Use of icariin in the preparation of a drug for preventing and treating myocardial infarction thrombolysis and anti-thrombus bleeding complications

Abstract

This invention belongs to the pharmaceutical field and relates to the medicinal uses of icariin. Specifically, it relates to the use of icariin in the preparation of drugs for the prevention and treatment of thrombolytic and antithrombotic bleeding complications in myocardial infarction. To achieve the prevention and treatment of thrombolytic and antithrombotic bleeding complications in myocardial infarction, this invention studies the effect of icariin. Experimental results show that icariin can significantly reduce the incidence of various bleeding complications caused by thrombolytic and antithrombotic drugs. Furthermore, while reducing the bleeding rate and shortening the bleeding time, it does not alter blood routine tests or coagulation parameters, nor does it affect the thrombolytic effect of thrombolytic drugs. This has positive and important significance for the prevention and treatment of thrombolytic and antithrombotic bleeding complications in myocardial infarction patients and for enhancing the short-term and long-term treatment of myocardial infarction patients.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to the use of icariin in the preparation of drugs for the prevention and treatment of myocardial infarction thrombolysis and antithrombotic hemorrhage complications. Background Technology

[0002] Acute myocardial infarction is one of the most serious and dangerous complications of coronary heart disease. It is characterized by rapid onset, rapid progression, and high mortality. Therefore, early intravenous thrombolysis in the acute phase of myocardial infarction is one of the effective methods to restore coronary artery patency, significantly reducing mortality and improving cardiac function in survivors. However, bleeding complications are also common, such as hematoma at the puncture site, gastrointestinal bleeding, gingival bleeding, and even intracranial hemorrhage.

[0003] Furthermore, primary prevention in healthy individuals and secondary prevention of recurrent infarction and other cardiovascular events in patients with coronary artery disease are also crucial for reducing the mortality rate of acute myocardial infarction. However, bleeding complications are unavoidable when administering these preventative medications. Therefore, how to reduce the incidence of bleeding complications during thrombolysis and antithrombotic therapy in myocardial infarction patients, and how to enhance the short-term and long-term treatment outcomes, has become an urgent problem for medical and pharmaceutical professionals.

[0004] Epimedium is the dried stem and leaves of several plants in the Berberidaceae family, including Epimedium brevicornum Maxim., Epimedium sagittatum Maxim., Epimedium pubescens Maxim., and Epimedium koreanum Nakai. Clinically, it is mainly used for kidney yang deficiency, impotence, frequent urination, infertility; rheumatic pain, numbness and contracture of limbs, weakness of muscles and bones, and difficulty walking; and kidney yang deficiency, wheezing, cough, and shortness of breath. Epimedoside can increase blood flow to the heart and brain, promote hematopoietic function, immune function, and bone metabolism, and has the effects of tonifying the kidney and strengthening yang, anti-aging, and anti-tumor.

[0005] Icaritin (IT) is a polyhydroxy flavonoid monomer from *Epimedium brevicornu*, a plant belonging to the Berberidaceae family. Pharmacological studies have shown that IT has a stronger anti-osteoporosis effect than other flavonoid glycosides in *Epimedium brevicornu*, and in vitro, it promotes osteoblast activity and inhibits osteoclast activity. In recent years, icariin and icariin, as important active components of *Epimedium brevicornu*, have received increasing attention from pharmaceutical researchers. For example, patent CN201310652615.8 discloses the application of icariin in the preparation of anti-fatigue drugs; patent CN201310373517.0 discloses the use of icariin in the preparation of drugs for treating asthma.

[0006] There are currently no literature reports on the effects of icariin on thrombolysis and prevention of complications such as myocardial infarction and bleeding. Summary of the Invention

[0007] The main objective of this invention is to prevent and treat complications related to thrombolysis and antithrombotic bleeding in patients with myocardial infarction, and to enhance the short-term and long-term therapeutic effects. This objective is achieved through the following technical solutions:

[0008] Specific Example 1: Effect of Icariin on Bleeding Complications Caused by Thrombolytic Drugs. Experimental results showed that icariin can significantly reduce the incidence of bleeding complications caused by thrombolytic drugs, and its use with thrombolytic drugs does not affect the thrombolytic effect.

[0009] Specific Example 2: Effect of Icariin on Heparin Sodium-Induced Prolongation of Bleeding Time in Mice; Specific Example 3: Effect of Icariin on Aspirin-Induced Prolongation of Bleeding Time in Mice. Experimental results showed that: Icariin can significantly reduce the prolongation of bleeding time induced by heparin sodium and aspirin, shorten the bleeding time, and does not affect blood routine and coagulation parameters while shortening the bleeding time.

[0010] Icariin has significant therapeutic effects on bleeding complications caused by thrombolysis and antithrombotic therapy in myocardial infarction. Thrombolysis includes, but is not limited to, thrombolytic therapy using alteplase; antithrombotic therapy includes, but is not limited to, anticoagulant therapy using heparin sodium and antiplatelet therapy using aspirin.

[0011] Antithrombotic therapy includes not only antithrombotic therapy during the onset of myocardial infarction, but also antithrombotic therapy during primary and secondary prevention.

[0012] Bleeding complications caused by the above-mentioned thrombolysis and antithrombosis include, but are not limited to, one or more of the following: subcutaneous hemorrhage, intracranial hemorrhage, upper gastrointestinal bleeding, or gingival bleeding.

[0013] Icariin can be administered via gastrointestinal and non-gastrointestinal routes. Non-gastrointestinal routes include, but are not limited to, subcutaneous, intradermal, arterial, venous, intramuscular, joint, intrathecal, intracranial, pleural, and intraperitoneal injections or infusions, as well as nasal, buccal, sublingual, tracheal, urethral, ​​rectal, or local administration to the lesion. It can be taken concurrently with other medications or as a preventative measure.

[0014] Another primary objective of this invention is to provide a pharmaceutical preparation containing icariin for the treatment of the aforementioned diseases, comprising icariin and pharmaceutically acceptable excipients.

[0015] Pharmaceutical preparations include, but are not limited to, injections, powders for injection, capsules, tablets, microemulsions, pellets, and enteric-coated soft capsules. Routes of administration include gastrointestinal and non-gastrointestinal routes.

[0016] The pharmaceutical excipients used in the formulations of this invention are commonly known excipients to those skilled in the art. For example, commonly used pharmaceutical excipients for preparing microemulsion formulations include, but are not limited to, soybean oil, polyoxyethylene-23-lauryl ether, 1,2-propanediol, hydrogenated coconut oil glyceride, lauroyl polyethylene glycol-32-glyceride, polyethylene glycol 3350, safflower oil, cottonseed oil, and decaglyceryl monostearate; commonly used pharmaceutical excipients for preparing pellet formulations include, but are not limited to, polyethylene glycol 6000 and polyethylene glycol 1000; commonly used pharmaceutical excipients for preparing capsule formulations include, but are not limited to, lactose and corn starch. Commonly used pharmaceutically acceptable carriers for preparing soft capsule formulations include, but are not limited to, medium-chain fatty acid glycerides, polyoxyethylene castor oil, and 1,2-propanediol.

[0017] Those skilled in the art can select suitable pharmaceutical excipients according to actual needs and formulate the formulations of the present invention using methods known in the art. The formulations include, but are not limited to, solids, liquids, oils, emulsions, gels, aerosols, inhalers, sprays, capsules, pills, patches, and suppositories.

[0018] Preferably, the dosage of the drug for the prevention and treatment of thrombolysis and antithrombotic bleeding complications in patients with myocardial infarction is 0.03 mg / kg to 300 mg / kg; more preferably, the dosage of the drug for the prevention and treatment of thrombolysis and antithrombotic bleeding complications in patients with myocardial infarction is 0.3 mg / kg to 30 mg / kg.

[0019] Compared with existing technologies, icariin has the following advantages in the prevention and treatment of thrombolysis and antithrombotic bleeding complications in patients with myocardial infarction:

[0020] 1. Significant therapeutic effect

[0021] Icariin can significantly reduce the incidence of various bleeding complications caused by thrombolytic and antithrombotic drugs. Furthermore, while reducing the bleeding rate and shortening the bleeding time, it does not change the values ​​of blood routine and coagulation parameters, nor does it affect the thrombolytic effect of thrombolytic drugs.

[0022] (2) Safe and non-toxic, convenient to take

[0023] Epimedium glycoside is an extract from traditional Chinese medicine. Compared with existing treatment methods, it not only has the advantage of fewer toxic side effects, but also has the characteristics of convenient administration and good patient compliance. Specific Implementation

[0024] The present invention is further described below through specific embodiments, but the present invention is not limited to the following embodiments.

[0025] Formulation Example 1: Icariin Tablets

[0026]

[0027] Preparation process: Icariin and excipients microcrystalline cellulose and sodium carboxymethyl starch are mixed evenly, and an appropriate amount of starch slurry is added to form a soft mass, which is then granulated through a 16-mesh sieve. The wet granules are dried at 60℃, and the dried granules are sieved through a 20-mesh sieve to remove fine powder. This powder is then mixed with magnesium stearate, and then mixed with the dry granules again. The mixture is then compressed into tablets, each containing approximately 200mg.

[0028] Formulation Example 2: Epimedium Aglycone Capsule Formulation

[0029]

[0030]

[0031] Preparation process: Mix 100g of icariin, 120g of lactose and 130g of corn starch in a mixer for 10-15 minutes, add 5g of magnesium stearate and mix for 1-3 minutes, then fill into 1000 capsule shells.

[0032] Formulation Example 3: Icariin Microemulsion Formulation

[0033]

[0034] Preparation process: Weigh the prescribed amounts of soybean oil, polyoxyethylene-23-lauryl ether, and 1,2-propanediol, mix them thoroughly, and then add icariin to dissolve. Ultrasonic treatment can also be used to accelerate dissolution, yielding a clear solution, which is the icariin microemulsion formulation. The particle size was measured using a laser particle size analyzer, with an average particle size of 15 nm.

[0035] Formulation Example 4: Icariin Microemulsion Formulation

[0036]

[0037] Preparation process: Weigh the prescribed amounts of hydrogenated coconut oil glyceride, lauroyl polyethylene glycol-32-glyceride, 1,2-propanediol, and polyethylene glycol 3350, mix them thoroughly, and then add icariin to dissolve. Ultrasonic treatment can also be used to accelerate dissolution, yielding a clear solution, which is the icariin microemulsion formulation. The particle size was measured using a laser particle size analyzer, with an average particle size of 40 nm.

[0038] Formulation Example 5: Icariin Enteric-coated Soft Capsule Formulation

[0039] Contents prescription:

[0040]

[0041] Rubber prescription:

[0042] 10g of gelatin

[0043] 5g of glycerin

[0044] 10g of purified water

[0045] Enteric coating solution prescription:

[0046]

[0047] Preparation process: Weigh the prescribed amounts of medium-chain fatty acid glycerides, polyoxyethylene castor oil, 1,2-propanediol, and anhydrous ethanol, mix and stir evenly, then add icariin to dissolve. Ultrasonic treatment can be used to accelerate dissolution, yielding a clear concentrate, which is the icariin microemulsion concentrate. Dilute the obtained microemulsion concentrate with water at a weight ratio of 1:10-20 to a clear solution, obtaining the soft capsule microemulsion contents. Weigh the prescribed amounts of gelatin, glycerin, and purified water, mix evenly, and press into a rubber sheet. Then weigh the prescribed amounts of Eudragit L30D-55, triethyl citrate, talc, and purified water, mix evenly to prepare an enteric coating solution. Encapsulate the soft capsule microemulsion contents containing icariin with the rubber sheet to form soft capsules, and then coat the soft capsules with an enteric coating to obtain enteric soft capsules.

[0048] Formulation Example 6: Epimedium Acid Glycoside Droplets Formulation

[0049]

[0050] Preparation process: Weigh the prescribed amount of icariin that has passed through a 100-mesh sieve, add it to a mixture of polyethylene glycol 6000 and polyethylene glycol 1000 that has been heated and melted in a water bath, stir thoroughly to make it uniform, pour it into a dropper bottle, and drop it at 95±2℃; drop it into a glass condenser column containing 4-6 mL of methyl silicone oil, remove it after it has solidified, and use absorbent paper to remove the adhering methyl silicone oil to obtain the final product.

[0051] Formulation Example 7: Icariin Injection

[0052]

[0053] Preparation process: Mix the prescribed amount of ethanol and Tween-80 evenly, add icariin, stir to dissolve, add water for injection to 10L, stir evenly, add 0.5% activated carbon for injection, stir, and decarbonize to obtain the final product.

[0054] Formulation Example 8: Epimedium Acid Injection

[0055]

[0056] Preparation process: Add icariin to the prescribed amount of PEG-400, stir to dissolve, add 0.9% sodium chloride solution to 10L, stir evenly, add 0.5% activated carbon for injection, stir, decarbonize, and the product is obtained.

[0057] Formulation Example 9: Epimedium Aglycone Injection

[0058] Epimedium aglycone 1g

[0059] 3.3L of ethanol

[0060] Add water for injection to 10L

[0061] Preparation process: Add the prescribed amount of ethanol to icariin, stir to dissolve, add water for injection to 10L, stir evenly, add 0.5% activated carbon for injection, stir, and decarbonize to obtain the product.

[0062] Formulation Example 10: Epimedium Aglycone Powder for Injection

[0063]

[0064] Preparation process: Weigh the prescribed amount of icariin for injection and dissolve it in an appropriate amount of water for injection. Then, add the specified amount of pre-sterilized and pyrogen-free treated material and mix well, then add water for injection to the specified volume of 1000 ml. Add 5 g of activated charcoal for injection to the above solution, heat at 60-80℃ for 30 minutes, filter through a filter membrane, and collect the filtrate. Filter the filtrate under aseptic conditions using a sterile filter under positive pressure, and then filter through a 0.22 μM microporous membrane. Perform pyrogen and semi-finished product content checks on the filtrate, and then dispense into vials. Pre-freeze in a dedicated freeze-drying chamber at -40℃ for 1.5-3.5 hours, sublimate under vacuum until 90% of the free water is removed, and then heat to dry (maximum temperature not exceeding 35℃). After freeze-drying, icariin powder for injection is obtained.

[0065] Pharmacological Example 1: Effect of icariin on prolonged bleeding time in mice induced by heparin sodium

[0066] 1. Experimental animals and grouping

[0067] Ninety-six 5-6 week old ICR mice, weighing 19-21g, were used, with half being male and half female. The mice were quarantined for 7 days after entering the laboratory, and healthy mice were selected as test animals. They were weighed on the first and last days of quarantine.

[0068] Based on their weight at the end of quarantine, male and female animals were divided into six groups using a simplified randomization method: normal group (C), model group (V), low, medium, and high dose groups of icariin (2, 6, and 18 mg / kg, L, M, and H), and positive control group (200 mg / kg ethamsylate, P).

[0069] 2. Pre-treatment and model establishment

[0070] After grouping, the normal group and model group were administered 10 ml / kg of icariin solvent by gavage. The icariin dosage groups were administered 2, 6, and 18 mg / kg of icariin by gavage, respectively, once daily for five consecutive days. The positive control group was injected intraperitoneally with 200 mg / kg ethamsylate injection once daily for five consecutive days. One hour after the last pre-administration, the model group and all drug administration groups were injected with 150 U / kg heparin sodium injection via tail vein to establish the model, while the normal group was injected with 10 ml / kg sodium chloride injection via tail vein.

[0071] 3. Detection indicators

[0072] 3.1 Bleeding time

[0073] Fifteen minutes after modeling, the tails of each mouse were clipped to measure the bleeding time.

[0074] 3.2 Complete blood count and coagulation panel

[0075] After determining the bleeding time, mice were anesthetized with sodium pentobarbital, and blood was collected from the abdominal main vein to test complete blood count and coagulation parameters (PT, APTT, TT, FIB).

[0076] 4. Test Results

[0077] 4.1 Bleeding time

[0078] The bleeding time of mice in each group is shown in Table 1. Compared with the normal group, the bleeding time of mice in the model group was significantly prolonged, indicating successful modeling. Compared with the model group, the bleeding time of mice in each treatment group was significantly shortened, indicating that icariin can shorten the bleeding time of bleeding mice. The shortening of bleeding time is more significant with increasing dose, indicating that the procoagulant effect of icariin is dose-dependent. Furthermore, the high-dose group showed a significant difference compared with the positive control group, indicating that the procoagulant effect of icariin is better than that of the positive control.

[0079] Table 1. Effect of icariin on heparin sodium-induced bleeding time in mice.

[0080] C 12 16.2±3.3 V 12 <![CDATA[35.5±9.8 ## ]]> P 12 <![CDATA[21.4±6.7 ﹩ ]]> L 12 <![CDATA[26.4±8.8 ﹩ ]]> M 12 <![CDATA[22.7±9.1 ﹩ ]]> H 12 <![CDATA[15.9±6.6 ﹩﹩& ]]>

[0081] Compared with the normal group, ## P<0.01;

[0082] Compared with the model group, ﹩ P<0.05, ﹩﹩ P<0.01;

[0083] Compared with the positive control group, & P<0.05.

[0084] 4.2 Complete blood count and coagulation panel

[0085] The results of routine blood tests and coagulation parameters for each group of mice are shown in Tables 2 and 3, respectively.

[0086] Table 2. Results of routine blood tests in mice of each group

[0087]

[0088] Table 3 Results of coagulation tests in mice of each group

[0089]

[0090] As can be seen from the table above, there were no significant differences in the blood routine and coagulation parameters among the groups of mice, indicating that icariin had no significant effect on blood routine and coagulation parameters when it shortened the bleeding time prolongation caused by heparin sodium.

[0091] Pharmacological Example 2: Effect of Icariin on Bleeding Complications Caused by Thrombolytic Drugs

[0092] 1. Model Preparation

[0093] Sixty male Wistar rats (SPF grade), weighing 220-260g, were randomly divided into a myocardial infarction model group (N=12) and a control group (N=48) using a randomized controlled random number table. They were housed in separate cages with four rats per cage. After recording normal electrocardiograms, the rats in the myocardial infarction model group were subcutaneously injected with isoproterenol (ISO) 150 mg / kg. -1 .d -1 The rats were administered isoproterenol at a dose of 0.2 mL / 100 g, with 24-hour intervals for two consecutive days. The control group received the same subcutaneous injection of an equal volume (0.2 mL / 100 g) of physiological saline for two consecutive days. Electrocardiograms were monitored 24 hours after the second subcutaneous injection of isoproterenol. After ether anesthesia, simultaneous six-lead (limb lead) electrocardiograms were recorded before and after the injection. Heart rate was measured, and the degree of Q wave and ST segment deviation was observed to assess the success of the model. ST segment elevation greater than 0.2 mV or a Q wave in lead II was used as the criterion for myocardial infarction.

[0094] 2. Grouping and administration

[0095] Thirty-six rats were selected for the modeling process and randomly divided into a model group, a thrombolytic group, and a thrombolytic drug + icariin group. The thrombolytic group was given rt-PA at 5 mg / kg via the femoral vein. The thrombolytic drug + icariin group was given the same dose of thrombolytic drug and icariin (18 mg / kg) by gavage. The model group was given a normal volume of saline via the femoral vein.

[0096] 3. Detection indicators

[0097] 3.1 Electrocardiogram monitoring of rats in each group

[0098] Rats were anesthetized by ether inhalation. Once the rats were in anesthetized state, their breathing was stable, their righting reflex disappeared, and their pain sensation was absent, they were placed in a supine position and fixed on the experimental table. Needle electrodes were inserted subcutaneously into the limbs of the rats (care should be taken to avoid inserting them into the muscles). Electrocardiogram (ECG) monitoring was performed using limb leads, with the following settings: right upper limb - red, left upper limb - yellow, left hind limb - green, right hind limb - black. The ECG machine was turned on, with a paper speed of 50 mm / s and a voltage of 1 mV. After the ECG was completed, the animals were returned to their cages.

[0099] 3.2 Morphological observation of rat heart tissue in each group

[0100] After the last administration, the animals were euthanized, fixed supine on a rat board, and the skin was disinfected with 75% alcohol. The chest was quickly opened, and the skin and subcutaneous tissue were cut along the midline of the sternum with tissue scissors. The left rib of the sternum was cut, the major blood vessels were cut, and the heart was removed. The remaining blood in the heart chambers was washed away with 0.9% sodium chloride solution at 4°C. The left and right atrial appendages and the remaining major blood vessels were removed and dried with filter paper. The lung mass and heart mass of the rat were calculated by weighing with an electronic balance. The actual weight of the heart (wet weight) was measured and the ratio of its weight to the body weight was calculated (HWI = heart weight / body mass).

[0101] 3.3 Observation of hemorrhage complications in rats of each group

[0102] The bleeding conditions of rats in each group were observed, including subcutaneous bleeding points. After dissection, the bleeding conditions of internal organs and intracranial hemorrhage were observed.

[0103] 4. Experimental Results and Discussion

[0104] 4.1 Electrocardiogram results of each group

[0105] Compared to the control group, the model group rats showed pathological Q waves, indicating successful model establishment. Compared to the model group, the pathological Q waves disappeared in both the thrombolysis group and the thrombolysis + icariin group, indicating that thrombolytic drugs can significantly improve the myocardial infarction status in rats with myocardial infarction, and that icariin does not affect the thrombolytic effect of the thrombolytic drugs.

[0106] 4.2 Comparison of gross morphology of the hearts of rats in different groups

[0107] Gross morphology of the rat hearts in each group was observed. The model group showed significantly larger heart volume and a significantly enlarged left ventricular cavity compared to the control group. Transmural necrosis of the infarcted myocardium was observed, resulting in a pale white and thinned appearance. The thrombolysis group and the thrombolytic drug + icariin group showed significantly less heart volume increase and transmural necrosis compared to the model group. The heart weight and heart weight to body weight ratio of each group are shown in the table below. The table shows a significant difference in the heart weight to body weight ratio between the model group and the control group (P<0.01), indicating successful model establishment. The thrombolysis group and the thrombolytic drug + icariin group showed significant differences compared to the model group (P<0.01), while there was no significant difference between the thrombolysis group and the thrombolytic drug + icariin group. This indicates that the thrombolytic drug significantly improved the myocardial infarction status in rats with myocardial infarction, and icariin did not affect the efficacy of the thrombolytic drug.

[0108] Table 4 Comparison of gross morphology of rat hearts in different groups

[0109]

[0110] Compared with the control group, ## P<0.01;

[0111] Compared with the model group, ﹩﹩ P<0.01.

[0112] 4.3 Comparison of hemorrhage complications in rats of the drug-treated groups

[0113] Table 5 Comparison of hemorrhage complications in rats of the treatment groups

[0114]

[0115]

[0116] Compared with the thrombolysis group, ## P<0.01.

[0117] As can be seen from the table above, the bleeding percentage in the thrombolysis group was significantly higher than that in the thrombolytic drug + icariin group, which was statistically significant (P<0.01). This result indicates that icariin can significantly reduce the incidence of bleeding complications caused by thrombolytic drugs.

[0118] Pharmacological Example 3: Effect of Icariin on Aspirin-Induced Prolongation of Bleeding Time in Mice

[0119] 1. Drugs and their sources

[0120] aspirin

[0121] Source: Shantou Jinshi Pharmaceutical Factory Co., Ltd.

[0122] Ethylphenidyl sulfonamide injection

[0123] Source: Shandong Fangming Pharmaceutical Group Co., Ltd.

[0124] 2. Experimental animals and grouping

[0125] Ninety-six 5-6 week old ICR mice, weighing 19-21g, were used, with half being male and half female. The mice were quarantined for 7 days after entering the laboratory, and healthy mice were selected as test animals. They were weighed on the first and last days of quarantine.

[0126] Based on their weight at the end of quarantine, male and female animals were divided into six groups using a simplified randomization method: normal group (C), model group (V), low, medium, and high dose groups of icariin (2, 6, and 18 mg / kg, L, M, and H), and positive control group (200 mg / kg ethamsylate, P).

[0127] 3. Pre-drug administration and model establishment

[0128] After grouping, the normal group and model group were administered 10 ml / kg of icariin solvent by gavage. The icariin dosage groups were administered 2, 6, and 18 mg / kg of icariin by gavage, respectively, once daily for five consecutive days. The positive control group was injected intraperitoneally with 200 mg / kg ethamsylate injection once daily for five consecutive days. One hour after the last pre-administration, the model group and all drug-administered groups were administered 20 mg / kg of aspirin by gavage to induce the model, while the normal group was administered an equal volume of physiological saline by gavage.

[0129] 4. Bleeding time detection

[0130] Fifteen minutes after modeling, the tails of each mouse were clipped to measure the bleeding time.

[0131] 5. Test Results

[0132] The bleeding time of mice in each group is shown in Table 6. Compared with the normal group, the bleeding time of mice in the model group was significantly prolonged, indicating successful modeling. Compared with the model group, the bleeding time of mice in each treatment group was significantly shortened, indicating that icariin can shorten the bleeding time of bleeding mice. The shortening of bleeding time is more significant with increasing dose, indicating that the procoagulant effect of icariin is dose-dependent. Furthermore, the high-dose group showed a significant difference compared with the positive control group, indicating that the procoagulant effect of icariin is better than that of the positive control.

[0133] Table 6. Effect of icariin on aspirin-induced bleeding time in mice.

[0134] C 12 19.2±4.5 V 12 <![CDATA[37.6±7.8 ## ]]> P 12 <![CDATA[26.4±6.4 ﹩ ]]> L 12 <![CDATA[28.4±9.8 ﹩ ]]> M 12 <![CDATA[24.7±7.3 ﹩ ]]> H 12 <![CDATA[16.7±7.2 ﹩﹩& ]]>

[0135] Compared with the normal group, ## P<0.01;

[0136] Compared with the model group, ﹩ P<0.05,﹩﹩ P<0.01;

[0137] Compared with the positive control group, & P<0.05.

Claims

1. The use of icariogenin in the preparation of a medicine for preventing and treating myocardial infarction thrombolysis and anti-thrombus hemorrhagic complications, characterized in that, The thrombolysis is thrombolysis performed using thrombolytic drugs; the antithrombotic therapy is antithrombotic treatment performed using one or more of anticoagulants or antiplatelet drugs; the bleeding complication is one or more of subcutaneous hemorrhage, intracranial hemorrhage, upper gastrointestinal bleeding, or gingival bleeding.

2. The use as described in claim 1, characterized in that, The thrombolysis described herein is thrombolysis performed using alteplase.

3. The use as described in claim 1, characterized in that, The aforementioned antithrombotic therapy refers to antithrombotic treatment during the onset of myocardial infarction and during primary and secondary prevention.

4. The use as described in claim 1, characterized in that, The antiplatelet drug is aspirin, and the anticoagulant is heparin sodium.

5. The use as described in claim 1, characterized in that, The drug for the prevention and treatment of myocardial infarction thrombolysis and antithrombotic bleeding complications is a pharmaceutical preparation containing icariin.

6. The use as described in claim 5, characterized in that, The pharmaceutical preparation is a solid or liquid preparation.

7. The use as described in claim 6, characterized in that, The pharmaceutical preparation is any one of the following: oil, emulsion, gel, aerosol, inhaler, spray, capsule, pill, patch, or suppository.

8. The use as described in claim 1, characterized in that, The dosage of the drug for the prevention and treatment of myocardial infarction thrombolysis and antithrombotic bleeding complications is 0.03 mg / kg-300 mg / kg.

9. The use as described in claim 8, characterized in that, The dosage of the drug for the prevention and treatment of myocardial infarction thrombolysis and antithrombotic bleeding complications is 0.3 mg / kg-30 mg / kg.

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