CN118615304A - Application of balrison B in preparing medicines for treating heart failure - Google Patents
Application of balrison B in preparing medicines for treating heart failure Download PDFInfo
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Abstract
The invention relates to the technical field of biological medicine, in particular to an application of balrison B in preparing a medicine for treating heart failure, which comprises the following steps: reversing the process of significantly decreasing the functional index of left ventricular ejection fraction (EF%), left ventricular short axis reduction (FS%), left ventricular diastolic and end systolic anterior wall thickness (LVAWd and LVAWs), left ventricular diastolic and end systolic posterior wall thickness (LVPWd and LVPWs) due to long-term doxorubicin injection; reversing the process of significant elevation of left ventricular diastole and end systole inner diameters (LVIDd and LVIDs) due to prolonged doxorubicin injection, improved myocardial contractility and reduced left ventricular dilatation. The balrison glycoside B can effectively relieve left ventricular dilatation and contraction dysfunction, heart contraction weakness, heart blood discharge reduction and ejection fraction reduction caused by doxorubicin, and the medium dose effect of the balrison glycoside B is superior to that of low dose, high dose and gastrodin.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of balrison B in preparation of a medicine for treating heart failure.
Background
The normal metabolic needs of the human body depend on the normal pumping function of the heart, i.e. normal cardiac output. Ventricular systole is the process of pumping out cardiac output. The normal contraction of the left chamber can complete the basic function of heart pumping blood to meet the requirement of human body. The left ventricular contractility is reduced, so that the heart is reduced to remove blood stasis, and symptoms caused by the blood stasis in the systemic circulation or the pulmonary circulation are correspondingly clinically diagnosed-cardiac insufficiency, and the left ventricular contractility is reduced and can be used as ultrasonic diagnosis of cardiac insufficiency. Cardiac insufficiency may include the whole course of disease from mild to severe, and the reduction of left ventricular contractility is also classified as mild to moderate to severe. Clinically, advanced and inappropriate treatments (treatments such as albumin supplementation, blood transfusion, excessive and rapid replacement of fluid, etc., blood volume increase, and cardiac burden increase) such as coronary heart disease, myocardial infarction, acute severe myocarditis, malignant arrhythmia (complete left bundle branch block, ventricular tachycardia and ventricular fibrillation), rheumatic mitral valve stenosis, left coronary fistula, left coronary abnormal origin, endocardial elastosis, cardiac muscle densification insufficiency, alcoholic cardiomyopathy, chronic renal insufficiency, perinatal cardiomyopathy, altitude cardiomyopathy, dilated cardiomyopathy, etc. all result in reduced left ventricular contractility and thus cause heart failure with contractile dysfunction, manifested by heart contractility, reduced cardiac ejection volume, and reduced ejection fraction. The present invention aims to provide a drug for preventing or reducing heart failure due to systolic dysfunction caused by reduced systolic function of the left ventricle.
Doxorubicin (DOX) is a broad-spectrum anthracycline that has been used to treat solid tumors in adults and children (e.g., breast cancer, ovarian cancer, and gastrointestinal malignancies) as well as hematological malignancies (e.g., lymphomas and leukemias). However, DOX is associated with cardiotoxicity and prolonged use of such drugs can cause serious side effects. There have been many studies suggesting that damage to cardiac function by anthracyclines may begin to progress from a relaxation function affecting the left ventricle to a decrease in ventricular contractility, ultimately leading to symptomatic heart failure. Doxorubicin-related myocardial toxicity is clinically manifested mainly by reduced left ventricular contractile function and left ventricular dilation.
Gastrodia elata is a traditional rare Chinese medicine in China, and is a dry tuber of Gastrodia elata (Gastrodia elaataBI.) belonging to genus Gastrodia of orchidaceae. The balison glycoside is one of the main active substances of rhizoma Gastrodiae, and has wide pharmacological effects such as brain protection, pain relieving, anti-tumor, and myocardial cell protecting effects.
The function of the gastrodia elata for preventing and treating heart failure is disclosed in the technical content, and the gastrodia elata is mainly an active ingredient gastrodin in the gastrodia elata for preventing and treating heart failure. The gastrodin and the balison compounds are effective active ingredients in the gastrodia elata, and the literature shows that the content of the gastrodin and the p-hydroxybenzyl alcohol in the gastrodia elata reaches 0.39%, and the total content of the balison compounds reaches 1.74% and far exceeds the content of the gastrodin. The invention researches show that 127mg/kg of the balison glycoside compound can be metabolized into 100mg/kg of gastrodin through dosage conversion of the balison glycoside compound into gastrodin in a mouse. By staining the mouse myocardial tissue H & E, the result of the mouse echocardiogram can find that the effect of 127mg/kg of the balisonoside B is better than that of 100mg/kg of gastrodin in reducing the inflammation corpuscles and bleeding points of the mouse myocardial tissue induced by doxorubicin and improving the abnormality of the heart structure of the mouse. Therefore, reasonable conjecture can be made that the effect of the monomer compound Balison B is better than that of gastrodin in an doxorubicin-induced cardiotoxicity experiment.
Based on the existing problems, the invention aims at exploring the application of the active ingredient of gastrodia elata, namely the barrison B and doxorubicin combined medicament in improving the heart failure caused by the contraction dysfunction of the left ventricle.
Disclosure of Invention
The invention aims to provide application of the balisonoside B in preparing a medicine for treating heart failure, and in vivo experiments show that myocardial cells in mice with independent administration of the doxorubicin show obvious cavitation-like degeneration, a large number of bleeding points, disordered muscle arrangement and increased inflammatory corpuscles, and the combined use of the balisonoside B can improve the lesion. The heart function detection of the whole animal shows that the function indexes such as the left ventricular Ejection Fraction (EF), the short axis shortening rate (FS), the left ventricular diastole and end systole anterior wall thickness (LVAWd and LVAWs), the left ventricular diastole and end systole posterior wall thickness (LVPWD and LVPWs) and the like of a tumor mouse injected with the doxorubicin for a long time are obviously reduced; the left ventricular diastole and end systole inner diameters (LVIDd and LVIDs) are obviously increased, the process can be reversed after the barrison glycoside B is combined with doxorubicin, the myocardial contraction function is improved, the left ventricular dilatation is lightened, and the medium dose effect of the barrison glycoside B is superior to that of low dose, high dose and gastrodin.
In order to achieve the technical purpose and the technical effect, the invention is realized by the following technical scheme:
use of balrison glycoside B in the preparation of a medicament for the treatment of heart failure.
Further, the application specifically includes: use of balisonoside B in the manufacture of a medicament for the treatment or prevention of anthracycline-induced left ventricular dilatation and contractile dysfunction heart failure.
Further, the medicament comprises effective dose of the barrison glycoside B and pharmaceutically acceptable pharmaceutical auxiliary agents.
Further, the effective dose is 63.5-190.5mg/kg.
Further, the effective dose is 127mg/kg.
Further, the application includes: reversing the course of significant decreases in left ventricular Ejection Fraction (EF), left ventricular short axis shortening (FS), left ventricular diastolic and end systolic anterior wall thickness (LVAWd and LVAWs), left ventricular diastolic and end systolic posterior wall thickness (LVPWd and LVPWs) functional index due to long-term doxorubicin injection by balrison B;
Reversing the process of significant elevation of left ventricular diastole and end systole inner diameters (LVIDd and LVIDs) due to prolonged doxorubicin injection, improved myocardial contractility and reduced left ventricular dilatation.
The invention has the beneficial effects that:
Previous studies have shown that gastrodin can inhibit ischemia reperfusion injury-induced apoptosis of mouse cardiomyocytes. However, the protective effect of gastrodin or balisonoside on doxorubicin-induced cardiotoxicity in mice has not been reported. Doxorubicin-induced cardiotoxicity in mice and ischemia reperfusion injury-induced apoptosis of cardiomyocytes in mice are two completely distinct events. Doxorubicin is a common chemotherapeutic agent that causes damage to cardiac function by gradually progressing from a relaxation affecting the left ventricle to a decrease in ventricular contractility, ultimately leading to symptomatic heart failure. It is clinically manifested mainly by a reduced function of left ventricular contraction and left ventricular dilation. The hypoxia reoxygenation injury model is an experimental model in which cells or tissues lack oxygen supply under hypoxia conditions, resulting in impaired energy metabolism and cell dysfunction. Subsequently, upon reoxygenation, cells may undergo oxidative stress and inflammatory reactions, resulting in damage to cells and tissues. Although doxorubicin and hypoxia-reoxygenation injury models are both associated with cell injury and death, their mechanisms of action and application scenarios are different. Doxorubicin is mainly used in cancer treatment, while the hypoxic reoxygenation injury model is used to study physiological and pathological changes of cells in hypoxic and reoxygenation environments. The invention mainly relieves heart failure caused by the reduction of the contraction function of the left ventricle and contraction dysfunction due to the induction of anthracyclines, the balrison B can effectively relieve the left ventricle expansion and contraction dysfunction, the heart contraction weakness, the heart blood discharge volume reduction and the ejection fraction reduction caused by doxorubicin, and the medium dose effect of the balrison B is superior to that of low dose, high dose and gastrodin.
Based on the synergistic effect of the barrison B and the doxorubicin, the invention discloses a more effective pharmaceutical composition for treating heart failure. Doxorubicin, a commonly used antitumor drug, has limited its clinical application due to its myocardial toxicity, although it has significant efficacy in the treatment of various malignant tumors. The introduction of the barrison glycoside B can effectively relieve the heart dysfunction induced by the doxorubicin. Studies have shown that Balison B not only produces synergistic therapeutic effects with doxorubicin, but also reduces the cardiotoxicity of doxorubicin through a variety of mechanisms (e.g., antioxidant, anti-inflammatory, anti-fibrotic, etc.). This new pharmaceutical combination provides a dual benefit: on the one hand, the anti-tumor effect of the doxorubicin is maintained; on the other hand, the heart is protected from its toxic effects.
The balrison B shows excellent effect in significantly improving left ventricular dilatation and contraction dysfunction caused by doxorubicin. In vivo experiments show that myocardial cells in HE staining of doxorubicin single administration group show obvious vacuolated degeneration, have a large number of bleeding points, have disordered muscle arrangement, have fracture of part of muscles and increase inflammation bodies, and the use of the barrison glycoside B can improve the lesion. The heart function detection of the whole animal shows that the function indexes such as the left ventricular Ejection Fraction (EF), the short axis shortening rate (FS), the left ventricular diastole and end systole anterior wall thickness (LVAWd and LVAWs), the left ventricular diastole and end systole posterior wall thickness (LVPWD and LVPWs) and the like of a tumor mouse injected with the doxorubicin for a long time are obviously reduced; the inner diameters (LVIDd and LVIDs) of the left ventricular diastole and the end systole are obviously increased, the process of the treatment of the barrison B combined with the doxorubicin can be reversed, the myocardial contraction function is improved, the left ventricular diastole is lightened, the medium dose effect of the barrison B is better than that of the low dose and the high dose, and the powerful support is provided for improving the safety of the doxorubicin.
Of course, it is not necessary for any one product to practice the invention to achieve all of the advantages set forth above at the same time.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed for the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of the experimental process of the animals of the balison B in preventing and treating anthracycline-induced left ventricular dilatation and contractility dysfunction heart failure;
FIG. 2 is a schematic representation of H & E staining of heart tissue of mice in a blank, doxorubicin-building block, doxorubicin + barrison B low dose, doxorubicin + barrison B medium dose, doxorubicin + barrison B high dose, doxorubicin + gastrodin, doxorubicin + dexrazoxane;
FIG. 3 (a) is a graph showing M-type ultrasound hearts recorded for each group of mice using a high resolution small animal dedicated ultrasound imaging system; (b) schematic of statistical analysis of the parameters.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The application of the balrison glycoside B in preparing the medicine for treating heart failure is provided.
In this embodiment, the application specifically includes: use of balisonoside B in the manufacture of a medicament for the treatment or prevention of anthracycline-induced left ventricular dilatation and contractile dysfunction heart failure.
In this embodiment, the medicament comprises an effective dose of barrison B and pharmaceutically acceptable pharmaceutical adjuvants.
In this example, the effective dose is 63.5-190.5mg/kg.
In this example, the effective dose is 127mg/kg.
In this embodiment, the application includes: reversing the course of significant decreases in left ventricular Ejection Fraction (EF), left ventricular short axis shortening (FS), left ventricular diastolic and end systolic anterior wall thickness (LVAWd and LVAWs), left ventricular diastolic and end systolic posterior wall thickness (LVPWd and LVPWs) functional index due to long-term doxorubicin injection by balrison B;
Reversing the process of significant elevation of left ventricular diastole and end systole inner diameters (LVIDd and LVIDs) due to prolonged doxorubicin injection, improved myocardial contractility and reduced left ventricular dilatation.
Example 2
Mouse heart tissue pathology test
Male C57 BL/6 mice were randomly divided into 7 groups: the control group, the doxorubicin making module group, the doxorubicin and barren glycoside B low dose group, the doxorubicin and barren glycoside B medium dose group, the doxorubicin and barren glycoside B high dose group, the doxorubicin and gastrodin group and the doxorubicin and dexrazoxane group. After the mice are freely adapted for one week, 3mg/ml DOX is injected intraperitoneally in the other groups except the blank control group according to the body (10 ml/kg) weight of physiological saline; the other groups were perfused with each dose of therapeutic drug according to body weight except for the blank control group and the model group, which were perfused with normal saline according to body weight (63.5 mg/kg for the low dose group of Barison glycoside B; 127mg/kg for the medium dose group of Barison glycoside B; 190.5mg/kg for the high dose group of Barison glycoside B; 100mg/kg for the gastrodin group; 25mk/kg for the right-hand rassin group). The first day of molding medicine starts abdominal cavity administration once every three days, the therapeutic medicine and molding medicine synchronously start administration, four consecutive days are a period, one period of administration treatment is performed every three days, four weeks are taken, and molding and administration are completed within 28 days. Mice were sacrificed after the end of the dosing cycle, heart tissue was fixed with 4% paraformaldehyde and histopathological examination (HE staining) was performed with prios.
Experimental results:
The pathological section detection result is shown in fig. 2, the myocardium of the blank group is arranged in order, and only a small amount of inflammation corpuscles and bleeding points are generated. The doxorubicin molding module has a large number of bleeding points and inflammatory corpuscles, and myocardial arrangement is relatively disordered. Compared with the doxorubicin molding group, the administration of the palmitoside B can obviously reverse the process, the myocardial arrangement of the medium dose group of the palmitoside B is tidy, bleeding points and inflammatory corpuscles are reduced, the effect is better than that of low dose, high dose and gastrodin, and the administration of the palmitoside B can almost recover to the level of the normal control group and the positive administration group.
The cardiomyocytes of the blank group, the doxorubicin+balrison glycoside B low dose group, the doxorubicin+balrison glycoside B medium dose group, the doxorubicin+balrison glycoside B high dose group, the doxorubicin+gastrodin group and the doxorubicin+dexrazoxane group have no obvious lesions, while the doxorubicin molding group cardiomyocytes show obvious vacuolated-like degeneration. The results of the echocardiography show that each dose of the balisonoside B can obviously improve the left ventricular dilatation and contraction dysfunction induced by the doxorubicin and the moderate dose effect of the balisonoside B is obviously superior to that of the low dose, the high dose and the gastrodin.
Example 3
Mouse heart function detection
After the end of the dosing period, mice were anesthetized with sodium pentobarbital at a dose of 50mg/kg. The anesthetized mice were examined and recorded under a high resolution special ultrasound imaging system for small animals and simultaneously analyzed for cardiac performance metrics such as EF% (left ventricular ejection fraction), FS% (left ventricular short axis systolic), left ventricular diastolic and end systolic anterior wall thickness (LVAWd and LVAWs), left ventricular diastolic and end systolic posterior wall thickness (LVPWd and LVPWs), and left ventricular diastolic and end systolic inner diameters (LVIDd and LVIDs).
Experimental results:
The M-type echocardiogram is shown in fig. 3, and the quantitative results of left ventricular ejection fraction and left ventricular short axis shrinkage are shown in fig. 3. The results show that compared with a blank control group, the left ventricular ejection fraction and the left ventricular short axis shrinkage rate of the doxorubicin manufacturing module are both obviously reduced; the functional indicators of left ventricular diastolic and end systolic anterior wall thickness (LVAWd and LVAWs), left ventricular diastolic and end systolic posterior wall thickness (LVPWd and LVPWs) and the like are significantly reduced; the left ventricular diastolic and end systolic inner diameters (LVIDd and LVIDs) are significantly elevated. The administration of the palmitoside B can obviously reverse the process, so that the doxorubicin-induced left ventricle expansion and contraction dysfunction of mice is improved, and the moderate dose effect of the palmitoside B is obviously superior to that of low dose, high dose and gastrodin.
The invention has better application prospect, can be widely applied to the heart failure with dysfunction of left ventricular expansion and contraction induced by anthracyclines, and provides a new treatment scheme for improving the survival quality of cancer patients. Meanwhile, the research result of the invention also provides important reference and guidance for the application of the natural plant extract in the aspect of protecting heart health.
The invention provides a novel pharmaceutical composition and research on action mechanism thereof, provides a novel solution for preventing and treating left ventricular dilatation and contraction dysfunction caused by chemotherapeutic drugs, and has good clinical popularization and application prospects.
The preferred embodiments of the invention disclosed above are intended only to assist in the explanation of the invention. The preferred embodiments are not exhaustive or to limit the invention to the precise form disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand and utilize the invention. The invention is limited only by the claims and the full scope and equivalents thereof.
Claims (6)
1. Use of balrison glycoside B in the preparation of a medicament for the treatment of heart failure.
2. The use according to claim 1, wherein: the application specifically comprises the following steps: use of balisonoside B in the manufacture of a medicament for the treatment or prevention of anthracycline-induced left ventricular dilatation and contractile dysfunction heart failure.
3. The use according to claim 1, wherein: the medicament comprises effective dose of the barrison glycoside B and pharmaceutically acceptable pharmaceutical auxiliary agents.
4. A use according to claim 3, wherein: the effective dose is 63.5-190.5mg/kg.
5. The use according to claim 4, wherein: the effective dose is 127mg/kg.
6. The use according to claim 1, wherein: the application comprises: reversing the process of significantly decreasing left ventricular ejection fraction, left ventricular short axis shortening rate, left ventricular diastolic and end systolic anterior wall thickness, left ventricular diastolic and end systolic posterior wall thickness functional index by barrison B due to long-term doxorubicin injection;
Reverse the process of the expansion of the left ventricle and the significant increase of the inner diameter at the end of systole caused by the long-term injection of the doxorubicin, improve the myocardial contraction function and relieve the expansion of the left ventricle.
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