Application of bletilla striata glycoside in preparation of medicine for treating or preventing heart failure and pulmonary edema

Abstract

The invention belongs to the field of respiratory and cardiovascular system disease treatment, and provides application of bletilla striata glycoside in preparation of a medicine for treating or preventing heart failure and pulmonary edema. It is found and proved for the first time that bletilla striata glycoside can remarkably improve heart function indexes of heart failure model mice, relieve pathological injuries of heart and lung tissue, effectively regulate and control arterial blood-gas indexes in a pulmonary edema model, reduce the level of inflammatory factors in alveolar lavage fluid and improve the pathological structure of lung tissue. The medicine can be applied in dosage forms such as oral administration, injection or spray, and the preferable dosage is 2.5-10 mg / kg. The invention provides a multi-target and multi-effect intervention strategy derived from a natural product for heart failure and concurrent or secondary pulmonary edema thereof, and has a remarkable clinical transformation prospect.

Description

Technical Field

[0001] This invention belongs to the field of treatment of respiratory and cardiovascular diseases. Specifically, this application provides the use of baicalein in the preparation of medicaments for treating or preventing heart failure and pulmonary edema. Background Technology

[0002] Heart failure and pulmonary edema are both major public health challenges worldwide: heart failure is characterized by high morbidity, high mortality, and a heavy healthcare burden. Although existing treatments, such as neurohormonal antagonists, cardiac resynchronization therapy, implantable cardioverter defibrillators (ICDs), and heart transplantation, have improved patient outcomes to some extent, significant limitations remain. Drug therapy often has limited efficacy and cannot reverse disease progression; device therapy and surgery have limited applicability, are highly invasive, and carry various risks of complications. Therefore, there is an urgent clinical need to develop safer, more effective, and universally applicable innovative treatment options to overcome current bottlenecks.

[0003] Pulmonary edema is a critical clinical syndrome leading to acute respiratory failure and multiple organ dysfunction, characterized by acute onset, rapid progression, and high mortality. Its main pathological changes include alveolar wall destruction, increased capillary permeability, inflammatory cell infiltration, and impaired gas exchange, often accompanied by systemic inflammatory responses. Current clinical treatment relies on empirical drugs and mechanical ventilation, which has limitations such as delayed intervention and numerous complications. Furthermore, it often focuses on reducing pulmonary edema without synergistically regulating blood gas parameters, lung function, inflammatory responses, and alveolar structure, thus limiting its effectiveness. A more precise and comprehensive intervention strategy is urgently needed.

[0004] Militarine is a component of the traditional Chinese medicine Bletilla striata (Bletilla striata). Bletilla striata Bletilla striata is one of the main bioactive components of Bletilla striata, belonging to the natural bibenzyl group. In the dried tubers of Bletilla striata, the content of bletilla striata glycoside is typically between 0.5% and 2%, making it an important indicator for evaluating the quality of the medicinal material. Recent studies have found that bletilla striata glycoside possesses significant anti-inflammatory, antioxidant, tissue repair-promoting, and vascular endothelial cell-protective functions, showing potential application value in the respiratory, digestive, and skin / mucous membrane injury repair fields. Existing research mainly focuses on optimizing its extraction process and exploring its in vitro pharmacological activity; however, its specific mechanism of action in acute lung injuries such as pulmonary edema, its multi-target regulatory effects, and its systemic efficacy evaluation remain insufficient, limiting its translation into clinical treatment. Therefore, further elucidating the role of bletilla striata glycoside in the pathological process of pulmonary edema is of significant research and development importance.

[0005] In view of this, this invention is the first to discover and confirm that militarine can exert a synergistic intervention effect on the complex pathological process of heart failure and pulmonary edema. It not only significantly improves cardiac function, but also simultaneously achieves multiple effects in a pulmonary edema model, including reducing pulmonary edema, improving lung function and arterial blood gas parameters, inhibiting inflammatory responses, and protecting the integrity of alveolar structure. This discovery indicates that militarine is a pleiotropic molecule with multi-target and multi-dimensional regulatory potential.

[0006] In summary, this invention provides a novel intervention strategy and potential therapeutic drug derived from natural products for the pathological state of heart failure and its complications or secondary pulmonary edema, demonstrating important clinical translational prospects. Summary of the Invention

[0007] This invention provides for the first time the use of baicalin in medicaments for the treatment or prevention of heart and lung diseases, particularly heart failure and pulmonary edema.

[0008] On the one hand, this application provides the use of bletilla striata glycoside in the preparation of medicaments for the treatment or prevention of heart failure and pulmonary edema.

[0009] Furthermore, the drug is an oral preparation.

[0010] Furthermore, baicalin is the only active ingredient in the drug.

[0011] In addition to oral formulations, the drug of this application can also be prepared into other dosage forms known in the art, such as injections or sprays, after verification of the selection of suitable excipients.

[0012] The drug may contain pharmaceutically acceptable excipients, preferably excipients for oral and injectable formulations, including but not limited to: solvents, solubilizers, pH adjusters, antioxidants, suspending agents, preservatives, fillers, coating agents, capsule shells, binders, lubricants, etc.

[0013] Furthermore, the minimum dosage unit of the drug can provide the recipient with a dose of 2.5-10 mg / kg of baicalin.

[0014] Furthermore, the minimum dosage unit of the drug can provide the recipient with a dose of 2.5 mg / kg of baicalin. Furthermore, the drug achieves one or more of the following effects: (1) Improve cardiac function (2) Improves cardiac pathological changes (3) Improve lung tissue pathological changes (4) Decrease the pH value in arterial blood gas parameters and increase the PaCO2 level in arterial blood gas parameters; (5) Increased arterial blood gas parameters PaO2, SaO2 and HCO3 - level; (6) Reduce the levels of IL-1β, IL-6 and TNF-α in bronchoalveolar lavage fluid.

[0015] Furthermore, the heart failure is pulmonary hypertension-related right heart failure.

[0016] Furthermore, the pulmonary edema described is high-altitude pulmonary edema.

[0017] On the other hand, this application provides the use of bletilla striata glycoside in the preparation of medicaments for the treatment or prevention of pulmonary inflammation or chronic obstructive pulmonary disease.

[0018] Furthermore, baicalin is the only active ingredient in the drug.

[0019] The baicalein described in this application is also known as "Bletilla striata glycoside", Militarin, or 1,4-bis[4-(glucoseoxy)benzyl]-2-isobutylmalate; its molecular formula is: C 34 H 46 O 17 Molecular weight: 726.719; CAS number: 58139-23-4; Chemical formula as follows:

[0020] This invention provides for the first time the application of bletilla striata glycoside in the treatment or prevention of heart and lung diseases, especially heart failure and pulmonary edema, offering new ideas for expanding the application scope of bletilla striata glycoside and for the prevention and treatment of these two types of diseases. Attached Figure Description

[0021] Figure 1 The effect of baicalein on cardiac function in mice with pulmonary hypertension-related right heart failure; Note: Results are expressed as mean ± standard deviation, n=6. Compared with the control group, ###P<0.001, ##P<0.01; compared with the model group, P < 0.05 P < 0.01, P < 0.001.

[0022] Figure 2 HE staining of cardiac tissue from mice with pulmonary hypertension-related right heart failure, using ginsenosides.

[0023] Figure 3 HE staining of lung tissue from mice with pulmonary edema by bletilla striata glycoside.

[0024] Figure 4The effect of baicalein on the levels of inflammatory factors in the BALF of mice with pulmonary edema; Note: Results are expressed as mean ± standard deviation, n=8, compared with the control group, ###P<0.001; compared with the model group, P < 0.01, P < 0.001. Detailed Implementation

[0025] Experimental drugs: Preparation of Bletilla striata glycoside: Take an appropriate amount of Bletilla striata glycoside powder and add it to 0.9% physiological saline. Vortex until the Bletilla striata glycoside powder dissolves.

[0026] Example 1: Establishment of a mouse model of pulmonary hypertension-related right heart failure and pulmonary edema SPF-grade male KM mice weighing 20±2 g were used in the experiment. Mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. They were housed under specific pathogen-free conditions at a constant temperature of 25±1℃ and relative humidity maintained between 55% and 65%, with a standard 12-hour light / dark cycle. Sufficient food and water were provided, ensuring all mice had free access to food. Animals were allowed acclimatization for 3 days prior to the experiment. All experimental procedures were approved by the Laboratory Animal Ethics Committee of the Chinese Academy of Medical Sciences.

[0027] Grouping: KM mice were randomly divided into 8 groups (n=14, 6 with heart failure, 15 with pulmonary edema): control group, single-drug group (DAN), pulmonary edema group (Model), positive control group (acetazolamide group, 50 mg / kg), low-dose group of bletilla striata (BJG-L) 2.5 mg / kg, medium-dose group of bletilla striata (BJG-M) 10 mg / kg, and high-dose group of bletilla striata (BJG-H) 20 mg / kg.

[0028] Administration: Mice in the control and model groups were administered 0.9% saline by gavage. The positive control group was administered 0.9% saline containing 50 mg / kg ACZ by gavage. Other treatment groups were administered 0.9% saline solution of either the alcoholic or aqueous extract of Panax notoginseng by gavage, once daily for 15 / 30 days.

[0029] Model Establishment: Mice were placed in a hypobaric hypoxic animal system (ProOx-830, Shanghai Tuowang Intelligent Technology). This system was equipped with a pump, chamber, piped oxygen supply, connecting pipes, and a communication system simulating a high-altitude environment. Temperature and humidity were maintained at 25°C and 55%, respectively. The altitude was set at 6000 meters, with an ascent rate of 20 m / s. Sodium lime was used during ascent to prevent excessive CO2 concentration. Food and water were freely available during hypobaric hypoxic exposure. Appropriate measures were taken to minimize the suffering of the experimental animals. Establishment of the pulmonary hypertension-related right heart failure model required 30 days; establishment of the pulmonary edema model required 15 days. After model establishment, the mice were removed from the experimental chamber and immediately anesthetized by intraperitoneal injection of sodium pentobarbital.

[0030] Example 2: Effects of Bletilla striata on cardiac function in mice with pulmonary hypertension-related right heart failure On day 29 of the model, after anesthesia, mice in the control group, model group, single-drug group, baicalein dosage group, and acetazolamide group were fixed in a supine position on a test plate. Chest hair was removed, and a suitable amount of coupling agent was applied. Echocardiography was performed using a 21 MHz echocardiogram (Vevo1100, Fujifilm Vision Acoustics, Toronto, Canada). Pulmonary artery acceleration time and pulmonary ejection time were measured using pulse wave and continuous Doppler modes. Right ventricular outflow tract measurements were performed using B-mode trajectory and continuous Doppler. Tricuspid annular plane systolic displacement, right ventricular diameter, and left ventricular end-diastolic diameter were measured using M-mode trajectory and continuous Doppler. Right ventricular output, right ventricular end-diastolic area, and right ventricular end-systolic area were calculated using formulas provided by high-resolution ultrasound.

[0031] Pulmonary hemodynamics and right ventricular function assessment (Figure 1) showed that pulmonary hypertension-related right ventricular failure was successfully induced in mice through hypobaric hypoxia. This was confirmed by the significant reductions in TAPSE, PAT, PAT / PET, and RVAW in the model group compared to the control group (p<0.001, p<0.001, p<0.01, p<0.001), indicating impaired cardiac structure and function. After treatment with BJG-L, BJG-M, BJG-H, and ACZ, all measured parameters—TAPSE and RVAW—were significantly improved compared to the model group (p<0.001). PAT and PAT / PET also showed a trend of improvement: the PAT value in the BJG-M / H group was significantly lower than that in the model group (p<0.01, p<0.05); and the PAT / PET ratio in BJG-M was also significantly lower than that in the model group (p<0.05). Therefore, baicalin can improve cardiac function in mice with heart failure.

[0032] Example 3: Effects of Bletilla striata glycosides on cardiac pathological changes in mice with pulmonary hypertension-related right heart failure Mouse heart tissue was collected, rinsed with physiological saline, fixed in 4% formaldehyde buffer, and stored at room temperature. Finally, the heart tissue was dewaxed, hydrated, and stained with hematoxylin and eosin. Heart tissue damage was confirmed under a microscope.

[0033] Figure 2 In this study, HE staining was used to detect pathological changes in the heart of mice. In the C and DAN groups, neoplasms in the heart tissue were regularly arranged, with intact nuclei and no obvious inflammatory infiltration. However, in the model group, inflammatory infiltration in the heart tissue was significantly increased, and myocardial fibers were disordered, suggesting significant myocardial damage in mice with heart failure. BJG administration to all groups and the ACZ group effectively improved the pathological changes in the myocardium.

[0034] Example 4: Effects of Bletilla striata glycosides on pathological changes in lung tissue of mice with pulmonary edema Mouse lung tissue was collected, rinsed with physiological saline, fixed in 4% formaldehyde buffer, and stored at room temperature. Finally, the lung tissue was dewaxed, hydrated, and stained with hematoxylin and eosin. Lung tissue damage was confirmed under a microscope.

[0035] Figure 3 The results showed that the alveolar structure was normal in the control group and the single-drug group. In contrast, the lung tissue in the model group showed severe pathological damage, characterized by extensive alveolar hemorrhage, alveolar wall thickening, accompanied by inflammatory cell infiltration and edema. Treatment with different doses of BJG and ACZ effectively alleviated these pathological changes.

[0036] Example 5: Effects of Bletilla striata glycosides on arterial blood gas parameters in mice with pulmonary edema After anesthesia, the mouse's thoracic cavity was flattened and protruded. The left hand gently pinched the mouse's abdominal skin as a point of leverage. Holding a 1 mL syringe with the needle bevel facing upwards at an angle of approximately 10-20° to the abdomen, the syringe was inserted at the junction of the xiphoid process and the left costal arch to collect blood from the heart. The blood was collected into a standard sampling tube containing lithium heparin. Then, 0.1 mL of blood was measured using a blood gas analyzer (EPOC, Siemens Healthcare) to obtain oxygen partial pressure, pH, carbon dioxide partial pressure, and bicarbonate.

[0037] Figure 4Arterial blood gas analysis was performed in this study to detect the protective effect of baicalein on PE mice. As shown in the figure, the high pH and low PaCO2 levels caused by hypoxia and hypoxia indicate alveolar hyperventilation (p<0.05). BJG-M / H significantly improved the hypoxia-induced increase in arterial blood pH (p<0.01), while the PaCO2 levels in each BJG dose group were significantly reduced (p<0.05, p<0.001, p<0.001). Impaired pulmonary gas exchange caused by exposure to hypoxia and hypoxia can lead to systemic arterial hypoxemia, manifested as low PaO2 in arterial blood gas. The PaO2 in the Model group was lower than that in the C group (p<0.001), while the baicalein groups improved the PaO2 in the arterial blood of mice (p<0.05, p<0.001, p<0.001). Alveolar HCO3 in the Model group - The decreased levels may be attributed to bicarbonate loss due to diuresis secondary to hypoxia exposure (p<0.001). HCO3 levels in each group of baicalein were... - The levels were significantly elevated (p<0.001, p<0.05, p<0.01).

Claims

1. Application of baicalin in the preparation of drugs for the treatment or prevention of heart failure and pulmonary edema.

2. In the application according to claim 1, baicalin is the only effective component in the drug.

3. The application according to claim 1, wherein the drug is an oral preparation.

4. The application according to any one of claims 1-3, wherein the minimum dose unit of the drug can provide a dose of 2.5-10 mg / kg of bletilla striata glycoside to the recipient.

5. In the application according to claim 4, the minimum dose unit of the drug can provide the recipient with a dose of 2.5 mg / kg of baicalin.

6. In the application according to any one of claims 1-5, the drug achieves one or more of the following effects: (1) Improves cardiac function; (2) Improves cardiac pathological changes; (3) Improves pathological changes in lung tissue; (4) Decrease the pH value in arterial blood gas parameters and increase the PaCO2 level in arterial blood gas parameters; (5) Increased arterial blood gas parameters PaO2, SaO2 and HCO3 - level; (6) Reduce the levels of IL-1β, IL-6 and TNF-α in bronchoalveolar lavage fluid.

7. The application according to claim 1, wherein the heart failure is pulmonary hypertension-related right heart failure.

8. The application according to claim 1, wherein the pulmonary edema is high-altitude pulmonary edema.

9. The use of baicalin in the preparation of drugs for the treatment or prevention of pulmonary inflammation or chronic obstructive pulmonary disease.

10. In the application according to claim 9, baicalin is the only active ingredient in the drug.

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