Use of Jingfang preparation in preparing medicine for preventing or treating myocardial infarction of cold coagulation and blood stasis type

Abstract

The present invention belongs to the field of pharmaceutical technology and specifically relates to the use of a Jingfang preparation in the preparation of a medicament for treating cold-coagulated and blood-stasis-type myocardial infarction. The Jingfang preparation comprises eleven Chinese medicinal herbs: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium incisum, Angelica dahurica, Bupleurum chinense, Peucedanum chinense, Chuanxiong rhizome, Fructus Aurantii Immaturus, Poria cocos, Platycodon grandiflorum, and Licorice root. Animal experiments have shown that the Jingfang preparation significantly reduces whole blood viscosity and plasma viscosity in rats with myocardial infarction induced by epinephrine hydrochloride and ice water stimulation, with an effect comparable to that of Yangxinshi tablets. The preparation can also alleviate the deterioration of cardiac function and reduce the degree of myocardial damage in rats after myocardial infarction induced by cold stimulation, and has broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to the use of a Jingfang preparation in preparing a medicament for preventing or treating cold coagulation and blood stasis type myocardial infarction. Background Art

[0002] Myocardial infarction, also known as myocardial infarction, refers to ischemic necrosis of the myocardium. It often occurs in the context of coronary artery disease. Coronary artery blood flow is sharply reduced or interrupted, causing severe and persistent acute ischemia in the corresponding myocardium, ultimately leading to myocardial ischemic necrosis. In Traditional Chinese Medicine, the symptoms of myocardial infarction fall into the categories of "chest pain," "heart pain," and "sudden heart pain." Modern Chinese medicine believes that myocardial infarction is caused by obstruction of the heart meridians by blood stasis, phlegm, cold stagnation, and qi stagnation, with blood stasis being the mainstay of treatment. Treatment focuses on promoting blood circulation and removing blood stasis, unblocking the meridians and dispersing nodules, and invigorating qi, nourishing blood, and restoring the meridians. Clinical observations and statistics have shown that due to the cold winters in northern China, the cold stagnation and blood stasis syndrome is the most common type. Cold evil is responsible for contraction, and "blood coagulates when it is cold and flows when it is warm", so the place where cold coagulates can easily cause blood stasis, and cold coagulation and blood stasis together block the heart meridian, making the heart qi unable to flow, and the heart loses nourishment, resulting in true heart pain. It was first recorded in "Huangdi Neijing", such as "heart disease starts with heart pain", "evil in the heart will cause heart pain", "true heart pain, hands and feet blue to the joints, severe heart pain, death by evening if it occurs in the morning, death by morning if it occurs in the evening", etc.

[0003] Myocardial infarction falls under the category of chest pain and palpitations in Traditional Chinese Medicine (TCM). Its fundamental pathogenesis is a combination of underlying deficiency and superficial excess. The underlying deficiency begins with deficiency of heart qi, further developing into deficiency of heart yang. In severe cases, yang deficiency or loss, or even exhaustion of both yin and yang, can occur. Some patients also experience deficiency of both qi and yin. The superficial excess is primarily blood stasis, which can be accompanied by cold coagulation, phlegm obstruction, qi stagnation, qi deficiency, and blood stasis. Blood stasis and phlegm turbidity block the heart vessels, leading to obstruction and the development of this condition. Promoting blood circulation and removing blood stasis is the fundamental principle in TCM treatment of myocardial infarction. Guided by this principle, clinical treatment should combine syndrome differentiation and treatment tailored to achieve the desired results.

[0004] Myocardial infarction caused by cold coagulation and blood stasis (cold coagulation heart pulse type myocardial infarction) is accompanied by angina pectoris, wheezing and other uncomfortable symptoms. These symptoms often occur suddenly or worsen when the temperature drops suddenly or when a cold wind invades. Huang Chahua et al. (Huang Chahua et al. Effects of cold stimulation on left ventricular systolic function in rats with acute myocardial infarction [J]. 2012. 22(25): 6-8) found that cold stimulation can significantly reduce the left ventricular systolic function of rats with myocardial infarction. The mechanism may be achieved by promoting the overexpression of Bim and Caspase3 in the left ventricular myocardial tissue. Xie Yao (Xie Yao. Effects of benazepril on the function of rats with myocardial infarction under cold stimulation [D]. 2011. Master's thesis of Nanchang University) found that cold stimulation can further deteriorate the systolic and diastolic function of the heart in rats after myocardial infarction. Therefore, taking effective measures to reduce the adverse effects of temperature on cardiovascular and cerebrovascular diseases can effectively prevent or reduce the occurrence of myocardial infarction, alleviate the pain and economic burden of patients, save medical resources, and have important significance for protecting people's health.

[0005] Jingfang Granules are derived from the ancient formula Jingfang Baidu San (Jingfang Baidu San). Made from eleven raw medicinal ingredients: Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Bupleurum chinense, Peucedanum chinense, Chuanxiong rhizome, Citrus aurantium, Poria cocos, Platycodon grandiflorum, and Licorice root, they have diaphoretic and anti-inflammatory properties, dispelling wind and dampness. They are clinically used to treat symptoms such as colds, headaches and body aches, aversion to cold without sweating, nasal congestion and runny nose, and cough with white sputum. The main herbs in the formula, Schizonepeta tenuifolia and Saposhnikovia divaricata, are pungent and warm, dispersing the exterior, dispelling wind pathogens and addressing the root causes of all ailments. The auxiliary herbs, Notopterygium wilfordii and Angelica dahurica, are pungent and warm, dispersing pathogens throughout the body. Chuanxiong promotes blood circulation and dispels wind, while Bupleurum chinense dispersing and tonifying muscles aids Notopterygium wilfordii and Angelica dahurica in dispelling external pathogens and relieving pain. Citrus aurantium depresses qi, Platycodon grandiflorum invigorates the lungs, Peucedanum dahurica dispels phlegm, and Poria cocos dissipates dampness and serves as an adjuvant. Licorice root harmonizes the herbs and serves as a guiding herb. When these medicines are used together, sweating will occur and fever will subside, blood circulation will be improved and wind and pain will stop, lung qi will be improved, phlegm and dampness will be eliminated, cough will stop, and all cold symptoms will be eliminated and the patient will recover. Summary of the Invention

[0006] The purpose of the present invention is to provide a use of a Jingfang preparation in preparing a medicament for preventing or treating myocardial infarction of cold coagulation and blood stasis type.

[0007] Cold stimulation can lower the ischemic threshold in patients with coronary artery disease and induce myocardial infarction. Patients with pre-existing coronary artery disease are particularly sensitive to the effects of cold stimulation. This is because cold stimulation excites the sympathetic nervous system, increasing the secretion of catecholamines in the body, constricting peripheral blood vessels, inducing myocardial ischemia, platelet aggregation, and even thrombosis, exacerbating heart disease.

[0008] In one embodiment of the present invention, the cold coagulation and blood stasis type myocardial infarction is a deterioration of cardiac function in patients with myocardial infarction caused by cold stimulation.

[0009] Furthermore, the Jingfang preparation is composed of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Bupleurum chinense, Peucedanum chinense, Chuanxiong, Fructus Aurantii Immaturus, Poria cocos, Platycodon grandiflorum, and Licorice.

[0010] Furthermore, the Jingfang preparation also includes pharmaceutically acceptable excipients.

[0011] Furthermore, the Jingfang preparation can be Jingfang granules, Jingfang oral liquid, Jingfang mixture, Jingfang pills, Jingfang dripping pills, Jingfang syrup, and Jingfang capsules.

[0012] The human dosage of the Jingfang preparation of the present invention is 0.02g / kg / d-2.50g / kg / d.

[0013] Furthermore, the human dosage of the Jingfang preparation is 0.30g / kg / d-1.45g / kg / d.

[0014] Compared with the prior art, the advantages of the present invention are:

[0015] 1. Jingfang preparation can significantly reduce the whole blood viscosity and plasma viscosity of rats with myocardial infarction caused by stimulation of epinephrine hydrochloride and ice water, and has the effect of preventing or treating myocardial infarction of cold coagulation and blood stasis type, and the effect is equivalent to that of Yangxinshi tablets.

[0016] 2. Jingfang preparations can significantly alleviate the deterioration of cardiac function in rats after myocardial infarction caused by cold stimulation. Jingfang preparations can alleviate the degree of myocardial ischemia in rats with myocardial infarction caused by cold stimulation, reduce the myocardial infarction rate by approximately 6%, reduce the myocardial infarction area, reduce the activity of myocardial enzymes CK and CK-MB, and alleviate the degree of myocardial damage. It has a significant preventive and therapeutic effect on the deterioration of cardiac function caused by cold stimulation in rats with myocardial infarction. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 : Heart sections of rats in each group. Figure 1 The various parts are represented as follows:

[0018] GZ: Heart sections of rats in the normothermic group after myocardial infarction;

[0019] GV: Heart sections of rats in the hypothermia group after myocardial infarction;

[0020] GJ: Heart sections of rats in the Jingfang granule + hypothermia group after myocardial infarction DETAILED DESCRIPTION

[0021] In order to enable those skilled in the art to fully understand the present invention, the present invention is further described below through specific examples. However, those skilled in the art should be aware that the examples of the present invention do not limit the present invention in any way. Specific embodiments

[0023] Example 1 Effect of Jingfang Granules on Hemodynamics in Rats with Cold-Coagulation and Blood Stasis Myocardial Infarction

[0024] 1 Experimental Materials

[0025] 1.1 Experimental Animals

[0026] Forty-eight KM rats, half male and half female, weighing (220 ± 10) g, were fed a standard diet for one week before the intervention experiment. Animal handling procedures throughout this experiment complied with relevant animal ethics requirements.

[0027] 1.2 Experimental drugs

[0028] Jingfang Granules, Shandong New Era Pharmaceutical Co., Ltd.

[0029] Epinephrine hydrochloride: Beijing Yongkang Pharmaceutical Co., Ltd.

[0030] Yangxinshi Tablets: Shanghai Pharmaceutical Group Qingdao Guofeng Pharmaceutical Co., Ltd.

[0031] 2 Experimental methods

[0032] Rats were randomly divided into 6 groups, 8 in each group. Each group of rats was given the drug by gavage once a day in the morning. The dosage was as follows:

[0033] Blank control group: the same volume of distilled water was given.

[0034] Model group: administered the same volume of distilled water.

[0035] Jingfang Granule high-dose group: Jingfang Granule, 9.00g / kg / d

[0036] Jingfang Granule medium dose group: Jingfang Granule, 4.50g / kg / d

[0037] Jingfang Granule low-dose group: Jingfang Granule, 2.25g / kg / d

[0038] Positive control group: Yangxinshi tablets, 1.00g / kg / d

[0039] The drug was administered continuously for 14 days, and the model was established 30 minutes after the last administration. Except for the blank control group, the animals in other groups were subcutaneously injected with epinephrine hydrochloride (1 mg / kg). After 2 hours, the animals were placed in ice water (4°C) and soaked for 5 minutes, removed, and injected with the same dose of epinephrine hydrochloride again 2 hours later. They were fasted for 20 hours. The next day, blood was collected through abdominal aorta puncture under ether anesthesia. 1 mL of blood was drawn and added to a BV-100 blood rheometer to measure whole blood viscosity. The remaining whole blood was centrifuged at 3000 r / min for 10 minutes, and 1 mL of the upper plasma was drawn and added to a BV-100 blood rheometer to measure plasma viscosity.

[0040] The experimental data are expressed as mean ± standard deviation The t-test was used for statistical analysis.

[0041] 3. Results and Analysis

[0042] 3.1 Effect of Jingfang Granules on Whole Blood Viscosity in Rats with Blood Stasis

[0043] Table 1 Effect of Jingfang Granule on Whole Blood Viscosity in Rats with Blood Stasis Syndrome ( n=8)

[0044]

[0045] Compared with the blank control group: *P<0.05, **P<0.01; compared with the model group: #P<0.05, ##P<0.01,

[0046] Compared with the positive control group: ΔP<0.05.

[0047] Table 2 Effects of Jingfang Granules on Plasma Viscosity in Rats with Blood Stasis

[0048]

[0049] Compared with the blank control group: *P<0.05, **P<0.01; compared with the model group: #P<0.05, ##P<0.01; compared with the positive control group: ΔP<0.05.

[0050] As shown in Tables 1 and 2, compared with the blank control group, the whole blood viscosity and plasma viscosity of the model rats were significantly increased, with extremely significant differences (P < 0.01), indicating successful model establishment. Compared with the model group, the whole blood viscosity and plasma viscosity of the rats in each dose group of Jingfang Granule decreased to varying degrees, with significant or extremely significant differences (P < 0.05, P < 0.01). Compared with the positive control group, except for the whole blood viscosity / high shear in the low-dose Jingfang Granule group, no other statistical differences were found (P > 0.05). Therefore, Jingfang Granule can significantly reduce the whole blood viscosity and plasma viscosity of rats with myocardial infarction, and has the effect of preventing or treating myocardial infarction caused by cold coagulation and blood stasis caused by epinephrine hydrochloride plus ice water stimulation, with an efficacy comparable to that of Yangxinshi Tablet.

[0051] Example 2 Effect of Jingfang Granules on Deterioration of Cardiac Function in Rats with Myocardial Infarction Under Cold Stimulation

[0052] 1 Experimental Materials

[0053] 1.1 Experimental Animals

[0054] Healthy male Wister rats, weighing (220 ± 10) g, were housed at 25°C, 40%-70% humidity, and a 12-hour light-dark cycle. They had free access to food and water (specialized standard feed and purified water). Animal handling throughout this experiment complied with relevant animal ethics requirements.

[0055] 1.2 Experimental drugs

[0056] Jingfang Granules, Shandong New Era Pharmaceutical Co., Ltd.

[0057] 2 Experimental methods

[0058] 2.1 Method for establishing rat myocardial infarction model

[0059] The myocardial infarction rat model in this experiment was established by referring to the coronary artery ligation method of Jia Ru (Jia Ru, et al. Study on the preparation method of myocardial infarction rat model [J]. China Continuing Medical Education. 2019.11(7): 159-161) and improving it.

[0060] (1) Male Wistar rats were anesthetized with 10% chloral hydrate (0.3 ml / 100 g intraperitoneally), intubated, and artificially respired. The ventilator parameters were set to: respiratory rate 70 breaths / min, I:E ratio 1:1, tidal volume 25 ml / kg. The success of the intubation was determined by observing whether the chest wall rise and fall frequency of the rats was consistent with the ventilator frequency.

[0061] (2) The thoracotomy was performed at the third and fourth intercostal spaces on the left side of the rat chest where the cardiac pulsation was most obvious. The subcutaneous tissue, pectoralis major muscle, and serratus anterior muscle of the rat were bluntly separated in layers using hemostatic forceps to expose the ribs and intercostal muscles. The pericardium was gradually torn apart using ophthalmic forceps to expose the myocardium.

[0062] (3) After the heart is exposed, the left atrial appendage and the pulmonary artery cone are quickly identified to determine the ligation site. A 6 / 0 round non-traumatic suture needle is placed 2 mm below the origin of the left anterior descending coronary artery and ligated. The myocardial color turns dark red, which is a sign of successful ligation.

[0063] (4) Depending on the situation after ligation, use sterile absorbent cotton to treat the blood and fluid accumulation in the chest cavity. After treatment, squeeze and tightly close the chest cavity, tightly suture the two ribs with sutures, and then gradually suture the muscles and skin in layers. Remove the endotracheal tube, place the rat in the right lateral position on the temperature-controlled plate, and disinfect the skin at the suture site with iodine.

[0064] 2.2 Experimental groups and treatments

[0065] Twenty-four rats with established myocardial infarction models were randomly divided into three groups, with eight rats in each group: normothermia after myocardial infarction (GZ), hypothermia after myocardial infarction (GV), and Jingfang granule + hypothermia after myocardial infarction (GJ). Rats in the normothermia group (GZ) were kept at room temperature; rats in the hypothermia group (GV) and the Jingfang granule + hypothermia group (GJ) were placed in a 4°C incubator from 9:00 to 15:00 daily and then returned to room temperature for three consecutive days.

[0066] 2.3 Administration:

[0067] Starting 11 days before coronary artery ligation, the drugs were administered by gavage once a day for 14 consecutive days. The drugs and their dosages were as follows:

[0068] Normal temperature group (GZ) after myocardial infarction: the same volume of normal saline

[0069] Hypothermia group after myocardial infarction (GV): same volume of normal saline

[0070] Jingfang granule + post-myocardial infarction hypothermia group (GJ): 2.1g / kg / d Jingfang granule

[0071] 2.4 Detection indicators and methods

[0072] After anesthesia, the rats in each group had their hearts removed, washed with saline, and the saline on the surface of the heart was dried. After freezing, the hearts were cut into thin slices with a thickness of approximately 1 to 2 mm from below the ligature. After incubation with TTC solution (37°C, protected from light, for 15 minutes), the hearts were removed, photographed, and the myocardial infarction area was measured. Figure 1 and Table 1. Myocardial infarction rate (%) = infarct area / (infarct area + non-infarct area) x 100%

[0073] 2.5 Statistical analysis

[0074] ˉ

[0075] SPSS 19.0 statistical software was used for analysis, and the experimental data were expressed as mean ± standard deviation (x ± S). One-way ANOVA was used for comparison among multiple groups, and P < 0.05 indicated a significant difference.

[0076] 3 Results

[0077] 3.1 Figure 1 Heart sections of rats in each group

[0078] Depend on Figure 1 In heart sections, the black areas represent normal myocardial cells, while the white areas represent necrotic myocardial tissue. Compared with the normothermia group, myocardial ischemia was aggravated in the hypothermia group. However, myocardial ischemia was somewhat improved in the Jingfang Granule + hypothermia group compared with the hypothermia group.

[0079] 3.2 Comparison of myocardial infarction rate in rats of each group

[0080] Table 1 Comparison of myocardial infarction rate in rats in each group

[0081]

[0082] Compared with the normothermic myocardial infarction group: *P<0.05, **P<0.01;

[0083] Compared with the myocardial infarction hypothermia group: #P<0.05, ##P<0.01.

[0084] As shown in Table 1, compared with the normothermia group after myocardial infarction, the myocardial infarction rate of rats in the hypothermia group after myocardial infarction was significantly increased (P<0.05), and the myocardial infarction area was significantly increased after hypothermia treatment; compared with the hypothermia group after myocardial infarction, the myocardial infarction rate of rats in the Jingfang granule + hypothermia group after myocardial infarction was significantly reduced (P<0.05), decreased by about 6%, and the myocardial infarction area was significantly reduced.

[0085] From the above, we know that cold stimulation can cause myocardial ischemia to worsen and myocardial infarction area to increase in rats with myocardial infarction; Jingfang Granule can reduce the degree of myocardial ischemia, alleviate the increase in myocardial infarction area, and stabilize the condition of patients with myocardial infarction.

[0086] Example 3 Effects of Drugs on the Activities of CK and CK-MB in Plasma of Rats with Myocardial Infarction Under Cold Stimulation

[0087] 1 Experimental Materials

[0088] 1.1 Experimental Animals

[0089] Healthy male Wister rats, weighing (220 ± 10) g, were housed at 25°C, 40% to 70% humidity, and a 12-hour light-dark cycle. They had free access to food and water (specialized standard feed and purified water). Animal handling throughout this experiment complied with relevant animal ethics standards.

[0090] 1.2 Medicines

[0091] The drug under test was the commercially available Jingfang granules

[0092] 2 Experimental methods

[0093] 2.1 Method for establishing rat myocardial infarction model

[0094] The method for establishing the rat myocardial infarction model is the same as that in Example 1

[0095] 2.2 Grouping and Processing

[0096] The method is the same as Example 1

[0097] 2.3 Administration

[0098] The method is the same as Example 1

[0099] 2.4 Detection indicators and methods

[0100] After the rats in each group were sacrificed, blood was collected. The blood was centrifuged (4°C, 3000 rpm, 15 min), and plasma was collected. The activities of plasma CK and CK-MB were measured using biochemical kits. The results are shown in Table 2.

[0101] 2.5 Statistical analysis

[0102] The method is the same as Example 1

[0103] 3 Results

[0104] 3.1 Detection of myocardial enzyme activity in rats in each group

[0105] Table 2 Comparison of plasma myocardial enzyme CK and CK-MB activities in rats of each group ( n=8,U / L)

[0106]

[0107] Compared with the normothermic myocardial infarction group: *P<0.05, **P<0.01;

[0108] Compared with the myocardial infarction hypothermia group: #P<0.05, ##P<0.01.

[0109] Elevated levels of the cardiac enzymes CK and CK-MB are sensitive indicators of myocardial damage. As shown in Table 2, compared with the normothermia group, the hypothermia group showed significantly elevated plasma CK and CK-MB activities after hypothermia (P < 0.01), indicating aggravated myocardial damage. Compared with the hypothermia group, the Jingfang Granule + post-MI hypothermia group showed significantly decreased plasma CK and CK-MB activities (P < 0.01), indicating less aggravated myocardial damage. This suggests that Jingfang Granule has a significant preventive and therapeutic effect on myocardial damage and other cardiac function deterioration caused by cold stimulation following myocardial infarction.

Claims

1. Use of a Jingfang preparation in the preparation of a medicament for preventing or treating cold coagulation and blood stasis type myocardial infarction, characterized in that: The raw materials of the Jingfang preparation are composed of Schizonepeta tenuifolia, Saposhnikovia divaricata, Notopterygium wilfordii, Angelica dahurica, Bupleurum chinense, Peucedanum chinense, Chuanxiong, Fructus Aurantii Immaturus, Poria cocos, Platycodon grandiflorum and Licorice.

2. The use according to claim 1, characterized in that The Jingfang preparation also includes pharmaceutically acceptable excipients.

3. The use according to claim 1-2, characterized in that The Jingfang preparation can be Jingfang granules, Jingfang oral liquid, Jingfang mixture, Jingfang pills, Jingfang syrup, or Jingfang capsules.

4. The use according to claim 3, characterized in that The human dosage of the Jingfang preparation is 0.02g / kg / d-2.50g / kg / d.

5. The use according to claim 4, characterized in that The human dosage of the Jingfang preparation is 0.30g / kg / d-1.45g / kg / d.

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