Traditional Chinese medicine composition for treating depression after coronary heart disease as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention discloses a traditional Chinese medicine composition for treating depression after coronary heart disease as well as a preparation method and application of the traditional Chinese medicine composition. The traditional Chinese medicine composition comprises the following components in parts by weight: 1500-1600 parts of oyster, 700-800 parts of salvia miltiorrhiza, 600-700 parts of fructus forsythiae, 400-500 parts of lignum dalbergiae odoriferae, 600-700 parts of radix ophiopogonis, 400-500 parts of sappan wood and 10-11 parts of borneol. The traditional Chinese medicine composition disclosed by the invention is suitable for treating post-myocardial infarction depression, and can improve the cardiac function, recover cognitive impairment, relieve negative emotion, stabilize the illness state and improve the quality of life.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating post-coronary heart disease depression, a preparation method thereof, and an application thereof. Background Art

[0002] Nowadays, more and more people suffer from two or more long-term diseases simultaneously, which is called multimorbidity or comorbidity. Currently, the situation of middle-aged and elderly people suffering from two or more diseases simultaneously is becoming increasingly serious, especially cardiovascular and cerebrovascular diseases and mental and neurological diseases are often comorbidities. Currently, the clinical prevalence rate of postmyocardial infarction depression (PMID) is as high as 79.5%, with the characteristics of comorbidity, seriously endangering human physical and mental health, and has become a common major clinical disease; at least half (more than 50 million people) of the population aged 65 or over in Europe suffers from comorbidity. In the UK, the proportion of the comorbid population is expected to rise from 54% in 2015 to 68% in 2035. However, the scientific and medical communities often aim at the diagnosis and treatment or research of a single disease with a specialized thinking mode, ignoring the internal relationship between the etiology, pathogenesis, diagnosis and treatment, etc. in the comorbid state, resulting in incomplete treatment strategies and plans.

[0003] Cardiovascular diseases often have comorbidities, and the number of deaths accounts for about 1 / 3 of all global deaths. Coronary atherosclerotic heart disease (CHD), also known as coronary heart disease, refers to a heart disease caused by atherosclerotic plaque in the coronary artery, resulting in lumen stenosis or occlusion, leading to myocardial ischemia, hypoxia or necrosis, with a high disability rate, recurrence rate, mortality rate, and many complications, imposing a heavy social burden. Typical acute myocardial infarction (AMI) is a severe coronary heart disease, which is a clinical syndrome caused by the occlusion or severe stenosis of the coronary artery, resulting in ischemic necrosis of myocardial cells, and is the leading cause of death and disability. Myocardial infarction often presents symptoms such as angina pectoris, and its symptoms belong to the categories of traditional Chinese medicine syndromes such as chest impediment and true chest pain.

[0004] Postmyocardial infarction depression (PMID) belongs to the comorbidity of "true chest pain" or "chest impediment" and "depression syndrome" in traditional Chinese medicine. It is the emergence of depression on the basis of coronary heart disease myocardial infarction. Due to the combined effects of qi stagnation, blood stasis, phlegm obstruction, fire stagnation, yin injury, etc., qi and blood are stagnated and not smooth, the liver qi fails to flow smoothly, and the mind loses clarity, resulting in low mood and the emergence of depression, with the characteristics of comorbidity.

[0005] With the intensification of population aging in China, the number of patients with coronary heart disease has been increasing year by year. There are various complications left after myocardial infarction, among which depression after myocardial infarction is a common complication, seriously affecting the rehabilitation effect and the quality of life of patients. This disease is mainly characterized by the simultaneous occurrence of cardiac function defects and cognitive dysfunction. In mild cases, it affects the rehabilitation outcome of myocardial infarction, and in severe cases, there is a tendency of despair, even leading to suicide. If the treatment is not timely, the condition will deteriorate from mild to severe, bringing a heavy burden to families and society.

[0006] PMID is an affective disorder characterized by low mood, decreased activity ability, retarded thinking function, etc., which occurs simultaneously in addition to various symptoms of coronary heart disease myocardial infarction after the occurrence of cardiovascular diseases. It is a secondary depression and the most common and important complication after coronary heart disease myocardial infarction.

[0007] Depression is a very common mental disorder, while PMID is a common complication after myocardial infarction, which is a special type of depression and not a simple combination of myocardial infarction and depression. It should not be confused with depression-induced myocardial infarction. Feng Limin et al. found that the prevalence of the combination of myocardial infarction and depression in Asian patients was 45.03%; Hasham Saeed et al. found that the prevalence of myocardial infarction combined with mild, moderate and severe depression was as high as 79.5%, and about 60% of them had mild and moderate depression; the results of a meta-analysis showed that depression after myocardial infarction could increase the risk of cardiovascular complications by 2 - 2.5 times. A cross-sectional survey of 435 CVD patients using opportunistic sampling and snowball sampling methods in the southeastern region of China from October to November 2020 showed that the incidence of anxiety was 11.72% and the incidence of depression was 9.20%. Leong et al. conducted a prospective cohort study. Through clinical depression assessment of 95 patients, they found that 88.4% of the patients had depressive symptoms. A study on the prevalence of depression after myocardial infarction showed that 64.3% of the patients had varying degrees of emotional problems, and the proportions of mild, moderate and severe patients were 66.1%, 23.6% and 10.2% respectively. Therefore, how to safely and effectively treat depression after myocardial infarction has attracted more and more attention.

[0008] At present, the identification methods of depression after myocardial infarction in Western medicine are relatively clear. Western medicine proposes that for PMID, a variety of treatment methods such as psychotherapy, drug treatment and rehabilitation training should be comprehensively used to achieve the best treatment effect. In terms of drug treatment, the compliance, efficacy, adverse reactions, symptom changes, etc. of drug treatment should be monitored and evaluated. "Chinese Expert Consensus on Psychological Prescriptions for Patients Visiting the Cardiovascular Department" proposes that when using cardiovascular drugs, anti-anxiety or anti-depressant related drugs should be added according to the situation. Commonly used ones are selective 5-HT reuptake inhibitors, benzodiazepines Drugs, tricyclic and tetracyclic drugs, monoamine oxidase inhibitors, etc. However, most psychiatric drugs have adverse reactions. The common adverse reactions of selective 5-HT reuptake inhibitors are gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, and also include agitation, sexual dysfunction, migraine, weight gain, etc.; the common adverse reactions of benzodiazepine drugs are dizziness, drowsiness, fatigue, and slow reaction. Large doses may cause ataxia, coma, and respiratory depression, etc.; the common adverse reactions of tricyclic antidepressants are dry mouth, constipation, blurred vision, difficulty urinating, orthostatic hypotension, etc. PMID gives treatment recommendations for antidepressants. Among them, citalopram, sertraline, and escitalopram have level 1 evidence and receive a class A recommendation (1 / A). It should be noted that all patients allergic to SSRIs or taking monoamine oxidase inhibitors (MAOIs) are prohibited. Patients with epilepsy and patients with active intracranial hemorrhage must use with caution.

[0009] In summary, at present, Western medicine treatment selects antidepressant drugs by comprehensively considering risk factors (such as epilepsy, falls, and delirium) and the adverse reactions of drugs. However, Western medicine has obvious toxic and side effects, high prices, problems such as patients' inability to bear and poor treatment compliance, and the efficacy needs to be improved are still difficult to solve. Especially in the actual clinical treatment, more than 80% of mild to moderate PMID patients and their families are not willing to take or take antidepressant Western medicine prematurely and hope to treat PMID with traditional Chinese medicine.

[0010] Traditional Chinese medicine treatment of post-myocardial infarction depression has obvious curative effect advantages in treating diseases and overall syndrome differentiation, and has no obvious side effects. Patients are easy to accept traditional Chinese medicine treatment. However, there is currently no new traditional Chinese medicine for treating PMID. To facilitate clinical medication and improve clinical efficacy, it is urgent to develop a new traditional Chinese medicine for treating PMID. Summary of the Invention

[0011] Aiming at the problems existing in the prior art, the first aspect of the present invention is to provide a traditional Chinese medicine composition for treating post-coronary heart disease depression, and the traditional Chinese medicine composition contains the following components in parts by weight:

[0012] Oyster 1500 - 1600 parts, Salvia miltiorrhiza 700 - 800 parts, Forsythia suspensa 600 - 700 parts, Dalbergia odorifera 400 - 500 parts, Ophiopogon japonicus 600 - 700 parts, Sappanwood 400 - 500 parts, Borneol 10 - 11 parts.

[0013] The second aspect of the present invention is to provide a preparation method of a traditional Chinese medicine composition for treating post-coronary heart disease depression, including the following steps:

[0014] 1) Take forsythia and dalbergia odorifera in the formula amount, impregnate them with water, extract by steam distillation, collect the volatile oil, wrap the volatile oil and borneol with β-cyclodextrin to obtain β-cyclodextrin-wrapped volatile oil and borneol, set them aside for later use. After centrifugally separating and removing impurities from the extracted medicinal liquid, collect the medicinal residues and the extract respectively, and set them aside for later use;

[0015] 2) Take oyster in the formula amount, decoct it with water, start timing from the boiling of the medicinal liquid, decoct for 1 h to obtain the decocted liquid;

[0016] 3) After the decoction in step 2) is completed, add danshen, sappanwood, ophiopogon japonicus in the formula amount and the medicinal residues in step 1) to the decocted liquid, and perform reflux extraction to obtain the reflux extract. After centrifugally separating and removing impurities from the reflux extract, combine it with the extract in step 1), and concentrate under reduced pressure to obtain the clear paste;

[0017] 4) Add the β-cyclodextrin-wrapped volatile oil and borneol prepared in step 1) to the clear paste, perform spray drying to obtain the dry powder, and then add excipients to prepare granules by dry granulation method.

[0018] Further, in step 1), the addition amount of water is 8 times the total amount of forsythia and dalbergia odorifera, the impregnation time is 0.5 h, and the steam distillation is carried out for 7 h.

[0019] Further, in step 2), the material-liquid ratio of oyster to water is 1 g:30 L.

[0020] Further, in step 3), the reflux extraction is carried out 2 times, each time for 0.5 h, the temperature of concentration under reduced pressure is 50 - 60 °C, and the relative density of the clear paste is 1.10 ± 0.02.

[0021] The third aspect of the present invention lies in providing an application of a traditional Chinese medicine composition in the preparation of a drug for treating post-coronary heart disease depression.

[0022] The traditional Chinese medicine composition of the present invention is applicable to the treatment of post-myocardial infarction depression, can improve cardiac function, restore cognitive impairment, relieve negative emotions, stabilize the condition, and improve the quality of life. Description of the Drawings

[0023] Figure 1 It is a schematic diagram of an AMI model for animal experiments;

[0024] Figure 2 It is the HAMD scores of each group before and after treatment in clinical application examples;

[0025] Figure 3 It is the comparison of the curative effects of each group after 4 weeks of treatment in clinical application examples;

[0026] Figure 4 It is the comparison of the curative effects of each group after 8 weeks of treatment in clinical application examples;

[0027] Figure 5 It is the average integral of traditional Chinese medicine syndromes before and after treatment in clinical application examples;

[0028] Figure 6 are the standard scores of each group's SCL-90 factors before and after treatment in the clinical application examples;

[0029] Figure 7 are the six-minute walking distances of each group before and after treatment in the clinical application examples;

[0030] Figure 8 is the number of occurrences of adverse reactions in the clinical application examples. Specific implementation manners

[0031] The present invention will be further described below in conjunction with specific embodiments to better understand the technical solution.

[0032] Example 1: The prescription composition of Guanxin Jieyu Granules (1000 g of granules):

[0033] Oyster 1562.9 g, Salvia miltiorrhiza 781.5 g, Forsythia suspensa 625.2 g, Dalbergia odorifera 468.9 g, Ophiopogon japonicus 625.2 g, Borneol 10.4 g, Sappanwood 468.9 g, adding excipients to make 1000 g of granules.

[0034] The specific preparation is as follows:

[0035] 1) Take Forsythia suspensa and Dalbergia odorifera, use 8 times the amount of water as the solvent, soak for 0.5 h, perform steam distillation for 7 h, extract and collect the volatile oil, wrap the volatile oil and borneol with β-cyclodextrin, and set aside separately. And obtain the extraction liquid. After the extraction liquid is centrifuged to remove impurities, set aside separately.

[0036] 2) Take oyster, use 30 times the material-liquid ratio of water as the solvent, start timing from the boiling of the liquid medicine, and decoct for 1 h.

[0037] 3) After the decoction of oyster is completed, add Salvia miltiorrhiza, Sappanwood, Ophiopogon japonicus and the medicinal residues after the extraction of the volatile oil of Forsythia suspensa and Dalbergia odorifera, reflux and extract 2 times, each time for 0.5 h. After the extraction liquid is centrifuged to remove impurities, it is combined with the extraction liquid of the volatile oil of Forsythia suspensa and Dalbergia odorifera, and concentrated under reduced pressure at 50-60 °C to obtain a clear paste with a relative density of 1.10 ± 0.02.

[0038] 4) Add the volatile oil and borneol wrapped with β-cyclodextrin to the clear paste, spray dry to obtain a dry powder, and then add an appropriate amount of maltodextrin and magnesium stearate, and make granules by dry method to obtain the product.

[0039] Verification Example 1

[0040] Volatile oil extraction experiment: According to the regulations of the Chinese Pharmacopoeia 2020 Edition, the medicinal materials that need to extract volatile oil in the present invention are Forsythia suspensa and Dalbergia odorifera.

[0041] Experimental investigation on the extraction of volatile oil alone and in combination: According to the prescription dosage, the content comparison of the volatile oil extracted from Forsythia suspensa and Dalbergia odorifera alone and the two herbs in combination was investigated respectively. The results are shown in Table 1.

[0042] Table 1

[0043]

[0044] As can be seen from Table 1, in terms of the extraction amount of volatile oil, there is no significant difference between the combined extraction amount of the two herbs and the total amount of separate extractions. For the convenience of industrial production, the combined extraction of Forsythia suspensa and Dalbergia odorifera was selected to extract the volatile oil.

[0045] Determination of the extraction method of volatile oil: The present invention studied the extraction process of volatile oil from Forsythia suspensa and Dalbergia odorifera. Currently, methods such as steam distillation and supercritical fluid extraction are mainly used. Therefore, it is necessary to compare the extraction efficiency of these two methods.

[0046] Take 2 portions of the two medicinal herb pieces according to the prescription dosage, and extract them by steam distillation and CO 2 supercritical fluid extraction respectively.

[0047] The experimental results show that the extraction rate of CO 2 supercritical fluid extraction is higher than that of steam distillation extraction, but there is no significant difference statistically. Considering the actual production, steam distillation extraction was selected.

[0048] Optimal process study on the extraction of volatile oil from two kinds of medicinal herb pieces by steam distillation method: The medicinal herbs used in the investigation of the volatile oil extraction process were 24 g of Forsythia suspensa and 18 g of Dalbergia odorifera. Two factors, extraction time (A) and solid-liquid ratio (B), were selected, and the volatile oil yield (C) was used as the index for optimization. The experiment adopted a 22 factorial design and repeated two blocks. The experimental combinations are shown in Table 2:

[0049] Table 2 Factorial experiment factors and levels table for the volatile oil extraction process

[0050]

[0051] As can be seen from Table 2, taking the extraction amount of volatile oil as the index, the model of this experiment is significant (P<0.05); the extraction time has a significant difference on the model (P<0.05), and the solid-liquid ratio has no effect. Taking the maximum value of the volatile oil extraction amount as the expected value, the design space was obtained and experimental verification was carried out. The experimental conditions were a solid-liquid ratio of 8 times and a decocting time of 7 hours. The results of the verification test were within the 95% confidence interval.

[0052] Therefore, through process screening with the extraction amount of volatile oil as the index, the optimal process was obtained as an extraction time of 7 h and a solid-liquid ratio of 1:8.

[0053] Volatile oil and borneol β-cyclodextrin (β-CD) inclusion: Take 0.3 mL of volatile oil, add 0.3 g of borneol and 2.7 mL of ethanol to make 3 mL of an ethanol solution of volatile oil / borneol. Take 3 g of β-CD, add 30 mL of water, stir at 60 °C for 10 min. Cool to room temperature to make a saturated solution of β-CD, then transfer it to a thermostatic magnetic stirrer. According to the ratio of β-cyclodextrin:volatile oil (10:1), dropwise add the ethanol solution of volatile oil / borneol under stirring. The magnetic stirring speed is 300 r / min, the temperature is 40 °C, and the inclusion is carried out for 60 min until it is in a suspension state. Cool to room temperature and refrigerate in the refrigerator for 24 h, then filter by suction. Wash 3 times with anhydrous ethanol. The obtained inclusion complex is dried at a low temperature of 40 °C for 5 h to obtain a dry inclusion complex, which is the volatile oil borneol cyclodextrin inclusion complex.

[0054] Study on the optimal extraction process of non-volatile components: The medicinal materials used for investigating the optimal extraction process of non-volatile components are from 1 prescription. Three factors, namely extraction time (A), extraction times (B), and solid-liquid ratio (C), are selected. The water extraction experiments are carried out with the extract yield (D), forsythoside A content (E), salvianolic acid B content (F), and phillyrin content (G) as response indexes. The experimental scheme adopts a 23 factorial design, in which the Std1 group repeats the experiment twice (Std9 and Std10). The experimental combinations are shown in Table 3:

[0055] Table 3 Factorial experiment factors and levels of water extraction process

[0056]

[0057] As can be seen from Table 3, the model of this experiment is significant. There are significant differences in the decoction time and decoction times for each index (P < 0.05), and there is no significant difference in the solid-liquid ratio factor. Set the expected values of the four indexes of extract yield, forsythoside A content, salvianolic acid B content, and phillyrin content to the maximum value to obtain several optimal processes. Select the process with the largest expected value for verification, and the indexes of the three verification experiments all fall within the 95% confidence interval.

[0058] Therefore, the optimal process obtained by screening the process with the four indexes of extract yield, forsythoside A content, salvianolic acid B content, and phillyrin content is extraction time 0.5 h, solid-liquid ratio 1:10, and extraction times 2 times.

[0059] Determination of the optimal extraction process parameters

[0060] Water extraction process: Take Forsythia suspensa and Dalbergia odorifera as the two medicinal materials, add 8 times the amount of water, extract for 7 hours to obtain volatile oil, collect the volatile oil, wrap the volatile oil and borneol with β-cyclodextrin, set aside for later use, and obtain the extraction liquid. After centrifuging and separating the impurities from the extraction liquid, set aside for later use. Take an appropriate amount of oyster, add 30 times the amount of water, extract for 1 hour to obtain the first decoction of oyster, then add Salvia miltiorrhiza, Sappanwood, Ophiopogon japonicus and the residue of the extraction of the volatile oil of Forsythia suspensa and Dalbergia odorifera, extract 2 times, each time for 0.5 h, filter the liquid medicine and combine it with the extraction liquid of the volatile oil of Forsythia suspensa and Dalbergia odorifera, and concentrate it into an extract for later use.

[0061] Separation and impurity removal process: In order to remove solid particles in the liquid, factories mostly use the filtration method. Since Ophiopogon japonicus in this formula contains more polysaccharides, the obtained liquid medicine is more viscous and not easy to filter. Through experiments, when the liquid medicine is concentrated to about 1.1, centrifugation with a tubular centrifuge can obtain a clearer liquid medicine. Calculated by salvianolic acid B and phillyrin, the loss rate before and after impurity removal is about 5%. According to the above experimental results, when producing, considering the liquid medicine and the factory equipment conditions, centrifugation with a tubular centrifuge can be considered for impurity removal.

[0062] Concentration and drying process: Since this process uses the water extraction process, conventional vacuum reduction (≤0.09 mPa) and low temperature (≤60 °C) concentration conditions are used for concentration.

[0063] This process uses spray drying to prepare the extract powder and then granulates. First, a single-factor experiment was conducted to investigate the influence of the relative density of the liquid medicine on the experiment. The results showed that when the density of the liquid medicine was 1.05 g / cm3, the extract powder could not be sprayed, when the density of the liquid medicine was 1.10, the extract powder with good properties could be obtained, and when the density of the liquid medicine was 1.20 g / cm 3 it would cause the spray needle of the instrument to be blocked. Therefore, in this experiment, the density of the liquid medicine was fixed at 1.10 g / cm 3 , taking the water content of the extract powder as the evaluation index, the influence of the inlet air temperature and the sample injection speed on the drying process was investigated, and the spray drying process conditions were screened according to the factorial experiment table. The results are shown in Table 4.

[0064] Table 4 Factorial experiment factors and level table of spray drying process

[0065]

[0066] It can be seen from Table 4 that: the test model in this experiment is significant, the inlet air temperature factor has a significant difference (P<0.05), and the sample injection speed factor has no significant influence. According to the design space, experimental verification was carried out, and all indexes of the two verification tests fell within the 95% confidence interval.

[0067] Therefore, the best spray conditions are: inlet air temperature 156 °C, peristaltic speed 12 rpm, relative density of the liquid medicine 1.10 g / cm 3 .

[0068] Forming process: The spray-dried powder prepared by the above process has strong hygroscopicity and is not suitable for wet granulation through preliminary tests. Since dry granulation does not have processes such as humidification and drying in wet granulation and has advantages such as low cost and energy conservation, the dry granulation process was selected for investigation.

[0069] Selection of types and dosages of excipients: According to the commonly used excipients for granule agents, dextrin and maltodextrin were selected as alternative excipients in this experiment, and the investigation was mainly carried out from the granule yield. 1% magnesium stearate was added to prevent sticking to the roller.

[0070] After dry granulation, the product was placed in 10-mesh and 80-mesh drug sieves, and the weight between the 10- and 80-mesh drug sieves was accurately weighed to calculate the yield. The results showed that the average forming rate of maltodextrin was higher than that of dextrin. Considering the price of excipients comprehensively, maltodextrin could be determined as the dry granulation excipient. According to the above experimental results, a mixture of 19% maltodextrin and 1% magnesium stearate was determined as the granulation excipient.

[0071] Dry granulation process parameters: Dry granulation conditions were selected to preliminarily study the environmental humidity, main pressure, and amount of added excipients. After preliminary experiments, the environmental relative humidity was 40%, the main pressure was 5 MPa, and the highest yield was obtained with 20% excipient dosage, and the granule yield was 70%.

[0072] Animal experiments

[0073] I. Preparation of rat acute myocardial infarction (AMI) model

[0074] The model was prepared by ligating the coronary artery to cause acute myocardial infarction, and a long-term survival model after acute myocardial infarction was established by the method of ligating the left anterior descending coronary artery in vivo.

[0075] After the rats were anesthetized (with Zoletil 50 combined with atropine), the hair on the chest was shaved with a small animal hair clipper. After fixation, tracheal intubation was performed and connected to a small animal ventilator. The position was located at the 3rd - 4th intercostal space on the left side beside the sternum of the rat. The skin was incised along the intercostal direction, about 1.5 cm long, and the subcutaneous tissue and muscle were separated layer by layer, and the pericardium was opened. The left anterior descending coronary artery was ligated with a 6.0 suture at 2 mm below the edge of the auricle, and the thread was tightened and knotted. During the operation, it could be seen macroscopically that the myocardial area of the anterolateral wall of the left ventricle distal to the ligature line turned white. An appropriate amount of lidocaine was dropped to prevent arrhythmia. The thoracic cavity was closed layer by layer, and an appropriate amount of penicillin was given to prevent postoperative infection. Then the ventilator was removed, and the rat chest was gently pinched to assist its breathing recovery. All the above operations were carried out under strict aseptic conditions. Pay attention to keeping warm during the operation and before the rats woke up after the operation. In the Control group, except for not ligating the coronary artery, the other operations were the same as those of the AMI model animals. See Figure 1 .

[0076] II. Preparation of post-myocardial infarction depression model

[0077] On the basis of screening out the successfully prepared AMI model, on the 4th day after modeling the AMI model rats, the rats to be modeled with depression were placed in separate cages for solitary rearing, and combined with the CUMS method. Every day, 2 methods were randomly selected from the following 9 methods by using the random number table method for stress treatment for 28 consecutive days. The detailed operation method was improved from the method of Willner P and slightly modified, as shown in Table 5 - Table 6.

[0078] Table 5:

[0079]

[0080] Table 6 Stress method arrangement order

[0081] Time Method Time Method Day 1 Fasting, shaking the mouse cage Day 15 Tail clamping, fasting Day 2 Water deprivation, circadian rhythm reversal Day 16 Shaking the mouse cage, water deprivation Day 3 Wet bedding, odor stimulation Day 17 Odor stimulation, wet bedding Day 4 Ice water swimming, restraint Day 18 Circadian rhythm reversal, ice water swimming Day 5 Tail clamping, fasting Day 19 Odor stimulation, tail clamping Day 6 Shaking the mouse cage, water deprivation Day 20 Restraint, shaking the mouse cage Day 7 Odor stimulation, wet bedding Day 21 Fasting, shaking the mouse cage Day 8 Circadian rhythm reversal, ice water swimming Day 22 Odor stimulation, ice water swimming Day 9 Shaking the mouse cage, tail clamping Day 23 Fasting, restraint Day 10 Restraint, crowding Day 24 Wet bedding, tail clamping Day 11 Fasting, stroboscopic light Day 25 Odor stimulation, tail clamping Day 12 Water deprivation, circadian rhythm reversal Day 26 Fasting, circadian rhythm reversal Day 13 Wet bedding, shaking the mouse cage Day 27 Ice water swimming, wet bedding Day 14 Ice water swimming, restraint Day 28 Restraint, water deprivation

[0082] Grouping and administration: The surviving rats after 24 hours of modeling will enter the experimental group. According to the random number table method, the rats are divided into Control group, Model group, Fluoxetine group, FM group, ZYDZ1 group, ZYDZ2 group, ZYDZ3 group, ZYDZ4 group, ZYDZ5 group, ZYDZ6 group, ZYDZ7 group, ZYDZ8 group, ZYDZ9 group, ZYDZ10 group, ZYDZ11 group, ZYDZ12 group, ZYDZ13 group, ZYDZ14 group, ZYDZ15 group, ZYDZ16 group, ZYDZ17 group, ZYDZ18 group, ZYDZ19 group. The rats in each group were given intragastric administration of an equal volume of solution. Among them, the Control group and the Model group were both intragastrically administered an equal volume of normal saline for 56 consecutive days. The dosage of traditional Chinese medicine in each group of this experiment was converted equally according to the clinical dosage.

[0083] 1. Fluoxetine hydrochloride group (0.01 g / kg / d)

[0084] 2. FM group Guanhxinyu Decoction: Salvia miltiorrhiza 15 g, Sappanwood 9 g, Oyster 30 g, Dalbergia odorifera 9 g, Forsythia suspensa 12 g, Raw Ophiopogon japonicus 12 g, Borneol 0.25 g.

[0085] 3. ZYDZ1 group (Application No.: CN201710062005.0): Raw Dragon Bone 20 g, Turmeric 10 g, Forsythia suspensa 10 g, Asparagus cochinchinensis 10 g, Scrophularia ningpoensis 12 g, Rehmannia glutinosa 12 g, Ophiopogon japonicus 10 g, Natrii Sulfas Exsiccatus 12 g, Aquilaria sinensis 5 g, Calcinated Haliotidis 10 g, Pyritum 15 g, Tangerine Peel 10 g, Fresh Pig Gallbladder 30 g, Poria cocos 10 g, Salvia miltiorrhiza 12 g, Licorice 7 g.

[0086] 4. ZYDZ Group 2 (Application No.: CN202210407573.0): 15 g of Astragalus membranaceus, 15 g of Codonopsis pilosula, 12 g of Ophiopogon japonicus, 9 g of Polygonum multiflorum, 9 g of Epimedium brevicornu, 12 g of Pueraria lobata, 9 g of Angelica sinensis, 15 g of Salvia miltiorrhiza, 8 g of Gleditsia sinensis spine, 9 g of Sargassum fusiforme, 9 g of Ecklonia kurome, 15 g of Oyster, 9 g of Aurantii Fructus Immaturus.

[0087] 5. ZYDZ Group 3 (Application No.: CN202111612514.9): 5 g of Panax notoginseng, 12 g of Astragalus membranaceus, 12 g of Salvia miltiorrhiza, 15 g of Trichosanthes kirilowii, 9 g of Curcuma aromatica, 9 g of Dalbergia odorifera, 12 g of Corydalis yanhusuo, 9 g of Aurantii Fructus Immaturus, 5 g of Choerospondias axillaris, 6 g of Rosa laevigata, 9 g of Ophiopogon japonicus, 30 g of Ziziphus jujuba var. spinosa, 3 g of Asarum sieboldii, 0.2 g of Borneol, 5 g of Moschus, 9 g of Benzoin.

[0088] 6. ZYDZ Group 4 (Application No.: CN201810606242.3): 5 g of Aquilaria sinensis, 9 g of Carthamus tinctorius, 6 g of Panax ginseng, 9 g of Ophiopogon japonicus, 10 g of Schisandra chinensis, 3 g of Panax notoginseng, 9 g of Angelica sinensis, 9 g of Salvia miltiorrhiza, 8 g of Ligusticum wallichii, 6 g of Curcuma aromatica, 9 g of Olibanum, 6 g of Sanguis draxonis, 12 g of Astragalus membranaceus, 8 g of Glycyrrhiza uralensis, 9 g of Succinum, 10 g of Acorus tatarinowii, 3 g of Cinnabaris, 9 g of Dalbergia odorifera, 5 g of Styrax tonkinensis, 5 g of Benzoin, 6 g of Santalum album, 0.4 g of Borneol.

[0089] 7. ZYDZ Group 5 (Application No.: CN201410059638.2): 9 g of Salvia miltiorrhiza, 12 g of Astragalus membranaceus, 10 g of Corydalis yanhusuo, 1 g of Ophiopogon japonicus, 9 g of Ligusticum wallichii, 12 g of Curcuma aromatica, 6 g of Citrus reticulata Blanco var. austera, 10 g of Spatholobus suberectus, 15 g of Crataegus pinnatifida, 15 g of Trichosanthes kirilowii, 8 g of Panax ginseng, 6 g of Prunus persica, 3 g of Crocus sativus, 6 g of Paeonia lactiflora, 9 g of Cyperus rotundus, 15 g of Citrus reticulata Blanco var. tangerina, 9 g of Glycyrrhiza uralensis, 12 g of Angelica sinensis, 8 g of Bupleurum chinense, 12 g of Dalbergia odorifera, 3 g of Amomum villosum, 6 g of Acorus tatarinowii, 5 g of Trogopterus dungarctus, 9 g of Polygonatum odoratum, 3 g of Panax notoginseng, 6 g of Jasminum sambac, 3 g of Santalum album, 0.2 g of Borneol.

[0090] 8. ZYDZ Group 6 (Application No.: CN201610833974.7): 9 g of Dalbergia odorifera, 6 g of Paeonia lactiflora, 2 g of Santalum album, 8 g of Salvia miltiorrhiza, 8 g of Angelica sinensis, 8 g of Curcuma aromatica, 5 g of Ligusticum wallichii, 10 g of Ophiopogon japonicus, 6 g of Ganoderma lucidum, 3 g of Hirudo, 3 g of Styrax tonkinensis, 0.15 g of Borneol.

[0091] 9. ZYDZ Group 7 (Application No.: CN201610017979.2): 10 g of Sargassum fusiforme, 10 g of Ecklonia kurome, 10 g of Salvia miltiorrhiza, 10 g of Oyster, 5 g of Poria cocos, 5 g of Ligusticum wallichii, 5 g of Angelica sinensis, 5 g of Paeonia lactiflora, 5 g of Pinellia ternata (Thunb.) Breit. var. corymbosa (Ohwi) Hsiao & K. M. Feng, 5 g of Citrus reticulata Blanco var. tangerina, 5 g of Carthamus tinctorius, 5 g of Sappanwood, 5 g of Dalbergia odorifera.

[0092] 10. ZYDZ Group 8 (Application No.: CN201610584682.4): American ginseng 6g, Salvia miltiorrhiza 15g, Caulis Spatholobi 9g, Glehnia littoralis 12g, Ophiopogon japonicus 9g, Rhodiola rosea 9g, Old tea tree root 3g, Panax notoginseng 8g, Radix Paeoniae Rubra 12g, Rhizoma Chuanxiong 15g, Lignum Dalbergiae Odoriferae 12g, Corydalis yanhusuo 15g, Curcuma aromatica 8g, Sophora flavescens 6g, Gentiana macrophylla 6g, Borneol 0.3g.

[0093] 11. ZYDZ Group 9 (Application No.: CN201410059640.X): Salvia miltiorrhiza 9g, Ginkgo biloba leaves 12g, Corydalis yanhusuo 15g, Rhizoma Chuanxiong 18g, Fructus Hordei Germinatus 12g, Cortex Moutan 9g, Fructus Crataegi 9g, Ginseng 3g, Semen Persicae 6g, Crocus sativus 3g, Radix Paeoniae Rubra 8g, Caulis Spatholobi 12g, Fructus Aurantii 9g, Pericarpium Citri Reticulatae 9g, Herba Artemisiae Anomalae 3g, Licorice 5g, Angelica sinensis 12g, Radix Rehmanniae 9g, Bupleurum chinense 15g, Lignum Dalbergiae Odoriferae 12g, Radix Paeoniae Alba 15g, Bulbus Allii Macrostemonis 8g, Platycodon grandiflorum 9g, Medulla Tetrapanacis 5g, Faeces Trogopterori 5g, Ramulus Cinnamomi 3g, Polygonatum odoratum 9g, Panax notoginseng 3g, Styrax 3g, Borneol 0.2g.

[0094] 12. ZYDZ Group 10 (Application No.: CN201510604049.2): American ginseng 30g, Salvia miltiorrhiza 30g, Glehnia littoralis 30g, Sophora flavescens 30g, Panax notoginseng 30g, Ophiopogon japonicus 30g, Radix Paeoniae Rubra 50g, Rhizoma Chuanxiong 30g, Lignum Dalbergiae Odoriferae 50g, Gentiana macrophylla 30g, Borneol 15g.

[0095] 13. ZYDZ Group 11 (Application No.: CN201410373829.6): Codonopsis pilosula 15g, Licorice 8g, Orobanche coerulescens 6g, Astragalus membranaceus 15g, Caesalpinia sappan 9g, Sparganium stoloniferum 9g, Carthamus tinctorius 9g, Crataegus pinnatifida var. major 9g, Salvia miltiorrhiza 9g, Borneol 0.2g, Rhizoma Chuanxiong 15g, Cinnamon 12g, Astragalus complanatus 9g, Radix Aristolochiae Manshuriensis 8, Radix Paeoniae Rubra 12g, Radix Rehmanniae Preparata 8g, Angelica sinensis 8g, Folium Bambusae 9g, Rice dew 8g, Lycopus lucidus Turcz. var. hirtus Regel 12g, Ophiopogon japonicus 15g, Semen Platycladi 15g.

[0096] 14. ZYDZ Group 12 (Application No.: CN201310110797.6): American ginseng 2g, Astragalus membranaceus 20g, Crocus sativus 2g, Salvia miltiorrhiza 20g, Trichosanthes kirilowii Maxim. 20g, Curcuma aromatica 6g, Fructus Hordei Germinatus 20g, Lignum Dalbergiae Odoriferae 2g, Ophiopogon japonicus 6g, Borneol 0.05g.

[0097] 15. ZYDZ Group 13 (Application No.: CN201410059637.8): Salvia miltiorrhiza 12g, Astragalus membranaceus 9g, Corydalis yanhusuo 8g, Rhizoma Chuanxiong 8g, Curcuma aromatica 6g, Ophiopogon japonicus 9g, Caulis Spatholobi 15g, Fructus Crataegi 8g, Curcuma longa 9g, Ginseng 6g, Sparganium stoloniferum 8g, Crocus sativus 8g, Radix Paeoniae Rubra 3g, Polygonatum sibiricum 12g, Ramulus Cinnamomi 8g, Pericarpium Citri Reticulatae 3g, Licorice 8g, Angelica sinensis 5g, Cistanche deserticola 15g, Lignum Dalbergiae Odoriferae 9g, Rhodiola rosea 15g, Acorus tatarinowii 9g, Faeces Trogopterori 6g, Polygonatum odoratum 9g, Panax notoginseng 15g, Rheum officinale 8g, Borneol 0.2g.

[0098] 16. ZYDZ Group 14 (Application No.: CN200410020621.2): Ginseng 3 g, Ophiopogon japonicus 9 g, Schisandra chinensis 15 g, Astragalus membranaceus 12 g, Dioscorea opposita 9 g, Atractylodes lancea 9 g, Scrophularia ningpoensis 12 g, Coptis chinensis 8 g, Pueraria lobata 8 g, Salvia miltiorrhiza 18 g, Crataegus pinnatifida 8 g, Rehmannia glutinosa 15 g, Trichosanthes kirilowii 20 g, Paeonia lactiflora 15 g, Dalbergia odorifera 15 g, Borneol 0.3 g.

[0099] 17. ZYDZ Group 15 (Application No.: CN200610010165.2): Ginseng 8 g, Ophiopogon japonicus 8 g, Schisandra chinensis 8 g, Panax notoginseng 8 g, Angelica sinensis 10 g, Salvia miltiorrhiza 16 g, Ligusticum wallichii 12 g, Curcuma aromatica 8 g, Olibanum 4 g, Sanguis draxonis 4 g, Astragalus membranaceus 20 g, Glycyrrhiza uralensis 8 g, Succinum 8 g, Acorus tatarinowii 4 g, Cinnabaris 2 g, Dalbergia odorifera 4 g, Styrax benzoin 6 g, Benzoin 4 g, Santalum album 4 g, Borneol 2 g.

[0100] 18. ZYDZ Group 16 (Application No.: CN01131203.3): Ginseng 15 g, Codonopsis pilosula 12 g, Pseudostellaria heterophylla 15 g, Astragalus membranaceus 9 g, Atractylodes macrocephala 12 g, Glycyrrhiza uralensis 9 g, Dioscorea opposita 8 g, Hirudo 12 g, Salvia miltiorrhiza 15 g, Ligusticum wallichii 9 g, Carthamus tinctorius 8 g, Paeonia lactiflora 12 g, Dalbergia odorifera 9 g, Panax notoginseng 6 g, Curcuma aromatica 8 g, Prunus persica 15 g, Corydalis yanhusuo 15 g, Eupolyphaga sinensis 9 g, Olibanum 9 g, Sanguis draxonis 8 g, Myrrha 9 g, Spatholobus suberectus 15 g, Aquilaria sinensis 8 g, Curcuma zedoaria 9 g, Sparganium stoloniferum 9 g, Leonurus japonicus 9 g, Trogopterus dungaricus 15 g, Achyranthes bidentata 9 g, Trichosanthes kirilowii 15 g, Pinellia ternata 9 g, Allium macrostemon 15 g, Armeniaca vulgaris 9 g, Aurantii Fructus Immaturus 15 g, Aurantii Fructus 9 g, Santalum album 9 g, Cyperus rotundus 15 g, Aucklandia lappa 9 g, Citrus reticulata 9 g, Platycodon grandiflorus 9 g, Corydalis yanhusuo 15 g, Polygonum multiflorum 9 g, Angelica sinensis 9 g, Rehmannia glutinosa 9 g, Paeonia lactiflora 15 g, Ophiopogon japonicus 15 g, Polygonatum sibiricum 9 g, Borneol 0.2 g, Acorus tatarinowii 9 g, Ziziphus jujuba var. spinosa 15 g, Polygala tenuifolia 9 g, Succinum 8 g, Asarum sieboldii 9 g, Aconitum carmichaelii 15 g, Cinnamomum cassia 8 g, Epimedium brevicornu 9 g, Schisandra chinensis 9 g, Crataegus pinnatifida 15 g, Pueraria lobata 15 g, Poria cocos 9 g, Angelica dahurica 6 g, Bupleurum chinense 9 g, Pheretima aspergillum 15 g, Gastrodia elata 9 g, Buthus martensii 9 g, Cryptotympana pustulata 8 g, Scolopendra subspinipes 8 g.

[0101] 19. ZYDZ Group 17 (Application No.: CN201510009879.0): Astragalus membranaceus 20 g, Pseudostellaria heterophylla 20 g, Polygala tenuifolia 10 g, Ziziphus jujuba var. spinosa 15 g, Aucklandia lappa 10 g, Rehmannia glutinosa 10 g, Ophiopogon japonicus 10 g, Lycium barbarum 15 g, Glycyrrhiza uralensis preparata 10 g, Cornus officinalis 12 g, Colla corii asini 10 g, Salvia miltiorrhiza 10 g, Pueraria lobata 10 g, Achyranthes bidentata 10 g, Dalbergia odorifera 10 g.

[0102] 20. ZYDZ Group 18 (Chen Chunlei, Cheng Xiaoyu. Cheng Xiaoyu's Experience in Treating Coronary Heart Disease Complicated with Anxiety and Depression [J]. Journal of Traditional Chinese Medicine Clinical Practice

[0103] Journal of Traditional Chinese Medicine, 2024, 36(08): 1460 - 1464. DOI: 10.16448 / j.cjtcm.2024.0810): Astragalus membranaceus 15g, Codonopsis pilosula 15g, Trichosanthes kirilowii 15g, Salvia miltiorrhiza 15g, Angelica sinensis 15g, Ligusticum wallichii 15g, Paeonia lactiflora 15g, Citrus reticulata Blanco 9g, Curcuma aromatica Salisb. 15g, Dalbergia odorifera T. Chen 15g, Ophiopogon japonicus 15g, Honey - fried Licorice Root 8g.

[0104] Group ZYDZ19 (Gu Yanpin, Tao Danhong. Study on the effect of Yixin Jieyu Decoction on mild depression after heart failure based on the theory of "the heart governing mental activities" [J]. China Medical Herald, 2017, 14(7): 73 - 76.): Salvia miltiorrhiza 20g, Curcuma aromatica Salisb. 15g, Trichosanthes kirilowii Maximowicz 8g, Allium macrostemon Bunge 18g, Dalbergia odorifera T. Chen 9g, Concha Margaritifera Usta 30g, Ophiopogon japonicus 15g, Rehmannia glutinosa Libosch. 40g, Polygala tenuifolia Willd. 9g, Albizia julibrissin Durazz. 8g, Polygonum multiflorum Thunb. var. thomsonii (Wall.) Stew. 15g, Citrus reticulata Blanco 15g, Platycodon grandiflorus (Jacq.) A. DC. 8g, Poria cocos (Schw.) Wolf 9g, Alisma orientale (Sam.) Juz. 8g, Cinnamomum cassia Presl 15g.

[0105] III. Detection Indexes

[0106] Body weight: The body weights of rats were measured before administration and 56 days after administration, and the average body weight growth rate was calculated = [(average body weight after administration - average body weight before administration) / average body weight before administration] × 100%.

[0107] Behavioral Experiments

[0108] Sucrose preference experiment: Rats were placed individually in a rat cage, and two weighed water bottles (1% sucrose solution and pure water respectively) were placed on each cage. After the rats were fasted and water - deprived for 24 hours, the experiment was carried out. The sucrose preference percentage of rats within 6 hours [(sucrose consumption / total liquid consumption) × 100%] was used as the evaluation index. The sucrose preference test was carried out on the 56th day after administration.

[0109] Open - field test: Rats were placed at the center of a self - made open box. After 2 minutes of adaptation, the total movement distance of the rats within the next 5 minutes was recorded. The test was carried out before administration and on the 56th day after administration.

[0110] Detection of neurotransmitters in rat brain tissue: The removed rat brain tissue was separated into cortex and hippocampus. The hippocampal tissue of rats was mixed and homogenized with ice - cold physiological saline at a ratio of 1:3. After centrifugation, the supernatant was taken, and the contents of serotonin (5 - HT), dopamine (DA), and norepinephrine (NE) were detected by ELSIA method, and the neurotransmitter concentration was calculated.

[0111] Test Conditions and Results

[0112] Effect of the present invention on the body weight of rats: After 56 days of administration, compared with the model group, the present invention group could significantly improve the state of body weight loss in rats caused by depression after myocardial infarction (P < 0.05). See Table 7.

[0113] Table 7 Effects of the present invention on the body weight of rats

[0114]

[0115] Note: Compared with the control group, *P < 0.05; compared with the model group, #P < 0.05.

[0116] Effects of the present invention on the preference degree of rats for sugar water: After administration for 56 days, compared with the model group, the present invention group could significantly increase the sugar water preference rate of the model group rats (P < 0.05). See Table 8.

[0117] Table 8 Effects of the present invention on the sugar water preference rate of rats

[0118]

[0119] Note: Compared with the control group, * P < 0.05; compared with the model group, # P < 0.05.

[0120] Effects of the present invention on the total movement distance of rats: After administration for 56 days, compared with the model group, the present invention group could significantly increase the total movement distance of the model group rats (P < 0.05). See Table 9.

[0121] Table 9 Effects of the present invention on the total movement distance of rats

[0122]

[0123]

[0124] Note: Compared with the control group, *P < 0.05; compared with the model group, #P < 0.05.

[0125] Effects of the present invention on the neurotransmitters in the rat brain: On the 56th day, compared with the Control group, the contents of 5-HT, DA, and NE in the brain tissue of the Model group rats were significantly decreased (P < 0.05). Compared with the Model group, the contents of 5-HT, DA, and NE in the brain tissue of the FM group rats were significantly increased (P < 0.05). See Table 10. It can be seen that the FM group increased the content of neurotransmitters.

[0126] Table 10 Effects of the present invention on the neurotransmitters in the rat brain

[0127]

[0128]

[0129] Note: Compared with the Control group, *P<0.05; compared with the Model group, #P<0.05.

[0130] The above research results show that the present invention has an obvious regulatory effect on depression-related indicators and has a positive effect. Compared with fluoxetine hydrochloride capsules, the effect is similar or even better; compared with other related Chinese medicines, the present invention has a better effect. Currently available Chinese medicines have many repeated medicinal flavors, generally composed of more than 10 Chinese medicines, or even more than 20 Chinese medicines, which will cause a waste of drug sources; and the Chinese medicine ingredients are complex and the mechanism is not clear. The present invention has fewer medicinal flavors, a reasonable prescription, and a scientific ratio.

[0131] Clinical application examples

[0132] The purpose of this application example is to explore the clinical efficacy of Guanxin Jieyu Decoction in treating depression caused by coronary heart disease and myocardial infarction, with symptoms of qi stagnation and blood stasis, heart fire disturbance, and restlessness.

[0133] Methods: A total of 186 patients with mild to moderate depression after myocardial infarction who visited the Department of Neurology, Cardiology, and Traditional Chinese Medicine Outpatient and Inpatient Departments of the First and Second Affiliated Hospitals of Zhejiang Chinese Medical University between September 2023 and August 2024 were collected and randomly divided into a Western medicine fluoxetine control group, a Chinese medicine Guanxin Jieyu Fang treatment group, and a Chinese and Western medicine combination group, with 62 cases in each group, and the total course of treatment was 8 weeks. The 24-item Hamilton Depression Rating Scale (HAMD-24) scores, Chinese medicine syndrome scores, Symptom Checklist-90 (SCL-90) factor standard scores, and six-minute walk test distance of the three groups of patients were compared before treatment, after 4 weeks of treatment, and after 8 weeks of treatment to analyze the clinical efficacy; adverse reactions were recorded and safety was evaluated.

[0134] Postmyocardial infarction depression (PMID) patients mainly show mental retardation, slow thinking, abnormal emotions and long duration. This depressive state is believed to increase the risk of poor prognosis of myocardial infarction. In the past 20 years, many studies have evaluated the epidemiology of PMID, but the prevalence reported in different studies varies greatly (13.6%-79.5%). Depression increases the occurrence of arrhythmias and sudden death in patients after myocardial infarction. Like patients with depression, patients with PMID will also suffer from social disorders due to depression, and even have suicidal tendencies and other adverse prognoses, which increases the medical burden and causes great harm to patients and their families.

[0135] Materials and Methods

[0136] General information: From September 2023 to August 2024, 186 patients with the syndrome of qi stagnation and blood stasis, heart fire disturbing upward, and restlessness of the mind were collected from the neurology department, cardiology department, outpatient and inpatient departments of traditional Chinese medicine in the First and Second Affiliated Hospitals of Zhejiang Chinese Medical University as the research objects. The patients were randomly divided into a western medicine fluoxetine control group, a traditional Chinese medicine Guanhxin Jieyu formula treatment group, and a combination of traditional Chinese and western medicine group. This clinical observation was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University (approval number: 2024 Research No. 046-01).

[0137] Diagnostic criteria

[0138] Western medicine diagnostic criteria: Refer to the fourth general definition of myocardial infarction published by the European Cardiac Society (ECS) in 2018. And the "Expert Consensus on the Diagnosis and Treatment of Anxiety, Depression and Somatization Symptoms in General Hospitals" formulated by the Neuropsychology and Behavioral Neurology Group of the Chinese Neurological Society of the Chinese Medical Association in 2016.

[0139] Traditional Chinese medicine diagnostic criteria: The diagnostic criteria for chest pain due to chest impediment refer to the "Diagnostic and Therapeutic Criteria for Traditional Chinese Medical Syndromes" and the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines" of the State Administration of Traditional Chinese Medicine; the diagnostic criteria for depressive syndrome refer to the "Diagnostic and Therapeutic Criteria for Traditional Chinese Medical Syndromes" of the State Administration of Traditional Chinese Medicine; the syndrome of qi stagnation and blood stasis, heart fire disturbing upward, and restlessness of the mind refers to the "Diagnostic and Therapeutic Criteria for Traditional Chinese Medical Syndromes" of the State Administration of Traditional Chinese Medicine and the textbook "Internal Medicine of Traditional Chinese Medicine" for general higher education.

[0140] Inclusion criteria: (1) Meeting the above diagnostic criteria; (2) Not receiving relevant drug treatment in the week before treatment; (3) Conscious, cooperative during physical examination, without severe cognitive impairment; (4) Scoring ≥8 points and ≤35 points on the Hamilton Depression Scale (HAMD-24 items), that is, patients with mild to moderate depression; (5) Aged 25 to 85 years old, regardless of gender; (6) The patient or family member is informed and signs an informed consent form, with good compliance.

[0141] Exclusion criteria: Any of the following conditions means the patient cannot participate in this trial

[0142] (1) Patients with a history of clearly diagnosed mental illness in the past or those currently taking psychotropic drugs; (2) Patients with severe heart failure, liver failure, kidney failure, respiratory failure, tumors, and severe cerebrovascular diseases; (3) Pregnant, lactating women, or women planning to become pregnant within 3 months; (4) Patients with allergic constitution or a history of allergies to multiple drugs in the past, or those allergic to the components in the study drugs; (5) Patients who participated in other clinical studies 3 months before the trial, and other patients considered by the researchers not suitable to participate in this study; (6) Incomplete data (such as general information including family history, personal history, past history, drug use history, etc.); (7) Patients who refuse to undergo examinations related to this study; (8) Those who are unwilling to sign the informed consent form.

[0143] Exclusion and dropout criteria: (1) patients who experience severe adverse reactions or other sudden critical illnesses during the study; (2) patients who take drugs that may affect the study results during the study; (3) patients who stop taking medication without reason or refuse to cooperate with the study during the study.

[0144] method

[0145] Treatment

[0146] Western medicine control group: conventional antidepressant treatment was used. Fluoxetine hydrochloride capsules (Prozac, Eli Lilly Suzhou Pharmaceutical Co., Ltd., National Medicine Standard No. J20181215) were used as antidepressants, taken orally once a day in the morning, 20 mg / time. The course of treatment was 8 weeks.

[0147] The Chinese medicine treatment group was treated with the Guanxin Jieyu Agreement prescription, which mainly consisted of seven herbs, including 15g of Danshen, 9g of Sappanwood, 30g of Oyster, 9g of Dalbergia odorifera, 12g of Forsythia suspensa, 12g of Radix Ophiopogonis, and 0.25g of Borneol. The prescription was decocted and sealed by the hospital and then provided to the patients. The course of treatment was 8 weeks.

[0148] The Chinese and Western medicine combined group: The Chinese medicine Guanxin Jieyu Agreement Formula and the Western medicine Fluoxetine Hydrochloride Capsules were given at the same time, with the same specific method as above. The course of treatment was 8 weeks.

[0149] Basic treatment: conventional myocardial infarction treatment is given according to the subject's condition, including antiplatelet aggregation (aspirin, etc.), beta-blockers (bisoprolol, etc.), ACEI or ARB drugs for anti-cardiac remodeling, statins for stabilizing plaques and other standardized drug treatments.

[0150] Observation indicators

[0151] (1) To compare the total clinical efficacy and cure rate (cure rate + marked efficacy) among the three groups of patients;

[0152] (2) Compare the differences in HAMD-24 scores, TCM syndrome scores, SCL-90 scores, and 6MWT distance among the three groups of patients. Fill out the form according to the patient's condition and evaluate once before treatment, in the fourth week of treatment, and in the eighth week of treatment;

[0153] (3) Observe and compare the frequency of clinical adverse reactions among the three groups of patients during treatment to conduct safety assessment.

[0154] Efficacy criteria

[0155] (1) The criteria for evaluating the efficacy of depression treatment refer to the "Handbook of Psychiatric Rating Scales in Modern Psychiatry Series". The Hamilton Depression Rating Scale (HAMD-24 items) was used to assess the degree of depression. A HAMD score of >35 was considered severe depression, 21-35 was moderate depression, 8-20 was mild depression, and <8 was no depression.

[0156] The clinical efficacy was evaluated by the score reduction rate: ① cured: HAMD score <8 points; markedly effective: HAMD score reduction rate >50%; effective: 25% < HAMD score reduction rate ≤50%; ineffective: HAMD score reduction rate ≤25%.

[0157] (2) The evaluation criteria for TCM syndrome efficacy were based on the Guiding Principles for Clinical Research of New Chinese Medicines. Symptoms such as lack of energy, depression, chest tightness and distension, sighing or loss of appetite, irritability and crying, foreign body sensation in the throat, insomnia and frequent dreams, excessive thinking and suspicion were graded and quantified. The score was 0 for none, 2 for occasionally, 4 for often, and 6 for always.

[0158] (3) SCL-90 self-rating scale assessment. SCL-90 contains a wide range of psychiatric symptomology content and tests 9 factors, namely, somatization, obsessive-compulsive symptoms, interpersonal sensitivity, depression, anxiety, hostility, phobia, paranoia and psychosis. Each item is scored on a 1-5 scale to evaluate oneself, as follows: 1 point: no, the individual does not feel the problem; 2 points: very mild, the individual feels the symptom, but it is not frequent and does not affect life; 3 points: moderate, the individual feels the symptom, and the frequency and severity range from mild to moderate; 4 points: moderately severe, the individual feels the symptom, and the frequency and severity range from moderate to severe; 5 points: severe, the individual feels the symptom is very severe in all aspects.

[0159] Factor standard score = (sum of scores of each item in the subscale) / total number of items in the subscale. The higher the score, the worse the state of the mental and psychological dimension. The efficacy is evaluated based on the changes in the SCL-90 factor standard score before and after treatment.

[0160] (4) Cardiac function assessment: The six-minute walk distance test (6MWD) can objectively reflect the cardiac function status and the patient's ability to carry out daily activities. It is a simple, effective and safe assessment method. A full assessment should be conducted before the test to eliminate possible risk factors during the test. Accompanied by two physicians, the patient is asked to walk back and forth on a flat road with walking distance landmarks without weight bearing. The patient decides the speed of walking according to his or her physical ability. The recorder will report the time every 2 minutes and record the patient's possible chest tightness, shortness of breath and other discomfort. If the patient is physically exhausted or has discomfort, he or she will take a temporary rest or terminate the test. The test time is 6 minutes, and the recorder will record and evaluate the patient's walking distance. According to the test standards set by the USCarvedilol study, a six-minute walk distance of <150m, 150-450m and >450m are severe, moderate and mild heart failure, respectively.

[0161] (5) Record adverse reactions: Make a comprehensive assessment of adverse reactions based on the patient's medical history and the relevant circumstances of the medication, and record the specific manifestations and corresponding treatment measures.

[0162] Statistical method: SPSS 26.0 statistical software was used for statistical analysis. For measurement data, according to whether the data conform to the normal distribution, the mean ± standard deviation (±S) (conforming to the normal distribution) and the median (interquartile range) (not conforming to the normal distribution) were used to represent them respectively. Analysis of variance was used for data conforming to the normal distribution, and the rank sum test was used for data not conforming to the normal distribution; count data were expressed as %, and the chi-square test was used; for repeated measurement results of the same specimens at different time points, analysis of variance was used. P < 0.05 was considered statistically significant.

[0163] Results

[0164] Comparison of general data: The general data of the 3 groups of patients, such as gender, age, underlying diseases, degree of depression, and PCI surgery conditions, were compared, and P > 0.05, indicating comparability. See Table 11.

[0165] Table 11 Comparison of general data of three groups of patients

[0166]

[0167]

[0168] Comparison of HAMD scores: The HAMD scores of the 3 groups of patients at 4 weeks and 8 weeks of treatment were significantly lower than those before treatment in the same group. The HAMD scores of the 3 groups of patients at 8 weeks of treatment were lower than those at 4 weeks of treatment in the same group (P < 0.05). After 4 weeks of treatment, compared with the western medicine control group, the HAMD scores of the traditional Chinese medicine treatment group and the combination of traditional Chinese and western medicine group were significantly lower (P < 0.05), and the HAMD score of the combination of traditional Chinese and western medicine group was significantly lower than that of the traditional Chinese medicine treatment group (P < 0.05). At 8 weeks of treatment, compared with the western medicine control group, the HAMD scores of the traditional Chinese medicine treatment group and the combination of traditional Chinese and western medicine group were significantly lower (P < 0.05), and there was no significant difference in the HAMD score between the combination of traditional Chinese and western medicine group and the traditional Chinese medicine treatment group (P > 0.05). The results are shown in Table 12. Figure 2 。

[0169] Table 12 Comparison of HAMD scores of three groups of patients (±S)

[0170]

[0171] Note: Compared with before treatment in the same group, △ P < 0.05; compared with 4 weeks of treatment in the same group, ▲ P < 0.05; compared with the western medicine control group at the same time, ﹟ P < 0.05; compared with the traditional Chinese medicine treatment group at the same time ＊ P < 0.05.

[0172] Remission rate and total effective rate of HAMD method for efficacy evaluation: The remission rate of the three groups of patients after 8 weeks of treatment was significantly higher than that after 4 weeks of treatment in the same group (P < 0.05), and there was no significant difference in the total effective rate (P > 0.05). After 4 weeks of treatment, compared with the western medicine control group, the remission rate of the combined traditional Chinese and western medicine group was higher (P < 0.05), and there was no difference in the remission rate of the traditional Chinese medicine treatment group (P > 0.05); there was no significant difference in the remission rate between the combined traditional Chinese and western medicine group and the traditional Chinese medicine treatment group (P > 0.05). After 8 weeks of treatment, compared with the western medicine control group, the remission rate of the combined traditional Chinese and western medicine group was higher (P < 0.05), there was no significant difference in the total effective rate (P > 0.05), and there was no significant difference in the remission rate and total effective rate of the traditional Chinese medicine treatment group (P > 0.05); there was no significant difference in the remission rate and total effective rate between the combined traditional Chinese and western medicine group and the traditional Chinese medicine treatment group (P > 0.05). The results are shown in Table 13, Figure 3 , Figure 4 .

[0173] Table 13 Comparison of clinical efficacy of three groups [case (%)]

[0174]

[0175] Note: Compared with the western medicine control group in the same period, #P < 0.05; compared with 4 weeks of treatment in the same group, ▲P < 0.05.

[0176] Comparison of traditional Chinese medicine syndrome scores: The traditional Chinese medicine syndrome scores of the three groups of patients after 4 weeks and 8 weeks of treatment were significantly lower than those before treatment in the same group, and the traditional Chinese medicine syndrome scores of the three groups of patients after 8 weeks of treatment were lower than those after 4 weeks of treatment in the same group (P < 0.05). After 4 weeks of treatment, compared with the western medicine control group, the traditional Chinese medicine syndrome scores of the traditional Chinese medicine treatment group and the combined traditional Chinese and western medicine group were significantly lower (P < 0.05), and the traditional Chinese medicine syndrome score of the combined traditional Chinese and western medicine group was significantly lower than that of the traditional Chinese medicine treatment group (P < 0.05). After 8 weeks of treatment, compared with the western medicine control group, the traditional Chinese medicine syndrome scores of the traditional Chinese medicine treatment group and the combined traditional Chinese and western medicine group were significantly lower (P < 0.05), and the traditional Chinese medicine syndrome score of the combined traditional Chinese and western medicine group was significantly lower than that of the traditional Chinese medicine treatment group (P < 0.05). The results are shown in Table 14, Figure 5 .

[0177] Table 14 Comparison of traditional Chinese medicine syndrome scores of three groups (±S)

[0178]

[0179] Note: Compared with before treatment in the same group, △P < 0.05; compared with 4 weeks of treatment in the same group, ▲P < 0.05; compared with the

[0180] western medicine control group in the same period, ﹟P < 0.05; compared with the traditional Chinese medicine treatment group in the same period, *P < 0.05.

[0181] Comparison of the factor standard scores of the Symptom Checklist 90 (SCL-90): The factor standard scores of SCL-90 in the three groups of patients at 4 weeks and 8 weeks of treatment were significantly lower than those before treatment in the same group. The factor standard scores of SCL-90 in the three groups of patients at 8 weeks of treatment were lower than those at 4 weeks of treatment in the same group (P < 0.05). After 4 weeks of treatment, compared with the western medicine control group, the factor standard scores of SCL-90 in the traditional Chinese medicine treatment group and the combination of traditional Chinese and western medicine group were significantly lower (P < 0.05), and the factor standard scores of SCL-90 in the combination of traditional Chinese and western medicine group were significantly lower than those in the traditional Chinese medicine treatment group (P < 0.05). After 8 weeks of treatment, compared with the western medicine control group, the factor standard scores of SCL-90 in the combination of traditional Chinese and western medicine group were significantly lower (P < 0.05), and there was no significant difference in the traditional Chinese medicine control group (P < 0.05); there was no significant difference in the factor standard scores of SCL-90 between the combination of traditional Chinese and western medicine group and the traditional Chinese medicine treatment group (P > 0.05). The results are shown in Table 15. Figure 6 。

[0182] Table 15 Comparison of SCL-90 results in three groups of patients (±S)

[0183]

[0184] Note: Compared with before treatment in the same group, △P < 0.05; compared with 4 weeks of treatment in the same group, ▲P < 0.05; compared with the western medicine control group at the same time, ﹟P < 0.05; compared with the traditional Chinese medicine treatment group at the same time, *P < 0.05.

[0185] Comparison of the six-minute walk test distance: The six-minute walk test distance of the three groups of patients at 4 weeks and 8 weeks of treatment was significantly lower than that before treatment in the same group. The six-minute walk test distance of the three groups of patients at 8 weeks of treatment was lower than that at 4 weeks of treatment in the same group (P < 0.05). After 4 weeks of treatment, compared with the western medicine control group, the six-minute walk test distance in the combination of traditional Chinese and western medicine group was significantly lower (P < 0.05), and there was no significant difference in the traditional Chinese medicine treatment group (P > 0.05); there was no significant difference in the six-minute walk test distance between the combination of traditional Chinese and western medicine group and the traditional Chinese medicine treatment group (P > 0.05). After 8 weeks of treatment, compared with the western medicine control group, the six-minute walk test distance in the combination of traditional Chinese and western medicine group was significantly lower (P < 0.05), and there was no significant difference in the traditional Chinese medicine treatment group (P > 0.05); there was no significant difference in the six-minute walk test distance between the combination of traditional Chinese and western medicine group and the traditional Chinese medicine treatment group (P > 0.05). The results are shown in Table 16. Figure 7 。

[0186] Table 16 Six-minute walk test distance of three groups of patients (±S)

[0187]

[0188] Note: Compared with before treatment in the same group, △P < 0.05; compared with 4 weeks of treatment in the same group, ▲P < 0.05; compared with the western medicine control group at the same time, ﹟P < 0.05.

[0189] Safety assessment: No severe adverse reactions occurred in all three groups. During the treatment period, the safety of the traditional Chinese medicine treatment group was higher than that of the western medicine control group, P < 0.05, and there was no significant difference between the traditional Chinese medicine treatment group and the combined traditional Chinese and western medicine group, P > 0.05. The safety of the combined traditional Chinese and western medicine group was higher than that of the western medicine control group, and it was statistically significant, P < 0.05. The results are shown in Table 17, Figure 8 .

[0190] Table 17 Safety assessment of three groups [case(%)]

[0191]

[0192] Note: Compared with the western medicine control group after treatment, ﹟ P < 0.05; compared with the western medicine control group after treatment, ＊ P < 0.05.

[0193] Discussion

[0194] The research results of this invention show that: whether it is 4 weeks or 8 weeks of treatment, compared with the HAMD score, traditional Chinese medicine syndrome score, SCL-90 factor standard score, six-minute walk test distance, etc. of patients in the western medicine control group, both the traditional Chinese medicine treatment group and the combined traditional Chinese and western medicine group have obvious improvements. At 4 weeks and 8 weeks of treatment, the total effective rates of the traditional Chinese medicine treatment group and the combined traditional Chinese and western medicine group are higher than that of the western medicine control group, indicating that the clinical treatment effect of using traditional Chinese medicine alone or in combination with western medicine is stronger than using western medicine alone. During the whole treatment process, the number of adverse reactions in the traditional Chinese medicine treatment group and the combined traditional Chinese and western medicine group is significantly less than that in the western medicine control group, suggesting that when PMID patients are averse to the adverse reactions brought by western medicine treatment and do not want to take western medicine to treat PMID, a pure traditional Chinese medicine treatment plan or a combined traditional Chinese and western medicine plan can be selected for patients to achieve the purpose of treating diseases and reducing adverse reactions. After 8 weeks of treatment, the HAMD score and SCL-90 factor standard score of the patients are lower than before treatment, and the six-minute walk test distance is longer than before treatment, indicating that Guanhxin Jieyu Prescription has the effect of restoring the heart function of patients, relieving the negative emotions of patients, and improving the quality of life of patients. During the treatment process of PMID, the traditional Chinese medicine treatment mode should be actively explored, making full use of the advantages of long-term conditioning and small adverse reactions of traditional Chinese medicine, while paying attention to the economic affordability and individual differences of patients, and formulating personalized treatment plans in order to achieve the best treatment effect and improve the quality of life of patients.

[0195] To sum up, Guanhxin Jieyu Prescription has a significant effect in treating depression with qi stagnation and blood stasis, heart fire disturbing upward, and restlessness of mind after coronary heart disease myocardial infarction, significantly improving the clinical symptoms of patients, relieving the mental tension of patients, improving the quality of life, having no obvious adverse reactions, being safe in medication, and having good patient compliance. It is an effective prescription for treating depression after coronary heart disease myocardial infarction and is worthy of popularization and application.

Claims

1. A Chinese medicine composition for treating post-coronary heart disease depression, characterized in that: The Chinese medicine composition comprises the following components in parts by weight: 1500-1600 parts of oysters, 700-800 parts of salvia miltiorrhiza, 600-700 parts of forsythia, 400-500 parts of dalbergia odorifera, 600-700 parts of ophiopogon japonicus, 400-500 parts of sappan wood, and 10-11 parts of borneol.

2. The method for preparing the Chinese medicine composition according to claim 1, characterized in that The following steps are involved: 1) taking a formula amount of Forsythia suspensa and Dalbergia odorifera and soaking them in water, extracting them by steam distillation, collecting volatile oil, encapsulating the volatile oil and borneol with β-cyclodextrin to obtain volatile oil and borneol encapsulated with β-cyclodextrin, and setting them aside for later use; and after centrifuging the extracted liquid to remove impurities, collecting the residue and the extract separately, and setting them aside for later use; 2) Take the prescribed amount of oysters and add water to boil. Start timing when the liquid boils. Boil for 1 hour to obtain the decoction. 3) After the decoction in step 2) is completed, the decoction liquid is added with the prescribed amount of Danshen, Sappan wood, Ophiopogon japonicus and the residues of step 1), and refluxed to obtain a reflux extract, the reflux extract is centrifuged to remove impurities, and then combined with the extract of step 1), and concentrated under reduced pressure to obtain a clear paste; 4) The volatile oil and borneol encapsulated by β-cyclodextrin obtained in step 1) are added to the clear paste, spray-dried to obtain dry powder, and then auxiliary materials are added to obtain granules by dry method.

3. The method for preparing the Chinese medicine composition according to claim 2, characterized in that: In step 1), the amount of water added is 8 times the total amount of Forsythia suspensa and Dalbergia odorifera, the immersion time is 0.5 h, and the steam distillation is 7 h.

4. The method for preparing the Chinese medicine composition according to claim 2, characterized in that: In step 2), the material-liquid ratio of oyster to water is 1 g:30 L.

5. The method for preparing the Chinese medicine composition according to claim 2, characterized in that: In step 3), reflux extraction is performed twice, each time for 0.5 h, and the temperature for vacuum concentration is 50-60° C. The relative density of the clear paste is 1.10±0.

02.

6. Use of the Chinese medicine composition according to any one of claims 1 to 5 in the preparation of a medicament for treating post-coronary heart disease depression.

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