Use of terazosin and dexborneol in preparation of drug for treating cerebral stroke

Abstract

The present invention belongs to the technical field of biomedicine, and relates to a drug and a pharmaceutical composition for treating a cerebral stroke and the use thereof. The drug comprises terazosin or a pharmaceutically acceptable salt thereof and dexborneol, wherein the terazosin or the pharmaceutically acceptable salt thereof is calculated to be terazosin, and the mass ratio of terazosin to dexborneol is (1:3)-(1:9). Studies of the present invention show that the combined use of terazosin or the pharmaceutically acceptable salt thereof and dexborneol can ameliorate neurological deficit symptoms, improve functional motor ability, and reduce the cerebral infarction loss rate. Meanwhile, the combination can alleviate the decrease in blood pressure caused by the administration of terazosin alone. Thus, the combination can be used as a drug for treating cerebral stroke.

Description

Application of terazosin and dextroborneol in the preparation of drugs for treating stroke

[0001] Cross-reference to related applications

[0002] This invention claims priority to Chinese patent application filed on March 28, 2025, with application number CN202510376488.6 and entitled "Use of terazosin and dexborneol in the preparation of drugs for the treatment of stroke", the entire contents of which are incorporated herein by reference and constitute a part of this invention for all purposes. Technical Field

[0003] This invention belongs to the field of biomedical technology and relates to the application of terazosin and dextroborneol in the preparation of drugs for treating stroke. Background Technology

[0004] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0005] Stroke is an acute cerebrovascular disease characterized by high incidence, high disability rate, and high mortality. Ischemic stroke is the main type of stroke, accounting for approximately 80% of all strokes. The treatment goals for stroke are to restore cerebral blood flow, protect neurons, reduce brain damage, and improve neurological deficits. Currently, medications for stroke treatment mainly include thrombolytic drugs, neuroprotective agents, antiplatelet drugs, and anticoagulants. Although research on stroke treatment drugs has made some progress, many challenges remain. Therefore, there is still a need to develop new drugs for treating stroke. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide the use of terazosin or a pharmaceutically acceptable salt thereof and dexborneol in the preparation of a stroke treatment drug, wherein the combined use of terazosin or a pharmaceutically acceptable salt thereof and dexborneol has a synergistic effect in improving the efficacy of stroke treatment, thereby enabling it to be used as a stroke treatment drug.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] The first aspect concerns the use of terazosin or its pharmaceutically acceptable salts and dextroborneol in the preparation of drugs for treating stroke.

[0009] In some embodiments, the mass ratio of terazosin or a pharmaceutically acceptable salt thereof to dexborneol is 1:3 to 1:9, based on terazosin; preferably, the mass ratio of terazosin to dexborneol is 1:5.5 to 1:6.5; more preferably, the mass ratio of terazosin to dexborneol is 1:3, 1:6 or 1:9, and most preferably 1:6.

[0010] In some embodiments, the treatment includes improving stroke, particularly ischemic stroke-related neurological deficits, functional motor abilities, and / or brain loss rates.

[0011] The drug described in this invention can be a single pharmaceutical product, for example, a pharmaceutical product made by combining terazosin or a pharmaceutically acceptable salt thereof with dexborneol. When administering the drug to a subject or patient, only this pharmaceutical product containing both terazosin or a pharmaceutically acceptable salt thereof and dexborneol is administered. Alternatively, it can be two pharmaceutical products used in combination, for example, two pharmaceutical products made by separately preparing terazosin or a pharmaceutically acceptable salt thereof and dexborneol. When administering the drug to a subject or patient, the two pharmaceutical products containing terazosin or a pharmaceutically acceptable salt thereof and dexborneol are administered in combination or mixed to achieve the purpose of combined administration of terazosin or a pharmaceutically acceptable salt thereof and dexborneol.

[0012] This invention has shown that the combined use of terazosin or its pharmaceutically acceptable salts with dexborneol has a synergistic effect in improving the treatment efficacy for stroke. In this invention, the combined use of terazosin or its pharmaceutically acceptable salts with dexborneol ensures that blood pressure is maintained at a relatively normal level, thereby alleviating the problem of blood pressure drop during terazosin administration for stroke.

[0013] Furthermore, the experimental results of this invention indicate that the aforementioned improvements in stroke treatment efficacy can at least be manifested in improving neurological deficit symptoms, improving neurological functional impairment, promoting neurological functional recovery, improving functional motor ability, and / or reducing brain loss rate. The aforementioned relief of blood pressure decline can at least be manifested in alleviating the decrease in systolic blood pressure, diastolic blood pressure, and / or mean arterial pressure caused by terazosin alone.

[0014] In some implementations, the stroke includes ischemic stroke.

[0015] In this invention, when preparing a stroke treatment drug using terazosin or a pharmaceutically acceptable salt thereof and dexborneol, both terazosin and dexborneol can be administered at conventional clinical dosages. For example, the dosage of terazosin can be 0.01–10 mg / day, and the dosage of dexborneol can be 1–40 mg / day. In some embodiments, the mass ratio of terazosin to dexborneol is 1:1 to 1:9. Studies have shown that this ratio is more effective.

[0016] In some implementations, the mass ratio of terazosin to dextroborneol is 1:3 to 1:9.

[0017] The mass ratio of terazosin to dexborneol can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or any two of these ratios. In some embodiments, the mass ratio of terazosin to dexborneol is 1:2 to 1:7.

[0018] In some implementations, the mass ratio of terazosin to dextroborneol is 1:2.5 to 1:6.5.

[0019] In some implementations, the mass ratio of terazosin to dextroborneol is 1:5.5 to 1:6.5.

[0020] In some implementations, the mass ratio of terazosin to dextroborneol is 1:6.

[0021] In some embodiments, the dosage of the drug is 0.5 to 10 mg / day, preferably 0.5 to 5 mg / day, and more preferably 0.5 to 2 mg / day, based on terazosin.

[0022] In some implementations, the dosage of the drug is 2–10 mg / day, calculated as dexborneol.

[0023] In some embodiments, the terazosin used in the drug is terazosin or a pharmaceutically acceptable salt thereof.

[0024] In a second aspect, a pharmaceutical composition comprising terazosin or a pharmaceutically acceptable salt thereof and dextroborneol; wherein the mass ratio of terazosin to dextroborneol, calculated as terazosin, is 1:1 to 1:9.

[0025] The mass ratio of terazosin to dextromethorphan can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or any two of these ratios.

[0026] In some implementations, the mass ratio of terazosin to dextroborneol is 1:3 to 1:9.

[0027] In some embodiments, the mass ratio of terazosin to dextroborneol is 1:2 to 1:7.

[0028] In some implementations, the mass ratio of terazosin to dextroborneol is 1:2.5 to 1:6.5.

[0029] In some implementations, the mass ratio of terazosin to dextroborneol is 1:5.5 to 1:6.5.

[0030] In some implementations, the mass ratio of terazosin to dextroborneol is 1:6.

[0031] In some embodiments, the dosage of the pharmaceutical composition is 0.5 to 10 mg / day, preferably 0.5 to 5 mg / day, and more preferably 0.5 to 2 mg / day, based on terazosin.

[0032] In some embodiments, the dosage of the pharmaceutical composition is 2–10 mg / day, calculated as dexborneol.

[0033] In some implementations, pharmaceutical excipients are also included. Specifically, the pharmaceutical excipients may be pharmaceutical carriers and / or excipients. The pharmaceutical carrier may be glycerol, ion exchangers, polyacrylates, beeswax, sorbitol, potassium sorbate, sodium carboxymethyl cellulose, aluminum stearate, alumina, serum albumin, polyvinylpyrrolidone, polyethylene glycol, lecithin, physiological saline, buffer solutions, etc. The excipients may be binders, fillers, disintegrants, pH adjusters, antioxidants, preservatives, etc.

[0034] In some implementations, the dosage form can be tablets, capsules, powders, solutions, suspensions, emulsions, granules, pellets, pills, etc. The tablets described in this invention, according to their route of administration or function, can be oral tablets, such as ordinary tablets, coated tablets, effervescent tablets, dispersible tablets, sustained-release tablets, controlled-release tablets, etc.

[0035] The pharmaceutically acceptable salts described in this invention can be inorganic salts, such as hydrochloride, sulfate, nitrate, phosphate, etc.; or organic salts, such as acetate, propionate, lactate, maleate, fumarate, etc.

[0036] Thirdly, the use of the above-mentioned pharmaceutical composition in the preparation of a medicine for treating stroke.

[0037] In some embodiments, the present invention also provides a medicament for treating stroke, the medicament comprising terazosin or a pharmaceutically acceptable salt thereof and dexborneol as a combination of active ingredients; wherein the medicament is a pharmaceutical product containing both terazosin or a pharmaceutically acceptable salt thereof and dexborneol, or a combination of a first pharmaceutical product and a second pharmaceutical product; the first pharmaceutical product comprises terazosin or a pharmaceutically acceptable salt thereof, the second pharmaceutical product comprises dexborneol, and the first pharmaceutical product and the second pharmaceutical product are used for combined administration or administration after mixing; wherein the mass ratio of terazosin to dexborneol, calculated as terazosin, is 1:3 to 1:9.

[0038] In some embodiments, the present invention also provides a method for treating stroke, comprising administering terazosin or a pharmaceutically acceptable salt thereof and dexborneol to a subject or patient in need; wherein the mass ratio of terazosin to dexborneol, calculated as terazosin, is 1:3 to 1:9. The administration includes administering a pharmaceutical product containing both terazosin or a pharmaceutically acceptable salt thereof and dexborneol, or administering two pharmaceutical products in combination or in a mixture, wherein one pharmaceutical product contains terazosin or a pharmaceutically acceptable salt thereof and the other pharmaceutical product contains dexborneol.

[0039] The drug or medicine described in this invention is used to treat stroke and its complications, including neurological complications (e.g., cerebral edema, epilepsy, altered consciousness), respiratory complications (e.g., respiratory failure), cardiovascular complications (e.g., arrhythmia, myocardial infarction), digestive complications (e.g., stress ulcers), urinary complications (e.g., urinary tract infection, urinary incontinence), musculoskeletal complications (e.g., joint contractures, deep vein thrombosis), and psychological and mental complications (e.g., depression and anxiety, cognitive impairment).

[0040] In some embodiments, the treatment includes improving stroke-related neurological deficits, neurological impairment, functional motor function, and / or brain loss rate. In some embodiments, the stroke includes ischemic stroke. In some embodiments, the treatment includes alleviating a drop in blood pressure caused by administration of terazosin alone.

[0041] The beneficial effects of this invention are as follows:

[0042] This invention uses a middle cerebral artery occlusion-cerebral ischemia-reperfusion model as an animal experimental model for studying stroke. Experiments show that the combined administration of terazosin or its pharmaceutically acceptable saline and dexborneol not only significantly improves neurological deficit symptoms, neurological functional impairment, and functional motor ability, but also significantly reduces the brain loss rate, demonstrating a good therapeutic effect on stroke. Therefore, terazosin or its pharmaceutically acceptable saline combined with dexborneol can be used as a drug for treating stroke. The combined administration of terazosin or its pharmaceutically acceptable saline and dexborneol can alleviate the problem of decreased blood pressure during terazosin administration in stroke patients, including a decrease in systolic blood pressure, a decrease in diastolic blood pressure, and / or a decrease in mean arterial pressure. Attached Figure Description

[0043] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0044] Figure 1 is a Bederson score chart in Embodiment 1 of the present invention, and the data are expressed as mean ± standard deviation (Mean ± SD);

[0045] Figure 2 shows the NSS score results of animals 1 day after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD. ** indicates P<0.01 compared with the model control group, *** indicates P<0.001 compared with the model control group, and **** indicates P<0.0001 compared with the model control group.

[0046] Figure 3 shows the NSS score results of animals 7 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD. * indicates P<0.05 compared with the model control group, ** indicates P<0.01 compared with the model control group, and **** indicates P<0.0001 compared with the model control group.

[0047] Figure 4 shows the NSS score results of animals 14 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD, and ** indicates P<0.01 compared with the model control group.

[0048] Figure 5 shows the NSS score results of animals 21 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD, and * indicates P<0.05 compared with the model control group.

[0049] Figure 6 shows the NSS score results of animals 28 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD, and * indicates P<0.05 compared with the model control group.

[0050] Figure 7 shows the trend of NSS changes in animals after drug intervention in Example 1 of the present invention;

[0051] Figure 8 shows the results of the fatigue rotarod test in rats 7 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD. * indicates P<0.05 compared with the model control group, and ** indicates P<0.01 compared with the model control group.

[0052] Figure 9 shows the results of the fatigue rotarod test in rats 14 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD, and * indicates P<0.05 compared with the model control group.

[0053] Figure 10 shows the results of the fatigue rotarod test in rats 28 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD, and * indicates P<0.05 compared with the model control group.

[0054] Figure 11 shows the trend of fatigue rotator changes in rats after drug intervention in Example 1 of the present invention. The data are expressed as Mean±SD.

[0055] Figure 12 shows the brain loss rate of rats 29 days after drug intervention in Example 1 of the present invention. The brain loss rate is expressed as a percentage; * indicates P<0.05 compared with the model control group.

[0056] Figure 13 is a curve of systolic blood pressure (SBP) in rats in Example 1 of the present invention. The data are expressed as Mean±SD, where * indicates P<0.05 compared with the model control group.

[0057] Figure 14 shows the diastolic blood pressure (DBP) curve of rats in Example 1 of the present invention. The data are expressed as Mean±SD, where * indicates P<0.05 compared with the model control group.

[0058] Figure 15 shows the mean arterial pressure (MAP) curve of rats in Example 1 of the present invention. The data are expressed as Mean±SD, where * indicates P<0.05 compared with the model control group, and ** indicates P<0.01 compared with the model control group. Detailed Implementation

[0059] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0060] Example 1: Evaluation of drug efficacy and blood pressure in a middle cerebral artery occlusion (MCAO) cerebral ischemia-reperfusion model.

[0061] Animals: SPF-grade male SD rats, weighing approximately 235.4g to 263.0g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The housing environment was maintained at a temperature of 20.0℃ to 26.0℃, humidity of 40.0% to 70.0%, light intensity ≥200Lux (12h / 12h light-dark alternation), and ventilation >8 to 10 times / h, with 100% fresh air intake.

[0062] I. Experimental Methods:

[0063] The content and procedures related to animal testing involved in this embodiment comply with the relevant laws and regulations concerning the use and management of laboratory animals, as well as the relevant regulations of the Institutional Animal Care and Use Committee (IACUC). The number of animals, the experimental design, and the handling of animals have all been approved by the IACUC and strictly carried out in accordance with the content submitted to the IACUC.

[0064] 1. Construct a cerebral ischemia-reperfusion model using the MCAO technique. The modeling process is as follows:

[0065] (1) Anesthesia:

[0066] Preparation of anesthetic stock solution: Take one box of Shutai 50 (250mg lyophilized powder; 5mL solvent), transfer all 5mL of solvent to the lyophilized powder, and gently shake until completely dissolved.

[0067] Prepare a solution of dissolved Shutai 50 and Sumianxin II injection at a ratio of 10:1, and store in the dark at 2-8℃.

[0068] (2) Anesthesia dosage and method for rats:

[0069] The prepared anesthetic stock solution was diluted 10 times with normal saline and administered via intraperitoneal injection at a rate of 3.75 mL / kg. Erythromycin ointment was applied to the eyes to protect the cornea. (100,000 units of penicillin were injected intraperitoneally half an hour before the operation).

[0070] (3) Fixed:

[0071] Animals induced by anesthesia are transferred to the operating table to observe the rats' eyelid reflexes and pain responses. Surgery can only begin after the eyelid reflexes and pain responses in the limbs and tail have disappeared.

[0072] (4) Cerebral ischemia-reperfusion surgery:

[0073] A. Dissection and Exposure of Blood Vessels: After preparing the surgical area, the rat skin is cut along the midline with ophthalmic scissors to a length of approximately 2 cm. Using a right paracervical approach, the muscles of the right neck are bluntly dissected and retracted with microforceps to expose the right common carotid artery (CCA). Then, the carotid artery is dissected upwards to further expose the external carotid artery (ECA) and internal carotid artery (ICA).

[0074] B. Ligate the ECA and temporarily clamp the ICA; thread a suture through the proximal and distal ends of the CCA, tie the proximal end tightly, and tie a loose knot at the distal end for later use; cut a small opening between the two sutures.

[0075] C. Insertion of the suture plug: Insert the suture plug through the incision of the CCA, and then slowly and gently push it into the internal carotid artery. Pause at the arterial clip of the ICA and further tighten the pre-ligated suture (to avoid excessive bleeding when pushing the suture plug). Then remove the arterial clip that blocks the blood flow of the ICA and immediately push the suture plug into the ICA until it enters the intracranial cavity.

[0076] D. Fixing the suture plug and suturing the incision: When the suture plug is inserted to a depth of about 18mm from the bifurcation of the common carotid artery, if there is a slight resistance, it means that the tip of the suture plug has entered the anterior cerebral artery (ACA) and the side wall of the suture plug has blocked the opening of the middle cerebral artery. At this time, stop the insertion, record the time, and close the incision after observing that there is no active bleeding.

[0077] E. Cerebral reperfusion: Ischemic rats were placed in an incubator after surgery and their body temperature was maintained at 37±0.5℃. After 90 minutes of ischemia, the suture thrombus was slowly and gently pulled under anesthesia to return the head end to the common carotid artery, thus achieving reperfusion of the middle cerebral artery.

[0078] F. Disinfect the incision with iodine solution.

[0079] After rats were modeled, they were randomly divided into groups, and the treatment regimens for each group are shown in Table 1.

[0080] Table 1 Treatment plans for each group

[0081] Note: Terazosin analogues (CO.1) have similar chemical structures and activities to terazosin, and their structural formulas are as follows:

[0082] 2. Behavioral evaluation of rats

[0083] (1) Bederson score:

[0084] 1-2 hours after reperfusion (while the animal is awake, used to assess whether ischemia was successful in rats); the Bederson scoring criteria are shown in Table 2.

[0085] Table 2 Bederson Scoring Criteria

[0086] (2) Rat NSS score:

[0087] The initial NSS score was given 24 hours post-surgery, and once a week after modeling, for a total of 5 scores. Motor function tests, sensory tests, balance tests, and reflex and abnormal movement tests were performed on the animals, specifically referring to the Rat Neurological Function Scoring Table 3 (NSS).

[0088] Table 3. Rat Neurological Function Scoring Scale (NSS)

[0089] (3) Fatigue rotating rod:

[0090] At weeks 1, 2, and 4 post-surgery, rat fatigue rotatores were used for testing. Rats were placed on a rotating rod, and the rotation speed was uniformly increased from 5 r / min to 30 r / min over 200 seconds using a constant acceleration mode. Four rats were tested simultaneously each time, one in each compartment. The time elapsed from the start of the rotator's rotation to the rat falling off was recorded, with a rest period of at least 1 hour between each test. This was repeated three times consecutively.

[0091] 3. Brain loss rate determination:

[0092] After anesthetizing the animal, the brain was removed, the cerebellum and olfactory bulb were removed, and the brain was cut in half along the midline with a blade. The fluid on the surface of the brain and the infarct area was dried with absorbent paper, and the weight of the two halves of the brain was weighed.

[0093] The efficacy of each drug treatment group was calculated by statistically analyzing the brain loss rate in each dosage group. The formula for calculating the brain loss rate is as follows:

[0094] 4. Blood pressure measurement:

[0095] The arterial pressure of rats was monitored at six time points: 1 day before surgery, 30 minutes after immediate postoperative administration, 1 day after surgery, 7 days after surgery, 14 days after surgery, and 28 days after surgery using a non-invasive rat tail artery blood pressure measurement and analysis system. The average value of the two blood pressure measurements was taken.

[0096] 5. Statistical Analysis:

[0097] The measured indicators are expressed as mean ± standard deviation (X ± SD). Data from groups with a sample size of less than 3 are not included in the statistical comparison.

[0098] Data were entered and statistically analyzed using Excel and GraphPad Prism 8.0 software. For the quantitative indicators, the LEVENE test for homogeneity of variance was first used. When the variances were homogeneous (P > 0.05), the results of the ANOVA were directly used to determine whether the overall difference was statistically significant. When the overall difference was statistically significant (P < 0.05), the Dunnett-t test was used to compare the differences between groups. When the overall difference was not statistically significant (P ≥ 0.05), the statistical analysis ended. When the LEVENE test for homogeneity of variance showed unequal variances (P ≤ 0.05), a nonparametric test (Kruskal-Wallis H test) was used. When the Kruskal-Wallis H test showed an overall difference that was statistically significant (P < 0.05), the Mann-Whitney U test was used to compare the differences between groups. When the Kruskal-Wallis H test showed no overall difference that was statistically significant (P ≥ 0.05), the statistical analysis ended.

[0099] To facilitate understanding of the experimental results of Example 1, the main evaluation indicators, detection time points, and statistical comparison objects in Example 1 are summarized in Table A below.

[0100] Table A. Summary of Main Evaluation Indicators for Example 1

[0101] II. Test Results

[0102] 1. Behavioral evaluation of rats:

[0103] (1) Bederson score:

[0104] The Bederson score was assessed in rats 1-2 hours after reperfusion to determine the degree of ischemia. Rats with a score below 2 were excluded. The Bederson score in the sham-operated group was 0, while the Bederson scores in the model control group and each drug-treated group were 2-3, indicating that the ischemia was successfully established in all rats undergoing surgical modeling. The Bederson score results of the experimental rats are shown in Figure 1.

[0105] (2) NSS rating:

[0106] Neurological function impairment in all rats was assessed using the NSS score at 24h, 7 days, 14 days, 21 days, and 28 days after modeling. The NSS scores are shown in Figures 2, 3, 4, 5, 6, and 7. The sham-operated group had an NSS score of 0 throughout the entire experimental period.

[0107] Figures 2, 3, 4, 5, 6, and 7 show that the NSS scores of the model control group and each drug-treated group were highest on the first day after surgery. The NSS scores gradually decreased with prolonged drug intervention, indicating that neurological function gradually recovered with drug intervention. The rat MCAO model exhibits a certain degree of self-healing; with prolonged treatment, the NSS scores of each dosage group gradually decreased, and the differences between them gradually narrowed.

[0108] One day after drug intervention, all drug groups showed improvement in postoperative neurobehavioral damage in rats, with statistically significant effects. Specifically, the positive control group, dexborneol, terazosin group, and terazosin analogue + dexborneol showed p < 0.01; the terazosin + dexborneol (1:3) group and the terazosin + dexborneol (1:6) group showed p < 0.001; and the terazosin + dexborneol (1:9) group showed p < 0.0001. Seven days after drug intervention, neurobehavioral damage in rats further improved, with the terazosin group showing p < 0.05; the terazosin + dexborneol (1:3) group and the terazosin + dexborneol (1:6) group showed p < 0.0001; and the terazosin + dexborneol (1:9) group showed p < 0.0001. The p-value for the terazosin + dexborneol (1:9) group was <0.01; after 14 days of drug intervention, the p-values ​​for the terazosin + dexborneol (1:3), terazosin + dexborneol (1:6), and terazosin + dexborneol (1:9) groups were <0.01; after 21 days of drug intervention, the p-values ​​for the positive control group, terazosin + dexborneol (1:6), and terazosin + dexborneol (1:9) groups were <0.05; after 28 days of drug intervention, the p-values ​​for the terazosin + dexborneol (1:6) and terazosin + dexborneol (1:9) groups were <0.05; with the extension of drug intervention time, the terazosin + dexborneol treatment groups showed good and sustained improvement in neurological function.

[0109] Based on the NSS scores during the entire drug intervention period, the neurological function of animals in the model control group and each drug administration group could be effectively restored as the observation time increased. However, the combined intervention of terazosin and dexborneol could effectively restore the neurological function of animals in a shorter time. That is, the combination of terazosin and dexborneol can accelerate the recovery of the neurological function of animals and has a synergistic effect.

[0110] Based on Figures 2 to 6 and the above results, the statistical significance of the NSS scoring results is summarized in Table B below.

[0111] Table B: Summary of NSS Scoring Results

[0112] (3) Assessment of functional motor abilities:

[0113] The functional motor ability of experimental rats was assessed using the rotador test. The results of the rotador test are shown in Figures 8, 9, 10, and 11.

[0114] Fatigue rotator tests were performed on days 7, 14, and 28 post-surgery. The results showed a significant difference in the latent fall time between the model control group and the sham surgery group, indicating that the model was successfully established. On postoperative days 7, 14, and 28, compared with the model control group, the latency to fall was prolonged in all other drug administration groups. Specifically, on day 7, the latency to fall in the positive control group, terazosin group, terazosin + dexborneol (1:3) group, terazosin + dexborneol (1:6) group, and terazosin + dexborneol (1:9) group showed significant differences compared with the model control group. On day 14, the latency to fall in the positive control group, terazosin + dexborneol (1:3) group, terazosin + dexborneol (1:6) group, and terazosin + dexborneol (1:9) group showed significant differences compared with the model control group. On day 28, the latency to fall in the terazosin + dexborneol (1:3) group, terazosin + dexborneol (1:6) group, and terazosin + dexborneol (1:9) group showed significant differences compared with the model control group.

[0115] The results of the fatigue rotarod test showed that the combined administration of terazosin and dextromethorphan improved the neurological deficits in the model animals and improved their functional motor parameters.

[0116] Based on Figures 8 to 10 and the above results, the statistical significance of the fatigue rotator test results is summarized in Table C below.

[0117] Table C: Summary of Fatigue Rotary Bar Test Results

[0118] 2. Brain Deficiency Rate Detection

[0119] On the 29th day after surgery, brains were harvested and weighed to calculate the brain loss rate for each dosage group. The brain loss rate of the animals is shown in Figure 12.

[0120] In Figure 12, the brain loss rates of the sham surgery group and the model control group were -0.39% ± 1.28% and 24.49% ± 6.27%, respectively. The brain loss rate of the model control group was significantly increased compared with that of the sham surgery group (P < 0.0001).

[0121] Compared with the model control group, the brain loss rate in each treatment group showed a significant decreasing trend. Compared with the model control group, the brain loss rate in the positive control group, terazosin, and terazosin combined with dexborneol was significantly lower (P<0.05). The brain loss rate reduction trend in the terazosin combined with dexborneol groups was more pronounced than that in the positive control group, terazosin group, and dexborneol group, suggesting a synergistic effect.

[0122] Based on Figure 12 and the above results, the brain loss rate results are summarized in Table D below.

[0123] Table D: Summary of Brain Loss Rate Results

[0124] 3. Arterial systolic blood pressure test results

[0125] Blood pressure was measured in rats in each group at 30 min immediately after drug administration, 1 day after surgery, 7 days after surgery, 14 days after surgery, and 28 days after surgery. The results are shown in Figure 13.

[0126] In Figure 13, the model control group showed a significant decrease in systolic blood pressure postoperatively, but recovered to levels similar to the sham-operated group one day after surgery. The terazosin group exhibited lower systolic blood pressure from one to 28 days postoperatively, with significant differences compared to the model control group at days 1, 7, and 14. This indicates that terazosin alone has the side effect of lowering systolic blood pressure. The systolic blood pressure of the terazosin combined with dexborneol at various doses was not significantly different from that of the model control group and the sham-operated group, suggesting that the combined use of terazosin and dexborneol can alleviate the hypotension side effect of terazosin alone.

[0127] 4. Diastolic blood pressure test results

[0128] Blood pressure was measured in rats in each group at 30 min immediately after drug administration, 1 day after surgery, 7 days after surgery, 14 days after surgery, and 28 days after surgery. The results are shown in Figure 14.

[0129] In Figure 14, the model control group showed a significant decrease in diastolic blood pressure postoperatively, but recovered to a level similar to the sham-operated group one day after surgery. The terazosin group exhibited lower mean diastolic blood pressure from one to 28 days postoperatively, with significant differences compared to the model control group at days 7, 14, and 28, indicating that terazosin alone has the side effect of lowering diastolic blood pressure. The diastolic blood pressure in each dose group of terazosin + dexborneol was not significantly different from that in the model control group and the sham-operated group, indicating that the combined use of terazosin and dexborneol can alleviate the hypotension side effect caused by terazosin alone.

[0130] 5. Mean arterial pressure (MAP = DBP + 1 / 3 (SBP - DBP)) test results

[0131] The tests were conducted 30 minutes after immediate postoperative administration, 1 day postoperatively, 7 days postoperatively, 14 days postoperatively, and 28 days postoperatively. The test results are shown in Figure 15.

[0132] In Figure 15, the mean arterial pressure in the model control group decreased significantly after surgery, but recovered to a level similar to that of the sham-operated group one day after surgery. The mean arterial pressure in the terazosin group was lower from one to 28 days after surgery, showing significant differences compared to the model control group at 7, 14, and 28 days post-surgery, indicating that terazosin alone has a blood pressure-lowering side effect. The mean arterial pressure in each dose group of terazosin + dexborneol was not significantly different from that in the model control group and the sham-operated group, indicating that the combined use of terazosin and dexborneol can alleviate the hypotension side effect caused by terazosin alone.

[0133] Based on Figures 13-15 and the above results, the blood pressure test results are summarized in Table E below.

[0134] Table E: Summary of Blood Pressure Test Results

[0135] Example 2

[0136] A tablet formulation of terazosin combined with dexborneol is prepared, wherein the mass ratio of terazosin hydrochloride (calculated as terazosin) to dexborneol is 1:3. The formulation is shown in Table 4.

[0137] Table 4 Prescription 1

[0138] The preparation method is as follows: Raw materials and excipients are passed through a 60-mesh sieve. Then, the prescribed amounts of microcrystalline cellulose, mannitol, silica, and magnesium stearate are added to a mixing tank. Finally, terazosin hydrochloride and dextromethorphan are added. The mixer speed is set to 15 rpm, and mixing is carried out for 40 minutes. A 7mm shallow arc punch is used for tableting, controlling the tablet thickness to approximately 2.7mm, with a hardness greater than or equal to 3.0kg.

[0139] Example 3

[0140] A tablet formulation of terazosin combined with dexborneol is prepared, wherein the mass ratio of terazosin hydrochloride (calculated as terazosin) to dexborneol is 1:6. The formulation is shown in Table 5.

[0141] Table 5 Prescription 2

[0142] Note: The preparation method is the same as in Example 2.

[0143] Example 4

[0144] A tablet formulation of terazosin combined with dexborneol is prepared, wherein the mass ratio of terazosin hydrochloride (calculated as terazosin) to dexborneol is 1:9. The formulation is shown in Table 6.

[0145] Table 6 Prescription 3

[0146] Note: The preparation method is the same as in Example 2.

[0147] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A drug for treating stroke, characterized in that, The drug comprises terazosin or a pharmaceutically acceptable salt thereof and dextroborneol as a combination of active ingredients; The drug is a pharmaceutical product containing terazosin or a pharmaceutically acceptable salt thereof and dextroborneol, or a combination of drugs including a first drug product and a second drug product. The first pharmaceutical product comprises terazosin or a pharmaceutically acceptable salt thereof, and the second pharmaceutical product comprises dextroborneol. The first and second pharmaceutical products are used for combined administration or administration after mixing. Wherein, the mass ratio of terazosin or its pharmaceutically acceptable salt, calculated as terazosin, to dextroborneol is 1:3 to 1:

9.

2. The drug as described in claim 1, characterized in that, The stroke mentioned is ischemic stroke.

3. The drug as described in claim 1, characterized in that, The mass ratio of terazosin to dextromethorphan is 1:5.5 to 1:6.

5.

4. The drug as described in claim 3, characterized in that, The mass ratio of terazosin to dextroborneol is 1:

6.

5. The drug as described in claim 1, characterized in that, The drug is used to improve symptoms of neurological deficits, improve neurological function, improve functional motor ability, promote neurological function recovery and / or reduce brain loss rate.

6. The drug as described in claim 1, characterized in that, The drug is used to relieve a drop in blood pressure caused by terazosin alone, including a drop in systolic blood pressure, a drop in diastolic blood pressure, and / or a drop in mean arterial pressure.

7. The drug as claimed in claim 1, characterized in that, The terazosin or its pharmaceutically acceptable salt is terazosin hydrochloride.

8. The drug as claimed in claim 1, characterized in that, The dosage of the drug is: 0.5–5 mg / day based on terazosin; or 2–10 mg / day based on dextroborneol.

9. The drug as claimed in claim 1, characterized in that, The drug is a pharmaceutical product containing terazosin or a pharmaceutically acceptable salt thereof and dextroborneol, and the dosage form of the pharmaceutical product is tablets, capsules, powders, solutions, suspensions, emulsions, granules, drops, or pills.

10. The medicament as claimed in claim 9, characterized in that, The pharmaceutical product is a tablet, and the tablet comprises terazosin hydrochloride, dextroborneol, mannitol, microcrystalline cellulose, silicon dioxide, and magnesium stearate.

11. A pharmaceutical composition, characterized in that, Including terazosin or its pharmaceutically acceptable salts and dextroborneol; Wherein, the mass ratio of terazosin or its pharmaceutically acceptable salt, calculated as terazosin, to dextroborneol is 1:3 to 1:

9.

12. The pharmaceutical composition according to claim 11, characterized in that, The mass ratio of terazosin to dextromethorphan is 1:5.5 to 1:6.

5.

13. The pharmaceutical composition according to claim 12, characterized in that, The mass ratio of terazosin to dextroborneol is 1:

6.

14. The pharmaceutical composition of claim 11, characterized in that, The terazosin or its pharmaceutically acceptable salt is terazosin hydrochloride.

15. The pharmaceutical composition of claim 11, characterized in that, The dosage of the pharmaceutical composition is: 0.5–5 mg / day based on terazosin; or 2–10 mg / day based on dextroborneol.

16. The pharmaceutical composition of claim 11, characterized in that, The dosage form of the pharmaceutical composition is tablet, capsule, powder, solution, suspension, emulsion, granule, drop pill or pill.

17. The pharmaceutical composition of claim 16, characterized in that, The pharmaceutical composition is in the form of tablets, and the tablets comprise terazosin hydrochloride, dextroborneol, mannitol, microcrystalline cellulose, silicon dioxide, and magnesium stearate.

18. A combination drug regimen for treating stroke, characterized in that, Including primary and secondary pharmaceutical products; The first pharmaceutical product comprises terazosin or a pharmaceutically acceptable salt thereof, and the second pharmaceutical product comprises dextroborneol; The first drug product and the second drug product are used for combined administration or administration after mixing; Wherein, the mass ratio of terazosin or its pharmaceutically acceptable salt, calculated as terazosin, to dextroborneol is 1:3 to 1:

9.

19. A method for treating stroke, characterized in that, This includes administering terazosin or its pharmaceutically acceptable salts and dextroborneol to subjects or patients in need; Wherein, the mass ratio of terazosin or its pharmaceutically acceptable salt, calculated as terazosin, to dextroborneol is 1:3 to 1:

9.

20. The method as described in claim 19, characterized in that, The stroke mentioned is ischemic stroke.

21. The method as described in claim 19, characterized in that, The mass ratio of terazosin to dextromethorphan is 1:5.5 to 1:6.

5.

22. The method as described in claim 21, characterized in that, The mass ratio of terazosin to dextroborneol is 1:

6.

23. The method as described in claim 19, characterized in that, The application includes the application of a pharmaceutical product containing both terazosin or a pharmaceutically acceptable salt thereof and dextromethorphan.

24. The method as described in claim 19, characterized in that, The administration includes the combined or mixed administration of two pharmaceutical products, one of which contains terazosin or a pharmaceutically acceptable salt thereof, and the other of which contains dextroborneol.

25. The method as described in claim 19, characterized in that, The terazosin or its pharmaceutically acceptable salt is terazosin hydrochloride.

26. The method as described in claim 19, characterized in that, The dosage is: 0.5–5 mg / day based on terazosin; or 2–10 mg / day based on dextromethorphan.

27. The method as described in claim 19, characterized in that, The method improves symptoms of neurological deficits, improves neurological function impairment, improves functional motor ability, promotes neurological function recovery and / or reduces brain loss rate.

28. The method as described in claim 19, characterized in that, The method alleviates the decrease in blood pressure caused by terazosin alone, including a decrease in systolic blood pressure, a decrease in diastolic blood pressure, and / or a decrease in mean arterial pressure.

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