CN101984965A - Application of epicatechin gallate and derivatives thereof for treating or preventing myocardial infarction and other ischemic heart diseases - Google Patents
Application of epicatechin gallate and derivatives thereof for treating or preventing myocardial infarction and other ischemic heart diseases Download PDFInfo
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- 208000010125 myocardial infarction Diseases 0.000 title claims abstract description 35
- LSHVYAFMTMFKBA-UHFFFAOYSA-N ECG Natural products C=1C=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 LSHVYAFMTMFKBA-UHFFFAOYSA-N 0.000 title abstract description 74
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Abstract
The invention relates to an application of natural compound epicatechin gallate obtained from tea and derivatives thereof for treating or preventing myocardial infarction and other ischemic heart diseases. The compound is used for preventing the myocardial injury of the heart caused by ischemia-reperfusion, and is a medicament for potentially treating or preventing the heart ischemia/reperfusion injury. Particularly, the compound has a novel effect on protecting the heart and has a function that the enhancement of the myocardial contractility does not depend on the increase of the concentration of calcium ions in myocardial cells. In the invention, it is discovered that the epicatechin gallate (ECG) and the derivatives thereof have pharmacological pre-adaptation functions and have pharmacological post-adaptation functions for the first time, thus the ECG and the derivatives thereof are possibly novel medicaments for treating or preventing myocardial infarction and other ischemic heart diseases. The ECG and the derivatives thereof not only can be used for clinically treating congestive heart diseases through pharmacological post-adaptation but also can be used for medically preventing the patient who suffers from myocardial infarction and then is cured from being subjected to myocardial infarction again through pharmacological pre-adaptation.
Description
Technical field
The invention belongs to natural drug and medical domain, related to the class native compound L-Epicatechin gallate and the purposes of derivant in ischemic heart desease such as treatment or prevention myocardial infarction thereof that derive from the Folium Camelliae sinensis.
Background technology
(ischemic heart disease is to cause the uneven cardiac damage that causes between coronary flow and the myocardium demand owing to coronary artery circulation changes IHD) to ischemic heart desease, is the archenemy that the world today threatens human life's health.IHD comprises that (myocardial infarction, MI) etc., wherein coronary stricture and the obturation that causes owing to coronary atherosclerosis accounts for 90% of IHD for coronary heart disease, angina pectoris, myocardial infarction.The ischemic heart patient has millions of crowds in the U.S..In China, along with the raising of living standards of the people, ischemic heart desease also becomes " first killer " who threatens compatriots' health day by day.
The drug effect principle that is used for the ischemic heart desease medicine at present is for reducing the load of heart, and to because ischemia/reperfusion (ischemia/reperfusion, I/R) heart and injury that causes does not play a protective role; Simultaneously, no matter be open heart operations under the extracorporeal circulation, or the thrombolytic art after the acute myocardial infarction and coronary artery bypass grafting all must experience myocardium I/R process, cause myocardial ischemia.The I/R damage can increase the weight of myocardium cell necrosis, apoptosis, myocardial stunning and not have the resurgent phenomenon, becomes a key factor that influences prognosis.The modal consequence that the I/R damage causes is a heart failure.How avoiding this " additionally " injury to the ischemic heart patient is that the secondary injury is the problem that medical circle is explored always.In the last few years, as the means of prevention of a kind of I/R damage, adapt to behind the ischemia (ischemic postconditioning, IPO) and ischemic preconditioning (ischemic preconditioning, IPC) because of its powerful potential clinical value, be the focus that people study always.Wherein IPO then has better predictability and controllability on clinical implementation, therefore has the good clinical application prospect.
The notion of IPO 2003 by propositions such as Zhao, be a kind of new myocardial preservation notion.After cardiac muscle IPO refers to myocardial ischemia, before pouring into again for a long time, carry out once or of short duration repetition myocardial ischemia/perfusion more for several times,, alleviate myocardial ischemia reperfusion injury to start the endogenic protection mechanism of body.The process of IPO protection cardiac muscle is actually the procedure of adaptation of myocardial cell to the secondary injury toleration; it can reduce reperfusion arrhythmia; reduce myocardial infarction area; improve myocardial function behind the ischemia; reduce cardiac energy consumption, delay myocardial ultrastructure and change, reduce vascular endothelial injury; make cardiac function learn leading indicator and significantly improve, thereby reach the protection action of the heart.The notion of IPC was proposed by Murry first in 1986.Cardiac muscle IPC is meant and utilizes the of short duration ischemia/reperfusion of heart to come excitating organism endogenous protection mechanism, and then heart produces tolerance to the ischemia of long period subsequently, postpones and alleviates induced myocardial injury, produces myocardium protecting action.Discovering in recent years, the possible endogenous protection mechanism of IPO and IPC mainly comprises the minimizing free-radical generating; Suppress in the cell and the mitochondrial calcium overload; Activate adenosine receptor; (protein kinase C PKC) activates the induced protein kinase c, starts the Cardioprotective signal path; Induce potassium channel (the mitochondrial K of mitochondrial ATP sensitivity
ATPChannel, mK
ATP) open; Reducing ATP consumes; Suppress mitochondrion cytochrome C release in the myocardial cell; Reduced apoptosis rate or the like.MK wherein
ATPPassage may be the final effect organ of IPO and IPC protection cardiac muscle.
In recent years; seeking medicine, to induce myocardium autoprotection Research on ability be to adapt to the research that adapts to behind (pharmacological postconditioning) and the pharmacologic preconditioning (pharmacologicalpreconditioning), particularly the former pharmacological after the pharmacological to have become a kind of trend with application.There are some researches show adenosine receptor agonist, PKC active inducing agent, K
ATPChannel opener can simulate the pre-adaptation protective effect.But very easily produce toleration with adenosine receptor agonist, the PKC active inducing agent all has tangible carcinogenecity, K
ATPChannel opener easily produces multiple untoward reaction etc.Current, particularly there is the medicine that adapts to after the pharmacological in many drugmakers from seeking new drug target and newtype drug,, will have great importance owing to the caused myocardial damage of ischemic heart desease in order to control in clinical practice for ischemic heart desease.
In the I/R damage, except using drug-induced generation IPO and IPC protection.In case after the I/R damage causes heart failure, also the utmost point is necessary to develop a kind of novel cardiac drug that influences but have the enhancing myocardium shrinkage function that cellular calcium concentration is not had, among the treatment and prevention that are applied to coronary heart disease, be used for the treatment of myocardial infarction or because the secondary damage of the caused heart I/R of myocardial infarction.
Folium Camelliae sinensis is as extensive drinking beverage in the world, and in the existing history of drinking thousands of years of China, and other country drinks the history in hundreds of years is also arranged in the world, is thought a kind of natural, safety and wholesome beverage by the traditional Chinese medical science and western sciences already.Folium Camelliae sinensis contains the active component based on polyphenols, caffeine and theanine etc.Wherein polyphenols accounts for the 10-40% of dry weight of tea leaves.In bright leaf of tea and green tea, it in the polyphenols catechin compounds, mainly comprise L-Epicatechin gallate (epicatechin3-O-gallate, ECG), epigallocatechin gallate (EGCG) (epigallocatechin gallate, EGCG), epigallo catechin and epicatechin, account for 15%, 50%, 15%, 10% of catechin total amount respectively.In black tea, Polyphenols is mainly the oxidation product theaflavin class and the thearubigins compounds of catechin, and a certain amount of catechin compounds., it is relevant with effects such as the prevention cardiovascular system diseases of Folium Camelliae sinensis, anti-cancer, anti-aging, antibiotic and sterilizings that these compositions had been proved to be already.
Summary of the invention
In order from active skull cap components, to seek the medicine that a class has ischemic heart desease such as treatment or prevention myocardial infarction, the invention discloses the L-Epicatechin gallate and the derivant thereof that derive from the Folium Camelliae sinensis and have the purposes of ischemic heart desease such as treatment or prevention myocardial infarction, these compositions might be developed to the cardiopathic medicine of the novel control of a class, adapt to the ischemical reperfusion injury that can be used for treating the ischemic heart patient who comprises myocardial infarction by the back, can be used for treating congestive heart failure again; Meet with the risk of I/R damage after also can preventing infraction more once more by pre-adaptation.
The present invention be derive from a class native compound epigallocatechin gallate (EGCG) in the Folium Camelliae sinensis and derivant thereof be used for the treatment of and (or) purposes in the ischemic heart desease such as prevention myocardial infarction.
Wherein said ischemic heart desease comprises acute myocardial infarction, and the myocardial infarction with secondary myocardial infarction risk.
Wherein said ischemic heart desease comprises congestive heart failure, coronary heart disease.
Wherein said ischemic heart desease also is included in the heart ischemia that is caused in organ transplantation, apoplexy and the operation ischemia.
Behind heart ischemia or before the ischemia, the release that L-Epicatechin gallate and derivant thereof all can reduce the area and the heart and injury mark lactic acid dehydrogenase that minimizing I/R causes of myocardial infarction significantly improves left ventricle development pressure and left chamber last diastolic pressure eventually; Its mechanism to myocardium protecting action is and activates PKC ε and mitochondrion mK
ATPPassage is relevant.In the heart reperfusion injury, has the defencive function that pre-adaptation and back adapt to.
The present invention also comprises the drug regimen that is used to prevent and treat ischemic heart desease, it is characterized in that comprising L-Epicatechin gallate and medicinal excipient or carrier.
Be used to prevent and treat the drug regimen of ischemic heart desease; it is characterized in that wherein also comprising with the L-Epicatechin gallate is basic structure; modify the derivant that is produced through appropriate configuration; as theaflavih digallate; EGCG; the methylating of ECG or EGCG, acetylation or glucoside or the like derivant, and medicinal excipient or the carrier of these derivants
The inventor shows through early-stage Study, derive from the Folium Camelliae sinensis catechins ECG and increase systaltic function by activating PKC ε path, and do not increase the concentration of intracellular calcium ion, this result is published in American Journal of Physiology:heart and circulatory physiology, 2008,294 (1): H345-353.Research in the present invention shows that further ECG can also produce protective effect to heart ischemia/reperfusion injury.The mechanism that ECG produces above-mentioned protective effect is by after activating PKC ε, opens mitochondrion mK
ATPPassage has the caused damage of protection heart ischemia reperfusion to strengthen myocardial contraction.
Experimentation conclusion of the present invention:
The present invention uses the external isolated rat heart filling system of Langendorff, has studied ECG prospective adaptation or the back adaptation protective effect to damage that heart ischemia reperfusion causes.The result shows, no matter be behind ischemia or before the ischemia, use ECG handles the area that all can reduce myocardial infarction and reduces heart and injury mark lactic acid dehydrogenase (the lactate dehydrogenase that I/R causes, LDH) release, significantly improve the left ventricle development and press (left ventricular developed pressure, LVDP) and left chamber eventually last diastolic pressure (leftventricular developed end-diastolic pressure, LVEDP).And the effect of this reduction myocardial damage of ECG can by the specific inhibitor TIP of PKC ε (
Translocation inhibitor peptide) and the potassium channel mKATP blocker 5-hydroxydecanoic acid of mitochondrial ATP sensitivity (5-hydroxydecanoate 5-HD) blocks, and illustrates that ECG to the mechanism of myocardium protecting action is and activates PKC ε and mitochondrion mK
ATPPassage is opened relevant.Therefore, the present invention has found a kind of native compound that is derived from Folium Camelliae sinensis, and adaptation after its existing pharmacological has pharmacological prospective adaptation function again.And this chemical compound can also increase the function of cardiac contractile force.As far as we know, this is to the unique a kind of chemical compound of finding so far that not only has adaptive functions after the pharmacological but also have pharmacological prospective adaptation function.
Therefore, one aspect of the present invention relates to the purposes that the L-Epicatechin gallate that derives from the Folium Camelliae sinensis has ischemic heart desease such as treatment or prevention myocardial infarction.Both can be used for preventing and treating congestive heart failure patient and coronary heart disease patient's ischemical reperfusion injury, can be used for treating congestive heart failure again.
Another aspect of the present invention relates to the medicine for the treatment of or preventing ischemic heart desease such as myocardial infarction, and it comprises as modified ECG derivant of active component ECG and medicinal excipient or carrier.
As a kind of medicine for the treatment of ischemic heart desease such as myocardial infarction, can adopt excipient or carrier that ECG is made injection, in the acute myocardial infarction diagnosis and treatment, can produce protective effect to heart ischemia by intravenous mode.And, can also adopt oral mode to carry out the prevention of ischemic heart desease, particularly face secondary myocardial infarction risk patient's prevention.
Medicine as ischemic heart desease such as a kind of treatment or prevention myocardial infarctions; can with the molecular structure of ECG basic structure; modify the derivant that is produced through appropriate configuration; (theaflavin 3 as theaflavih digallate that ECG and EGCG produced; 3 '-digallate; TF4), the derivant that the methylating of EGCG and EGCG or ECG, acetylation, glucose glycosidation etc. are produced, and they are used for the treatment of or prevent the medicine of ischemic heart desease such as myocardial infarction.
Beneficial effect of the present invention
A kind of as in the catechin compounds of originating in the Folium Camelliae sinensis of ECG, and the abundantest EGCG of content in the catechin compounds in the Folium Camelliae sinensis.EGCG be removed in the last few years free radical, anticancer, prevent and treat " star " chemical compound in the research such as cardiovascular disease because the antioxidant activity of ECG is weaker than EGCG, therefore relevant special very few at the biological activity research of ECG.The present invention has found first that not only ECG and derivant thereof not only have pharmacological prospective adaptation function, and has more adaptive functions after the pharmacological, therefore might be as the newtype drug of ischemic heart desease such as a kind of treatment or prevention myocardial infarction.This is to a unique compounds that not only has adaptive functions after the pharmacological but also have pharmacological prospective adaptation function and can improve the cardiac contractile force function of finding so far.
ECG and derivant thereof not only can be used for the treatment of congestive heart disease clinically by adaptation after the pharmacological, but also can be applied to face secondary myocardial infarction risk patient's preventive medicine treatment by the pharmacological prospective adaptation.
In addition, the present invention also provides new purposes for the exploitation of ECG and derivant thereof, helps the comprehensive development and utilization of natural component in the Folium Camelliae sinensis.
Description of drawings
Fig. 1 is the chemical structural drawing of ECG and derivant thereof.A, ECG and derivant thereof; B, a kind of derivant theaflavih digallate TF4 of ECG.
Fig. 2 is a technical scheme specific embodiment design drawing.The 1st group, the I/R matched group; 2nd, the processed group of 3,4 groups of ECG pre-adaptation; Adapt to processed group behind the 5th group of ECG; The 6th group of ECG pre-adaptation and TIP Combined Treatment group; The 7th group of ECG pre-adaptation and 5-HD Combined Treatment group.
Fig. 3 is the influence of ECG pre-adaptation processing to cardiac function index LVDP and LVEDP.A, ECG pre-adaptation is handled the influence to LVDP; B, ECG pre-adaptation is handled the influence to LVEDP.
Fig. 4 is the dose-effect relationship figure of ECG to heart LVDP influence.
Fig. 5 is that ECG pre-adaptation and back adapt to the influence that heart LDH is discharged.
Fig. 6 is that ECG pre-adaptation and back adapt to the influence to the heart myocardial infarction area.
Fig. 7 is the influence that adapts to behind the ECG cardiac function index LVDP and LVEDP.A adapts to the kymogram of handling heart contraction diastole influence behind the ECG; B adapts to the influence of handling LVDP behind the ECG; C adapts to the influence of handling LVEDP behind the ECG.
Fig. 8 be TIP or 5-HD to ECG LVDP recover and the LDH release action on blocking effect.A, TIP or 5-HD associating ECG pre-adaptation are handled the influence that heart LVDP is recovered; B, TIP or 5-HD associating ECG pre-adaptation are handled the influence that heart LDH is discharged.
The specific embodiment
Embodiment 1:ECG is to the protective effect of heart ischemia/reperfusion injury
Purpose: inventor's early-stage Study shows that ECG has function that activates PKC ε and the effect that increases the isolated rat myocardial contraction.The present invention is on the early stage basis; utilize the external isolated rat heart filling system of Langendorff; whether research ECG still has the effect that activates PKC ε in the perfusion of heart ischemia/again, and detects it whether have the defencive function that pre-adaptation and back adapt in ischemical reperfusion injury.
Material and method:
1) reagent: the specific inhibitor TIP of PKC ε is available from Calbiochem company, and the potassium channel mKATP blocker 5-HD of mitochondrial ATP sensitivity is available from Sigma company.
2) test grouping: the group that the ischemia/reperfusion pre-adaptation of ECG and back adapt to designs as shown in Figure 2, respectively as experiment processed group and matched group.Every group be 5～7 11～12 the week age SD rat.
3) ischemia/reperfusion of the external rat heart of Langendorff: behind the heparin sodium 30min of rats by intraperitoneal injection 2000USP, lumbar injection pentobarbital sodium (60mg/Kg) again.After treating that rat goes into a coma fully, carry out outside thoracic incision, take out heart fast, place Krebs-Henseleit (K-H, the mmolL of pre-cooling
-1: 118NaCl, 4.7KCl, 1.3CaCl
2, 0.8MgSO
4, 1.2KH
2PO
4, 0.3EGTA, 25.0NaHCO
3, 11.0D-Glucose) in the buffer, again heart is suspended on the Langendorff perfusion device, with O
2: CO
2(95: 5) equilibrated K-H buffer 37 ℃ through the aorta perfusion that drives in the wrong direction, perfusion pressure maintains about 100mmHg.The polyethylene tube that will be connected with a latex balloon (interior dress 0.2CC distilled water) inserts left ventricle through annulus of mitral valve, and regulates LVEDP about 5mmHg.Simultaneously, heart adds the 4.5Hz stimulating electrode.With P23XL BectonDickinson pressure sensor systems record heart LVDP, left constant pressure development speed (± dp/dtmax) curve etc.After treating that heart is stablized 20min, according to the operation that experimentizes of the method for Fig. 2, wherein make ischemia model again with stopping the K-H perfusion.
4) detect index: preceding 30min coronary artery effluent in the refilling process behind the collection ischemia.After perfusion finishes again, take off the freezing 2h of heart-20 ℃ refrigerator after, measure myocardial infarction area.The concentration of LDH utilizes the test kit of Sigma company to measure in the coronary artery effluent, and myocardial infarction area is measured with the TTC staining.
5) statistical disposition: data are represented with mean ± SE.Relatively employing one factor analysis of variance (One-way ANOVA) between many groups is also checked (Tukey post hoc test), relatively employing Student ' the s t-of data check between group in conjunction with Tukey afterwards.
Result and discussion:
1) ECG pre-adaptation is handled the protective effect to the I/R damage
In I/R damage, carry out the pre-adaptation processing with ECG (500ng/ml) after, main parameters of left ventricular function is as shown in table 1.ECG carry out pre-adaptation handle behind the 30min heart compared with the control, LVDP obtains significance and recovers, almost return to the preceding normal value (as table 1, Fig. 3 A, shown in Figure 4) of I/R, and the LVEDP rising that the I/R damage is caused also obtains significance inhibition (as table 1, shown in Fig. 3 B).Simultaneously, ECG pre-adaptation is handled to the dose-effect relationship of heart stimulation as shown in Figure 4, even ECG is when being low to moderate 10ng/ml, the LVDP that the I/R damage is caused also obtains significance to be improved.
Table 1 L-Epicatechin gallate (ECG) prospective adaptation and back adapt to handles the influence of isolated rat heart at ischemia-reperfusion (I/R) process cardiac contractility
Annotate: data are represented with mean value SE;
*Represent significant difference p＜0.05,
*Represent extremely significantly p＜0.01 of difference; LVESP, left chamber is shunk the end and is pressed: LVEDP, left chamber is last diastolic pressure eventually; LVDP, left ventricular developed pressure.
As seen from Figure 5, the I/R that handles through ECG pre-adaptation causes that the mark LDH concentration of myocardial damage significantly reduces compared with the control, and presents dose-effect relationship preferably.When 10ng/ml, ECG pre-adaptation is handled back LDH concentration and is low to moderate about 8% of contrast.As seen from Figure 6, the heart infarct size increase that the I/R that handles through ECG pre-adaptation causes is significantly suppressed, and the ECG pre-adaptation of 500ng/ml is handled back heart infarct size compared with the control, has reduced about 40%.
In sum, ECG handles and can resist isolated rat heart I/R damage and the protective effect of generation pharmacologic preconditioning.
2) adapt to the protective effect of handling the I/R damage behind the ECG
In the I/R damage, to carry out the back with ECG (100ng/ml) and adapt to processing, main parameters of left ventricular function obtains significance to be improved, shown in table 1, Fig. 7 A and Fig. 7 B.ECG carry out the back adapt to handle behind the 30min heart compared with the control, LVDP obtains significance and recovers, and almost returns to the normal value before the I/R, and the LVEDP that the I/R damage is caused raises and also obtains significance and suppress (Fig. 7 C).
As seen from Figure 5, behind ECG (100ng/ml), adapt to the mark LDH concentration significantly reduction compared with the control that the I/R that handles causes myocardial damage, be about 28% of contrast.Simultaneously as seen from Figure 6, the heart infarct size increase that the I/R that adaptation is handled behind ECG (100ng/ml) causes is significantly suppressed, and the ECG pre-adaptation of 500ng/ml is handled back heart infarct size compared with the control, has reduced about 60%.
In sum, the ECG processing adapts to protective effect after resisting isolated rat heart I/R damage and producing pharmacological.
3) ECG handles protective effect and PKC ε and the mitochondrion mK to the I/R damage
ATPPassage is relevant
In ECG pre-adaptation is handled, PKC ε specific inhibitor TIP and mitochondrion mK
ATPThe recovery of channel blocker 5-HD heart LVDP all capable of blocking (Fig. 8 A) also increases the release (Fig. 8 B) of LDH.The result shows that ECG pre-adaptation is handled activation and the mK of protective effect and PKC ε
ATPThe opening of passage is relevant.
Embodiment 2:ECG derivant EGCG and TF4 are to the protective effect of heart ischemia/reperfusion injury
With embodiment 1; in the external isolated rat heart ischemia of Langendorff injection system; adopt derivant EGCG or the TF4 of ECG to carry out the pre-adaptation processing; the LVDP that can make rat heart 35.0 ± 5.0% rises to 87.0 ± 6.2% (n=5 respectively behind the ischemia; p＜0.01) and 78.0 ± 7.2% (n=6; p＜0.01), this result shows that EGCG and TF4 have protective effect to heart ischemia/reperfusion injury.
Claims (7)
1. deriving from class native compound L-Epicatechin gallate in the Folium Camelliae sinensis and derivant thereof is being used for the treatment of or is preventing purposes in the ischemic heart desease such as myocardial infarction.
2. purposes according to claim 1 is characterized in that wherein said ischemic heart desease comprises acute myocardial infarction, and the myocardial infarction with secondary myocardial infarction risk.
3. purposes according to claim 1 is characterized in that wherein said ischemic heart desease comprises congestive heart failure, coronary heart disease.
4. purposes according to claim 1 is characterized in that wherein said ischemic heart desease also is included in the heart ischemia that is caused in organ transplantation, apoplexy and the operation ischemia.
5. purposes according to claim 1, it is characterized in that behind heart ischemia or before the ischemia, L-Epicatechin gallate and derivant thereof all can reduce the release of the area and the heart and injury mark lactic acid dehydrogenase (LDH) that minimizing IR causes of myocardial infarction, significantly improve the left ventricle development and press the whole art diastolic pressure (LVEDP) of (LVDP) and left chamber; Its mechanism to myocardium protecting action is and activates PKC ε and mitochondrion mK
ATPPassage is relevant; In the heart ischemia reperfusion damage, has the defencive function that pre-adaptation and back adapt to.
6. purposes according to claim 1 is used to prevent and treat the drug regimen of ischemic heart desease, it is characterized in that comprising L-Epicatechin gallate and medicinal excipient or carrier.
7. purposes according to claim 1; be used to prevent and treat the drug regimen of ischemic heart desease; it is characterized in that wherein also comprising with the L-Epicatechin gallate is basic structure; modify the derivant that is produced through appropriate configuration; as theaflavih digallate; EGCG, the methylating of ECG or EGCG, acetylation or glucose glycosidation or the like derivant, and medicinal excipient or the carrier of these derivants.
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| CN107648211A (en) * | 2017-11-10 | 2018-02-02 | 大连医科大学附属第医院 | Application of the gallic acid in angiocardiopathy is prevented and treated |
| CN109875993A (en) * | 2019-04-25 | 2019-06-14 | 吉林大学 | A kind of application of EGCG after improving myocardial infarction in anxiety symptom |
| CN114869878A (en) * | 2022-04-08 | 2022-08-09 | 南通大学 | Application of epicatechin gallate in preparation of medicine for treating high altitude cerebral edema |
| CN114869878B (en) * | 2022-04-08 | 2024-02-23 | 南通大学 | Application of epicatechin gallate in preparing medicament for treating altitude cerebral edema |
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