Use of terazosin and dextrorbornol in the preparation of a drug for treating stroke

Abstract

The present invention belongs to the field of biomedical technology and relates to the use of terazosin and (+)-camphor in the preparation of drugs for treating stroke. The research of the present invention shows that the combined use of terazosin and (+)-camphor has a synergistic effect in improving the therapeutic effect of stroke, which can not only significantly improve the neurological deficit symptoms, but also significantly reduce the brain infarction rate, demonstrating a good therapeutic effect on stroke, and thus can be used as a drug for treating stroke.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and relates to the use of terazosin and (+)-campholenic alcohol in the preparation of drugs for treating stroke. Background Art

[0002] Disclosing the information of this background art section is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Stroke is an acute cerebrovascular disease, characterized by high incidence, high disability rate and high mortality rate. The main type of stroke is ischemic stroke, accounting for about 80% of the total number of strokes. The treatment goals of stroke are to restore cerebral blood flow, protect neurons, reduce brain damage, and improve neurological deficits. Currently, the treatment drugs for stroke mainly include thrombolytic drugs, neuroprotective agents, antiplatelet drugs, anticoagulant drugs, etc. Although certain progress has been made in the research of treatment drugs for stroke, many challenges still remain. Therefore, there is still a need to provide new drugs for treating stroke. Summary of the Invention

[0004] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide the use of terazosin and (+)-campholenic alcohol in the preparation of drugs for treating stroke. The combined use of terazosin and (+)-campholenic alcohol has a synergistic effect in improving the therapeutic effect of stroke, and thus can be used as a drug for treating stroke.

[0005] In order to achieve the above purpose, the technical solution of the present invention is as follows:

[0006] First aspect, the use of terazosin and (+)-campholenic alcohol in the preparation of drugs for treating stroke.

[0007] The drug described in the present invention can be a drug product. For example, when terazosin and (+)-campholenic alcohol are made into a drug product, when administering the drug to a subject or patient, only this drug product containing both terazosin and (+)-campholenic alcohol needs to be administered; it can also be two drug products for combined use. For example, when terazosin and (+)-campholenic alcohol are respectively made into two drug products, when administering the drug to a subject or patient, the two drug products containing terazosin and (+)-campholenic alcohol respectively are administered in combination or mixed before administration to achieve the purpose of combined administration of terazosin and (+)-campholenic alcohol.

[0008] The experiments of the present invention found that the combined use of terazosin and (+)-campholenic alcohol has a synergistic effect in improving the therapeutic effect of stroke. In the present invention, the combined use of terazosin and (+)-campholenic alcohol can ensure that the blood pressure is maintained at a relatively normal level, thereby alleviating the problem of blood pressure drop during the use of terazosin for stroke treatment.

[0009] When the invention uses terazosin and borneol to prepare a drug for treating stroke, the dosages of both terazosin and borneol can be those of conventional clinical medications. For example, the dosage of terazosin can be 0.01 - 10 mg / day, and the dosage of borneol can be 1 - 40 mg / day. In some embodiments, the mass ratio of terazosin to borneol is 1:1 - 1:9. Research shows that the effect is more obvious at this ratio.

[0010] The mass ratio of terazosin to borneol can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc. or the range between any two of these ratios. In some embodiments, the mass ratio of terazosin to borneol is 1:2 - 1:7.

[0011] In some embodiments, the mass ratio of terazosin to borneol is 1:2.5 - 1:6.5.

[0012] In some embodiments, the mass ratio of terazosin to borneol is 1:5.5 - 1:6.5.

[0013] In some embodiments, the mass ratio of terazosin to borneol is 1:6.

[0014] In some embodiments, the dosage of the drug is: calculated based on terazosin, 0.5 - 10 mg / day, preferably 0.5 - 5 mg / day, and more preferably 0.5 - 2 mg / day.

[0015] In some embodiments, the dosage of the drug is: calculated based on borneol, 2 - 10 mg / day.

[0016] In some embodiments, the terazosin used in the drug is terazosin or a pharmaceutically acceptable salt thereof.

[0017] In a second aspect, a pharmaceutical composition includes terazosin or a pharmaceutically acceptable salt thereof and borneol; wherein, calculated based on terazosin, the mass ratio of terazosin to borneol is 1:1 - 1:9.

[0018] The mass ratio of terazosin to borneol can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc. or the range between any two of these ratios. In some embodiments, the mass ratio of terazosin to borneol is 1:2 - 1:7.

[0019] In some embodiments, the mass ratio of terazosin to borneol is 1:2.5 - 1:6.5.

[0020] In some embodiments, the mass ratio of terazosin to borneol is 1:5.5 - 1:6.5.

[0021] In some embodiments, the mass ratio of terazosin to dextrorotatory borneol is 1:6.

[0022] In some embodiments, the administration dose of the pharmaceutical composition is: calculated based on terazosin, 0.5 - 10 mg / day, preferably 0.5 - 5 mg / day, and more preferably 0.5 - 2 mg / day.

[0023] In some embodiments, the administration dose of the pharmaceutical composition is: calculated based on dextrorotatory borneol, 2 - 10 mg / day.

[0024] In some embodiments, it further comprises pharmaceutical excipients. Specifically, the pharmaceutical excipients can be pharmaceutical carriers and / or excipients. The pharmaceutical carriers can be glycerol, ion exchangers, polyacrylates, beeswax, sorbitans, potassium sorbate, sodium carboxymethyl cellulose, aluminum stearate, alumina, serum albumin, polyvinylpyrrolidone, polyethylene glycol, lecithin, physiological saline, buffer solutions, etc. The excipients can be binders, fillers, disintegrants, pH regulators, antioxidants, preservatives, etc.

[0025] In some embodiments, the dosage form can be tablets, capsules, powders, solutions, suspensions, emulsions, granules, dripping pills, pills, etc. The tablets described in the present invention can be oral tablets according to the administration route or function, such as ordinary tablets, coated tablets, effervescent tablets, dispersible tablets, sustained-release tablets, controlled-release tablets, etc.

[0026] The pharmaceutically acceptable salts described in the present invention can be inorganic salts, such as hydrochloride, sulfate, nitrate, phosphate, etc.; or organic salts, such as acetate, propionate, lactate, maleate, fumarate, etc.

[0027] In the third aspect, an application of the above-mentioned pharmaceutical composition in the preparation of a medicine for treating stroke.

[0028] The drug or medicine described in the present invention is used for treating stroke and its complications. The complications of the stroke include nervous system complications (such as cerebral edema, epilepsy, disturbance of consciousness), respiratory system complications (such as respiratory failure, etc.), cardiovascular system complications (such as arrhythmia, myocardial infarction, etc.), digestive system complications (such as stress ulcer, etc.), urinary system complications (such as urinary tract infection, urinary incontinence, etc.), musculoskeletal system complications (such as joint contracture, deep vein thrombosis, etc.), psychological and mental complications (such as depression and anxiety, cognitive dysfunction, etc.), etc.

[0029] The beneficial effects of the present invention are:

[0030] The present invention uses the middle cerebral artery occlusion cerebral ischemia-reperfusion model as an animal experimental model for studying stroke. Experiments have shown that the combined administration of terazosin and (+)-camphor can not only significantly improve neurological deficit symptoms, but also significantly reduce the brain infarction rate, demonstrating a good therapeutic effect on stroke. Therefore, the combination of terazosin and (+)-camphor can be used as a drug for treating stroke. The combined administration of terazosin and (+)-camphor can alleviate the problem of blood pressure drop during terazosin treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The accompanying drawings forming a part of this invention are used to provide a further understanding of the invention. The schematic embodiments and descriptions thereof of the invention are used to explain the invention and do not constitute an improper limitation of the invention.

[0032] Figure 1 It is the Bederson score chart in Example 1 of the present invention, and the data are expressed as mean ± standard deviation (Mean ± SD);

[0033] Figure 2 It is the result chart of the NSS score 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 animals in the model control group, *** indicates P < 0.001 compared with the animals in the model control group, and **** indicates P < 0.0001 compared with the animals in the model control group;

[0034] Figure 3 It is the result chart of the NSS score 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 animals in the model control group, ** indicates P < 0.01 compared with the animals in the model control group, and **** indicates P < 0.0001 compared with the animals in the model control group;

[0035] Figure 4 It is the result chart of the NSS score of animals 14 days after drug intervention in Example 1 of the present invention. The data are expressed as Mean ± SD. ** indicates P < 0.01 compared with the animals in the model control group;

[0036] Figure 5 It is the result chart of the NSS score of animals 21 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 animals in the model control group;

[0037] Figure 6 It is the result chart of the NSS score of animals 28 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 animals in the model control group;

[0038] Figure 7It is the graph of the change trend of NSS in animals after drug intervention in Example 1 of the present invention;

[0039] Figure 8 It is the graph of the results of the fatigue rotarod test of rats in Example 1 of the present invention 7 days after drug intervention. The data are expressed as Mean±SD. * indicates P<0.05 compared with the animals in the model control group, and ** indicates P<0.01 compared with the animals in the model control group;

[0040] Figure 9 It is the graph of the results of the fatigue rotarod test of rats in Example 1 of the present invention 14 days after drug intervention. The data are expressed as Mean±SD. * indicates P<0.05 compared with the animals in the model control group;

[0041] Figure 10 It is the graph of the results of the fatigue rotarod test of rats in Example 1 of the present invention 28 days after drug intervention. The data are expressed as Mean±SD. * indicates P<0.05 compared with the animals in the model control group;

[0042] Figure 11 It is the graph of the change trend of the fatigue rotarod of rats in Example 1 of the present invention after drug intervention. The data are expressed as Mean±SD;

[0043] Figure 12 It is the graph of the rat deletion rate results of rats in Example 1 of the present invention 29 days after drug intervention, with the brain deletion rate %. * indicates P<0.05 compared with the animals in the model control group;

[0044] Figure 13 It is the curve graph of the arterial systolic blood pressure (SBP) of rats in Example 1 of the present invention. The data are Mean±SD, where * indicates P<0.05 compared with the model group;

[0045] Figure 14 It is the curve graph of the arterial diastolic blood pressure (DBP) of rats in Example 1 of the present invention. The data are Mean±SD, where * indicates P<0.05 compared with the model group;

[0046] Figure 15 It is the curve graph of the mean arterial pressure (MAP) of rats in Example 1 of the present invention. The data are Mean±SD, where * indicates P<0.05 compared with the model group, and ** indicates P<0.01 compared with the model group. Detailed implementation manners

[0047] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0048] Example 1

[0049] Animals: SPF-grade SD rats, male, weighing 263.0 - 235.4 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Breeding environment: Temperature: 20.0 - 26.0 °C; Humidity: 40.0 - 70.0 %; Illumination: ≥200 Lux (12h / 12h light-dark cycle); Ventilation: >8 - 10 times / h, fresh air only.

[0050] I. Experimental methods:

[0051] All the content and procedures related to animal experiments in this embodiment comply with the relevant laws and regulations on the use and management of experimental animals and the relevant regulations of the Institutional Animal Care and Use Committee (IACUC) of this institution. The number of animals, experimental design, and treatment of animals have all been approved by the IACUC and strictly implemented in accordance with the content reported to the IACUC.

[0052] 1. Establish a middle cerebral artery occlusion (MCAO) cerebral ischemia-reperfusion model. The modeling process is as follows:

[0053] (1) Anesthesia:

[0054] Preparation of anesthetic stock solution: Take 1 box of Zoletil 50 (250 mg freeze-dried powder; 5 mL solvent), transfer all 5 mL of the solvent to the freeze-dried powder, and gently shake until completely dissolved.

[0055] Mix the dissolved Zoletil 50 with Ximianxin II injection in a ratio of 10:1, protect from light, and store at 2 - 8 °C.

[0056] (2) Anesthetic dose and method for rats:

[0057] Dilute the prepared anesthetic stock solution 10 times with normal saline and inject it intraperitoneally at a dose of 3.75 mL / kg for anesthesia. Apply erythromycin ointment to the eyes to protect the cornea. (Inject 100,000 units of penicillin intraperitoneally half an hour before the operation).

[0058] (3) Fixation:

[0059] Transfer the animals induced by anesthesia to the operating table, observe the eyelid reflex and pain sensation of the rats, and start the operation only after the eyelid reflex and the pain sensation in the limbs and tail disappear.

[0060] (4) Cerebral ischemia-reperfusion surgery:

[0061] A. Isolate and expose the blood vessel: After preparing the skin of the surgical area, use an ophthalmic scissors to cut the rat's skin along the midline, with a length of about 2 cm. Through the right paracervical approach, bluntly separate and retract the muscle tissue on the right side of the neck with microsurgical forceps to expose the right common carotid artery (CCA). Then, separate upward along the common carotid artery to further expose the external carotid artery (ECA) and internal carotid artery (ICA).

[0062] B. Ligate the ECA and temporarily clamp the ICA; Pass threads through the proximal and distal ends of the CCA respectively. Tie the proximal end tightly and tie a loose knot at the distal end for standby. Make a small incision between the two threads.

[0063] C. Insert the suture: Insert the suture through the incision of the CCA, and then slowly and gently push it into the internal carotid artery. Pause when reaching the artery clip of the ICA, further tighten the pre-ligated thread (to avoid excessive bleeding when pushing the suture), then remove the artery clip blocking the blood flow of the ICA, and immediately push the suture into the ICA until it enters the skull.

[0064] D. Fix the suture and suture the incision: When the insertion depth of the suture is about 18 mm from the bifurcation of the common carotid artery, if there is a slight resistance, it indicates that the tip of the suture has entered the anterior cerebral artery (ACA), and the side wall of the suture has blocked the opening of the middle cerebral artery. At this time, stop inserting, record the time, and close the incision after observing no active bleeding.

[0065] E. Cerebral reperfusion: Place the ischemic rats in a postoperative incubator to maintain the body temperature at 37 ± 0.5 °C. After 90 minutes of ischemia, slowly and gently pull the suture under anesthesia to make its tip return to the common carotid artery, that is, to achieve reperfusion of the middle cerebral artery.

[0066] F. Disinfect the incision with iodophor.

[0067] After the rat model is established, random grouping is carried out, and the treatment plans for each group are shown in Table 1.

[0068] Table 1 Treatment plans for each group

[0069]

[0070] Note: The terazosin analogue (CO.1) has a chemical structure and activity similar to terazosin, and the structural formula is as follows:

[0071]

[0072] 2. Evaluation of rat behavior

[0073] (1)Bederson score:

[0074] 1 - 2 h after reperfusion (when the animal is awake, used to evaluate whether the ischemia in rats is successful); the Bederson scoring criteria are shown in Table 2.

[0075] Table 2 Bederson Scoring Criteria Table

[0076]

[0077] (2)Rat NSS score:

[0078] The first NSS score is at 24 h after surgery, once a week for 1 week after modeling, with a total of 5 scores; the animal is subjected to motor function test, sensory test, balance test, and reflex and abnormal movement test, specifically referring to the rat neurological function scoring table 3 (NSS).

[0079] Table 3 Rat Neurological Function Scoring Table (NSS)

[0080]

[0081] (3)Rotarod fatigue test:

[0082] At the 1st, 2nd, and 4th weeks after surgery; tested using a rat rotarod fatigue tester. The rat is placed on the rotating rod, and the uniformly accelerated test mode is adopted, with the rotation speed accelerating uniformly from 5 r / min to 30 r / min within 200 seconds. Each time, 4 rats are measured simultaneously, with 1 rat in each compartment. Record the time from the start of the rod rotation until the rat falls off the rod. Each time, the interval between tests is not less than 1 h, and the test is conducted continuously for 3 times.

[0083] 3. Determination of brain loss rate:

[0084] After the animal is anesthetized, the brain is taken, the cerebellum and olfactory bulb are removed, and the brain is cut in half along the midline with a blade. The liquid on the brain surface and the infarct area is blotted dry with absorbent paper, and the weights of the two half - brains are measured.

[0085] The brain loss rate of each dose group is statistically analyzed to calculate the efficacy of each drug treatment group. The formula for calculating the brain loss rate is as follows:

[0086] .

[0087] 4. Blood pressure measurement:

[0088] The arterial pressure of rats is monitored at 6 time points: 1 day before surgery, 30 min after immediate administration after surgery, 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 blood pressure is measured 2 times and the average value is taken.

[0089] 5. Statistical analysis:

[0090] The measurement indexes are expressed as mean ± standard deviation (X±SD). When the sample size is less than 3, the data of this group are not included in the statistical comparison.

[0091] The data were entered and statistically analyzed using Excel and GraphPad Prism 8.0 software. For the measurement indexes, the LEVENE homogeneity of variance test was first used. When the variances were homogeneous (P>0.05), the results of the analysis of variance could be directly cited to judge whether there was a statistically significant overall difference. When there was a statistically significant overall difference (P<0.05), the Dunnett-t test was used to compare the differences between groups. When there was no statistically significant overall difference (P≥0.05), the statistical analysis ended; when the LEVENE homogeneity of variance test showed that the variances were not homogeneous (P≤0.05), non-parametric tests (Kruskal-Wallis H test) were used. When the Kruskal-Wallis H test showed that there was a statistically significant overall difference (P<0.05), the Mann-Whitney U test was used to compare the differences between groups. When the Kruskal-Wallis H test showed that there was no statistically significant overall difference (P≥0.05), the statistical analysis ended.

[0092] III. Experimental Results

[0093] 1. Behavioral evaluation of rats:

[0094] (1) Bederson score:

[0095] The rats were given Bederson scores 1-2 h after reperfusion to judge the ischemia condition of the animals. Rats with a score lower than 2 were excluded. The Bederson score of the sham operation group animals was 0, and the Bederson scores of the model control group and each drug administration group rats were 2-3, indicating that all the rats subjected to surgical modeling were successfully ischemic. The Bederson score results of the experimental rats are shown in Figure 1 .

[0096] (2) NSS score:

[0097] All rats were evaluated for neurological function injury by NSS score at 24 h, 7 days, 14 days, 21 days, and 28 days after modeling. The NSS scores of the rats are shown in Figure 2 、 Figure 3 、 Figure 4 、 Figure 5 、 Figure 6 、 Figure 7 . The NSS scores of the sham operation group animals were all 0 during the entire experimental period.

[0098] Figure 2 、 Figure 3 、Figure 4 , Figure 5 , Figure 6 , Figure 7 It was shown that the NSS scores of the animals in the model control group and each drug administration group were the highest on the first day after surgery, and the NSS scores gradually decreased with the prolongation of the drug intervention time, indicating that the nerve function gradually recovered with the drug intervention. The MCAO model of rats had a certain degree of self-healing ability. With the prolongation of the treatment time, the NSS scores of each dose group gradually decreased, and the gap gradually became smaller.

[0099] One day after drug intervention, all drug groups had an improved effect on the nerve behavior injury of the postoperative rats, and all were statistically significant. Among them, the positive control group, (+)-camphor, terazosin group and terazosin analog + (+)-camphor had p < 0.01, the terazosin + (+)-camphor (1:3) group and the terazosin + (+)-camphor (1:6) group had p < 0.001, and the terazosin + (+)-camphor (1:9) group had p < 0.0001; seven days after drug intervention, the nerve behavior injury of the rats was further improved. Among them, the terazosin group had p < 0.05, the terazosin + (+)-camphor (1:3) group and the terazosin + (+)-camphor (1:6) group had p < 0.0001, and the terazosin + (+)-camphor (1:9) group had p < 0.01; fourteen days after drug intervention, the terazosin + (+)-camphor (1:3) group, the terazosin + (+)-camphor (1:6) group and the terazosin + (+)-camphor (1:9) group had p < 0.01; twenty-one days after drug intervention, the positive drug group, the terazosin + (+)-camphor (1:6) group and the terazosin + (+)-camphor (1:9) group had p < 0.05; twenty-eight days after drug intervention, the terazosin + (+)-camphor (1:6) group and the terazosin + (+)-camphor (1:9) group had p < 0.05; with the drug intervention, the improvement effect of each treatment group of the drug terazosin + (+)-camphor on nerve function was better than that of the positive drug.

[0100] From the NSS score results during the entire drug intervention period, with the prolongation of the observation time, the nerve function of the animals in the model control group and each drug administration group could be effectively restored. However, after the combined intervention of terazosin and (+)-camphor, the nerve function of the animals could be effectively restored in a shorter time, that is, the combination of terazosin and (+)-camphor could accelerate the recovery of the nerve function of the animals and had a synergistic effect.

[0101] (3) Evaluation of functional motor ability:

[0102] The functional motor ability of the experimental rats was evaluated by using the fatigue rotarod test (Rotarod). The test results of the fatigue rotarod are shown in Figure 8 , Figure 9 , Figure 10 , Figure 11 .

[0103] The fatigue rod rotation test was conducted on the 7th, 14th, and 28th days after surgery. From the results, there was a significant difference in the latent fall duration between the model group and the sham operation group, indicating that the model was successfully established. On the 7th, 14th, and 28th days after surgery, compared with the model control group, the latent fall duration of each drug administration group was prolonged. Among them, on the 7th day, there were significant differences in the latent fall duration of the positive drug control group, terazosin group, terazosin + borneol (1:3) group, terazosin + borneol (1:6) group, and terazosin + borneol (1:9) group compared with the model group; on the 14th day, there were significant differences in the latent fall duration of the positive drug control group, terazosin + borneol (1:3) group, terazosin + borneol (1:6) group, and terazosin + borneol (1:9) group compared with the model group; on the 28th day, there were significant differences in the latent fall duration of the terazosin + borneol (1:3) group, terazosin + borneol (1:6) group, and terazosin + borneol (1:9) group compared with the model group.

[0104] From the results of the fatigue rod rotation test, the combined administration of terazosin and borneol improved the state of motor nerve function deficiency in the model and improved the functional movement parameters of the model animals.

[0105] 2. Detection of brain loss rate

[0106] On the 29th day after surgery, the brain was taken and weighed to calculate the brain loss rate of each dose group. The brain loss rate of the animals is shown in Figure 12 .

[0107] Figure 12 Among them, the brain loss rates of the sham operation 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 the sham operation group (P < 0.0001).

[0108] The brain loss rate of each drug administration group showed an obvious decreasing trend compared with the model control group. Compared with the animals in the model control group, the brain loss rates of the positive drug control group, terazosin, and each dose group of the combination of terazosin and borneol were significantly decreased (P < 0.05). Moreover, the decreasing trend of the brain loss rate in each dose group of the combination of terazosin hydrochloride and borneol was more obvious than that in the positive drug group, terazosin hydrochloride group, and borneol group, showing the same synergistic effect.

[0109] 3. Detection results of arterial systolic blood pressure

[0110] The blood pressure of each group of rats was measured at 30 min after immediate administration after surgery, 1 day, 7 days, 14 days, and 28 days after surgery. The detection results are as shown in Figure 13 shown.

[0111] Figure 13Among them, the arterial systolic blood pressure in the model control group decreased significantly after surgery, but returned to a level similar to that of the sham operation group after 1 day. The arterial systolic blood pressure in the terazosin group was lower from 1 day to 28 days after surgery, and there were significant differences compared with the model control group at 1 day, 7 days, and 14 days after surgery. This indicates that terazosin alone has the side effect of reducing systolic blood pressure. The arterial systolic blood pressure in each dose group of terazosin combined with (+)-camphor was not much different from that of the model control group and the sham operation group, indicating that the combined use of terazosin and (+)-camphor can alleviate the side effect of hypotension caused by the single administration of terazosin.

[0112] 3. Detection results of arterial diastolic blood pressure

[0113] Blood pressure was measured in each group of rats at 30 min after immediate administration after surgery, 1 day, 7 days, 14 days, and 28 days after surgery. The detection results are as Figure 14 shown.

[0114] Figure 14 Among them, the arterial diastolic blood pressure in the model control group decreased significantly after surgery, but returned to a level similar to that of the sham operation group after 1 day. The average diastolic blood pressure in the terazosin group was lower from 1 day to 28 days after surgery, and there were significant differences compared with the model control group at 7 days, 14 days, and 28 days after surgery, indicating that terazosin alone has the side effect of reducing diastolic blood pressure. The arterial diastolic blood pressure in each dose group of terazosin + (+)-camphor was not much different from that of the model control group and the sham operation group, indicating that the combined use of terazosin and (+)-camphor can alleviate the effect of hypotension caused by the single administration of terazosin.

[0115] 3. Detection results of mean arterial pressure (MAP = DBP + 1 / 3(SBP - DBP))

[0116] The detection time was 30 min after immediate administration after surgery, 1 day, 7 days, 14 days, and 28 days after surgery. The detection results are as Figure 15 shown.

[0117] Figure 15 Among them, the mean arterial pressure in the model control group decreased significantly after surgery, but returned to a level similar to that of the sham operation group after 1 day. The mean arterial pressure in the terazosin group was lower from 1 day to 28 days after surgery, and there were significant differences compared with the model control group at 7 days, 14 days, and 28 days after surgery, indicating that terazosin alone has the side effect of reducing blood pressure; the mean arterial pressure in each dose group of terazosin + (+)-camphor was not much different from that of the model control group and the sham operation group, indicating that the combined use of terazosin and (+)-camphor can alleviate the side effect of hypotension caused by the single administration of terazosin.

[0118] Example 2

[0119] Preparation of tablets of terazosin combined with (+)-camphorol, mass ratio of terazosin hydrochloride (calculated as terazosin) to (+)-camphorol = 1:3. The prescription is shown in Table 4 as follows.

[0120] Table 4 Prescription 1

[0121]

[0122] The preparation method is as follows: Pass the raw and auxiliary materials through a 60-mesh sieve respectively, then add the prescribed amounts of microcrystalline cellulose, mannitol, silicon dioxide and magnesium stearate into the mixing barrel, and finally add terazosin hydrochloride and (+)-camphorol. Set the rotation speed of the mixer at 15 rpm and mix for 40 min. Use a 7-mm shallow arc punch for the tablet press mold, control the tablet thickness at about 2.7 mm, and the hardness is greater than or equal to 3.0 kg for tableting.

[0123] Example 3

[0124] Preparation of tablets of terazosin combined with (+)-camphorol, mass ratio of terazosin hydrochloride (calculated as terazosin) to (+)-camphorol = 1:6. The prescription is shown in Table 5 as follows.

[0125] Table 5 Prescription 2

[0126]

[0127] Note: The preparation method is the same as that of Example 2.

[0128] Example 4

[0129] Preparation of tablets of terazosin combined with (+)-camphorol, mass ratio of terazosin hydrochloride (calculated as terazosin) to (+)-camphorol = 1:9. The prescription is shown in Table 6 as follows.

[0130] Table 6 Prescription 3

[0131]

[0132] Note: The preparation method is the same as that of Example 2.

[0133] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of terazosin and dextrorotatory borneol in the preparation of a medicament for treating stroke; The mass ratio of terazosin to dextrorotatory borneol is 1:3 to 1:

9.

2. The application according to claim 1, characterized in that, The mass ratio of terazosin to dextrorotatory borneol is 1:5.5 to 1:6.

5.

3. The application according to claim 2, characterized in that, The mass ratio of terazosin to dextrorotatory borneol is 1:

6.

4. The application according to claim 1, characterized in that, The administration dose of the medicament is: calculated by terazosin, 0.5 to 5 mg / day; Or, the administration dose of the medicament is: calculated by dextrorotatory borneol, 2 to 10 mg / day.

5. The application according to claim 1, characterized in that, The terazosin used in the medicament is terazosin or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, characterized in that, It includes terazosin or a pharmaceutically acceptable salt thereof and dextrorotatory borneol; wherein, calculated by terazosin for terazosin or a pharmaceutically acceptable salt thereof, the mass ratio of terazosin to dextrorotatory borneol is 1:3 to 1:

9.

7. The pharmaceutical composition according to claim 6, characterized in that, The mass ratio of terazosin to dextrorotatory borneol is 1:5.5 to 1:6.

5.

8. The pharmaceutical composition according to claim 7, characterized in that, The mass ratio of terazosin to dextrorotatory borneol is 1:

6.

9. The pharmaceutical composition according to claim 6, wherein, The administration dose of the pharmaceutical composition is: calculated by terazosin, 0.5 to 5 mg / day; Or, the administration dose of the pharmaceutical composition is: calculated by dextrorotatory borneol, 2 to 10 mg / day.

10. The pharmaceutical composition according to claim 6, characterized in that, It further includes pharmaceutical excipients.

11. The pharmaceutical composition according to claim 6, wherein The dosage form is tablet, capsule, powder, solution, suspension, emulsion, granule or pill.

12. Use of a pharmaceutical composition according to any one of claims 6 to 11 in the preparation of a medicament for treating stroke.

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