New application of salvianolic acid B
Through the combination of sanphenolic acid B and panax notoginseng total saponin, the heart function of the mice with lung cancer and heart disease was improved, and the problem of poor results in the treatment of lung cancer combined with heart disease was solved, and significant improvement of heart function was achieved.
Patent Information
- Application Number
- CN202311806684.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-10-25
- Publication Date
- 2025-04-11
- Estimated Expiration
- 2043-10-25
AI Technical Summary
The existing technology of treating lung cancer combined with heart disease is not effective. Traditional heart disease treatment drugs are ineffective against heart disease caused by lung cancer, and chemotherapy drugs have problems such as cardiac toxicity and difficulty in operation, which leads to difficulties in clinical application.
By improving cardiac function, the left ventricular ejection fraction and left ventricular shortening rate are used, the left ventricular end-stage internal diameter and left heart output are reduced, the right heart free wall thickness, right heart end-diastolic internal diameter, right ventricular stroke and right heart output are reduced, the right heart rate is achieved to prevent and treat lung cancer heart disease.
Through the combination of sanphenolic acid B and panax notoginseng total saponin, the heart function of mice with lung cancer and heart disease was significantly improved. The effect was comparable to that of sacubalivalsartan and had broad application prospects.
Smart Images
Figure CN117883432B_ABST
Abstract
Description
[0001] This application is a divisional application for the invention patent with application number 2023113872712, invention name "Composition of salvianolic acid B and / or Panax notoginseng total saponins and its application", and application date October 25, 2023. Technical Field
[0002] The present invention specifically relates to a salvianolic acid B and / or notoginseng total saponin composition and application thereof. Background Art
[0003] Heart disease is a type of disease involving the heart or blood vessels, including coronary heart disease, heart failure, myocardial hypertrophy, myocarditis, etc. Different types of heart disease have different symptoms. Common symptoms include: palpitations, dyspnea, cyanosis, cough, chest pain, edema, etc. Severe cases may cause pulmonary edema, respiratory failure, systemic water and electrolyte disorders, etc. The main causes of heart disease are congenital heart disease, that is, abnormal development of the heart during the fetal period, and the lesions involve various tissues of the heart; acquired heart disease, that is, the heart is affected by external or internal factors after birth. Such as: coronary atherosclerotic heart disease, rheumatic heart disease, hypertensive heart disease, cor pulmonale, infectious heart disease, endocrine heart disease, hematological heart disease, nutritional metabolic heart disease, etc.
[0004] Lung cancer is also a malignant disease. Clinical studies have found that the treatment of lung cancer combined with heart disease is very difficult. There are currently two treatment options for patients with lung cancer combined with heart disease. One is to use common drugs for the treatment of heart disease in clinical practice, such as digoxin, a cardiotonic drug, and beta-blockers to improve heart rate, for lung cancer combined with heart disease. Patients cannot benefit from it. The ARB drug sacubitril-valsartan, which has been clinically confirmed to be effective in the treatment of lung cancer combined with heart disease, also has side effects such as angioedema, hypotension, renal impairment, and hyperkalemia. The other is to focus on tumor treatment. Studies have shown that dripping cisplatin, a representative drug of the first generation of platinum-based anti-tumor chemotherapy drugs, into the pericardial cavity of the heart can significantly prevent the recurrence of malignant pericardial effusion in lung cancer patients. However, these chemotherapy drugs often have certain cardiotoxicity, which may aggravate heart damage. In addition, cisplatin drip also has serious problems in clinical operation, high incidence of adverse events, and secondary losses to patients, which makes clinical application difficult. Other targeted drugs such as EGFR inhibitors are less toxic and more targeted than chemotherapy drugs, but studies have found that they also have significant cardiac toxicity.
[0005] There are abundant plant resources of natural origin, and there is great potential for exploration in the treatment of lung cancer combined with heart disease. It is necessary to find effective ingredients with fewer side effects and better efficacy in the treatment of lung cancer combined with heart disease from medicinal plants, so as to enrich the drugs for the treatment of lung cancer combined with heart disease and benefit patients with lung cancer combined with heart disease.
[0006] Salvianolic acid B is the active ingredient in Salvia miltiorrhiza, which has a strong antioxidant effect. In vitro and in vivo experiments have shown that salvianolic acid B can scavenge oxygen free radicals and inhibit lipid peroxidation. It is currently reported to be used for heart protection or anti-tumor. Total saponins of Panax notoginseng are the main active substances of Panax notoginseng, which have the effects of inhibiting platelet aggregation and increasing cerebral blood flow. It is currently used for cerebrovascular sequelae, central retinal vein occlusion, anterior chamber hemorrhage, etc. There is no research evidence to suggest that the active ingredients of Salvia miltiorrhiza and Panax notoginseng have a protective effect on lung cancer combined with heart disease. Summary of the invention
[0007] In order to solve the above problems, the present invention provides the use of salvianolic acid B or notoginseng total saponins in the preparation of drugs for preventing and / or treating lung cancer and heart disease.
[0008] The present invention also provides the use of salvianolic acid B combined with notoginseng total saponins in the preparation of medicines for preventing and / or treating lung cancer and heart disease.
[0009] The lung cancer heart disease described in the present invention refers to the heart disease caused by lung cancer, including the situation where the original heart disease becomes progressively worse during the treatment of lung cancer. According to the inventor's research, the heart disease caused by lung cancer is different from the common heart disease. The main reason is that the lung cancer cells metastasize to the pericardium, which can cause pericardial effusion, and then lead to malignant arrhythmia, heart failure, etc., resulting in poor effect of using traditional heart disease treatment drugs to treat it. The survival time of patients is very short, and the clinical treatment is difficult and the effect is very poor.
[0010] Furthermore, the mass ratio of the salvianolic acid B to the total saponins of Panax notoginseng is 120-800:30-240, preferably 200:60.
[0011] Furthermore, the drug has the effect of improving the cardiac function of heart disease caused by lung cancer.
[0012] Furthermore, the drug has the effects of increasing the left ventricular ejection fraction and the left ventricular minor axis shortening rate, and reducing the left ventricular end-systolic diameter and left cardiac output.
[0013] Furthermore, the drug has the effect of reducing the thickness of the right heart free wall, the right heart end-diastolic inner diameter, the right ventricular stroke volume and the right heart output.
[0014] Furthermore, the drug is a drug for preventing and treating heart failure caused by lung cancer.
[0015] The present invention also provides a combined medicine for preventing and / or treating lung cancer and heart disease, which comprises salvianolic acid B and notoginseng total saponins for simultaneous or separate administration; the active ingredients of the combined medicine consist of salvianolic acid B and notoginseng total saponins.
[0016] Furthermore, the mass ratio of the salvianolic acid B to the total saponins of Panax notoginseng is 120-800:30-240, preferably 200:60.
[0017] Finally, the present invention provides a composition for preventing and / or treating lung cancer and heart disease, wherein the active ingredients of the composition are composed of salvianolic acid B and notoginseng total saponins; the composition is a preparation prepared by adding the active ingredients to pharmaceutically acceptable excipients.
[0018] Furthermore, the mass ratio of the salvianolic acid B to the total saponins of Panax notoginseng is 120-800:30-240, preferably 200:60.
[0019] The use of salvianolic acid B and / or Panax notoginseng total saponins in the preparation of drugs for preventing and / or treating lung cancer heart disease, and the lung cancer heart disease model experiment constructed with urethane and benzopyrene, determined that salvianolic acid B, Panax notoginseng total saponins, especially salvianolic acid B combined with Panax notoginseng total saponins, can improve the heart function of mice with lung cancer heart disease by increasing left ventricular ejection fraction and left ventricular minor axis shortening rate, reducing left ventricular end-systolic diameter and left cardiac output, and reducing right heart free wall thickness, right heart end-diastolic diameter, right ventricular stroke volume and right cardiac output. Under the condition that many drugs for treating heart-related diseases have poor effects on the heart function of lung cancer heart disease, the effect of salvianolic acid B combined with Panax notoginseng total saponins on improving heart function is comparable to that of sacubitril-valsartan, which is currently commonly used in clinical practice, and has achieved unexpected therapeutic effects, with broad application prospects.
[0020] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.
[0021] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 Research roadmap. DETAILED DESCRIPTION
[0023] The raw materials, equipment and reagents used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
[0024] Example 1 Application of Salvia miltiorrhiza and Panax notoginseng monomer components in the treatment of lung cancer and heart disease
[0025] 1. Experimental Reagents
[0026] Urethane (Sigma, USA); benzopyrene (Shanghai Yuanye Biotechnology Co., Ltd.); salvianolic acid B (Shanghai Myrel Biochemical Technology Co., Ltd.); notoginseng total saponins (Shanghai Yuanye Biotechnology Co., Ltd.); sacubitril valsartan (Beijing Novartis Pharmaceuticals Co., Ltd.); digoxin tablets (Chengdu Betadeno Pharmaceuticals Co., Ltd.); metoprolol succinate tablets (AstraZeneca Pharmaceuticals Co., Ltd.); normal saline (Sichuan Kelun Pharmaceuticals Co., Ltd.).
[0027] Experimental animals and groups
[0028] Experimental groups: 8-week-old SPF Balb / c mice were purchased from Guangdong Animal Experimental Center, with a total of 120 mice, divided into 8 groups, with 15 mice in each group, namely: 1. blank control group; 2. model group; 3. salvianolic acid B (200 mg / kg) group; 4. Panax notoginseng total saponins (60 mg / kg) group; 5. salvianolic acid B + Panax notoginseng total saponins group (200 mg / kg + 60 mg / kg); 6. sacubitril valsartan group (60 mg / kg); 7. digoxin group (0.1 mg / kg orally); 8. metoprolol succinate (20 mg / kg orally) group.
[0029] Experimental equipment
[0030] Ultrapure water machine (Guangzhou Feidi Biotechnology Co., Ltd.); electronic balance (BP2215, Germany); high-resolution small animal ultrasound imaging system (VisualSonics, Canada).
[0031] Experimental methods
[0032] 4.1 Preparation of mouse lung cancer heart disease model
[0033] SPF Balb / c mice were kept in an SPF environment with a temperature of 20-26℃, a relative humidity of 40%-70%, and a 12 / 12 hour light-dark alternation. They were free to drink water and eat. Urethane solution (normal saline as solvent) and benzopyrene solution (corn oil as solvent) were given. Urethane solution was injected intraperitoneally at a dose of 1 g / kg once a week for 4 consecutive weeks, and benzopyrene solution was gavaged (ig) at a dose of 50 mg / kg twice a week for 8 consecutive weeks. The control group mice were given an equal amount of normal saline and corn oil in the same way and at the same time. Ten weeks after administration, the number of lung tumors was calculated, the size of lung tumors was measured, and cardiac function was tested to evaluate whether the mouse model of lung cancer and heart disease was successfully established. Research evidence shows that the modeling success rate of this method is 100%.
[0034] Drug administration
[0035] Drug administration: The mice in the salvianolic acid B (200 mg / kg) group, Panax notoginseng total saponins (60 mg / kg) group, and salvianolic acid B + Panax notoginseng total saponins group (200 mg / kg + 60 mg / kg) were continuously gavaged with the corresponding doses of drugs after the last administration of urethane. The mice in the positive drug group were continuously gavaged with 60 mg / kg of sacubitril-valsartan after the last administration of urethane. The mice in the digoxin group were continuously gavaged with 0.1 mg / kg of digoxin tablets after the last administration of urethane. The mice in the metoprolol succinate group were continuously gavaged with 20 mg / kg of metoprolol succinate tablets after the last administration of urethane. The drugs were continuously gavaged for 10 weeks.
[0036] The mice in the blank control group and the model group were gavaged with an equal volume of normal saline for 10 weeks.
[0037] After the administration, 10 mice were selected from each group for subsequent experiments.
[0038] Echocardiography was used to detect changes in cardiovascular function in mice:
[0039] The cardiovascular function of mice was measured using the Vevo3100 high-resolution small animal ultrasound imaging system produced by VisualSonics, Canada. After the mice were anesthetized with 1% isoflurane, they were placed in a supine position, the hair on the chest of the mice was removed, and an ultrasonic coupling agent was applied to the chest of the mice to detect the right heart function (right heart free wall thickness (RVWT), right heart end-diastolic diameter (RVID;d), right ventricular stroke volume (RV SV), right heart output (RV CO) and left heart function (left ventricular ejection fraction (EF), left ventricular short axis shortening (FS), left ventricular end-systolic diameter (LVID;s), left heart stroke volume (LV SV), left heart output (LV CO)).
[0040] Calculation of tumor number and volume in mouse lung tissue:
[0041] After the cardiac function test, the mice in each group were immediately killed, the intact lung tissue was separated, and the number of tumors (number of lung cancer tumor nodules) and the tumor volume in the lung tissue were detected.
[0042] Data processing
[0043] SPSS 24.0 was used to analyze all data. Data were expressed as mean ± SD. The data between two groups were analyzed by t-test, and the data between each group were analyzed by one-way ANOVA. P A value ≤ 0.05 was considered to be significantly different.
[0044] Research technology route:
[0045] See Figure 1 .
[0046] Experimental results:
[0047] 4.7.1 Effects of Salvia miltiorrhiza and Panax notoginseng on left ventricular function in mice with lung cancer and heart disease
[0048] The results are shown in Table 1: After urethane + benzopyrene modeling, the left heart function of the mice in the model group was significantly damaged, as reflected in: the left ventricular ejection fraction (EF%) and the left ventricular short axis shortening rate (FS%) were significantly reduced ( P <0.01), left ventricular end-systolic diameter (LVID;s) ( P <0.01) and left ventricular output (LV CO) were significantly increased ( P <0.05); after treatment with salvianolic acid B, Panax notoginseng total saponins, salvianolic acid B+Panax notoginseng total saponins, and sacubitril-valsartan, the left ventricular function of mice was improved, as shown by: the left ventricular ejection fraction (EF%) and left ventricular fractional shortening (FS%) increased significantly ( P <0.01), left ventricular end-systolic diameter (LVID;s) ( P <0.01) Left ventricular output (LV CO) P <0.05) was significantly reduced, and the therapeutic effect of salvianolic acid B + Panax notoginseng total saponins was better than that of the group given salvianolic acid B or Panax notoginseng total saponins alone. This evidence shows that salvianolic acid B and Panax notoginseng total saponins can improve the left ventricular function of mice with lung cancer and heart disease, and the combined use of drugs has a better effect.
[0049] Table 1: Left ventricular function in mice
[0050] Group Left ventricular ejection fraction (EF%) Left ventricular fractional shortening (FS%) Left ventricular end-systolic diameter (mm) (LVID;s) Left ventricular output (LV SV) Left ventricular output (ml / min) (LV CO) Blank control group 83.34±4.06 61.87±4.99 1.40±0.11 32.24±1.06 13.14±1.10 Model Group <![CDATA[66.72±5.39 ** ]]> <![CDATA[42.69±6.27 ** ]]> <![CDATA[2.16±0.15 ** ]]> 34.16±1.78 <![CDATA[15.51±0.70 * ]]> Salvianolic acid group B <![CDATA[74.48±7.89 ## ]]> <![CDATA[53.55±5.67 ## ]]> <![CDATA[1.81±0.27 ## ]]> 32.93±1.88 <![CDATA[14.33±0.84 # ]]> Panax notoginseng saponins group <![CDATA[75.19±7.40 ## ]]> <![CDATA[53.69±6.02 ## ]]> <![CDATA[1.56±0.16 ## ]]> 33.08±1.46 <![CDATA[14.31±0.99 # ]]> Salvianolic acid B + Panax notoginseng saponins group <![CDATA[77.78±4.21 ## ]]> <![CDATA[55.49±4.51 ## ]]> <![CDATA[1.54±0.20 ## ]]> 32.89±1.52 <![CDATA[14.22±1.17 # ]]> Sacubitril-Valsartan Group <![CDATA[77.89±4.95 ## ]]> <![CDATA[55.09±6.33 ## ]]> <![CDATA[1.54±0.20 ## ]]> 32.88±1.62 <![CDATA[14.21±1.12 # ]]> Digoxin group 63.37±4.53 40.95±3.99 2.14±0.18 34.25±1.57 15.37±0.86 Metoprolol group 65.87±6.18 43.11±4.15 2.02±0.31 34.00±1.19 14.98±0.93
[0051] Note: ** P <0.01 compared with the blank control group; ## P <0.01 compared with the model group.
[0052] Effects of single components of Danshen and Panax notoginseng on right ventricular function in mice with lung cancer and heart disease
[0053] The results are shown in Table 2: After urethane + benzopyrene modeling, the right heart function of the mice in the model group was significantly damaged, as shown in: right heart free wall thickness (RVWT) ( P <0.05), right ventricular end-diastolic diameter (RVID;d), right ventricular stroke volume (RV SV) ( P <0.05) and right ventricular output (RV CO) increased significantly ( P <0.01); after treatment with salvianolic acid B, Panax notoginseng total saponins, salvianolic acid B+Panax notoginseng total saponins, and sacubitril-valsartan, the right heart function of mice was improved, as shown in: right heart free wall thickness (RVWT) (P <0.05), right ventricular end-diastolic diameter (RVID;d) ( P <0.01)、right ventricular stroke volume(RV SV)( P <0.05) and right ventricular output (RV CO) were significantly decreased ( P <0.05). Moreover, the therapeutic effect of salvianolic acid B+Panax notoginseng total saponins was better than that of the group given salvianolic acid B or Panax notoginseng total saponins alone. This evidence shows that salvianolic acid B and Panax notoginseng total saponins can improve the right heart function of mice with lung cancer and heart disease, and the combined use has a better effect.
[0054] Table 2: Right heart function in mice
[0055] Group Right ventricular free wall thickness (mm) (RVWT) Right ventricular end-diastolic diameter (mm) (RVID;d) Right ventricular stroke volume (RV SV) Right cardiac output (ml / min) (RV CO) Blank control group 0.6±0.035 3.07±0.14 29.70±1.22 13.10±1.12 Model Group <![CDATA[0.664±0.048 * ]]> <![CDATA[3.52±0.09 ** ]]> <![CDATA[31.94±2.36 * ]]> <![CDATA[14.86±1.50 ** ]]> Salvianolic acid group B <![CDATA[0.604±0.055 # ]]> <![CDATA[3.29±0.16 ## ]]> <![CDATA[30.01±1.21 # ]]> <![CDATA[13.44±1.35 # ]]> Panax notoginseng saponins group <![CDATA[0.603±0.051 # ]]> <![CDATA[3.27±0.17 ## ]]> <![CDATA[29.85±1.21 # ]]> <![CDATA[13.39±1.06 # ]]> Salvianolic acid B + Panax notoginseng saponins group <![CDATA[0.599±0.058 # ]]> <![CDATA[3.12±0.20 ## ]]> <![CDATA[29.93±1.19 # ]]> <![CDATA[13.26±0.72 # ]]> Sacubitril-Valsartan Group <![CDATA[0.601±0.035 # ]]> <![CDATA[3.14±0.17 ## ]]> <![CDATA[29.86±1.20 # ]]> <![CDATA[13.23±1.14 # ]]> Digoxin group 0.652±0.059 3.54±0.11 32.49±2.18 15.03±1.02 Metoprolol group 0.646±0.036 3.49±0.45 31.76±1.93 14.92±1.31
[0056] Note: * P <0.05, ** P <0.01 compared with the blank control group; # P <0.05, ## P <0.01 compared with the model group.
[0057] Effects of single components of Danshen and Panax notoginseng on tumors in mice with lung cancer and heart disease
[0058] The results are shown in Table 3. After urethane + benzopyrene modeling, a large number of tumors were detected in the lung tissues of the model group mice ( P <0.01), indicating that the lung cancer heart disease model was successfully established. After treatment with salvianolic acid B, Panax notoginseng total saponins, sacubitril valsartan, digoxin and metoprolol succinate, there was no significant change in the number and volume of tumors in the lung tissue of mice ( P >0.05), which suggested that salvianolic acid B, notoginseng total saponins, sacubitril-valsartan, digoxin and metoprolol succinate had no effect on the treatment of lung cancer.
[0059] Table 3: Number and volume of tumors in mouse lung tissue
[0060] Group Number of tumors Tumor volume (mm) Blank control group 0.00±0.00 0.00±0.00 Model Group <![CDATA[6.6±1.07 ** ]]> <![CDATA[1.54±0.42 ** ]]> Salvianolic acid group B 6.7±1.88 1.56±0.27 Panax notoginseng saponins group 6.8±2.10 1.54±0.31 Salvianolic acid B + Panax notoginseng saponins group 6.3±1.34 1.59±0.22 Sacubitril-Valsartan Group 6.4±1.07 1.51±0.44 Digoxin group 6.5±1.51 1.50±0.28 Metoprolol group 6.7±1.34 1.52±0.32
[0061] Note: ** P <0.01 compared with the blank control group.
[0062] The above results highly suggest that both salvianolic acid B and Panax notoginseng total saponins can improve the cardiac function of mice with lung cancer and heart disease, and the effect is better when used in combination, but they have no therapeutic effect on lung cancer. They mainly improve the cardiac function of mice with lung cancer and heart disease through their cardioprotective effect.
[0063] 5. Discussion
[0064] With the progress of lung cancer, the human body will experience organ failure to varying degrees, among which heart damage is the most concerned issue in clinical practice: during the occurrence and development of lung cancer, the heart will be damaged, causing serious arrhythmias and abnormal cardiac electrophysiological conduction, leading to heart enlargement and eventually heart failure. Heart failure can cause patients to feel hypoxia, chest tightness, breathlessness and dyspnea, and lung cancer itself can also reduce respiratory function. If the progression of heart failure caused by lung cancer cannot be controlled, pleural effusion and large-volume lung space-occupying will occur, affecting ventilation, and dyspnea will be severe, which will then develop into respiratory failure. Therefore, if heart failure occurs in patients with lung cancer and heart disease, it often means that the disease has entered the terminal stage and the survival period will be greatly shortened. The present invention, combined with the total saponins of Panax notoginseng, increases the left ventricular ejection fraction and the left ventricular short-axis shortening rate, reduces the left ventricular end-systolic internal diameter and left cardiac output, and reduces the right heart free wall thickness, the right heart end-diastolic internal diameter, the right ventricular stroke volume and the right cardiac output, thereby improving the heart function of lung cancer and heart disease, achieving the effect of preventing and treating heart failure, and the effect is comparable to the currently commonly used sacubitril valsartan in clinical practice. Preliminary experiments also showed that reducing the combined dose by half in proportion can still achieve the effect of improving heart function. Therefore, the combined use of salvianolic acid B and Panax notoginseng total saponins in the prevention and treatment of lung cancer and heart disease has prospects for clinical promotion and application.
Claims
1. Use of salvianolic acid B in the preparation of a drug for preventing and / or treating heart disease caused by lung cancer, characterized in that: The heart disease caused by lung cancer is a disease with symptoms of decreased left ventricular ejection fraction, decreased left ventricular short axis shortening rate, increased left ventricular end-systolic diameter, increased left cardiac output, increased right heart free wall thickness, increased right heart end-diastolic diameter, increased right ventricular stroke volume and increased right cardiac output; The drug has the effects of increasing left ventricular ejection fraction and left ventricular short axis shortening rate, reducing left ventricular end-systolic inner diameter and left cardiac output, and reducing right cardiac free wall thickness, right cardiac end-diastolic inner diameter, right ventricular stroke volume and right cardiac output.
2. The use according to claim 1, characterized in that: The medicine is a medicine for preventing and treating heart failure caused by lung cancer.