CN111084770A - Application of salvianolic acid A in preparing anti-cerebral hemorrhage drugs - Google Patents

Abstract

The invention discloses an application of salvianolic acid A in preparing a medicament for treating cerebral hemorrhage, wherein the cerebral hemorrhage comprises simple cerebral hemorrhage apoplexy, hemorrhage caused by cerebral embolism and thrombolytic medicament treatment. Experimental research shows that the salvianolic acid A can remarkably reduce the cerebral infarction volume and the cerebral edema of rats, improve the nerve function and protect blood brain barrier injury caused by thrombolytic drugs such as t-PA and the like, thereby reducing the risk and degree of hemorrhagic transformation when the thrombolytic drugs are used. The salvianolic acid A can be used for preparing medicines for treating cerebral hemorrhage and hemorrhage caused by thrombolytic drug therapy, relieving secondary hemorrhage in ischemic region, and improving patient prognosis.

Description

Application of salvianolic acid A in preparing anti-cerebral hemorrhage drugs

Technical Field

The invention relates to a new application of a salvianolic acid A compound in preparation of a medicament, mainly relates to an application of salvianolic acid A in preparation of a medicament for treating side effects of cerebral hemorrhage caused by hemorrhagic stroke and thrombolytic medicaments, and particularly relates to an application of salvianolic acid A in preparation of a medicament for hemorrhagic transformation after cerebral embolism is caused and cerebrovascular accidents caused by thrombolytic medicaments.

Background

Cerebral embolism refers to the blockage of cerebral vessels by various factors such as various emboli in blood (such as mural thrombus in heart, atherosclerotic plaque and the like) entering cerebral arteries along with blood flow, when collateral circulation can not be compensated, ischemic necrosis of cerebral tissues in the artery blood supply area is caused, and focal neurological defect is further generated. One of the key measures for treating cerebral embolism in clinic is to relieve vascular embolism and restore blood supply in an ischemic area. Therefore, thrombolytic therapy becomes a key link for clinical treatment of acute stroke. Currently, the official approval of clinical drugs is very limited, and the FDA in the united states approved the thrombolytic therapy of acute cerebral infarction (acute cerebral infarction) using recombinant tissue plasminogen activator (t-PA) in 1996, and thus t-PA thrombolytic therapy is the only internationally accepted drug therapy.

Thrombolytic therapy is a major breakthrough in acute cerebral ischemia treatment, effectively reduces morbidity mortality, and saves lives of patients with acute cerebral ischemia. However, clinical treatment with t-PA is likely to show a strong side effect, i.e. Hemorrhagic Transformation (HT). Clinical studies found that the incidence of HT was 13-43%, and necropsy results showed this proportion to be as high as 38-71%. After the t-PA is used for thrombolysis, the incidence rate of HT can be increased by 10 times, and the death rate reaches 60%. Even with the expansion of the treatment window from 3h to 4.5h, only about 3.4% -5.2% of patients with acute stroke receive t-PA treatment. The narrow therapeutic window and high incidence of HT limits the clinical utility of t-PA. The risk of development of HT by thrombolysis is mainly related to the dose, route, time of administration and type of thrombolytic drug. At present, no medicine for effectively reducing the incidence rate of HT or treating HT exists clinically. Therefore, the medicine for reducing the injury of reperfusion to blood vessels to inhibit cerebral hemorrhage is a development direction of the medicine for relieving cerebrovascular accident, improving the prognosis of stroke patients and treating ischemic stroke and hemorrhagic stroke.

Salvia miltiorrhiza (Salvia miliiorrhiza Bge.) is a dried root of a plant of the genus Salvia of the family Labiatae. The salvia miltiorrhiza is an important traditional Chinese medicine, and the traditional medicine considers that the salvia miltiorrhiza has the effects of removing blood stasis, relieving pain, activating blood, stimulating the menstrual flow, clearing away the heart-fire and relieving restlessness. Recently, the research on the effect of the salvia miltiorrhiza mainly focuses on improving the ischemia reperfusion injury of organs such as heart, brain, liver, lung and the like; damage to liver cells, liver fibrosis and liver cancer; regulating immune response, resisting infection and tumor, etc.

Salvianolic acid A is a water-soluble effective component which is firstly separated from Salvia miltiorrhiza bge by professor of Rilienne who is a pharmaceutical research institute of Chinese academy of medical sciences, and the chemical structure of the component is firstly determined. The systematic chemical name is (2R) -3- (3, 4-hydroxyphenyl) -2- [ (E) -3- [2- [ (E) -2- (3, 4-dihydroxyphenyl) ethenyl ] -3, 4-dihydroxyphenyl ] prop-2-enoyl ] oxypropionic acid. Salvianolic acid A has wide pharmacological activity, and plays an important role in regulating cardiovascular and cerebrovascular diseases, liver diseases, diabetes and complications thereof, tumors and other diseases. In cerebral ischemia research, the salvianolic acid A can improve nerve function, reduce infarct volume and cerebral edema and reduce the nerve damage degree of related brain areas. Further research shows that the salvianolic acid A can inhibit nerve cell apoptosis through an Akt pathway, improve the activity of enzymes such as SOD, GSH-PX and the like to play an antioxidation role by activating an Nrf2/HO-1 signal pathway, and has a better anti-cerebral ischemia role in different cerebral ischemia models of different species. At present, no application report of salvianolic acid A in preparing anti-cerebral hemorrhage medicines is available.

Disclosure of Invention

The invention aims to provide the application of salvianolic acid A in preparing anti-cerebral hemorrhage medicaments, in particular to preparing hemorrhagic transformation after cerebral embolism and cerebral microvascular hemorrhage caused by thrombolytic medicaments and other factors, thereby providing a solution for thrombolytic treatment of cerebral embolism, which reduces the risk of HT occurrence, improves the survival rate of patients and improves the prognosis.

Therefore, the invention provides the following technical scheme:

the first aspect of the technical proposal of the invention provides the application of salvianolic acid A shown as the formula I in preparing anti-cerebral-hemorrhage drugs,

the cerebral hemorrhage is cerebrovascular hemorrhage caused by hemorrhagic transformation after cerebral embolism. The hemorrhagic transformation after the cerebral embolism is the vascular secondary hemorrhage in an infarct area caused by the blood flow restoration of the blood vessels in an ischemic area due to the movement of embolus and other reasons during the pathogenesis.

The cerebral hemorrhage comprises simple cerebral hemorrhage apoplexy, and cerebrovascular hemorrhage caused by spontaneous hemorrhagic transformation after cerebral ischemia or by thrombolytic drug after cerebral thrombosis. The simple cerebral hemorrhagic stroke refers to hemorrhage caused by rupture of blood vessels in primary non-traumatic brain parenchyma. The cerebral hemorrhage caused by thrombolytic drugs refers to intracranial hemorrhage generated when cerebral embolism is treated by tissue plasminogen activator, recombinant human tissue plasminogen activator, urokinase and streptokinase, and the intracranial hemorrhage comprises cerebral hemorrhage, intracranial hematoma, subarachnoid hemorrhage, hemorrhagic stroke and hemorrhagic transformation of ischemic stroke.

The intracranial hematoma is a cerebrovascular accident generated in the venous thrombolysis treatment, and after the hemorrhage is gathered at a certain part of a cranial cavity and reaches a certain volume, the intracranial pressure is increased, and the brain tissue is pressed to cause corresponding clinical symptoms. The subarachnoid hemorrhage is a cerebrovascular accident generated in the intravenous thrombolysis treatment, and comprises two conditions of primary subarachnoid hemorrhage and secondary subarachnoid hemorrhage. The thrombolytic drug is only effective in treatment within a certain time window, and the salvianolic acid A can effectively prolong the treatment window of the thrombolytic drug and show better treatment effect.

The primary subarachnoid hemorrhage refers to cerebrovascular accident caused by vein thrombolysis treatment of blood vessels at the bottom of brain or surface of brain and spinal cord.

The primary subarachnoid hemorrhage refers to the condition that blood penetrates through brain tissues and flows into the subarachnoid space in the cerebral parenchyma, cerebral ventricle, epidural or subdural cerebral vascular accidents in the venous thrombolysis treatment.

The cerebrovascular hemorrhage caused by the thrombolytic drug refers to the condition that the permeability of microvessels is increased due to the side effect of the thrombolytic drug, so as to cause hemorrhage and vascular rupture.

The second aspect of the technical scheme of the invention provides application of a pharmaceutical composition in preparing a medicament for resisting cerebral hemorrhage, which is characterized in that the pharmaceutical composition contains therapeutically effective amount of salvianolic acid A shown as formula I and a pharmaceutically acceptable carrier;

the cerebral hemorrhage comprises cerebral hemorrhage caused by hemorrhagic transformation after cerebral embolism and cerebral hemorrhage caused by thrombolytic drugs.

The dosage forms of the pharmaceutical composition comprise oral preparations, injection administration dosage forms and skin mucosa route administration dosage forms.

The oral preparation comprises tablets, sustained-release agents, capsules, controlled-release agents, dripping pills and liquid preparations, and the injection administration dosage forms comprise intramuscular injection, intravenous injection and intravenous drip.

Further, the salvianolic acid A and a pharmaceutically acceptable carrier are prepared into various dosage forms of anti-cerebral-hemorrhage medicaments according to a conventional preparation method;

further, the salvianolic acid A and a pharmaceutically acceptable carrier are prepared into an anti-cerebral-hemorrhage medicament of an injection according to a conventional preparation method and are used together with a thrombolytic medicament.

The invention therefore also relates to pharmaceutical compositions containing the compounds according to the invention as active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like. The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.

For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.

In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or the mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field are added, wherein the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- β -cyclodextrin and the like, the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like, the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like, and the mannitol, glucose and the like can be added as a propping agent when preparing freeze-dried powder injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired. For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method. The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable dosage range for the compounds of the invention is from 0.001 to 250mg/Kg body weight per day. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.

The invention has the beneficial effects that: the application of a rat intravascular thrombogenic acute cerebral apoplexy model to the cerebral hemorrhage resistance of salvianolic acid A, particularly the prevention of hemorrhagic transformation after cerebral embolism and the cerebral microvascular hemorrhage caused by factors such as thrombolytics and the like is investigated, and the results show that in the rat intravascular thrombogenic acute cerebral apoplexy model, through the combined use of the salvianolic acid A and t-PA, the salvianolic acid A can remarkably reduce the cerebral infarction volume and the cerebral edema, improve the nerve function, play a role in neuroprotection, simultaneously inhibit the blood brain barrier injury in the t-PA thrombolysis process, reduce the seepage amount of Evans blue and hemoglobin in ischemic brain tissues, have remarkable blood brain barrier protection effect, and can be used together with the thrombolytics in the thrombolysis treatment to reduce the risk of HT occurrence or relieve the hemorrhage degree. Therefore, the preparation method is suitable for preparing compound preparations used together with t-PA and similar thrombolytic drugs.

In addition, the main limiting factor of the clinical application of the current thrombolytic drugs is the narrow effective time window, generally 3-4.5 hours, which is the reason of the narrow time window, and the thrombolytic activity of the drugs is not reduced, but the hemorrhagic tendency of ischemic areas caused by the prolonged embolism time is related, and the application of salvianolic acid A can slow down the hemorrhagic tendency, possibly prolong the effective treatment time window of the thrombolytic drugs.

Drawings

FIG. 1 is a graph showing the effect of salvianolic acid A (5, 10, 20mg/kg) on the volume of cerebral infarction after a delay of 6h in the treatment of t-PA thrombolysis in a rat intravascular thrombolysis acute stroke model.^#P<0.05, compared to the t-PA group, n is 5.

FIG. 2 shows the effect of salvianolic acid A (5, 10, 20mg/kg) on cerebral edema after a delay of 6h in the rat model of intravascular thrombolysis and acute stroke.^#P<0.01, compared to the normal group,^**P<0.01, compared to the t-PA group, n is 5.

FIG. 3 shows the effect of salvianolic acid A (5, 10, 20mg/kg) on the nerve function of a rat model with intravascular thrombolysis and acute stroke after a delay of 6h for t-PA thrombolytic therapy. A: a neurological score; b: suspension experiment; c: rotating a rod for experiment; d: inclined plate experiment.^#P<0.05，^##P<0.01, compared to the t-PA group, n is 5.

FIG. 4 shows content of Evans blue in brain tissue after delay of 6h of treatment of rat intravascular thrombolysis with salvianolic acid A (5, 10, 20mg/kg) in acute stroke modelInfluence.^#P<0.05，^##P<0.01, compared to the normal group,^*P<0.05, compared to the t-PA group, n is 5.

FIG. 5 shows the effect of salvianolic acid A (5, 10, 20mg/kg) on the hemoglobin content in brain tissue after a delay of 6h in the treatment of t-PA thrombolysis in a rat intravascular thrombolysis acute stroke model.^#P<0.05, compared to the normal group,^*P<0.05, compared to the t-PA group, n is 5.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings, in which:

example 1 reduction of brain caused by delayed administration of t-PA in model of rat intravascular thrombogenic acute cerebral apoplexy by Salvianolic acid A

Infarct volume.

Experimental materials: sprague Dawley (SD) rats were purchased from Wintolite (Experimental animal technologies, Inc., Weitonlite, Beijing). t-PA was purchased from Boehringer Invighland (Boehringer-Ingelheim, Germany). The salvianolic acid A powder is provided by the drug screening center of the institute of medicine of Chinese academy of medical sciences. The injection is administered by adding injectable physiological saline (Shijiazhu pharmaceutical IV factory) at dosage of 5, 10, and 20 mg/kg. SD rats in the weight range of 250-300g were anesthetized by intraperitoneal injection of chloral hydrate (350 mg/kg). The hair near bregma is shaved, and the top skin is cut and bregma is exposed. Selecting 2mm behind bregma and 5mm at the right side as a cerebral blood flow measuring point, and positioning and fixing a probe seat of the laser Doppler blood flow meter. The supine position was fixed on a mouse plate, and the blood flow reference value within 5min was recorded after the PU reading was stabilized.

The skin of the neck of the rat was incised, the common carotid artery and the external carotid artery were separated, and the external carotid artery was clamped with an artery clamp. The common carotid artery is placed in a groove of a blood vessel electric stimulation clamp of a YLS-14B small animal thrombosis generator, and electric shock is carried out by selecting the current intensity of 1.00mA and the stimulation time of 240 s. After the electric shock is finished, the carotid artery at the distal end is clamped by an artery clamp. The thrombus is crushed by soft forceps from the far end to the near end. And (3) releasing the artery clamps, observing 1-5s after thrombus fragments are washed away, clamping the proximal end of the common carotid artery again for 15min, then taking down all the artery clamps, sterilizing and suturing, and determining that the target embolism model is formed when the blood flow value is reduced to below 30% of the reference value. After suturing, rats were placed in a 37 ℃ thermostatted system. Then, according to the experimental design, rats were placed in a 37 ℃ constant temperature system for 6 hours, and then administered by tail vein instillation for 20 min. The combined medicine group is injected with different dosages of salvianolic acid A immediately after t-PA is instilled.

Grouping experiments: blank group (except the electric shock operation, the rest is the same as the model group), n is 5; model group (injecting normal saline after 6h after molding), n is 5; t-PA group (t-PA is instilled according to 10mg/kg after 6h of molding), wherein n is 5; the combination medicine (t-PA is instilled according to 10mg/kg after molding for 6h, and salvianolic acid A5, 10 and 20mg/kg are immediately injected after instillation is finished), wherein n is 5.

The results show that after 6h of ischemia, the brain tissue is obviously infarcted, the infarct volume is increased by t-PA intravenous injection, and the dose-dependent cerebral infarct volume is reduced by various groups of salvianolic acid A, wherein the groups of 10 and 20mg/kg have statistical difference compared with the groups of t-PA, and the 20mg/kg effect is most obvious.

Table 1. influence of salvianolic acid A on cerebral infarction volume after delaying treatment of t-PA thrombolysis for 6h in a rat intravascular thrombolysis acute cerebral apoplexy model.

Example 2 Salvianolic acid A reduction of brain edema in a rat model of intravascular thrombogenesis acute stroke caused by delayed administration of t-PA

Animal models and administration methods were the same as in example 1. After 24h of ischemia, the brain tissue is taken and the wet weight and the dry weight are respectively weighed, and the brain water content is calculated by a dry-wet weight method so as to reflect the severity of the cerebral edema.

The results are shown in FIG. 2, in which the brain water content was significantly increased after ischemia and t-PA administration, and the brain water content was decreased dose-dependently in each group of salvianolic acid A, wherein the group of 20mg/kg was statistically different from the group of t-PA.

Effect of t-PA thrombolysis on post-cerebral infarction volume.^#P<0.05, compared to the t-PA group, n is 5.

Table 2. influence of salvianolic acid A on cerebral edema after delaying treatment of t-PA thrombolysis for 6h in a rat intravascular thrombolysis acute cerebral apoplexy model.

Example 3 Salvianolic acid A ameliorates neurological impairment caused by delayed administration of t-PA in a rat model of intravascular thrombogenic acute stroke.

Animal models and administration methods were the same as in example 1. After 24h of ischemia, rats were evaluated for neurological impairment by neurological scoring, bar transfer, suspension and ramp.

The results are shown in fig. 3, where each group of salvianolic acid A had a certain effect on neurological function, and the 20mg/kg group was statistically different from the t-PA group in the neurological scoring and rotarod experiments.

Table 3. influence of Salvianolic acid A on nerve function of the rat model with intravascular thrombolysis and acute cerebral apoplexy delayed for 6h after t-PA thrombolysis treatment.

Example 4 Salvianolic acid A reduces blood brain barrier damage caused by delayed administration of t-PA in a rat model of intravascular thrombogenic acute stroke.

In the experiment, the leakage of Evans' blue (EB) in brain tissues is used as an index of Blood Brain Barrier (BBB) damage, and the animal modeling and administration method are the same as in example 1. Rats were injected with 4% Evans blue (2ml/kg) intravenously at the tail 2h before sacrifice and brains were harvested after perfusion. 50% trichloroacetic acid was added at a ratio of 1:3 to the homogenate, and after centrifugation, the supernatant was collected and the absorbance at 620nm was measured.

As a result, as shown in FIG. 4, the EB content in the non-ischemic brain tissue was not significantly changed in each group. After 6h of ischemia, the EB content of the model group is increased, which shows that BBB is damaged, t-PA can further promote BBB damage, and the EB content is obviously increased. The EB content of the salvianolic acid A administration groups is reduced in a dose-dependent manner, wherein the 10mg/kg group and the 20mg/kg group have statistical difference compared with the t-PA group. Suggesting that the salvianolic acid A has protective effect on BBB injury caused by t-PA.

Table 4. influence of salvianolic acid A on brain EB content in rat intravascular thrombolysis acute cerebral apoplexy model after delay of 6h for t-PA thrombolysis treatment.

Example 5 Salvianolic acid A reduces bleeding caused by delayed administration of t-PA in a rat model of intravascular thrombogenic acute stroke.

Animal models and administration methods were the same as in example 1. The perfused brain tissue was homogenized and then measured for absorbance at 400nm according to the instruction of a hemoglobin measurement kit (DIHB-250, Bosch Biotechnology Co., Ltd., USA) to calculate the hemoglobin content in the brain tissue.

As a result, as shown in FIG. 5, the brain tissue was bled after the ischemia, and the bleeding injury was further aggravated by the intravenous drop of t-PA, and the hemoglobin content in the brain tissue was significantly increased. After the injection of the salvianolic acid A, the content of hemoglobin can be reduced in a dose-dependent manner, wherein the 20mg/kg group has statistical difference compared with the t-PA group. Meanwhile, the hemoglobin content in the non-ischemic side brain tissues among the groups has no obvious difference, which indicates that the salvianolic acid A can obviously inhibit bleeding caused by t-PA.

Table 5. influence of salvianolic acid A on brain hemoglobin content after delay of 6h in rat intravascular thrombolysis acute stroke model for t-PA thrombolysis treatment.

In conclusion, the invention adopts an intravascular thrombosis acute cerebral apoplexy model to investigate the cerebral hemorrhage resisting effect of the salvianolic acid A, and the result shows that: the salvianolic acid A can obviously inhibit t-PA from delaying cerebral tissue infarction and encephaledema caused by thrombolysis, improve nerve function, protect BBB and reduce hemorrhagic transformation caused by BBB injury. Therefore, the salvianolic acid A has a remarkable anti-cerebral hemorrhage effect. The salvianolic acid A is taken as an active substance and is singly used or/and combined with other compounds and/or extracts with pharmacological activity for compound use, and the salvianolic acid A is prepared into various preparations of anti-spontaneous cerebral hemorrhage medicaments according to the conventional preparation method in the pharmaceutical field, or is prepared into compound preparations with other thrombolytic medicaments such as t-PA, streptokinase, urokinase and the like for reducing the occurrence of hemorrhage in the thrombolytic process, thereby providing a more efficient and safer solution for the thrombolytic treatment of the thrombotic cerebral embolism.

Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (16)

1. The application of salvianolic acid A shown as formula I in preparing anti-cerebral hemorrhage drugs,

2. use according to claim 1, characterized in that said cerebral haemorrhage is a cerebral haemorrhage resulting from a haemorrhagic transformation including after the onset of cerebral embolism.

3. The use according to claim 2, wherein said hemorrhagic transformation after the onset of cerebral embolism is vascular secondary bleeding in the infarcted area caused by revascularization of the blood vessels in the ischemic area due to emboli migration or the like during the onset.

4. The use according to claim 1, wherein the cerebral hemorrhage comprises a cerebral haemorrhagic stroke alone, a cerebral hemorrhage induced by spontaneous haemorrhagic transformation following cerebral ischemia or by the administration of thrombolytic drugs following cerebral thrombosis.

5. The use according to claim 4, wherein said isolated cerebral haemorrhagic stroke is a hemorrhage due to rupture of blood vessels within primary non-traumatic brain parenchyma.

6. The use according to claim 4, wherein the cerebrovascular hemorrhage due to thrombolytic drug is intracranial hemorrhage occurring when cerebral embolism is treated by tissue plasminogen activator, recombinant human tissue plasminogen activator, urokinase, and streptokinase, and the intracranial hemorrhage includes cerebral hemorrhage, intracranial hematoma, subarachnoid hemorrhage, hemorrhagic stroke, and hemorrhagic transformation of ischemic stroke.

7. The use according to claim 6, wherein said intracranial hematoma is a cerebrovascular accident caused by the intravenous thrombolysis, and the blood is accumulated in a certain part of the cranial cavity and reaches a considerable volume, which causes an increase in intracranial pressure, and the brain tissue is compressed, which causes the corresponding clinical symptoms.

8. The use of claim 6, wherein the subarachnoid hemorrhage is a cerebrovascular accident resulting from a thrombolytic intravenous therapy, including both primary and secondary subarachnoid hemorrhage.

9. The use of claim 6, wherein the thrombolytic drug is therapeutically effective only within a time window, and the salvianolic acid A is effective to prolong the therapeutic window of the thrombolytic drug and to exhibit a better therapeutic effect.

10. The use according to claim 8, wherein said primary subarachnoid hemorrhage is a cerebrovascular accident caused by the treatment of blood vessels at the base of the brain or at the surface of the brain and spinal cord by venous thrombolysis.

11. The use according to claim 8, wherein said primary subarachnoid hemorrhage is a cerebral vascular accident occurring within the brain parenchyma, in the cerebral ventricle, epidural or subdural during the venous thrombolytic treatment, and a situation in which blood penetrates the brain tissue and flows into the subarachnoid space.

12. The use according to any one of claims 4 to 11, wherein the cerebrovascular bleeding caused by thrombolytic drugs is a condition in which the permeability of microvessels is increased due to side effects of thrombolytic drugs, which results in bleeding and vascular rupture.

13. The application of a pharmaceutical composition in preparing a medicament for resisting cerebral hemorrhage is characterized in that the pharmaceutical composition contains salvianolic acid A shown in formula I with a therapeutically effective amount and a pharmaceutically acceptable carrier; (ii) a

14. The use according to claim 13, wherein said cerebral hemorrhage comprises cerebral hemorrhage due to hemorrhagic transformation after cerebral embolism, cerebral hemorrhage due to thrombolytic drugs.

15. Use according to any one of claims 13 to 14, wherein said pharmaceutical composition is in the form of an oral preparation, an injectable preparation, or a transdermal mucosal route.

16. The use of claim 15, wherein the oral preparation comprises tablets, sustained release preparations, capsules, controlled release preparations, drop pills, and liquid preparations, and the injection administration forms comprise intramuscular injection, intravenous injection, and intravenous drip.

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