Application of terazosin in preparation of product for preventing and / or treating aortic dissection

Abstract

The invention discloses application of terazosin in preparation of drugs or health care products for preventing and / or treating aortic dissection, and relates to the technical field of medicines. Animal test and clinical research are carried out on the current clinical common drug terazosin, and the result shows that the small dose of terazosin can effectively prevent and treat the aortic dissection, so that important technical support is provided for early treatment or prevention of aortic related diseases. Experimental and clinical research results also prove that the terazosin with the dosage of 0.5 mg has a good effect in the aspects of improving the vascular elasticity and reducing the vascular pulse wave conduction velocity, the dosage can be greatly reduced, the medication cost can be saved, and the medical burden of a patient can be relieved. Meanwhile, due to the fact that the dosage of terazosin used in the human body is extremely low, adverse side effects related to terazosin are basically eradicated.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the use of terazosin in the preparation of pharmaceutical products for the prevention and / or treatment of aortic dissection. Background Technology

[0002] Aortic dissection (AD) is a fatal cardiovascular disease that severely impacts health, with a mortality rate increasing by 1-2% per hour after the onset of symptoms. The aortic diameter increases with age due to long-term blood flow and pathological factors such as genetics and inflammation. Uncontrolled increases in aortic diameter can lead to aortic aneurysms and even AD. The primary cause is medial degeneration, including changes in the extracellular matrix such as the breakage of elastic fibers and collagen, loss of smooth muscle cells, and infiltration of inflammatory cells. This process is accompanied by vascular remodeling and impaired or lost arterial elasticity. Impaired arterial elasticity not only exacerbates the burden of hypertension on the vessel wall but can also lead to micro-damage to the vessel wall and smooth muscle dysfunction, resulting in AD.

[0003] Terazosin (TZ), a highly selective α1-adrenergic receptor antagonist, treats benign prostatic hyperplasia primarily through blocking α1 receptor subtypes on the bladder neck and prostatic stromal smooth muscle, significantly reducing urethral resistance and improving urodynamic parameters. Simultaneously, due to the low density of α1 receptors in the bladder body, this drug can precisely relieve lower urinary tract obstruction without affecting detrusor muscle contraction function. Furthermore, terazosin competitively inhibits α1 receptors in vascular smooth muscle, effectively reducing peripheral vascular resistance and producing a dose-dependent hypotensive effect. The chemical structure of this active ingredient is clearly defined as (4-(4-amino-6,7-dimethoxyquinazoline-2-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methyl ketone (molecular formula C). 19 H 25 N5O4, with its specific receptor binding properties and tissue distribution differences, constitutes the molecular basis for its dual therapeutic effect. Its chemical structure is as follows: .

[0004] Tz, an α1-adrenergic receptor antagonist, has been widely used to treat hypertension and benign prostatic hyperplasia (BPH). Recent studies have found that, in addition to its antihypertensive effect, Tz exhibits antioxidant, anti-inflammatory, and anti-apoptotic effects at low doses (2.5 nM to 0.5 μM in vitro). Activation of Tz / Pgk1 promotes ATP production, autophagy to degrade pathological substances, and enhances glycolysis in the digestive tract, demonstrating anti-inflammatory effects. Tz activation of Pgk1 and Hsp90 to promote stress resistance has reduced organ damage and improved survival rates in rodent models of stroke and sepsis. These findings suggest that Tz possesses a dual mechanism of regulating metabolic homeostasis and antagonizing α-adrenergic receptors, potentially serving as a treatment for AD. Summary of the Invention

[0005] To overcome the shortcomings of the above-mentioned technologies, the purpose of this invention is to provide an application of terazosin in the preparation of drug products for the prevention and / or treatment of aortic dissection, thereby opening up avenues for clinical practice to intervene in the early stages of vascular degenerative changes that lead to the development of aortic dissection.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The use of terazosin in the preparation of products for the prevention and / or treatment of aortic dissection.

[0007] Application of low-dose terazosin in the preparation of products for the prevention and / or treatment of aortic dissection.

[0008] As a preferred embodiment, the terazosin is terazosin or its pharmaceutical salt or its solvate.

[0009] Furthermore, the pharmaceutical salt is one or more of the following: hydrochloride, phosphate, benzenesulfonate, methanesulfonate, sulfate, and nitrate of terazosin.

[0010] Furthermore, the solvate is a hydrate of terazosin or its pharmaceutical salt.

[0011] Furthermore, the hydrate is a monohydrate or a dihydrate.

[0012] Furthermore, the solvate of terazosin is terazosin hydrochloride dihydrate.

[0013] As a preferred option, the product is a health supplement or a medicine.

[0014] As a preferred embodiment, the product is a drug, the subject is a human, the dosage is 0.5~1 mg / day / person based on the active ingredient terazosin, and the route of administration is at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection or oral administration.

[0015] Furthermore, the dosage of the drug is 0.5 mg / day / person based on the active ingredient terazosin.

[0016] As a preferred embodiment, the product is a drug, the subjects are mice, and the dosage is 5-10 μg / 20 g / day based on the mouse's body weight and the active ingredient of terazosin. The route of administration is intraperitoneal injection.

[0017] Furthermore, the dosage of the drug is 10 μg / 20 g / day based on the mouse body weight and the active ingredient of terazosin.

[0018] As a preferred embodiment, the terazosin reduces vascular stiffness and improves vascular structural stability by reducing damage to the vascular wall and breakage of elastin, thereby reducing arterial stiffness and vascular pulse wave conduction velocity, and thus achieving the prevention and / or treatment of aortic dissection.

[0019] This invention also provides the use of terazosin in the preparation of products for the prevention and / or treatment of loss of arterial elasticity and increased arterial stiffness, wherein the terazosin is terazosin or its pharmaceutical salt or its solvate.

[0020] The present invention also provides a medicament for the prevention and / or treatment of aortic dissection, wherein the active ingredient of the medicament comprises terazosin or its pharmaceutical salt or its solvate, and the dosage is 0.5~1 mg / day / person based on the active ingredient of terazosin.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention, through animal experiments and clinical studies on the commonly used clinical drug terazosin, has found that low doses of terazosin can effectively prevent and treat aortic dissection, providing important technical support for the early treatment or prevention of aortic-related diseases. The experimental and clinical research results of this invention also demonstrate that 0.5-1 mg doses of terazosin are effective in improving vascular elasticity and reducing vascular pulse wave velocity. Compared with the currently conventional dosage of 2-5 mg terazosin, this significantly reduces the dosage, saves on medication costs, and alleviates the medical burden on patients. Furthermore, because the dosage of terazosin used in humans is extremely low, the occurrence of adverse side effects associated with terazosin is virtually eliminated. Attached Figure Description

[0022] Figure 1 The figures show the blood pressure and ultrasound results of the aortic dissection mouse model in Experiment Example 1 of this invention. Figure 2 This is a graph showing the relationship between pulse wave conduction velocity in patients with aortic dissection and healthy individuals observed in a clinical study in Experimental Example 2 of this invention. Figure 3This is a schematic diagram of the nomogram model based on Logistic regression analysis in Experiment Example 2 of this invention; Figure 4 for Figure 3 ROC curve validation results of the midline graph model; Figure 5 This is a graph showing the relationship between the pulse wave conduction velocity of the aortic dissection mouse model and the control group in the animal experiment study of Experiment Example 2 of the present invention; Figure 6 This is a diagram showing the results of reducing the incidence of aortic dissection in experimental animals using a low dose of terazosin in Experimental Example 3 of this invention. Figure 7 This is a graph showing the survival rate analysis results of mice in each group in Experiment Example 3 of the present invention; Figure 8 This is a graph showing the morbidity analysis results of mice in each group in Experiment Example 3 of this invention; Figure 9 This is a graph showing the relationship between low-dose terazosin and the reduction of pulse wave conduction velocity in experimental animals in an animal model in Experimental Example 3 of the present invention; Figure 10 This is a schematic diagram of staining after a small dose of terazosin improved the elastic fiber state of vascular tissue in experimental animals in Experiment Example 3 of the present invention; Figure 11 This is a bar chart showing the reduction in pulse wave conduction velocity in test patients by a low dose of terazosin in Experiment Example 3 of this invention; In the results analysis, * represents P<0.1, ** represents P<0.05, *** represents P<0.01, and **** represents P<0.0001. Detailed Implementation

[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0024] The following experimental examples will further analyze and illustrate the content of this invention.

[0025] Terazosin, an α1-adrenergic receptor antagonist, has been widely used to treat hypertension and benign prostatic hyperplasia. Recent studies have found that, in addition to its antihypertensive effect, terazosin, at low doses (2.5 nM-0.5 μM in vitro), possesses antioxidant, anti-inflammatory, and anti-apoptotic effects. Studies have shown that terazosin can also improve the biomechanical properties of blood vessels in vivo, reducing arterial stiffness and enhancing vascular elasticity. Notably, terazosin's effect on improving arterial stiffness is not limited to lowering blood pressure; research indicates that aortic dissection (AS) occurs before hypertension, and its mechanism of action may also involve improving endothelial function, reducing inflammatory responses, and influencing the proliferation and migration of vascular endothelial cells (VSMCs). Therefore, terazosin may further reduce arterial stiffness and the risk of aortic dissection by improving the structure and elasticity of the vascular wall.

[0026] In the specific experimental examples of this invention, unless otherwise specified, terazosin hydrochloride dihydrate was used for the experiments.

[0027] In the specific clinical examples of this invention, unless otherwise specified, terazosin was used for clinical observation based on the daily dose of its active ingredient. The effective dose of terazosin for human use can be adjusted according to various factors such as weight, age, and disease state. In this invention, the daily dose for adults is 0.5-1 mg, which is comparable to the dose used in the specific experimental studies of this invention, but significantly lower than the currently routine clinical dose of terazosin. Furthermore, terazosin can be administered via various routes, such as oral, injection, and transdermal. As a drug for early intervention in vascular elasticity, oral administration is optimal and is consistent with existing routes of administration. Once the route of administration is determined, the choice of drug formulation is straightforward. In animal experiments, due to the close anatomical location of the esophagus and aorta, gavage may lead to aortic rupture under external force, affecting the experimental results; therefore, intraperitoneal injection was chosen, with a daily dose of 5-10 μg / 20 g / day.

[0028] The dosage of terazosin is 0.5-1 mg / day (human) or 5-10 μg / 20 g / day (mouse). This dosage range was determined by the interspecies dose conversion formula and has been experimentally verified to have a good risk-benefit ratio.

[0029] Dosage determination is based on the following description: 1. Determine the clinical dosage (0.5~1mg / day) The dosage range of terazosin for human administration in this invention was determined based on the following considerations: First, pharmacologically, referencing the starting dose (1 mg / day) for the approved indication (benign prostatic hyperplasia), which has shown good safety in long-term clinical use; second, considering the risk-benefit balance: using a dosing regimen lower than the conventional antihypertensive dose (2-5 mg / day) aims to achieve vascular protection while minimizing excessive blood pressure fluctuations. Finally, considering the optimization of the therapeutic window, this dosage range is located in the rising plateau phase of the dose-response curve, ensuring efficacy while maintaining a sufficient safety margin; specifically, 0.5 mg / day / person was used in the trial.

[0030] 2. Dosage conversion for animal experiments (5-10 μg / day / 20g mouse) The equivalent dose in mice was determined using the following standardized procedure: body surface area normalization, and dose conversion based on body surface area according to the FDA-recommended interspecies dose conversion guidelines. The conversion formula used was the standard interspecies dose conversion formula: Animal equivalent dose (mg / kg) = Human dose (mg / kg) × (Human Km coefficient / Animal Km coefficient); The Km coefficient for humans was 37, and for mice it was 3. Specific calculations: For humans, 0.5~1mg / day (based on a 60kg adult) is equivalent to 0.008~0.017mg / kg; The equivalent dose for mice is 0.008~0.017 × (37 / 3) = 0.10~0.21 mg / kg; The daily dosage, converted to 20g mice, is 2-4μg. Considering the differences in bioavailability, the final dosage range was determined to be 5-10μg / day. In the specific experiment, 10μg / 20g mice / day was used.

[0031] As one of the validation protocols, the efficacy evaluation of drugs for preventing aortic dissection is clinically assessed by measuring pulse wave velocity (PWV) to evaluate the degree of aortic remodeling and by observing the morphology and structure of the aorta using imaging equipment such as ultrasound. The most commonly used method for assessing arterial elasticity is pulse wave velocity (PWV). PWV refers to the propagation speed of the pressure wave perpendicular to the aortic wall generated after each cardiac ejection, traveling from proximal to distal along the aorta during blood flow. Commonly used clinical methods include carotid-femoral pulse wave velocity and brachial-ankle pulse wave velocity (BaPWV), with BaPWV being a frequently used indicator. As a non-invasive method for assessing the degree of arteriosclerosis, BaPWV is a useful biomarker in the management of cardiovascular diseases and / or their risk factors related to loss of arterial elasticity and has been widely used clinically to evaluate the elasticity and compliance of large arteries.

[0032] As the second validation scheme, the efficacy evaluation of drugs for preventing aortic dissection is to assess the degree of aortic remodeling in animal models by measuring pulse wave conduction velocity and to observe the morphology and structure of the aorta using animal ultrasound equipment.

[0033] As the third validation protocol, the efficacy of drugs for preventing and treating aortic dissection is evaluated by assessing the incidence rate of a mouse aortic dissection model in animal models through morbidity and survival curves.

[0034] As the fourth validation protocol, the efficacy of drugs for preventing aortic dissection was evaluated in the experiment by assessing the integrity of arterial tissue through HE and EVG staining.

[0035] Terazosin used in the following experiments was in its hydrochloride dihydrate form. It should be noted that different salt forms and solvates (such as sulfates, phosphates, or free bases) of the active pharmaceutical ingredient primarily affect its physicochemical properties (such as solubility, crystallinity, and stability), but have no substantial impact on its specific binding affinity to α1-adrenergic receptors and the resulting biological activity. Based on established consensus in drug development (referencing ICH Q6A guidelines) and the structure-activity relationship principles of receptor pharmacology, any pharmaceutically acceptable salt form of terazosin is expected to exhibit in vitro and in vivo pharmacodynamic characteristics equivalent to those of the hydrochloride dihydrate at equivalent molar doses, including but not limited to smooth muscle relaxation effects, peripheral vascular resistance modulation, and the resulting therapeutic benefits.

[0036] Experimental Example 1: Construction of a Mouse Aortic Dissection Model A mouse aortic dissection model was established using β-aminopropionitrile fumarate (BAPN). Normal male C57 mice were randomly divided into two groups: a normal control group (CON group) and an aortic dissection model group (BAPN group). Mice in the BAPN group were routinely bred for 3 weeks, and when they reached 8-10g in weight, they were administered BAPN via drinking water at a concentration of 0.6g per 100mL for 4 weeks to induce aortic dissection. Mice in the control group (CON group) were bred for 3 weeks and, when they reached 8-10g in weight, drank water without BAPN. Four weeks after modeling, blood pressure was measured and vascular ultrasound was performed. The diameters of the ascending, arching, and descending portions of the aorta were measured to determine the extent of vascular lesions and to observe for aortic lesions such as intimal flap movement and vascular dilation. The results are shown in the attached table. Figure 1 .

[0037] 1. Blood pressure detection in mice Mice were placed in a restraint unit on a warm, quiet, temperature-controlled experimental platform set at 38°C, ensuring the mice remained at a constant temperature and did not move. The sphygmomanometer's protective sleeve was gently wrapped around the mouse's tail, ensuring a comfortable fit and accurate positioning to prevent it from being too tight or too loose, which could affect the measurement results. Next, the sphygmomanometer was activated. The instrument gradually applied pressure to the cuff, simulating blood flow occlusion, and then gradually released the pressure. By observing the changes in the tail pressure waveform, the instrument could calculate the mouse's systolic blood pressure, diastolic blood pressure, and mean arterial pressure. Maintaining the mouse's rest during the measurement process is crucial. Each mouse was typically measured 15 times, and the blood pressure data for each measurement was recorded to improve the accuracy and reliability of the results.

[0038] 2. Ultrasound detection of mouse blood vessels Aortic ultrasound examination was performed on mice using a portable digital color ultrasound diagnostic instrument and a small animal ultrasound probe. Mice were first anesthetized with isoflurane and placed supine on a 38°C constant-temperature platform. Hair was removed from the mouse's chest with depilatory cream, and the limbs were extended and fixed to the experimental table. A small animal-specific ultrasound probe was gently placed on the left side of the mouse's chest, and an appropriate probe angle was selected to obtain clear images of the aorta, including transverse and longitudinal sections of the ascending, arched, descending, and abdominal portions. The structure and blood flow of the mouse aorta were observed in real-time using color Doppler ultrasound imaging. First, the diameter of the aorta was measured using two-dimensional ultrasound imaging. Multiple measurements were taken at different locations in the aorta to obtain accurate vessel diameter data and assess the degree of aortic dilation. In addition, morphological changes in the aortic wall were observed in detail, especially focusing on early signs of aortic dissection, such as aortic dilation, presence or absence of an intimal flap, tearing of the aortic wall, and blood flow entering the dissected lumen to form a pseudo-lumen. By observing these abnormal images, it was determined whether aortic dissection had occurred in the mouse, and the size and location of the dissection.

[0039] like Figure 1 As shown in figure a, in mice with aortic dissection induced by BAPN, the aorta showed significant dilation and lesions, and the aortic diameter was significantly higher than that in the control group. Figure 1 As shown in b, BAPN-induced increases in systolic blood pressure, diastolic blood pressure, and mean arterial pressure in mice were significantly higher than those in the control group. This indicates that the aortic dissection model mouse was successfully established.

[0040] Experimental Example 2: Correlation Analysis between Vascular Stiffness and Aortic Dissection I. The Relationship Between Arterial Stiffness and the Occurrence of Aortic Dissection The brachial-ankle pulse wave velocity (BaPWV) of patients presenting with chest and abdominal pain was measured using the OMRON (BP-203 RPEIII VP-1000) arteriosclerosis detector to assess aortic elasticity and its correlation with the occurrence of aortic dissection. The results are shown in [Table missing]. Figure 2 .

[0041] like Figure 2 As shown in a, the arterial stiffness of patients with aortic dissection is significantly higher than that of other patients, and as... Figure 2 As shown in b, the incidence of aortic dissection was significantly increased in patients with arterial stiffness significantly higher than normal. The results indicate a close association between increased arterial stiffness and the formation of aortic dissection. Loss of arterial elasticity is closely related to structural and functional changes in the arterial wall, particularly the destruction of elastic fibers and alterations in the matrix, which may make the aorta more susceptible to injury and rupture. Loss of arterial elasticity reflects increased vessel wall stiffness, and changes in hemodynamics may promote rupture of the aortic intima, further leading to aortic dissection.

[0042] II. The predictive role of arterial stiffness in the occurrence of aortic dissection The foregoing analysis shows a significant correlation between changes in arterial stiffness and the occurrence of aortic dissection. This suggests that arterial stiffness is not only an important risk factor for aortic dissection but may also serve as a potential early warning indicator. In particular, for patients with known high-risk factors (such as hypertension, family history, etc.), regular monitoring of arterial stiffness levels may help detect potential aortic dissection risks early.

[0043] The following method is used to construct a nomogram model based on logistic regression analysis: First, variables with statistical significance (P<0.05) from the univariate analysis were included in a multivariate logistic regression analysis to identify independent predictors such as arterial stiffness (baPWV), history of hypertension, and age. Then, using the "rms" package in R 4.2.0, the regression coefficients of each predictor were converted into an intuitive scoring system of 0-100 points, with BaPWV given the highest weight due to its highest contribution. Different values ​​of each variable correspond to specific score values. After summing all variable scores to obtain a total score, the predicted probability of an individual developing aortic dissection can be directly read using the bottom total score-risk probability conversion scale.

[0044] The above steps construct a nomogram model based on logistic regression analysis, which quantitatively predicts the probability of aortic dissection in patients by comprehensively considering clinical risk factors and arterial stiffness. Figure 3 As shown, this nomogram model combines multiple factors, including BMI, pulse rate, PWV, AST, ALT, creatinine, NTproBNP, and the presence or absence of hypertension, coronary heart disease, and diabetes. It calculates the probability of aortic dissection for each patient by summing the scores of these variables. The nomogram model predicting the severity of aortic dissection was validated using ROC curves, and the results are as follows: Figure 4As shown, the AUC reached 0.85, the sensitivity was 0.24, and the specificity was 0.80, indicating that arterial stiffness can be used to effectively predict the risk of aortic dissection.

[0045] III. Mouse Experiment Validation The mouse aortic dissection model constructed in Experiment 1 was used, and normal mice were used as the normal control group. PWV was detected in both the normal control group (CON group) and the aortic dissection model group (BAPN group).

[0046] Mouse PWV detection method Pulse wave velocity (PWV) in mice was assessed using a non-invasive hemodynamic monitoring system. The procedure was as follows: After isoflurane inhalation anesthesia, the experimental animals were placed in a supine position and fixed on a 38°C constant-temperature operating table. Conductive gel was applied to the limbs and connected to ECG monitoring electrodes, and ECG signals in standard limb leads were recorded simultaneously. A high-frequency ultrasound probe (20MHz) was used for vascular localization and signal acquisition: pressure waveforms were acquired in the thoracic descending aorta and abdominal aorta regions, with stable waveforms continuously acquired for at least five cardiac cycles at each site, while simultaneously recording the ECG signal. The vascular distance (L) between the two detection sites was then precisely measured as the basis for PWV calculation. The time for the Q wave to travel to the chest on the ECG was defined as T. n The time it takes for the signal to travel to the abdomen is X. n The difference is the time it takes for the wave to travel from the chest to the abdomen (X). n -T n Let n be the number of repeated cardiac cycles, and take their mean. The formula for calculating the PWV of mice is as follows: PWV (m / s) = L / Average (X n -T n ).

[0047] The results of mouse PWV detection are shown in the figure. Figure 5 .

[0048] like Figure 5 As shown, the PWV value of BAPN-induced mice was significantly higher than that of the control group, and the arterial stiffness was significantly increased, further confirming that the occurrence of aortic dissection is related to the damage or loss of arterial elasticity and the increase in arterial stiffness.

[0049] Experimental Example 3: Terazosin for the prevention and treatment of aortic dissection I. Mouse Experiment 1. Grouping mice and constructing the model A mouse aortic dissection model was constructed using the method described in Example 1. Normal mice were used as a control group (CON group), and a treatment group (BAPN+TZ group) was established: male C57 mice, aged 3 weeks, were administered via drinking water at 8-10g, with 0.6g of β-aminopropionitrile (BAPN) added to every 100mL of water. Terazosin was administered daily for four weeks. Terazosin was administered intraperitoneally by dissolving TZ powder in sterile, enzyme-free water to prepare a 1mg / ml solution. The solution was then injected intraperitoneally daily at a dose of 10μg of active ingredient per 20g of mouse body weight. The condition of each group of mice was observed daily. If signs of dissection such as ischemia appeared, the aortic wall was surgically removed, and the survival rate and morbidity were monitored. After four weeks, vascular function tests were performed on each group. The diameters of the ascending, arched, and descending portions of the aorta were measured, and peripheral venous blood was collected from the mice, and the aortic wall was surgically removed for further analysis.

[0050] 2. Calculation of morbidity and survival curves in mice The morbidity rate of mice in each group was continuously monitored for four weeks after the start of drug administration. The morbidity rate was calculated using the following formula: Incidence rate = (number of cases / total number of initial cases) × 100%.

[0051] Survival curves (Kaplan-Meier) were plotted for each group of mice based on the incidence rate to compare survival differences between groups (Log-rank test, etc.). In the survival curve plotting, the event is death. The cumulative survival probability S(t_i) = S(t_{i-1}) × (1-(d_i / n_i)) was calculated daily. Here, t_i represents the i-th time point. These time points are arranged sequentially (t1, t2, t3, ...), representing the specific moments when at least one event (such as death) occurred in the study. S(t_i): Represents the cumulative survival probability at time point t_i. It represents the estimated probability that a study subject is still alive from the start of the study to time point t_i. S(t_{i-1}): Represents the cumulative survival probability at the previous time point t_{i-1}. This is the basis for calculating the survival probability at the current time point. d_i: Represents the number of deaths at time point t_i. It refers to the number of study subjects who experienced the endpoint event of our interest at exactly this time point. n_i: Represents the number of individuals in the "risk set" starting at time point t_i. It refers to the number of study subjects who have not yet experienced an event (i.e., are still "at risk") and have not been censored before time point t_i. The step-shaped curve connects the survival probabilities at each time point.

[0052] 3. Vascular function testing The methods for ultrasound and blood pressure detection in mice are the same as in Experiment Example 1, and the methods for PWV detection in mice are the same as in Experiment Example 2.

[0053] 4. Immunohistochemical staining detection 4.1 Mouse tissue collection and processing Mice were anesthetized by intraperitoneal injection of 3% pentobarbital at a dose of 10 μL / g based on mouse body weight. After anesthesia, blood was collected from the eyeballs. Heparin was instilled into EP tubes beforehand, and 1 mL of blood was collected from the mice. The blood was centrifuged at 2000 rpm for 20 min, and the supernatant serum was collected and stored at -80℃ for subsequent experiments.

[0054] The mice were then opened along the midline of the chest and abdomen, and one renal artery was freed, cut open, and physiological saline was injected into the left ventricle to flush the entire vascular lumen. The entire aorta was dissected under a surgical stereomicroscope, and its ascending part, arch, branches of the arch, descending part, abdomen, and iliac artery were completely preserved. The specimens were preserved by soaking in formalin for subsequent experiments.

[0055] Remove the tissue block and immerse it sequentially in a gradient of increasing alcohol concentrations (e.g., 70%, 80%, 95%, 100% alcohol) to thoroughly remove moisture. After dehydration, soak the tissue in a clearing agent (e.g., xylene). Then remove the tissue and place it in molten paraffin at 60-62°C for two separate infusions, each lasting 60-120 minutes, for a total of 2-4 hours. The specific time should be adjusted according to the tissue type and size, allowing the paraffin to fully penetrate every intercellular space. Place the paraffin-soaked tissue block into an embedding cassette, inject fresh molten paraffin, and allow it to cool and solidify into a hard wax block. Use a microtome to cut the wax block into extremely thin slices (typically 4-6 micrometers thick). Spread the cut wax strips in warm water, then place them on a glass slide and air-dry or bake them to ensure the tissue slices adhere firmly to the slide, obtaining tissue sections.

[0056] 4.2 Hematoxylin and Eosin (HE) staining The sections were dewaxed with xylene solution and then gradually hydrated using ethanol solutions of varying concentrations. They were then immersed in hematoxylin staining solution for 5–10 minutes, followed by washing and differentiation, resulting in deep blue or purple nuclei. Next, the sections were immersed in eosin solution for 2–5 minutes, staining the cytoplasm and connective tissue to pink to red. They were then dehydrated using a gradient of ethanol solutions, cleared with xylene, and finally mounted with a mounting medium and covered with a coverslip. HE staining clearly reveals the nuclei, cytoplasm, collagen fibers, and other structures of the aortic wall, facilitating observation of the overall tissue morphology and cell distribution.

[0057] 4.3. Elastin Van Gieson (EVG) staining The sections were dewaxed using xylene and hydrated using a gradient ethanol solution. They were then immersed in EVG staining solution, where elastic fibers were specifically stained black or dark blue. Acid Red in Van Gieso solution stained collagen fibers red. The samples were then dehydrated and cleared using xylene and ethanol. Finally, they were mounted with mounting media and coverslips. EVG staining, by specifically marking elastic fibers, makes them appear dark in tissue sections, thus identifying the elastic structures of the aortic wall, which is particularly important in pathological conditions such as arteriosclerosis and elastic fiber degeneration.

[0058] II. Clinical Trials Subjects with elevated arterial stiffness (BaPWV ≥ 1400 cm / s) were recruited and started low-dose TZ (0.5 mg / day) treatment after completing BaPWV testing, administered orally.

[0059] Exclusion criteria were: age ≤40 years or ≥85 years; history of cardiovascular disease, cancer, pregnancy, liver or kidney dysfunction or acute infection; individuals with abnormal blood glucose or blood lipid levels while receiving hypoglycemic or lipid-lowering drugs; and patients who were non-compliant or unable to accept follow-up.

[0060] BaPWV was tested again 3 months after the subjects took the medication.

[0061] III. Results Analysis 1. Low-dose TZ treatment reduces the incidence of BAPN-induced aortic dissection in mice. like Figure 6 The vascular ultrasound results shown indicate that no intimal flaps, tears, ruptures, or vascular dilation were observed in the aorta of mice in the BAPN+TZ group, suggesting that terazosin inhibited vascular wall structural damage to some extent. Measurements of the ascending, arching, and descending portions of the aorta in mice revealed significant vascular dilation in the BAPN group, but this change was mitigated in the BAPN+TZ group. Figure 7 and Figure 8 Survival curves and morbidity analysis showed that the survival rate of mice in the BAPN+TZ group was significantly higher than that in the BAPN group, and the morbidity rate was significantly lower. These results indicate that low-dose terazosin treatment can effectively slow down the occurrence of BAPN-induced aortic dissection, improve vascular structural stability, and significantly improve the survival rate of mice.

[0062] 2. Low-dose TZ can improve BAPN-induced arterial stiffness in mice. Further investigation is needed to explore the effects of low-dose TZ on reducing arterial stiffness and improving vascular wall structure and function, which may be a key mechanism in its prevention and treatment of Alzheimer's disease (AD). Various physiological and histological indicators of mice in the CON group, BAPN group, and BAPN+TZ group were compared, such as... Figure 9 As shown in figure a, compared with the BAPN group mice, the PWV of the BAPN+TZ group mice was significantly decreased, consistent with the CON group, suggesting that TZ treatment can effectively improve arterial stiffness in mice. PWV is an important parameter for measuring vascular compliance; the decrease in PWV indicates that TZ can alleviate vascular stiffness, thereby improving vascular function. Meanwhile, as... Figure 9 As shown in b, the blood pressure level of mice in the BAPN+TZ group was also significantly lower than that in the BAPN group, further supporting the role of TZ in reducing arterial stiffness and blood pressure.

[0063] 3. Immunohistochemical staining results like Figure 10 As shown, in the BAPN group mice, aortic wall thickening and elastin breakage were typical pathological changes, indicating that BAPN induced significant vascular damage and elastic fiber destruction. In contrast, no significant aortic wall thickening was observed in the BAPN+TZ group mice, and the elastin fiber structure remained intact, demonstrating the effectiveness of TZ treatment in protecting aortic structure.

[0064] In conclusion, TZ treatment not only significantly reduced BAPN-induced arterial stiffness in mice, but also reduced damage to the vascular wall and elastin breakage, demonstrating a potential protective effect in the prevention and treatment of AD.

[0065] 4. Low-dose TZ can reduce arterial stiffness in patients. This study included 169 participants, of whom 117 (69.23%) were male, with a mean age of 55.62 ± 9.03 years and a BMI of 24.65 ± 3.49 kg / m². 2 Of the participants, 71 (42.77%) had hypertension, 45 (26.95%) had a history of smoking, and 52 (31.14%) had a history of alcohol consumption. At enrollment, the left BaPWV was 1508.00 (1442.75, 1695.50) cm / s, and the right BaPWV was 1501.50 (1422.25, 1643.00) cm / s.

[0066] like Figure 11The results indicate that after treatment with low-dose TZ, the BaPWV levels of the subjects were significantly reduced, and the difference was statistically significant. As shown in the figure, the BaPWV value on the left decreased from 1508.00 (1442.75, 1695.50) cm / s at baseline to 1436.00 (1371.50, 1539.00) cm / s, P<0.05; the BaPWV value on the right decreased from 1501.50 (1422.25, 1643.00) cm / s at baseline to 1438.50 (1364.50, 1528.50) cm / s, P<0.05. These results demonstrate that TZ treatment significantly improves arterial stiffness, especially in patients with high arterial stiffness at baseline. As an important indicator of arterial stiffness, higher BaPWV values ​​are often associated with an increased risk of cardiovascular events. Therefore, TZ may reduce the risk of cardiovascular disease by decreasing arterial stiffness and reducing the burden on blood vessels.

[0067] In summary, low-dose TZ demonstrated a reduction in arterial stiffness in both mouse and human studies. Mouse studies showed that low-dose TZ treatment not only significantly reduced BAPN-induced arterial stiffness in mice but also reduced vascular wall damage and elastin breakage, thus decreasing the incidence of BAPN-induced aortic dissection. As previously demonstrated, the occurrence of aortic dissection is closely related to impaired or lost aortic elasticity and increased arterial stiffness. Therefore, these experimental results effectively confirm that low-dose TZ can effectively prevent and treat aortic dissection.

[0068] The above description is merely a preferred embodiment of the present invention and does not limit the patent scope of the present invention. All equivalent transformations made using the contents of the present invention under the inventive concept of the present invention, or direct / indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. Use of terazosin in the preparation of products for the prevention and / or treatment of aortic dissection.

2. The application according to claim 1, characterized in that: The terazosin is terazosin or its pharmaceutical salt or its solvate.

3. The application according to claim 2, characterized in that: The pharmaceutical salt is one or more of the following: hydrochloride, phosphate, benzenesulfonate, methanesulfonate, sulfate, and nitrate of terazosin; the solvate is a hydrate of terazosin or its pharmaceutical salt.

4. The application according to claim 1, characterized in that: The terazosin is terazosin hydrochloride dihydrate.

5. The application according to claim 1, characterized in that: The product in question is a health supplement or a medicine.

6. The application according to claim 1, characterized in that: The product is a drug, the subject is a human, and the dosage is 0.5~1 mg / day / person based on the active ingredient terazosin. The route of administration is at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection or oral administration.

7. The application according to claim 1, characterized in that: The product is a drug, the subjects are mice, the dosage is 5~10μg / 20g / day based on the active ingredient of terazosin, and the route of administration is intraperitoneal injection.

8. The application according to any one of claims 1 to 7, characterized in that: Terazosin reduces vascular stiffness and improves vascular structural stability by decreasing damage to the vascular wall and breakage of elastin, thereby reducing arterial stiffness and vascular pulse wave conduction velocity, achieving the prevention and / or treatment of aortic dissection.

9. The use of terazosin in the preparation of products for the prevention and / or treatment of loss of arterial elasticity and increased arterial stiffness, characterized in that, The terazosin is terazosin or its pharmaceutical salt or its solvate.

10. A medicament for the prevention and / or treatment of aortic dissection, characterized in that, The active ingredient of the drug includes terazosin or its pharmaceutical salt or its solvate, and the dosage is 0.5~1 mg / day / person based on the active ingredient of terazosin.

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