 parts of Notoginseng.

[0051] Example 11 Preparation of a Chinese medicine composition for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis (XI)

[0052] 290 parts of Salvia miltiorrhiza, 330 parts of Chrysanthemum indici, 270 parts of Codonopsis pilosula, 210 parts of Trichosanthes, 70 parts of Cloves, 100 parts of Vinegar-processed Corydalis, 230 parts of Astragalus, 270 parts of Chuanxiong, and 30 parts of Notoginseng.

[0053] Example 12 Preparation of Chinese medicine composition tablets / capsules for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis

[0054] Take any one of the Chinese medicine compositions described in Examples 1-11, add 9-11 times the amount of water, decoct for 2-3.5 hours, and filter out the medicinal juice. Add 9 times the amount of water again, decoct for 2.5 hours, filter out the medicinal juice, combine the two decoctions, let stand, filter out the supernatant, concentrate, cool, add 3 times the amount of alcohol of the concentrate, stir and precipitate overnight. Take the supernatant, concentrate to a thick extract; add pharmaceutical excipients, vacuum dry, crush and granulate, press into tablets or fill in capsules.

[0055] Example 13 Preparation of Chinese medicine composition granules for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis

[0056] Take the Chinese medicine composition described in any one of Examples 1-11, add 8-10 times the amount of water, decoct for 3 hours, and filter out the juice. Add 10 times the amount of water again, decoct for 2.5 hours, filter out the juice, combine the two decoctions, let stand, filter out the supernatant, concentrate, cool, add 2 times the amount of alcohol of the concentrate, stir and precipitate overnight. Take the supernatant, concentrate to a thick extract; add appropriate pharmaceutical excipients, granulate, dry, granulate, and pack 15g / bag.

[0057] Example 14 Preparation of a Chinese medicine decoction for treating angina pectoris of coronary heart disease caused by qi deficiency and blood stasis

[0058] Take any of the Chinese medicine compositions described in Examples 1-11, add water and boil twice, add 6 times the amount of water for the first time, boil for 1.5 hours, add 4 times the amount of water for the second time, boil for 1.5 hours, filter the decoction, combine, let stand for 8-10 hours, take the supernatant and concentrate it to 950ml, add 3g of benzoic acid and 200g of sucrose, stir well, filter, add water to the filtrate to make 1000ml, stir well, and package it in 200ml bottles.

[0059] Example 15 Clinical Trial

[0060] 1. Research Materials

[0061] 1.1 Research subjects

[0062] The Department of Cardiology of Shanghai Hospital of Traditional Chinese Medicine selected outpatient and inpatient patients with stable angina pectoris due to coronary heart disease (diagnosed as qi deficiency and blood stasis in Traditional Chinese Medicine) who met the inclusion criteria from August 2021 to January 2023 as the research subjects.

[0063] 1.1.2 Diagnostic criteria

[0064] The Western medicine diagnosis and grading diagnostic standards for this study were formulated based on the "Guidelines for the Diagnosis and Treatment of Stable Angina Pectoris in Coronary Heart Disease" revised by the Cardiovascular Branch of the Chinese Association of Traditional Chinese Medicine in 2019.

[0065] 1.1.2.1 Western medicine diagnostic criteria for stable angina pectoris

[0066] (1) Recurrent angina pectoris lasting for more than 30 days;

[0067] (2) Chest pain is usually dull or tight, mainly located behind the sternum and in the precordial area, with radiating pain to other parts of the body;

[0068] (3) It is more common in the middle-aged and elderly population or those with a family history of genetic diseases;

[0069] (4) Emotional fluctuations, overwork, cold weather, overeating and over-accumulation can easily induce angina pectoris;

[0070] (5) The attack lasts about 3 to 5 minutes, usually lasting from a few minutes to more than 10 minutes, and can be relieved by rest. Sublingual nitroglycerin can quickly relieve the symptoms.

[0071] (6) Electrocardiogram examination revealed abnormal changes such as ST segment shift or T wave inversion;

[0072] (7) Differentiate angina pectoris from angina caused by other diseases.

[0073] 1.1.2.2 Classification of diagnostic criteria for stable angina pectoris

[0074] Grade I: Daily activities do not cause symptoms, such as running on flat ground, climbing three floors with heavy objects, and other physical activities that are heavier than daily behaviors can cause angina pectoris;

[0075] Grade II: Physical activities such as walking at normal speed for 3 to 4 stations or climbing three floors can cause angina pectoris, and daily activities are slightly restricted.

[0076] Grade III: Physical activities lighter than daily activities such as walking 1-2 stations or climbing two floors under normal conditions can cause angina pectoris, and daily activities are significantly restricted.

[0077] Grade IV: Mild physical activity can cause angina pectoris, such as walking slowly, and in severe cases, it can also occur during rest.

[0078] Grade IV patients are in more serious condition and are not included in the observation plan of this trial.

[0079] 1.1.2.3 Standards for TCM Syndrome Differentiation

[0080] According to the 2019 "Guidelines for the Diagnosis and Treatment of Stable Angina Pectoris in Coronary Heart Disease in Traditional Chinese Medicine", "Expert Consensus on the Diagnosis and Treatment of Stable Angina Pectoris in Coronary Heart Disease in Traditional Chinese Medicine", and "Guidelines for Clinical Research of New Chinese Medicines", it meets the diagnostic criteria for Qi deficiency and blood stasis syndrome in traditional Chinese medicine differentiation.

[0081] The main symptoms are chest tightness or chest pain, followed by palpitations, shortness of breath, and fatigue. The patient may have a pale purple tongue and a weak or astringent pulse. If the main symptom and the secondary symptom are greater than or equal to one, the diagnosis can be made by combining the tongue and pulse.

[0082] 1.1.3 Inclusion criteria

[0083] (1) Aged 35 to 80 years old, regardless of gender;

[0084] (2) Those who meet the diagnostic criteria for stable angina pectoris due to coronary heart disease;

[0085] (3) Those who meet the angina pectoris classification standards of grade I, grade II, and grade III;

[0086] (4) Those who meet the diagnostic criteria of qi deficiency and blood stasis syndrome in traditional Chinese medicine;

[0087] (5) The electrocardiogram showed myocardial ischemia (the ST segment of the normal electrocardiogram was depressed by ≥1.0 mm, or / and the T wave inversion of the lead dominated by the R wave was ≥2.0 mm);

[0088] (6) Patients with ischemic changes in the electrocardiogram but not meeting the criteria in the fifth item above, and with a positive result on exercise electrocardiogram, or with coronary artery stenosis confirmed by one of the three examination methods: coronary angiography, radionuclide myocardial scanning, or 64-row CT;

[0089] (7) The patient is expected to be able to adhere to follow-up within six months;

[0090] (8) According to the good clinical trial management standards, volunteers should be included in the trial after obtaining informed consent.

[0091] 1.1.4 Exclusion criteria

[0092] (1) Patients with stable angina pectoris grade IV;

[0093] (2) Those who had myocardial infarction or pre-infarction symptoms within three months before the trial;

[0094] (3) Those with chest pain caused by other heart diseases clinically diagnosed such as myocardial infarction, dissection, hyperthyroidism, perimenopausal syndrome, gastric and esophageal reflux, severe neurosis, etc.;

[0095] (4) Those who had undergone coronary artery revascularization within six months;

[0096] (5) Patients with severe cardiopulmonary insufficiency, severe arrhythmia, grade III hypertension (systolic blood pressure ≥180 mmHg, diastolic blood pressure ≥110 mmHg), severe primary diseases of other systems, and mental illness;

[0097] (6) Pregnant, lactating women or women who intend to become pregnant;

[0098] (7) Those with allergic constitution or allergic to this drug;

[0099] (8) history of drug abuse;

[0100] (9) Currently participating in clinical research of other drugs.

[0101] If any of the above conditions are met, the patient cannot be included in this clinical trial.

[0102] 1.1.5 Shedding Standard

[0103] Case dropout occurs when the following situations occur: patients withdraw due to subjective will, patients cannot continue the study due to severe adverse reactions, or patients withdraw due to accidental death.

[0104] 1.1.6 Treatment of dropout cases

[0105] Inquire about the reasons for dropout, record the last symptom improvement, medication level, and laboratory tests; save all data and information of the patient during the trial to facilitate subsequent dropout analysis; if the treatment is ineffective or serious adverse reactions occur during the period, symptomatic treatment should be given, and records should be kept and reported to the ethics committee in a timely manner.

[0106] 1.2 Research Methods

[0107] 1.2.1 Sample size estimation

[0108] According to previous clinical results and literature, the effective rate of TCM combined with conventional Western medicine in treating patients with angina pectoris due to coronary heart disease is about 86% (ie PA), and the effective rate of conventional Western medicine is about 65% (ie PB). α is a type I error, which is usually set at 0.05, and β is a type II error, which is usually defined as 0.2. Considering the possibility of a 10% dropout rate, it is calculated that the number of clinical cases included in this study should be at least 108. The calculation formula is as follows:

[0109]

[0110] 1.2.2 Case grouping

[0111] A randomized, double-blind, placebo-controlled method was used to screen eligible patients with stable angina pectoris (Qi deficiency and blood stasis syndrome) of grade I to III coronary heart disease. After randomization, they entered an 8-week treatment period. The study was divided into 2 groups, the experimental group and the placebo group. They used 20 ml / time of Trichosanthes Guanxin Mixture and 20 ml / time of placebo, respectively, both 3 times a day.

[0112] 1.2.3 Randomized Controlled Setting

[0113] After comprehensive screening of qualified subjects according to diagnostic criteria, inclusion criteria, and exclusion criteria, SAS software was used to obtain random numbers and randomize qualified patients included in the study. In order to explore the absolute therapeutic effect of the test drug, this trial selected placebo as the control drug, referring to the dosage of Trichosanthes Guanxin Mixture, which was 20 ml each time, 3 times a day. Because the subjects selected in this trial were all patients with grade I to III angina pectoris, and nitroglycerin tablets could be used in combination during angina attacks, the use of placebo would not cause harm to the patients. However, since placebos are easy to cause psychological fear in patients, they may lead to unnecessary withdrawal or unreal disease reactions in subjects. Therefore, it is necessary to patiently explain to the subjects before the trial to eliminate their fear, especially for some subjects who are overly worried about their physical health.

[0114] 1.2.4 Blind setting

[0115] This study adopts the double-blind principle. All drugs must be packaged uniformly and blinded by a designated person. The drug blinding work is completed by a dedicated person. This study adopts a two-level blinding method, as well as blinding of drugs and groups.

[0116] Primary blinding: The packaging of the Gualou Guanxin Mixture Simulator and the Gualou Guanxin Mixture should be uniform and the taste should be similar. The two drugs should be as similar as possible in appearance, color, and taste. The Gualou Guanxin Mixture in the treatment group and the placebo group should be numbered according to the blind bottom.

[0117] Secondary blinding: From the beginning to the end of the trial, neither the patients nor the clinical case collectors know the groups of the subjects, and other relevant persons in charge are also unaware of their actual groups. The placebo group and treatment group are temporarily represented by A and B.

[0118] The blinding process needs to be recorded. Each subject has an emergency envelope containing the subject's drug number and Group A and Group B. It is filled out on the spot by the blinding staff and sealed. The emergency unblinding letter is kept along with the trial drug by a dedicated person until the completion of the trial, and the letter must not be opened at will during the trial.

[0119] Unblinding method: This clinical study is unblinded twice. The first unblinding will be used for statistical analysis according to Group A and Group B. The second unblinding will be carried out later, and the person who keeps the blind bottom will announce the true group of Group A and Group B.

[0120] Emergency unblinding: Unblinding can be considered when patients have serious adverse reactions, complications, and deterioration: With the consent of the person in charge, the emergency unblinding letter can be opened to analyze the cause and whether it is related to the drug. Unblinding shall not be performed for cases that withdraw due to efficacy reasons.

[0121] 1.2.5 Treatment options

[0122] (1) Western medicine treatment: Western medicine treatment was given according to the 2007 "Guidelines for the Diagnosis and Treatment of Chronic Stable Angina Pectoris". Antiplatelet aggregation: aspirin (Bayer Healthcare Co., Ltd.) 100 mg / day. For patients who cannot tolerate aspirin, clopidogrel bisulfate (Plavix, Sanofi (Hangzhou) Pharmaceutical Co., Ltd.) 75 mg / day was used instead. Ventricular rate control: metoprolol succinate sustained-release tablets (Betaloc, AstraZeneca Pharmaceuticals Co., Ltd.) 47.5 mg / day. Lipid-lowering and plaque-stabilizing: atorvastatin calcium tablets 10 mg / day. Coronary dilation: isosorbide mononitrate tablets (Lunan, Lunan Beite Pharmaceutical Co., Ltd.) 20 mg / day. During treatment and follow-up, the dosage of the drugs was adjusted according to the patient's blood lipids, blood pressure and clinical symptoms.

[0123] (2) Treatment group: Western medicine combined with Gualou Guanxin mixture, 20 ml orally three times a day (composition: salvia miltiorrhiza 250 g wild chrysanthemum 350 g Codonopsis pilosula 250 g Trichosanthes kirilowii 250 g clove 50 g vinegar-processed Corydalis 100 g Astragalus 250 g Chuanxiong 250 g Panax notoginseng 50 g). The drugs were provided by the pharmacy of Shanghai Traditional Chinese Medicine Hospital, with a fixed source of drugs.

[0124] (3) Placebo group: Western medicine treatment combined with a simulation of Trichosanthes Guanxin Mixture, three times a day, 20 ml each time, orally, the drugs were uniformly prepared by the Traditional Chinese Medicine Preparation Room of Shanghai Hospital of Traditional Chinese Medicine.

[0125] (4) Treatment course: 8 weeks in total.

[0126] (5) General treatment: control diet, regulate emotions, get enough rest, and exercise regularly.

[0127] (6) Treatment-related regulations:

[0128] During the trial, patients should follow the doctor's instructions, including taking medications on time, adjusting necessary lifestyles, and avoiding other bad habits, such as smoking and drinking. If patients feel unwell or have any concerns, they should contact their doctor immediately.

[0129] Generally, it is not recommended to adjust medication during the trial period, but if the patient's condition progresses or adverse reactions occur, researchers can adjust the medication as needed and inform the patient of their condition.

[0130] During the trial, patients cannot take any other forms of Chinese medicine or Chinese patent medicine except for the study medication to avoid interfering with the results of the study. If patients need to use other medications, such as local Chinese medicine for the treatment of skin diseases, they should first consult a doctor and obtain approval.

[0131] In addition to following the doctor's instructions and trial protocols, patients should also cooperate with the researchers' monitoring and follow-up, including going to the hospital for regular check-ups and providing necessary information.

[0132] 1.2.6 Serological testing methods

[0133] (1) Serum extraction: Take 5 ml of fasting blood in the morning and put it into a blood collection tube. Let it stand upright for 30 min. Centrifuge it at 3000 rpm for 10 min in a laboratory centrifuge. Take 1-1.5 ml of the supernatant and put it into aliquot tubes. Label it and immediately store it in a -80°C refrigerator.

[0134] (2) Serum endothelin-1 (ET-1) level detection: Enzyme-linked immunosorbent assay was used according to the instructions. The Human Endothelin ELISA kit was from Wuhan Boster Biotechnology Co., Ltd. (EK0945).

[0135] (3) Serum nitric oxide (NO) level detection: Enzyme-linked immunosorbent assay was used according to the instructions. The kit was obtained from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd. (A013-2-1).

[0136] 1.3 Observation indicators

[0137] 1.3.1 General Information

[0138] (1) Demographic information: gender, age, height, weight, nature of work, etc.

[0139] (2) Vital signs: respiration, blood pressure, heart rate, etc.

[0140] (3) General clinical data: course of disease, treatment history, allergy history, comorbidities and medication.

[0141] 1.3.2 Efficacy indicators

[0142] (1) Clinical observation: recording the patient's chief complaint, physical signs, angina attacks, changes in TCM syndrome scores, and Seattle Angina Scale during the follow-up period;

[0143] (2) Blood lipids: including TC, TG, HDL-C and LDL-C, recorded once before and after treatment;

[0144] 1.3.3 Safety indicators

[0145] (1) Liver function (AST, ALT, total bilirubin, alkaline phosphatase, γ-glutamyl transaminase) and renal function (urea nitrogen, creatinine) were recorded once before and after treatment;

[0146] (2) Blood routine, urine routine, and stool routine results were recorded once before and after treatment;

[0147] (3) Creatine kinase CK, recorded once before and after treatment;

[0148] (4) If adverse reactions occur during the trial, the patient's symptoms, severity, treatment methods, recovery time, etc. must be carefully observed and recorded to objectively evaluate safety and keep records in a timely manner.

[0149] 1.3.4 Serological indicators

[0150] (1) NO: Record once before and after treatment.

[0151] (2) ET-1: Record once before and after treatment.

[0152] 1.3.5 End point event indicators

[0153] (1) Survival rate: Observe whether any patient dies during treatment. Follow-up for 2 months after the treatment period is completed to observe whether any patient dies.

[0154] (2) Recurrence rate of cardiovascular events: observe whether the patient has acute cardiovascular events during treatment and conduct causal analysis. After the treatment period, continue to follow up for 2 months to observe the recurrence of cardiovascular events.

[0155] 1.4 Efficacy determination

[0156] 1.4.1 Determination of therapeutic efficacy for angina pectoris

[0157] The improvement of angina pectoris scores of patients before and after treatment was compared, and the efficacy was determined according to Appendix 4, including marked effect, effectiveness, ineffectiveness and aggravation, and statistical analysis was performed.

[0158] 1.4.2 TCM symptom efficacy evaluation criteria

[0159] The reduction of TCM syndrome scores of patients before and after treatment was compared, and the efficacy was determined according to Appendix 4, including marked effect, effectiveness, ineffectiveness and aggravation, and statistical analysis was performed.

[0160] 1.5 Ethics Committee Approval

[0161] This clinical trial study was reviewed and approved by the Ethics Expert Committee of Shanghai Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine (approval number: 2021SHL-KY-16-01). All subjects who met the inclusion criteria and entered this clinical trial were given fully informed consent and signed the consent form and related information.

[0162] 1.6 Statistical methods

[0163] The information and data of the subjects who completed the experiment were entered into the computer. SPSS25.0 program was used for statistics, calculation and analysis. Descriptive statistics and methods: If the measurement data meet the normal distribution, it is expressed as mean ± standard deviation. The paired sample t test is used for intra-group comparison, and the two independent sample t test is used for inter-group comparison; if it does not meet the normal distribution, it is expressed as median (quartile). The non-parametric test-two related sample rank sum test is used for intra-group comparison, and the non-parametric test-two independent sample rank sum test is used for inter-group comparison. The enumeration data are all expressed as number of cases (%), and the inter-group ratio is used by chi-square (Pearson X2) test or calculation of Fisher's exact probability. This clinical study stipulates that P < 0.05 is recorded as statistically significant.

[0164] 2. Experimental results

[0165] 2.1 Case enrollment

[0166] A total of 11 patients dropped out of this clinical study, and 120 patients were actually included, with a dropout rate of 8.4%, which was less than the set value of 10% during sample estimation. After unblinding, there were 64 patients in the treatment group and 56 patients in the placebo group (see Table 1).

[0167] Table 1

[0168]

[0169] 2.2 Changes in angina scores during treatment in the two groups of patients, see Figure 1a , 1b .

[0170] Figure 1a The changes in angina scores of the two groups of patients before treatment, 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment were statistically analyzed. Both groups could significantly reduce the angina scores of patients. Figure 1b This is the distribution of angina scores in the two groups of patients after 8 weeks of treatment, indicating that the treatment group can significantly reduce the angina scores after 8 weeks of treatment, and is better than the placebo group.

[0171] 2.3 Comparison of angina pectoris attack frequency between the two groups after treatment, see Figure 2a , 2b .

[0172] Figure 2aThe changes in the frequency of angina attacks in the two groups of patients before treatment, 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment were statistically analyzed. The frequency of angina attacks in both groups was reduced. Figure 2b This is the distribution of angina attack frequency in the two groups of patients after 8 weeks of treatment, indicating that the treatment group can significantly reduce the frequency of angina attacks after 8 weeks of treatment, and is better than the placebo group.

[0173] 2.4 Comparison of the average duration of angina pectoris between the two groups after treatment, see Figure 3a , 3b .

[0174] Figure 3a The changes in the average duration of angina pectoris before treatment, 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment were statistically analyzed. Both groups were able to reduce the duration of angina pectoris. Figure 3b This is the distribution of angina pectoris duration in the two groups of patients after 8 weeks of treatment, indicating that the treatment group can significantly reduce the average duration of angina pectoris after 8 weeks of treatment, and is better than the placebo group.

[0175] 2.5 Comparison of the efficacy of angina pectoris between the two groups after treatment, see Figure 4 .

[0176] Figure 4 The efficacy results of the two groups of patients after treatment were statistically analyzed. The total effective rate of the treatment group was 81.3%, and the effective rate of the placebo group was 64.3%, indicating that the improvement rate of angina pectoris in the treatment group was significantly better than that in the placebo group.

[0177] 2.6 Comparison of TCM syndrome scores between the two groups after treatment, see Figure 5a , 5b .

[0178] Figure 5a The changes in TCM syndrome scores of the two groups of patients were statistically analyzed before treatment and at 2, 4, 6 and 8 weeks after treatment, indicating that both groups could reduce their TCM syndrome scores. Figure 5b This is the distribution of TCM syndrome scores of the two groups of patients at 8 weeks of treatment, indicating that the improvement of TCM syndrome scores in the treatment group was significantly better than that in the placebo group.

[0179] 2.7 Comparison of TCM symptom efficacy between the two groups after treatment, see Figure 6 .

[0180] Figure 6 The results of the TCM syndrome efficacy evaluation of the two groups of patients after treatment were statistically analyzed. The total effective rate of the treatment group was 84.4%, and the effective rate of the placebo group was 66.1%, indicating that the treatment group was significantly better than the placebo group in improving TCM symptoms.

[0181] 2.8 Comparison of blood lipids after treatment, see Figure 7a , 7b , 7c, 7d.

[0182] Figure 7a , 7b , 7d showed that the treatment group could reduce the levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol, and was better than the placebo group; Figure 7c This indicates that after treatment, both the treatment group and the placebo group could increase the level of high-density lipoprotein cholesterol, but there was no difference between the two groups.

[0183] 2.9 Comparison of Seattle Angina scores between the two groups after treatment, see 8a, 8b, 8c, 8d, and 8e.

[0184] The Seattle Angina Rating Scale includes the degree of limitation of physical activity (PL), stable state of angina (AS), attack of angina (AF), satisfaction with treatment (TS), and degree of disease cognition (DS), and evaluates the efficacy of angina patients before and after treatment from five dimensions. Figure 8a , 8b , 8c, 8d, and 8e indicate that the treatment group can improve the degree of limitation of physical activity, stable state of angina pectoris, angina attacks, and treatment satisfaction of patients, and is superior to the placebo group.

[0185] Example 16 Animal Experiment

[0186] 1. Experimental Materials

[0187] 1.1 Animal modeling and grouping

[0188] ApoE males aged 6 weeks were used - / - Mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were fed a high-fat diet for 12 weeks to establish a mouse atherosclerosis model. After 1 week of adaptive feeding with a normal diet, they were randomly divided into 3 groups, 3 mice in each group, including a control group, a model group, and a treatment group.

[0189] 1.2 Drugs

[0190] The control group was given a normal diet, and the model group and the model administration group were given a high-fat diet. From the first day of the experiment, the treatment group was given Gualou Guanxin Mixture by gavage once a day, and the control group and the model group were given an equal volume of saline by gavage for a total of 12 weeks. According to the equivalent dose ratio table between humans and animals converted by body surface area, the gavage dose of Gualou Guanxin Mixture was 7.8ml / kg / day.

[0191] 1.3 Detection Method

[0192] On the last day of the experiment, after fasting for 12 hours, the weight of each mouse was measured, and the mice were anesthetized with 3% sodium pentobarbital (90 mg / kg). After taking pictures of the body, blood was collected and placed in an enzyme-free EP tube. The tube was left at room temperature for 2 hours. After the serum was precipitated, it was centrifuged at 3000 g for 15 minutes, and the supernatant was placed in an enzyme-free EP tube and stored in a -80°C refrigerator for later use.

[0193] The mice were fixed on a water-permeable sampling board, and the chest and abdominal hair of the mice were disinfected with 75% alcohol. The skin was cut in a V shape along the middle of the abdomen, and the sternum and the entire thorax were removed to expose the entire abdominal cavity and thoracic cavity. The aorta was dissected and separated from the origin of the aorta to the bifurcation of the common iliac artery of the abdominal aorta, and the left and right brachiocephalic arteries and the innominate artery were separated upward at the aortic arch; the heart and blood vessels were removed together; after the tissue specimens were trimmed, the heart was cut off close to the root of the ascending aorta and fixed in 4% paraformaldehyde; at the same time, the mouse carotid artery was taken for tissue section staining, and the arteries used for gross staining and tissue section staining were fixed in 4% paraformaldehyde, and the remaining tissues were quickly put into liquid nitrogen and later transferred to a -80℃ refrigerator for storage.

[0194] After 12 weeks, the body weights of mice in each group were compared. Serum lipid levels such as triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were detected using a blood lipid detection kit. Oil red O staining of aortic sinus sections was used to detect the size of atherosclerotic lesions.

[0195] 2. Experimental results

[0196] 2.1 Effect of Gualou Guanxin Mixture on the Body Weight of Mice in Each Group

[0197] The results of in vivo experiments showed that the mice in the model group had a significant increase in weight, dry hair, slow movements, and a gradual decrease in food intake. The drug administration could significantly inhibit the weight gain of mice caused by a high-fat diet (P < 0.05) and improve the general condition of the mice. Fig. 9 .

[0198] 2.2 Effect of Gualou Guanxin Mixture on Blood Lipids of Mice in Each Group

[0199] The results of in vivo experiments showed that the blood lipid level of mice in the model group was significantly increased, and the levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol were significantly reduced after administration (P < 0.05). Fig.10 .

[0200] 2.3 Effects of Gualou Guanxin Mixture on the Aortic Sinus of Mice in Each Group

[0201] The results of in vivo experiments showed that the area of ​​atherosclerotic lesions in the model group mice increased, and the area of ​​atherosclerotic lesions was significantly reduced after administration. Fig.11a , 11b .

[0202] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A Chinese medicine composition for treating angina pectoris of coronary heart disease of Qi deficiency and blood stasis type, characterized in that: The drug is prepared from the following raw materials in parts by weight: 210-290 parts of salvia miltiorrhiza, 310-390 parts of wild chrysanthemum, 210-290 parts of codonopsis pilosula, 210-290 parts of trichosanthes, 30-70 parts of cloves, 80-120 parts of vinegar-processed corydalis, 210-290 parts of astragalus, 210-290 parts of chuanxiong and 30-70 parts of notoginseng.

2. The Chinese medicine composition according to claim 1, characterized in that: The drug is prepared from the following raw materials in parts by weight: 230-270 parts of salvia miltiorrhiza, 330-370 parts of wild chrysanthemum, 230-270 parts of codonopsis pilosula, 230-270 parts of trichosanthes, 40-60 parts of cloves, 90-110 parts of vinegar-processed corydalis, 230-270 parts of astragalus, 230-270 parts of chuanxiong and 40-60 parts of notoginseng.

3. The Chinese medicine composition according to claim 2, characterized in that: The drug is prepared from the following raw materials in parts by weight: 250 parts of salvia miltiorrhiza, 350 parts of wild chrysanthemum, 250 parts of codonopsis pilosula, 250 parts of trichosanthes, 50 parts of cloves, 100 parts of vinegar-processed corydalis, 250 parts of astragalus, 250 parts of chuanxiong and 50 parts of notoginseng.

4. The Chinese medicine composition according to any one of claims 1 to 3, characterized in that: The dosage form of the Chinese medicine composition is decoction, granules, tablets, capsules, oral liquid, mixture or syrup.

5. Use of the Chinese medicine composition according to any one of claims 1 to 3 in the preparation of a drug for treating angina pectoris caused by coronary heart disease.

6. The use according to claim 5, characterized in that: The angina pectoris of coronary heart disease is angina pectoris of coronary heart disease of qi deficiency and blood stasis type.

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