CN112870190A - Application of isovitexin in preparation of medicine for treating nerve injury caused by ischemia and/or hypoxia - Google Patents
Application of isovitexin in preparation of medicine for treating nerve injury caused by ischemia and/or hypoxia Download PDFInfo
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention provides application of isovitexin in preparing a medicament for treating nerve injury caused by ischemia and/or hypoxia, and solves the problem that only thrombolytic therapy is available for treating ischemic stroke at present and the medicament is relatively deficient; the invention researches the neuroprotective effect of isovitexin on an in-vivo and in-vitro cerebral ischemia injury model, proves that the isovitexin can remarkably reduce cerebral injury induced by ischemia and/or anoxia, is expected to be developed into a medicine for preventing and treating ischemic stroke, and effectively solves the problem of the lack of medicines for treating the cerebral stroke clinically at present.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of isovitexin in preparation of a medicine for treating nerve injury caused by ischemia and/or hypoxia.
Background
Stroke is one of the major causes of death and disability in adults. In recent years, although medical science has made many breakthrough progresses, in the aspect of treatment of ischemic stroke, only thrombolytic therapy is currently approved, but the treatment time window of thrombolytic therapy is about 4.5 hours, thrombolytic conditions are harsh, most patients cannot use thrombolytic therapy due to exceeding the treatment time window or other contraindications, and other therapeutic drugs are not available, so that timely and effective treatment cannot be achieved, and sequelae are left. In view of this, there is still a great need to explore more effective drug therapies.
Disclosure of Invention
The invention aims to solve the problem that only thrombolytic therapy is needed for treating ischemic stroke at present and the medicine is deficient, and provides application of isovitexin in preparing a medicine for treating nerve injury caused by ischemia and/or hypoxia and a medicine for treating nerve injury caused by ischemia and/or hypoxia.
The conception of the invention is as follows:
at present, the pathogenesis of ischemic stroke is not clear, but cerebral ischemic injury induces a large amount of free radicals to be released, so that oxidation and antioxidation are unbalanced, and therefore, the ischemic stroke is suggested to have a certain relation with oxidative stress injury. From the perspective of antioxidation, the application searches for a medicine which can have positive effect on the prevention and treatment of ischemic brain injury.
Isovitexin (Isovitexin, IVX, C)21H20O10) Belongs to the flavonoid active substance of the carbon glycoside, widely exists in dozens of plants in the nature, and has various biological effects; the chemical structure is as follows:
at present, researches on pharmacological actions of isovitexin mainly focus on aspects of reducing blood sugar, regulating memory, inhibiting alpha-glucosidase, reducing blood pressure, resisting oxidation and the like, although the application in the aspect of preventing and treating ischemic brain injury is not reported, because isovitexin carries more hydroxyl groups, the application aims to take the isovitexin as an effective component for treating nerve injury (for example, ischemic stroke) caused by ischemia and/or hypoxia, and verify the effect of the isovitexin.
In order to achieve the purpose, the technical solution provided by the invention is as follows:
use of isovitexin in the manufacture of a medicament for the treatment of neurological damage caused by ischemia and/or hypoxia.
Further, the nerve injury is ischemic stroke.
Further, the nerve damage comprises ischemia reperfusion and/or hypoxia reoxygenation induced nerve cell damage.
Furthermore, the preparation of the medicine comprises an injection, powder, pills, granules, capsules, oral tablets or oral liquid preparation which is prepared by singly using the isovitexin or mixing the isovitexin with other nerve protection medicines and/or pharmaceutically acceptable auxiliary materials.
The invention also provides a medicament for treating nerve damage caused by ischemia and/or hypoxia, which is characterized in that the effective component of the medicament is isovitexin.
Further, the pharmaceutical preparation comprises an injection, powder, pill, granule, capsule, oral tablet or oral liquid preparation which is prepared by using the isovitexin alone or in a ratio with other nerve protection medicaments and/or pharmaceutically acceptable auxiliary materials; wherein the content of isovitexin is not less than 30%.
Further, the medicine is granules, capsules or oral tablets, and the specific formula is as follows: 50mg of isovitexin, 10mg of sodium carboxymethyl cellulose and 100mg of soluble starch.
Further, the medicine is an injection, and the specific formula is as follows: 200mg of isovitexin, 30mmol/L sodium bicarbonate buffer solution and 0.2mL of sodium sulfite, wherein the total volume is 2 mL.
Meanwhile, the invention also provides a preparation method of the medicine for treating nerve injury caused by ischemia and/or anoxia, which is characterized in that,
when the medicine is granules, capsules or oral tablets; the preparation method comprises the following steps:
1) sieving dry powder of isovitexin under aseptic condition, weighing 50mg, adding 10mg sodium carboxymethylcellulose and 100mg soluble starch, mixing well, and granulating;
2) packaging the obtained granules to obtain granules;
packaging the obtained granule in empty capsule shell to obtain capsule;
the obtained granule is directly compressed into tablets and coated with film to obtain oral tablets.
When the medicine is an injection; the preparation method comprises the following steps:
1) taking 200mg of isovitexin and 0.2mL of sodium sulfite, and adding 30mmol/L sodium bicarbonate buffer solution until the total volume is 2 mL;
2) completely dissolving under aseptic condition, filtering with microporous membrane, packaging in 2mL ampoule, and sterilizing at 100 deg.C for 30 min.
The invention has the advantages that:
1. the invention combines the pathogenesis of nerve injury caused by ischemia and/or hypoxia and the specific pharmacological action of isovitexin, takes the isovitexin as the effective component for preparing the medicament for treating the nerve injury caused by ischemia and/or hypoxia, and proves that the isovitexin has obvious application value in preparing the medicament for treating the nerve injury caused by hypoxia/ischemia through a hippocampal neuron cell (HT22) oxygen sugar deprivation injury model and a rat middle cerebral artery occlusion Model (MCAO).
2. The invention provides a candidate drug for developing a new cerebral ischemic injury prevention and treatment drug, can be further developed as a new cerebral apoplexy treatment drug, effectively solves the problem of lack of clinical cerebral ischemic stroke drugs, and has wide source of isovitexin, good drug effect and good application prospect.
3. The isovitexin has strong antioxidant activity, can relieve a large amount of free radicals induced by cerebral ischemia injury, further plays a role in resisting ischemic stroke, and has no toxic or side effect after long-term use.
Drawings
FIG. 1 is a bar graph of the effect of different concentrations of isovitexin on the viability of HT22 neurons treated with oxygen deprivation/reoxygenation sugars.
FIG. 2 is a bar graph of the effect of different concentrations of isovitexin on the viability of the HT22 neural cell lactate dehydrogenase in an oxygen deprivation/reoxygenation sugar treatment.
FIG. 3 is a line graph showing the effect of low, medium and high doses of isovitexin on survival in MCAO rats.
FIG. 4 is a line graph showing the effect of low, medium and high dose of isovitexin on the neurological scores of MCAO rats.
FIG. 5 is a representative graph and bar chart of infarct size measurements of MCAO rats affected by low, medium and high doses of isovitexin.
Detailed Description
The invention is described in further detail below with reference to the following figures and specific examples:
drug effect verification of vitexin
Protective effect of A-isovitexin on HT22 cell oxygen sugar deprivation/reoxyglucose injury
1. Cell culture
The frozen mouse HT22 cell line is recovered and placed in a 25ml culture flask, and DMEM/F12 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin double antibody is added at 37 deg.C, 98% relative humidity and 5% CO2The culture box of (1) is used for conventional culture, when the cells are cultured to 70-80% of fusion degree, the liquid is changed, 0.25% of pancreatin is added for digestion and passage, and the cells in logarithmic growth phase are collected for subsequent experiments.
2. Cell grouping and drug pretreatment
Cells from the logarithmic growth phase were resuspended to a density of 5X 104cells/mL were inoculated into 96-well plates at 100. mu.L per well, and medium was added for conventional culture. The cells were divided into normal group (Control), oxygen sugar deprivation group (OGD/R), and different concentrations of isovitexin (1-40. mu.M IVX + OGD/R) pretreatment groups, each group being provided with 6 multiple wells. Complete medium, OGD/R and IVX + OGD/R, was used for Control group cellsThe group cells are respectively added with a solvent or IVX with the concentration of 1-40 mu M and cultured for 6h before the OGD molding is started.
3. Cellular OGD/R injury model
After the pretreatment of the drugs was completed, the stock culture was replaced with low-sugar DMEM. Placing the cells in a 37 deg.C constant temperature oxygen-deficient box, charging 95% N into the container2+ 5% CO2Mixing the gas, and culturing for 2h under oxygen deficiency. After the anoxic culture is finished, the cells are taken out from the ischemia box, and the low-sugar DMEM is replaced by a normal DMEM medium in 95% O2+5％CO2And (5) continuously culturing for 24h under normal culture conditions, thereby establishing a cell OGD/R model. The Control group cells were not treated to low sugar and oxygen deprivation.
4. Cell viability and lactate dehydrogenase Activity assays
And (3) detecting the survival rate of the cells by an MTT method, adding a culture solution containing 0.5 percent of MTT after the OGD/R molding is finished, and continuously culturing for 4 hours in an incubator at 37 ℃. Then 150. mu.L of DMSO was added to each well, the mixture was shaken on a shaker to dissolve the crystals sufficiently, and the OD value of each well was measured at 490nm using a microplate reader, and each set was repeated 6 times. Relative survival rate of each group of cells (OD samples-OD zeroed/OD controls-OD zeroed) x 100%
The activity of cell Lactate Dehydrogenase (LDH) is detected by a colorimetric method, after cell OGD/R is molded, the cell is centrifuged and supernatant liquid of each hole is absorbed, LDH working solution is added and mixed evenly, and incubation is carried out at room temperature in a dark place. The absorbance of each well was measured at 490 nm. LDH activity was calculated for each group of cells according to a standard curve.
5. Statistical analysis
Statistical analysis was performed using SPSS 18.0 software, all values are expressed as means ± standard deviation, and comparisons between groups were performed using one-way analysis of variance (ANOVA) and Tukey test. P <0.05 indicates statistical significance.
6. Results of the experiment
The results of the cell viability assay are shown in Table 1 and FIG. 1. Compared with the normal Control group (Control) cells, the survival rate of the cells after OGD/R injury is obviously reduced (P is less than 0.01), and the survival rate of the cells of the Isovitexin (IVX) pretreatment group is improved. Compared with the OGD/R group, the IVX pretreatment groups with 5. mu.M, 10. mu.M, 20. mu.M and 40. mu.M have obviously higher cell survival rate and have significant statistical difference (P < 0.05). The cell survival rate result shows that IVX has obvious protective effect on mouse hippocampal neuron OGD/R injury and presents a certain concentration dependence.
LDH is an enzyme released from the cell after cell death, and measuring the activity of LDH allows assessment of cell death. The results are shown in figure 2, compared with the Control group cells, the LDH activity of the cells after OGD/R injury is obviously improved (P is less than 0.01); compared with the OGD/R group, IVX (10/20/40 mu M) pretreated cells have significantly reduced LDH relative activity (P <0.05) after OGD/R-induced injury. The LDH determination result shows that IVX has obvious protective effect on mouse hippocampal neuron OGD/R injury.
Table 1 results for cell viability and LDH release in each group (n ═ 6)
| Group of | Cell viability (%) | LDH Activity (%) |
| |
100±1.87 | 100±1.28 |
| OGD/R | 53.02±5.52** | 163.42±14.93 |
| OGD/R+IVX(1μM) | 57.93±8.65 | 164.81±10.08 |
| OGD/R+IVX(5μM) | 66.30±8.51# | 153.25±9.19 |
| OGD/R+IVX(10μM) | 73.60±5.56# | 138.23±9.26# |
| OGD/R+IVX(20μM) | 80.66±7.32# | 128.03±5.70# |
| OGD/R+IVX(40μM) | 82.74±5.90# | 131.45±6.91# |
7. Conclusion of the experiment
The isovitexin has protective effect on ischemia reperfusion injury simulated by nerve cell hypoxia sugar/reoxyglucose.
In order to fully confirm the protective effect of isovitexin on ischemic stroke, further verification is performed by animal experiments below.
Protection effect of B isovitexin on cerebral ischemic injury of rats
1. Preparation of experimental animal and cerebral ischemia model
Healthy male SD, weight 200 ~ 250g, 7 ~ 8 weeks old, rat are provided by air force military medical university experimental animals center, and the animal ethics complies with the experimental animals management and use guide 2016 edition. Rats were fasted for 12h before surgery, but had free access to water, and a model of cerebral ischemia/reperfusion injury was made in rats by the wire embolization Method (MCAO). Rats were anesthetized with isoflurane inhalation (induction 3%, maintenance 1.5%), a vertical port was cut with surgical scissors in the middle of the neck, and the right common carotid artery, external carotid artery and internal carotid artery were isolated bluntly; a silk thread is threaded into the root of the right common carotid artery for standby. And (3) separating the common carotid artery upwards to a bifurcation, cutting a round small opening at the bifurcation of the common carotid artery, and inserting a 4A-grade nylon thread into the internal carotid artery for about 17-18 mm until slight resistance exists. After 2h of ischemia, the nylon thread of the internal carotid artery is gently pulled out, and the blood circulation is restored to realize reperfusion. The sham group was identical in all the operative procedures except that no nylon suture plug was inserted.
2. Animal grouping and administration
Rats were divided into: sham (Sham), Model (MCAO), low (5mg/kg), medium (10mg/kg), high (20mg/kg) isovitexin treatment (MCAO + IVX), 10 individuals per group. Each group was administered with 0.5mL of isovitexin solution or physiological saline at different concentrations by intraperitoneal injection, followed by 1 administration every 24 hours for 7 days.
3. Survival and neurological scoring
Survival rates were calculated by recording the number of surviving rats per group within 7 days of MCAO surgery. Animals were scored for neurological function on days 1, 3, 5 and 7 post MCAO, respectively, with reference to an improved neurological scoring criterion: the rat nerve injury degree indicator comprises six items of autonomic activity, limb paralysis, climbing, limb movement, somatosensory sensation and nerve reflex, wherein each item is divided into 0, 1, 2 and 3 points, the total score is 18 points, and the lower the score is, the more serious the rat nerve injury degree is.
4. Cerebral infarction area determination
After completion of the neurosurgical scoring on day 7 after the operation of the rats, the rats were deeply anesthetized, sacrificed to take out the brains, and placed in ice saline to wash the blood tracks. And (3) cutting the brain into 2 mm-thick coronal sections by using an animal brain section die, and dyeing the coronal sections in a water bath at 37 ℃ in a dark place for 5-10 min by placing the coronal sections in a 2% TTC (2, 3, 5-triphenyltetrazolium chloride) solution. After staining was complete, fixation was performed with 4% paraformaldehyde buffer. Brain sections were photographed immediately after 24h fixation and percent cerebral infarct size was calculated using Image J (red for normal tissue and white for infarcted tissue). To correct for cases where the infarct size due to edema is larger than the actual value, the relative infarct size percentage is used for calculation: the relative cerebral infarction area percentage is [ contralateral cerebral hemisphere area- (ischemic cerebral hemisphere area-infarct area)/contralateral cerebral hemisphere area ] x 100%.
5. Statistical method
Statistical analysis was performed using SPSS 18.0 software, all data expressed as means ± standard deviation, and comparisons between groups were performed using one-way analysis of variance (ANOVA) and Tukey test. P <0.05 indicates statistical significance. The plots were plotted using GraphPad Prism Version 5.0(GraphPad Software, La Jolla, Calif.).
6. Results of the experiment
The survival rate calculation results are shown in figure 3. Sham (Sham) rats all survived with 100% survival. Model group (MCAO) rats died 4 on day 1 after molding, 1 on each of day 3 and 5, and had a survival rate of 40% within 7 days. IVX rats in the low dose group died 5 rats (1 unconscious death) within 7 days after MCAO surgery, and the survival rate was 50%; IVX the rat dies within 7 days after MCAO operation, the survival rate is 70%; IVX the high-dose rat died 1 rat within 7 days after MCAO operation, and the survival rate was 90%.
The results of the neurosurgical scoring are shown in table 2 and figure 4. No obvious neurological deficit was seen in the Sham group. Compared with the Sham group, the neurological scores of the MCAO group were significantly reduced on days 1, 3, 5 and 7 (P <0.01), indicating severe neurological impairment. IVX rats in the low dose group had significantly higher neurological scores on day 5 compared to the MCAO group; while the neurological score of IVX rats in the medium and high dose groups was significantly increased on days 5 and 7 (P < 0.05). The results of neuroscience experiments prove that IVX can obviously improve the neurological function defect caused by cerebral ischemia-reperfusion.
TABLE 2 neurological scoring results (n > 5) for each group of rats
The cerebral infarct size measurements are shown in table 3 and figure 5. No white infarct was observed in Sham, a large area of white infarct was observed in MCAO, and fewer infarcts were observed in MCAO + IVX. The statistical result of the cerebral infarction area shows that the cerebral infarction area of the MCAO group is obviously increased (P is less than 0.01) compared with the Sham group; compared with MCAO, MCAO + IVX group rat cerebral infarction area is reduced significantly (P <0.05), proves IVX has obvious protective effect on cerebral ischemia reperfusion injury.
TABLE 3 cerebral infarction area determination results (n > 5) for each group of rats
| Group of | Cerebral infarction area (%) |
| |
0 |
| MCAO | 39.35±4.74** |
| MCAO+IVX(5mg/kg) | 34.67±8.13# |
| MCAO+IVX(10mg/kg) | 28.19±5.32# |
| MCAO+IVX(20mg/kg) | 19.17±6.86# |
7. Conclusion of the experiment
The isovitexin has a protective effect on cerebral ischemia reperfusion injury of rats, and the isovitexin can be used for preparing a medicament for treating ischemic stroke.
Preparation of medicine for treating nerve injury caused by ischemia and/or anoxia
The isovitexin is used as an effective component, can be independently used or prepared into injections, powder, pills, granules, capsules, oral tablets or oral liquid preparations by being matched with other nerve protection medicaments and/or pharmaceutically acceptable auxiliary materials, and the content of the isovitexin in the medicaments is not lower than 30%. Now, the following examples are given:
when the medicine A is granules, capsules or oral tablets, the preparation method comprises the following steps:
1) sieving dry powder of isovitexin under aseptic condition, weighing 50mg, adding 10mg sodium carboxymethylcellulose and 100mg soluble starch, mixing well, and granulating;
2) packaging the obtained granules to obtain granules;
packaging the obtained granule in empty capsule shell to obtain capsule;
the obtained granule is directly compressed into tablets and coated with film to obtain oral tablets.
When the B medicament is an injection, the preparation method comprises the following steps:
1) taking 200mg of isovitexin and 0.2mL of sodium sulfite, and adding 30mmol/L sodium bicarbonate buffer solution until the total volume is 2 mL;
2) completely dissolving under aseptic condition, filtering with microporous membrane, packaging in 2mL ampoule, and sterilizing at 100 deg.C for 30 min.
While the invention has been described with reference to specific embodiments, the invention is not limited thereto, and various equivalent modifications or substitutions can be easily made by those skilled in the art within the technical scope of the present disclosure.
Claims (10)
1. Use of isovitexin in the manufacture of a medicament for the treatment of neurological damage caused by ischemia and/or hypoxia.
2. Use according to claim 1, characterized in that:
the nerve injury is ischemic stroke.
3. Use according to claim 1, characterized in that:
the nerve damage comprises ischemia reperfusion and/or hypoxia reoxygenation induced nerve cell damage.
4. Use according to any one of claims 1 to 3, wherein:
the preparation of the medicine comprises an injection, powder, pills, granules, capsules, oral tablets or oral liquid preparation which is prepared by singly using the isovitexin or mixing the isovitexin with other nerve protection medicines and/or pharmaceutically acceptable auxiliary materials.
5. A medicament for treating neuronal damage caused by ischemia and/or hypoxia, characterized by: the effective component is isovitexin.
6. The medicament of claim 5, wherein:
the pharmaceutical preparation comprises isovitexin used alone or injection, powder, pill, granule, capsule, oral tablet or oral liquid preparation prepared by mixing with other nerve protection drugs and/or pharmaceutically acceptable adjuvants;
wherein the content of isovitexin is not less than 30%.
7. The medicament according to claim 5 or 6, wherein:
the medicine is granules, capsules or oral tablets, and the specific formula is as follows: 50mg of isovitexin, 10mg of sodium carboxymethyl cellulose and 100mg of soluble starch.
8. The medicament according to claim 5 or 6, wherein:
the medicine is an injection, and the specific formula is as follows: 200mg of isovitexin, 30mmol/L sodium bicarbonate buffer solution and 0.2mL of sodium sulfite, wherein the total volume is 2 mL.
9. The process for the preparation of a medicament according to claim 5 for the treatment of neuronal damage caused by ischemia and/or hypoxia, characterized in that:
the medicine is granules, capsules or oral tablets;
the preparation method comprises the following steps:
1) sieving dry powder of isovitexin under aseptic condition, weighing 50mg, adding 10mg sodium carboxymethylcellulose and 100mg soluble starch, mixing well, and granulating;
2) packaging the obtained granules to obtain granules;
packaging the obtained granule in empty capsule shell to obtain capsule;
the obtained granule is directly compressed into tablets and coated with film to obtain oral tablets.
10. The process for the preparation of a medicament according to claim 5 for the treatment of neuronal damage caused by ischemia and/or hypoxia, characterized in that:
the medicine is an injection;
the preparation method comprises the following steps:
1) taking 200mg of isovitexin and 0.2mL of sodium sulfite, and adding 30mmol/L sodium bicarbonate buffer solution until the total volume is 2 mL;
2) completely dissolving under aseptic condition, filtering with microporous membrane, packaging in 2mL ampoule, and sterilizing at 100 deg.C for 30 min.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0873360A (en) * | 1994-09-01 | 1996-03-19 | Yoshihide Hagiwara | Suppressing agent against brain nerve cell injury |
| CN105287499A (en) * | 2015-10-09 | 2016-02-03 | 成都普瑞法科技开发有限公司 | Natural pharmaceutical composition for preventing and treating cardiovascular and cerebrovascular diseases and application of pharmaceutical composition |
| CN105848659A (en) * | 2013-08-14 | 2016-08-10 | 大化制药株式会社 | Pharmaceutical composition for treating or preventing neuropsychitric disease, containing flavone-6-c-glucose derivatives as active ingredients |
| CN107865837A (en) * | 2016-09-23 | 2018-04-03 | 淄博齐鼎立专利信息咨询有限公司 | Isovitexin is preparing the application in treating ischemic brain damage medicine |
| CN107865842A (en) * | 2016-09-23 | 2018-04-03 | 淄博齐鼎立专利信息咨询有限公司 | Applications of the Isovitexin in anti-anoxic medicine is prepared |
-
2021
- 2021-01-19 CN CN202110071595.XA patent/CN112870190A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0873360A (en) * | 1994-09-01 | 1996-03-19 | Yoshihide Hagiwara | Suppressing agent against brain nerve cell injury |
| CN105848659A (en) * | 2013-08-14 | 2016-08-10 | 大化制药株式会社 | Pharmaceutical composition for treating or preventing neuropsychitric disease, containing flavone-6-c-glucose derivatives as active ingredients |
| CN105287499A (en) * | 2015-10-09 | 2016-02-03 | 成都普瑞法科技开发有限公司 | Natural pharmaceutical composition for preventing and treating cardiovascular and cerebrovascular diseases and application of pharmaceutical composition |
| CN107865837A (en) * | 2016-09-23 | 2018-04-03 | 淄博齐鼎立专利信息咨询有限公司 | Isovitexin is preparing the application in treating ischemic brain damage medicine |
| CN107865842A (en) * | 2016-09-23 | 2018-04-03 | 淄博齐鼎立专利信息咨询有限公司 | Applications of the Isovitexin in anti-anoxic medicine is prepared |
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