CN109223749A - The bromo- 2-(α-Hydroxy pentyl of 5-) medicinal usage of the benzoic acid sodium salt in treatment myocardial hypertrophy and heart failure - Google Patents
The bromo- 2-(α-Hydroxy pentyl of 5-) medicinal usage of the benzoic acid sodium salt in treatment myocardial hypertrophy and heart failure Download PDFInfo
- Publication number
- CN109223749A CN109223749A CN201811350619.XA CN201811350619A CN109223749A CN 109223749 A CN109223749 A CN 109223749A CN 201811350619 A CN201811350619 A CN 201811350619A CN 109223749 A CN109223749 A CN 109223749A
- Authority
- CN
- China
- Prior art keywords
- myocardial hypertrophy
- heart
- heart failure
- bzp
- bromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
The invention belongs to biomedicine fields, disclose the bromo- 2-(Alpha-hydroxy amyl of 5-) medicinal usage of the benzoic acid sodium salt (BZP) in the myocardial hypertrophy and heart failure for the treatment of pressure load induction.It is tested with the myocardial hypertrophy model mice of the postoperative pressure load induction of aortic coaractation, it was found that BZP takes orally the heart weight weight ratio after capable of reducing mouse aorta Constriction, the heart weight long ratio of shin bone, it reduces the cross-sectional area of hypertrophic cardiomyocytes, mitigate cardiac muscular tissue's Fibrosis levels, reduce loose related gene expression, improve the heart function damage of pressure load induction, mitigate myocardial hypertrophy, reduce the generation of myocardial remodelling, while delaying the process of heart failure.Exploitation will be expected into the cardiovascular kind new medicine for the treatment of.
Description
Technical field
The invention belongs to biomedicine fields, are related to the bromo- 2- of 5- (Alpha-hydroxy amyl) benzoic acid sodium salt (BZP) and press in treatment
Medicinal usage in the myocardial hypertrophy and heart failure of the induction of power load.
Background technique
Myocardial hypertrophy is that cardiac muscle cell is anti-to a kind of adaptability of a variety of pathology stimulations such as mechanical load, neurohumor stimulation
It answers.Early stage, because ventricle wall thickening, myocardium shrinkage function improve due to be considered as compensatory process, but lasting pathologic stress
In the case of, expand with interstitial fibrosis, contractile function imbalance, the chambers of the heart, it is even sudden finally to will lead to decompensated heart failure
Extremely.So far, myocardial hypertrophy is considered as the independent hazard factor that adverse cardiac events occur.Prevent and treats the heart in time
Flesh plumpness receives extensive concern and the attention of researcher.However, myocardial hypertrophy mechanism is complicated, so far not yet completely
It illustrates, therapeutic agent is confined to anti-stomodaeal nervous system, anti-renin-angiotensin-aldosterone system (RAAS) drug.
Chinese invention patent 201410313214.4 makes public for the first time the bromo- 2- of 5- (Alpha-hydroxy amyl) benzoic acid sodium salt
(BZP) different crystal forms and preparation method thereof are the research achievement of inventor's early period.Bromo- 2- (the a- of 5- is disclosed in its specification
Hydroxy pentyl) benzoic acid sodium salt can brain tissue impairment caused by substantially reduced rat cerebral arteries emphraxis, mitigate cerebral infarction volume, subtract
Few edema volume, but it is not directed to application of the BZP in the myocardial hypertrophy and heart failure for the treatment of pressure load induction.
Summary of the invention
It is used to treat the medicinal usage in the myocardial hypertrophy and heart failure of pressure load induction the present invention provides BZP.
Purpose to realize the present invention, the myocardial hypertrophy model mice that the present invention is induced with the postoperative pressure load of aortic coaractation
It is tested, studies protective effect of the BZP to the C57BL/6 mouse pressure load myocardial hypertrophy induced and heart failure, discovery
BZP takes orally the heart weight weight ratio after capable of reducing mouse aorta Constriction, the heart weight long ratio of shin bone, reduces the cross of hypertrophic cardiomyocytes
Sectional area mitigates cardiac muscular tissue's Fibrosis levels, reduces loose related gene expression, improves the heart function damage of pressure load induction
Wound mitigates myocardial hypertrophy, reduces the generation of myocardial remodelling, while delaying the process of heart failure.
BZP can be used as treatment myocardial hypertrophy and heart failure drugs effective component, the especially heart of pressure load induction
Flesh plumpness and heart failure drugs effective component, can be made the oral preparations such as tablet, particle or injection, preferably give prescription
Formula be it is oral, dosage 20mg/kg/ times or 40mg/kg/ times, once a day.
Innovative point of the present invention is: being tried with the myocardial hypertrophy model mice of the postoperative pressure load induction of aortic coaractation
It tests, the discovery bromo- 2- of 5- (Alpha-hydroxy amyl) benzoic acid sodium salt (BZP) can obviously improve heart function damage, mitigate myocardial hypertrophy, drop
The generation of low myocardial remodelling, while delaying the process of heart failure, exploitation is expected into the cardiovascular kind new medicine for the treatment of.
Detailed description of the invention
Fig. 1 is the myocardial hypertrophy and heart failure ultrasonic analysis legend of C57BL/6 mouse pressure load induction；
Weight ratio, the heart weigh shin to the heart again after oral BZP when Fig. 2 is C57 mouse aorta constriction (TAC) postoperative 4 weeks and 10 weeks
The long ratio of bone, lung weight weight ratio histogram；
Oral BZP rear myocardium tissue HE dyeing, WGA when Fig. 3 is C57 mouse aorta constriction (TAC) postoperative 4 weeks and 10 weeks
Dyeing and Masson dye representative picture；
Fig. 4 be C57 mouse aorta constriction (TAC) postoperative 4 weeks and 10 weeks when take orally BZP after cardiomyocytes cross-sectional area,
Cardiac muscular tissue's fibrosis quantifies histogram；
Fig. 5 be C57 mouse aorta constriction (TAC) postoperative 4 weeks and 10 weeks when take orally BZP after to loose related gene ANF,
The histogram that the mRNA of BNP, β-MHC influence；
Fig. 6 is representative C57 mouse heart ultrasound legend；
Fig. 7 is the protective effect column of the BZP important myocardium shrinkage function index EF (%) postoperative to C57 mouse row TAC
Figure；
Fig. 8 is the protective effect column of the BZP important myocardium shrinkage function index FS (%) postoperative to C57 mouse row TAC
Figure；
Fig. 9 is protective effect histogram of the BZP to the postoperative interventricular septum end-diastolicthickness IVSd of C57 mouse row TAC；
Figure 10 is protective effect histogram of the BZP to the postoperative left ventricular end diastolic diameter LVIDd of C57 mouse row TAC；
Figure 11 is protective effect column of the BZP to the postoperative left ventricular mass LV Mass (Corrected) of C57 mouse row TAC
Figure；
Specific embodiment
The following examples can help those skilled in the art that the present invention is more completely understood, but not in any way
The limitation present invention.
Embodiment: BZP tests the protective effect of the C57BL/6 mouse pressure load myocardial hypertrophy induced and heart failure
Material and method
(1) experimental material
8 week old C57BL/6 mouse, weight 19-22g are male, BZP (the bromo- 2- of 5- (Alpha-hydroxy amyl) sodium benzoate
Salt) powder, it is configured with distilled water.
(2) experimental group
4 groups are randomly divided into, sham-operation group (Sham) is respectively as follows:；Myocardial hypertrophy model group (TAC)；BZP (bromo- 2- (the α-of 5-
Hydroxy pentyl) benzoic acid sodium salt) high dose group (40mg/kg), low dose of BZP (the bromo- 2- of 5- (Alpha-hydroxy amyl) benzoic acid sodium salt)
Amount group (20mg/kg).
(3) long term administration method
Treatment group: stomach-filling is given BZP (the bromo- 2- of 5- (Alpha-hydroxy amyl) benzoic acid sodium salt) after TAC model foundation, dosage point
It Wei not 20mg/kg, 40mg/kg.Administered volume is 0.01ml/g.
Control group: physiological saline is given in stomach-filling after TAC model foundation, and administered volume is same as above.
The preparation of TAC model: preoperative weighing carries out inhalation anesthesia to mouse using the isoflurane of mass percentage 1%,
Dorsal position is taken to be fixed on mouse plate.The cotton balls for being moistened with isoflurane is placed in 1.5ml EP pipe, and covers in mouse nose, of short duration intensification
75% alcohol disinfecting neck of mass percentage and skin of chest are used after anesthesia.Skin is cut off about downwards from neck cartilagines larynigs
The notch of 1cm long pushes thyroid gland aside from centre, successively separates throat flesh to exposure tracheae, ventilator is opened, by ventilator capacity
Long-pending and frequency is adjusted to correct position, and whether detection breathing machine pipeline is unobstructed, closes ventilator.With tweezers by mouse tongue gently to
Outer pull-out keeps larynx-meeting pharyngeal unobstructed, intubation is inserted into throat (being not fully inserted into), a hand fixes exposure with the curved tweezer of ophthalmology
Tracheae, one it is slow with one's hands slowly will intubation be sent into tracheae, can from exposed tracheae will intubation guided bone be inserted into tracheae, open breathing
Machine.Exposure arch of aorta position, from cutting downwards from lower cut between median sternotomy to the second rib front end, left and right successively separates flesh
Meat, until arch of aorta exposure, 7-0 line is passed through under the arch of aorta between Arteria carotis communis, by No. 27 needles at full right angle
First side and the arch of aorta are placed in parallel the side of the arch of aorta, and syringe needle and the arch of aorta are ligatured together, under ligation two, by needle
Head is gently extracted from ligation place, trimming.As sham-operation group, line passes through the arch of aorta but does not ligature.With 6-0 line layer-by-layer suture flesh
Meat finally uses the continuous skin suture of 5-0 line.
(4) noninvasive ultrasound Evaluation heart function: it is preoperative and 2 weeks, 4 weeks and 10 weeks postoperative respectively at TAC, use diasonograph
It is measured with heart function of the 30MHz high frequency probe to mouse, the isoflurane of mass percentage 1% carries out sucking fiber crops to mouse
It is liquor-saturated, pareordia hair is shaved, mouse dorsal position is fixed on hot plate, keeps the constant of body temperature.Apply appropriate ultrasonic coupling agent in
Pareordia starts to acquire parasternal long axis section on the mouse wall of the chest, takes the left room of parasternal short with the probe of Ultrasound Instrument 30MHz
Axis obtains M type tangent plane picture and measures left room diastole and systole phase front and back wall thickness, left ventricular ejection fraction (EF%) etc..It is right
In different individuals, diasonograph is respectively provided with identical parameter.The super each measurement index of M chooses 5 continuous weeks aroused in interest
EF%, the average value of FS% etc. are found out after phase.Such as Fig. 1.
(5) mouse of each group Similar numbers was put to death respectively at TAC postoperative 4 weeks and 10 weeks, coring is dirty, lungs and weighs, and surveys
Measure left tibias length.Then by above-mentioned mouse part of heart paraffin embedding, paraffin section is made and carries out HE, Masson, WGA dye
Color observes heart tissue morphological change；Rest part heart extracts RNA detection hypertrophy related gene ANF, BNP, β-MHC's
MRNA expression.
(6) statistical analysis: data indicate with mean ± standard deviation, and are examined and One-Way with comparing t two-by-two
ANOVA carries out statistical analysis, and P < 0.05 thinks that difference is statistically significant.
Experimental result:
(1) BZP is oral can reduce C57 mouse aorta constriction (TAC) postoperative 4 weeks and the heart weighs weight ratio, the heart weight at 10 weeks
The long ratio of shin bone
At aortic coaractation (TAC) postoperative 4 weeks and 10 weeks, BZP takes orally 20mg/kg, 40mg/kg administration group and TAC model
Group is compared, and heart weight weight ratio, the long ratio of heart weight shin bone are substantially reduced, and lung weight weight ratio changes unobvious (Fig. 2, *: with sham-operation group
(Sham) the corresponding time compares P < 0.05；#: P < 0.05 compared with the time corresponding with model group (TAC)).
(2) BZP it is oral can reduce C57 mouse aorta constriction (TAC) postoperative 4 weeks and at 10 weeks hypertrophic cardiomyocytes cross
Sectional area mitigates cardiac muscular tissue's Fibrosis levels
At aortic coaractation (TAC) postoperative 4 weeks and 10 weeks, BZP takes orally 20mg/kg, 40mg/kg administration group and TAC model
Group is compared, and the cross-sectional area of hypertrophic cardiomyocytes is reduced significantly, cardiac muscular tissue's Fibrosis levels substantially reduced (Fig. 3, *: with artificial hand
Art group (Sham) the corresponding time compares P < 0.05；#: P < 0.05 compared with the time corresponding with model group (TAC)).
(3) BZP takes orally hypertrophy related gene expression when can reduce postoperative 4 weeks of C57 mouse aorta constriction (TAC) and 10 weeks
At aortic coaractation (TAC) postoperative 4 weeks and 10 weeks, BZP takes orally 20mg/kg, 40mg/kg administration group and TAC model
Group is compared, and the mRNA expression of loose related gene ANF, BNP, β-MHC significantly reduces (Fig. 4, *: corresponding to sham-operation group (Sham)
Time compares P < 0.05；#: P < 0.05 compared with the time corresponding with model group (TAC)).
(4) the oral heart function damage that can improve the postoperative pressure load induction of C57 mouse aorta constriction (TAC) of BZP, prolongs
The generation of slow heart failure
Using the myocardial hypertrophy model (TAC) in body aortic coaractation building pressure load induction, respectively at preoperative and art
The cardiac systolic function of 2,4,10 weeks toy Ultrasound Instruments record mouse afterwards, as the result is shown BZP take orally 20mg/kg/day and
Successive administration 10 weeks, compared with model group (TAC group), it is postoperative to can obviously improve aortic coaractation (TAC) by 40mg/kg/day
Cardiac systolic function, comprising: ejection fraction (EF%), percentage of contraction (FS%) delay the generation (*: with sham-operation group of heart failure
(Sham) the corresponding time compares P < 0.05；#: P < 0.05 compared with the time corresponding with model group (TAC)).
(5) the oral generation that can reduce C57 mouse aorta constriction (TAC) postoperative myocardial plumpness, reduce myocardial remodelling of BZP
Using the myocardial hypertrophy model (TAC) in body aortic coaractation building pressure load induction, respectively at preoperative and art
2,4,10 weeks toy Ultrasound Instrument record mouse cardiac muscle plumpnesses and the index of correlation of reconstruct afterwards, BZP takes orally 20mg/ as the result is shown
Kg/day and 40mg/kg/day successive administration 10 weeks, compared with model group (TAC group), can obviously reduce interventricular septum diastasis
The increase of thickness (IVSd), reduces left ventricular mass (LV Mass at the expansion for reducing left ventricular end diastolic diameter (LVIDd)
(Corrected)) increase reduces the generation of myocardial remodelling, delays the process of heart failure.(*: corresponding to sham-operation group (Sham)
Time compares P < 0.05；#: P < 0.05 compared with the time corresponding with model group (TAC)).
Experiment conclusion:
The heart weight weight ratio after can reducing mouse aorta Constriction, the heart weight long ratio of shin bone is administered orally in BZP, reduces loose
The cross-sectional area of cardiac muscle cell mitigates cardiac muscular tissue's Fibrosis levels, reduces loose related gene expression, improves pressure load and lures
The heart function damage led, mitigates myocardial hypertrophy, reduces the generation of myocardial remodelling, while delaying the process of heart failure.This, which is found to be, seeks
It seeks medical advice and treats the novel drugs of myocardial hypertrophy and heart failure and provide direction.
The above description is only a preferred embodiment of the present invention, thus it is all according to the configuration described in the scope of the patent application of the present invention,
The various modifications or change that feature and principle etc. are done equally fall within the application appended claims as equivalent form
Within limited range.
Claims (4)
1. the bromo- 2-(α-Hydroxy pentyl of 5- as follows) benzoic acid sodium salt preparing the purposes in cardiovascular drugs, and it is special
Sign is, the preparation as active constituent, for myocardial hypertrophy or heart failure drugs；
。
2. the bromo- 2-(α-Hydroxy pentyl of 5- as described in claim 1) benzoic acid sodium salt preparing the use in cardiovascular drugs
On the way, which is characterized in that as active constituent, for treating the myocardial hypertrophy of pressure load induction or the system of heart failure drugs
It is standby.
3. the bromo- 2-(α-Hydroxy pentyl of 5- as claimed in claim 1 or 2) benzoic acid sodium salt is in preparing cardiovascular drugs
Purposes, which is characterized in that be made into tablet, particulate oral preparation or injection.
4. the bromo- 2-(α-Hydroxy pentyl of 5- as claimed in claim 1 or 2) benzoic acid sodium salt is in preparing cardiovascular drugs
Purposes, which is characterized in that administration mode be it is oral, dosage 20mg/kg/ times or 40mg/kg/ times, once a day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811350619.XA CN109223749A (en) | 2018-11-14 | 2018-11-14 | The bromo- 2-(α-Hydroxy pentyl of 5-) medicinal usage of the benzoic acid sodium salt in treatment myocardial hypertrophy and heart failure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811350619.XA CN109223749A (en) | 2018-11-14 | 2018-11-14 | The bromo- 2-(α-Hydroxy pentyl of 5-) medicinal usage of the benzoic acid sodium salt in treatment myocardial hypertrophy and heart failure |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109223749A true CN109223749A (en) | 2019-01-18 |
Family
ID=65074534
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811350619.XA Pending CN109223749A (en) | 2018-11-14 | 2018-11-14 | The bromo- 2-(α-Hydroxy pentyl of 5-) medicinal usage of the benzoic acid sodium salt in treatment myocardial hypertrophy and heart failure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109223749A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113577285A (en) * | 2021-07-30 | 2021-11-02 | 中国医学科学院阜外医院深圳医院(深圳市孙逸仙心血管医院) | Application of SLC25A26 in preparation of medicine for inhibiting myocardial hypertrophy |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| CN101402565A (en) * | 2008-11-14 | 2009-04-08 | 郑州大学 | Halogenated 2-(a-hydroxyl pentyl) benzoate, production method and uses thereof |
| CN104086399A (en) * | 2013-07-17 | 2014-10-08 | 郑州大学 | Different crystal forms of sodium 5-bromo-2-(alpha-hydroxyamyl)benzoate and preparation method thereof |
-
2018
- 2018-11-14 CN CN201811350619.XA patent/CN109223749A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| CN101402565A (en) * | 2008-11-14 | 2009-04-08 | 郑州大学 | Halogenated 2-(a-hydroxyl pentyl) benzoate, production method and uses thereof |
| CN104086399A (en) * | 2013-07-17 | 2014-10-08 | 郑州大学 | Different crystal forms of sodium 5-bromo-2-(alpha-hydroxyamyl)benzoate and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113577285A (en) * | 2021-07-30 | 2021-11-02 | 中国医学科学院阜外医院深圳医院(深圳市孙逸仙心血管医院) | Application of SLC25A26 in preparation of medicine for inhibiting myocardial hypertrophy |
| CN113577285B (en) * | 2021-07-30 | 2022-09-06 | 中国医学科学院阜外医院深圳医院(深圳市孙逸仙心血管医院) | Application of SLC25A26 in preparation of medicine for inhibiting myocardial hypertrophy |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Isoyama et al. | Effect of age on the development of cardiac hypertrophy produced by aortic constriction in the rat. | |
| Nanning | Prophylactic effect of antivaccinia gamma-globulin against post-vaccinal encephalitis | |
| WO2018224016A1 (en) | Use of berberine or derivative thereof in preparing myocardial perfusion imaging agent | |
| Morici et al. | Intravenous alfaxalone anaesthesia in leopard geckos (Eublepharis macularius) | |
| CN108567775B (en) | Application of lipoic acid in preparation of pharmaceutical composition for treating pressure-loaded myocardial damage | |
| JP6796601B2 (en) | Cosmetic methods and therapeutic uses to reduce fat | |
| CN109223749A (en) | The bromo- 2-(α-Hydroxy pentyl of 5-) medicinal usage of the benzoic acid sodium salt in treatment myocardial hypertrophy and heart failure | |
| Ihara et al. | Effects of anaesthesia and recent surgery on diastolic function | |
| CN106177960B (en) | Angiotensin receptor antagonist and the compound of enkephalinase inhibitor and application thereof | |
| AU2018446089B2 (en) | Pharmaceutical use of anemoside B4 against acute gouty arthritis | |
| CN111514124A (en) | Application of 3-hydroxyphenylacetic acid in preparation of medicine for improving pathologic ventricular remodeling and/or heart failure after myocardial infarction | |
| CN110038002A (en) | Salviandic acid A prevents and treats the purposes of muscular atrophy, myopathy and muscle skeleton complication | |
| CN113952377A (en) | Traditional Chinese medicine composition for treating qi deficiency syndrome and preparation method and application thereof | |
| CN100356952C (en) | Chinese medicinal composition for treating heart failure and oral preparation | |
| CN109432085A (en) | Application of the eurycomanone in preparation prevention and treatment male's Delayed onset hypogonadism drug, food and health care product | |
| RU2784896C2 (en) | Medical use of anemoside b4 against acute gouty arthritis | |
| CN115998737B (en) | Application of amodiaquine in preparation of medicine for treating pressure-loaded myocardial injury | |
| CN114984087B (en) | Traditional Chinese medicine composition, decoction and pharmaceutical composition, and preparation method and application thereof | |
| CN108653446B (en) | A kind of surface anesthesia pharmaceutical composition, micro emulsion and its preparation method and application | |
| CN114917346B (en) | Medicine and pharmaceutical composition for treating ischemic heart disease | |
| CN113425731B (en) | Medicine for treating myocardial infarction by synergistic stem cells and application thereof | |
| CN106265673B (en) | A kind of application of compound | |
| CN102379873A (en) | Acute general Parkinson's disease monkey model and medicament screening method thereof | |
| Ifedili et al. | Correlation of long term recurrence of atrial fibrillation with early occurrence during the blanking period post ablation and factors that influence this | |
| CN104688886B (en) | It is a kind of to treat Chinese medicine composition of chronic heart failure and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190118 |