CN106511462B - Application of the coronary heart disease compound preparation in the drug that preparation improves remodeling ventricle - Google Patents
Application of the coronary heart disease compound preparation in the drug that preparation improves remodeling ventricle Download PDFInfo
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Abstract
The invention discloses application of the coronary heart disease compound preparation in the drug that preparation improves remodeling ventricle.Coronary heart disease compound preparation group of the invention becomes red ginseng tri- or seven ﹕ dalbergia heartwood oil of ﹕=200g ﹕ 200g ﹕ 1.75mL.Application of the present invention is the remodeling ventricle occurred after ST-Elevation Acute Myocardial Infarction (STEMI) Coronary recanalization, the level of glutamic-oxalacetic transaminease (AST) after STEMI Coronary recanalization, lactic dehydrogenase (LDH) and creatine kinase isozyme (CKMB) can be effectively reduced in coronary heart disease compound preparation, improve cardiac systolic function, myocardial fibrosis area is reduced, the significant role for being effectively improved remodeling ventricle is played.
Description
Technical field
The invention belongs to the field of Chinese medicines, and in particular to coronary heart disease compound preparation improves in cardiac-related diseases drug in preparation
Application.
Background technique
Coronary heart disease is the highest disease of the death rate in cardiovascular disease, and death toll increases from the 573.7 ten thousand of nineteen ninety
It is added to 2013 813.9 ten thousand.In the numerous types of coronary heart disease, acute myocardial infarction AMI is the important original for causing sudden cardiac death
Cause, clinical manifestation are pain after violent chest, and are increased with serum cardiac zymetology index and electrocardiogram, haemodynamics
Progressive deteriorates；Pathological characters are myocardium cell necrosis, and are divided into coagulating type necrosis and/or shrinkage band necrosis.Clinically, it emphasizes
Whether raised and classified in hunchbacked sample with ST sections, that is, is divided into ST sections of elevation myocardial infarction (ST-segment elevation
Myocardial infarction, STEMI) and Non-ST Elevation Acute type myocardial infarction (Non-ST-segment elevation
myocardial infarction,NSTEMI).Wherein, for STEMI treatment available strategy be thrombolysis and sufficiently it is lasting
Blood vessel Reperfu- sion, and general revascularization surgical operation is better than drug thromboembolism treatment, therefore mostly uses cardiovascular surgical procedure such as
Percutaneous coronary intervention (percutaneous coronary intervention, PCI) and coronary artery bypass grafting
Art (coronary artery bypass grafting, CABG) is treated.But the hemoperfusion of continuous and effective is easily made
At myocardial tissue damage, such as oxidative stress, calcium overload, fibrosis, terminal phase feature is remodeling ventricle, and then developing is the heart
Force failure leads to death, this is the ineffective key factor place of current clinically myocardial infarction treatment.It can be seen that prevention ventricle
The generation of reconstruct or the process for reversing remodeling ventricle are the key that reduce the death rate.
Coronary heart disease side is the classical blood-activating and stasis-removing compound recorded in 2005 and 2010 editions pharmacopeia, by Radix Salviae Miltiorrhizae, three
Seven, dalbergia heartwood oil is made.The compound contains tanshin polyphenolic acid B, tanshinone IIA, three ginseng saponin(e R1, ginsenoside Rg1, ginsenoside Rb1
Etc. a variety of active ingredients, it is adjuvant that the dalbergia heartwood oil with promoting qi circulation and relieving pain effect is selected in side, cooperate the Radix Salviae Miltiorrhizae of activating microcirculation and removing stasis medicinal with
The Radix Notoginseng for dissipating blood analgesic therapy has significant curative effect to by the coronary heart disease of main pathogenesis of qi depression to blood stasis.Pharmacology activity research shows hat
Heart red sage formulation have it is anti-inflammatory, anti-oxidant, resist myocardial ischemia, the cardiovascular correlation diseases of a variety of treatments such as anti-arrhythmia, blood pressure lowering
The effect of disease.Based on traditional effect, coronary heart disease compound preparation is mainly used for treating thoracic obstruction, shouting pain uncomfortable in chest, shortness of breath and palpitation, coronary disease
The symptoms such as sick angina pectoris；Based on modern study, coronary heart disease compound preparation is mainly used for the protection of the diseases such as myocardial ischemia, anoxic
Effect.But currently without about the compound preparation and its simple Radix Salviae Miltiorrhizae, Radix Notoginseng and dalbergia heartwood oil prevention or treatment STEMI hat
Basic research and the clinical application report of remodeling ventricle after arteries and veins leads to again.After the present invention is by establishing generally acknowledged STEMI Coronary recanalization
Remodeling ventricle animal model studies coronary heart disease compound preparation heart after improving ST-Elevation Acute Myocardial Infarction Coronary recanalization
The effect of room reconstruct, provides research example for the secondary development of Chinese herbal medicine and its compound, is also ventricle weight after exploitation treatment STEMI
The new Chinese medicine of structure provides scientific basic.
Summary of the invention
The invention discloses coronary heart disease compound preparation in preparation for improving the application in cardiac-related diseases drug.
More specifically, the invention discloses coronary heart disease compound preparation in preparation for improving ST-Elevation Acute cardiac muscle
Application after infarct Coronary recanalization in the drug of remodeling ventricle.
The coronary heart disease compound preparation that the present invention uses is made of Radix Salviae Miltiorrhizae, Radix Notoginseng, dalbergia heartwood oil, matches as Dan Can ﹕ tri- Qi ﹕ drop
Sesame oil=200g ﹕ 200g ﹕ 1.75mL, index ingredient contained by each single medicinal material meet the rule of 2015 editions " Chinese Pharmacopoeia "
It is fixed, active constituent can also be obtained in method specified in pharmacopeia according to said ratio, and then be prepared by commercially available
Other dosage forms commonly used in the art.
The present invention establishes remodeling ventricle Animal diseases mould after generally acknowledged ST-Elevation Acute Myocardial Infarction Coronary recanalization
Type carries out ramus descendens anterior arteriae coronariae sinistrae ligation operation to SD rat, causes ST-Elevation Acute Myocardial Infarction to damage, from the heart
Three enzyme of flesh (glutamic-oxalacetic transaminease AST, lactate dehydrogenase L DH, creatine kinase isozyme CK-MB), ultrasonic cardiography index (left ventricular ejection
Score LVEF, left room short axis shortening rate LVFS), cardiac muscular tissue HE dyeing and horse pine dyeing etc. multi objectives verifying model foundation at
Function.
The present invention is by establishing generally acknowledged animal disease model, and from myocardium three enzymes, (glutamic-oxalacetic transaminease AST, lactic acid are de- respectively
Hydrogen enzyme LDH, creatine kinase isozyme CK-MB), ultrasonic cardiography index (Left Ventricular Ejection Fraction LVEF, left room short axis shortening rate
LVFS), the multi objectives such as the expression of infarct size, the dyeing of horse pine and myocardial fibrosis marker α-SMA, sufficiently research hat
Heart red sage compound preparation improves the effect of remodeling ventricle after ST-Elevation Acute Myocardial Infarction Coronary recanalization, for the upper of the compound
Secondary development provides solid scientific basic behind city.
Coronary heart disease compound preparation of the present invention can significantly inhibit glutamic-oxalacetic transaminease (AST), lactic acid after STEMI Coronary recanalization
The level of dehydrogenase (LDH) and creatine kinase isozyme (CKMB), has obvious protective function to cardiac muscular tissue；Significantly improve a left side
Maximum rate that room ejection fraction (LVEF), left room short axis shortening rate (LVFS) and isovolumic contraction period left ventricular pressure power rise (+
Dp/dt), dose dependent reduces the isovolumic relaxation time (Tau) of reflection cardiac diastolic function, effectively improves the heart after Coronary recanalization
Functional level；Coronary heart disease compound preparation can inhibit the expression of the smooth muscle actin (α-SMA) in cardiac muscular tissue simultaneously, show
The area for reducing myocardial fibrosis is write, the significant role of anti-remodeling ventricle is played.
The invention has the following advantages:
1. establishing remodeling ventricle animal disease model after mature ST-Elevation Acute Myocardial Infarction Coronary recanalization, it is
Subsequent drug development provides solid foundation.
2. the animal disease model based on foundation, it was found that a kind of improvement ST-Elevation Acute Myocardial Infarction Coronary recanalization
The compound Chinese medicinal preparation of remodeling ventricle afterwards.
3. effect of the compound preparation after improving ST-Elevation Acute Myocardial Infarction Coronary recanalization in remodeling ventricle is aobvious
Write, provide solid pharmacodynamic basis for the new clinical research of the compound and application, wide market after system development, also for
Secondary development provides example after the listing of Chinese herbal medicine and its compound.
4. the compound preparation can significantly inhibit the level of AST, LDH and CK-MB after STEMI Coronary recanalization, protection cardiac muscle
Tissue；LVEF, LVFS and+dp/dt value are significantly improved, dose dependent reduces Tau value；After effectively improving cardiac muscular tissue's Reperfu- sion
Heart function is horizontal；The compound preparation significantly reduces the face of myocardial fibrosis by inhibiting α-SMA expression in cardiac muscular tissue simultaneously
Product, plays the effect of anti-remodeling ventricle.
Detailed description of the invention
Fig. 1 difference fill again the time to myocardium three enzyme AST, LDH, CK-MB indexs influence (N=8), note: with vacation
Operation group compares, P < 0.001 * P < 0.05, * * P < 0.01, * * *.
Fig. 2 difference fills the result of the cardiac muscular tissue HE dyeing of time again
Fig. 3 difference fills the result of the cardiac muscular tissue horse pine dyeing of time again
Fig. 4 difference fill again the time cardiac muscular tissue ultrasonic cardiography index LVEF and LVFS detection result ( N=8),
Note: compared with sham-operation group, P < 0.001 * * P < 0.01, * * *.
The coronary heart disease side Fig. 5 to myocardium three enzyme AST, LDH, CK-MB indexs of blood plasma influence (N=10), note: with
Sham-operation group compares,###P<0.001；Compared with model group, P < 0.001 * * *.
The coronary heart disease side Fig. 6 to cardiac function LVEF and LVFS influence (N=10), note: with sham-operation group ratio
Compared with,###P<0.001；Compared with model group, P < 0.01 * P < 0.05, * *.
The coronary heart disease side Fig. 7 to cardiac function LVSP, LVEDP, ± dp/dt, Tau value influence (N=10), note:
Compared with sham-operation group,#P<0.05；Compared with model group, P < 0.001 * P < 0.05, * * P < 0.01, * * *.
The coronary heart disease side Fig. 8 to myocardial fibrosis influence (N=3), note: compared with sham-operation group,###P<
0.001；Compared with model group, P < 0.01 * *.
The coronary heart disease side Fig. 9 to the improvement result of remodeling ventricle caused by myocardial ischemia-reperfusion (N=3), note: with
Sham-operation group compares,###P<0.001；Compared with model group, P < 0.001 * * *.
Specific embodiment
The present invention is described in further details below with reference to specific embodiment, is not constituted to of the invention further
Limitation.
Embodiment 1: the foundation of remodeling ventricle animal disease model after ST-Elevation Acute Myocardial Infarction Coronary recanalization
1.1 experimental animal of embodiment
Healthy adult male SD rat 90, SPF grades, 300~330g of weight, tonneau China experimental animal technology is tieed up by Beijing
Co., Ltd provides.
1.2 experimental material of embodiment and instrument
Yellow Jackets, physiological saline, AD Instruments polygraph, the breathing of ALC-V8S type toy
Machine (Shanghai Alcott Biotechnology Co., Ltd), surgery hand speed instrument is quickly according to the (beauty of sterilizer Germinator 500
State Harvard apparatus), animal heat-preservation blanket ALC-HTP (Shanghai Alcott Biotechnology Co., Ltd) is disposable quiet
Arteries and veins transfusion needle, medical sterile gauze, medical operation are cut, Medical forceps, medical suture needle, medical knitting litzendraht wire 6-0, are can absorb
Property surgical sutures PGA is purchased from Shanghai Pudong Jinhuan Medical Products Co., Ltd..
1.3 modelling of embodiment
After 8~12h of Rat Fast, with yellow Jackets (press weight 40mg/kg) intraperitoneal injection of anesthesia (buttocks object after stimulation
Contractile response, absent corneal reflex), take dorsal position to be fixed on mouse plate.After diameter mouth intubation, toy ventilator, breathing frequency are connected
70 beats/min of rate, breathe ratio 1:1, tidal volume 1mL.Rat is recorded using AD Instruments polygraph in real time
Electrocardiogram.After rat neck and its skin of chest depilation, row thoracotomy, at the about 0.5cm of breastbone left side, 3 to 4 intercostals
About 2~3cm is cut off, struts rib cage with chest expander, when expiration cuts off pericardium, exposure heart.It is mark with great cardiac vein trunk
Will, between pulmonary conus and left auricle of heart, the place 2mm about below left auricle of heart, with 6-0 silk thread inserting needle pass through cardiac muscle surface layer about 1~
1.5mm, span are 2~3mm.It is after stablizing 5min, silk thread is soft across the single intravenous infusion of a root long about 3.5cm
Pipe, line gently mention the end of a thread after being pierced by, push down on hose, fixed after being clamped with haemostatic clamp.After ischemic 30min, haemostatic clamp is unclamped, is removed
1d, 3d, 7d and 14d are filled after ligature again, establishes Model of Myocardial Ischemia-Reperfusion Injury.Judgement ligatures successful standard are as follows:
It is raised for ST sections in electrocardiogram, local myocardial tissue color is by red graying white；After Reperfu- sion 30min, ST sections fall 50% or more after rise, the heart
Flesh color is reddened by greyish white.
Embodiment 1.4 is grouped
70 SD male rats are randomly divided into 7 groups, every group 10 by weight；According to the multiple different distribution groups for filling the time:
Sham-operation group fills 1d group again, fills 3d group, 7d sham-operation group again, fills 7d group, 14d sham-operation group again and fill 14d group again.
1.5 model evaluation of embodiment
The myocardium three enzyme Indexs measures of embodiment 1.5.1
After multiple filling, abdominal aortic blood.With full automatic biochemical apparatus detection blood plasma in three enzyme of cardiac muscle (AST, LDH,
CKMB) horizontal.
As a result as shown in Figure 1, myocardial ischemia-reperfusion causes acute myocardial injury, reach peak value in multiple filling 14d, react
The optimum time point of heart pathology damage.
Embodiment 1.5.2 histopathological examination
Take rat heart, be soaked in 10% neutral buffered formalin (fixed >=for 24 hours), it is fixed after tissue through repairing
Block materials, dehydration of alcohol, paraffin embedding, sliding microtome slice are dyed through Hematoxylin-eosin (HE), are carried out under light microscopic step by step
It checks.
As a result as shown in Fig. 2, sham-operation group, left ventricle are shown no obvious abnormalities；3d is filled again, and myocardium of left ventricle cell degeneration is bad
Extremely, cell infiltration, a small amount of proliferation of fibrous tissue in infarcted region；7d is filled again, and left ventricle and apex part cardiac muscle cell are by fiber
Tissue replaces, inflammatory cell infiltration；14d, left ventricle middle and lower part and apex local myocardial vanished cell, irregular bar rope are filled again
Shape fibr tissue and blood vessel hyperplasia, cell infiltration, and visible left ventricular wall thin down portions.
The dyeing of embodiment 1.5.3 horse pine
Take rat heart, be soaked in 10% neutral buffered formalin (fixed >=for 24 hours), it is fixed after tissue through repairing
Block materials, dehydration of alcohol, paraffin embedding, sliding microtome slice are dyed through Ma Song (Masson), are examined under light microscopic step by step
It looks into.
As a result as shown in figure 3, sham-operation group and filling 1d again, visible a small amount of fibr tissue around blood vessel, but have no obvious fibre
Tie up hyperblastosis；3d, visible fibr tissue around blood vessel, a small amount of proliferation of fibrous tissue in infarcted region are filled again；7d, left ventricular wall are filled again
It is thinning, infarcted region proliferation of fibrous tissue；14d is filled again, and left ventricle low portion cardiac muscle cell disappears, and fibr tissue and blood vessel increase
It is raw.
Embodiment 1.5.4 ultrasonic cardiography index LVEF and LVFS detection
Using ultrahigh resolution toy ultrasonic image system, to multiple filling 7d, 14d, 7d sham-operation group and 14d vacation are filled again
Operation group detects rat left chamber's ejection fraction LVEF and rat left chamber's shortening fraction LVFS two indices.
As a result as shown in figure 4, M-mode ultrasonic cardiography is the results show that compared with 14d sham-operation, before 14d model group heart
Wall is significantly thinning；And cardiac function index of correlation LVEF and LVFS significantly decline (7d vs 7d sham-operation group；14d vs
14d sham-operation group).
Embodiment 2: coronary heart disease side improves the protection of remodeling ventricle after ST-Elevation Acute Myocardial Infarction Coronary recanalization
Effect
2.1 experimental animal of embodiment
Healthy adult male SD rat 60, SPF grades, 300~330g of weight, tonneau China experimental animal technology is tieed up by Beijing
Co., Ltd provides.
The grouping of embodiment 2.2 and administration
60 SD rats are randomly divided into 6 groups, every group 10 by weight: sham-operation group, model group, Simvastatin group (5mg/
Kg), coronary heart disease side's low dose group (4 times of clinical usual amounts), coronary heart disease side's middle dose group (8 times of clinical usual amounts), coronary disease
Red sage root formula high dose group (16 times of clinical usual amounts).By the animal disease model of foundation, chooses and fill 14d again as acute ST-segment
Caused remodeling ventricle model after elevation myocardial infarction Coronary recanalization, it is postoperative continuously to give gentamicin sulphate prevention infection.Art
Afterwards for 24 hours after, the above each group is administered (by weight 10mL/kg) in a manner of stomach-filling, continuous 14d.After the last administration, the rat heart is detected
Dirty changes of function, myocardium three enzyme levels, heart pathology variation and fibrosis situation, while investigating the table of fibrosis indices in hepatic α-SMA
Up to situation.
2.3 statistical method of embodiment
With 19.0 software of SPSS, each group experimental data is all made of mean ± standard deviation (x ± s) expression, and multiple groups mean compares
Using variance analysis, P < 0.05 is statistically significant.
2.4 experimental result of embodiment
Influence of the embodiment coronary heart disease side 2.4.1 to myocardium three enzyme indexs
As a result as shown in figure 5, compared with sham-operation group, blood plasma cardiac muscle three enzyme AST, LDH and CKMB of model group are horizontal
Significant to increase, positive drug Simvastatin can significantly reduce myocardium three enzyme levels, and basic, normal, high three dosage in coronary heart disease side can be shown
Write the level for reducing myocardium three enzymes.Wherein, the dose-dependent relationship of LDH and CK-MB index is more apparent.
Influence of the embodiment coronary heart disease side 2.4.2 to parameters of left ventricular function LVEF and LVFS
As a result as shown in fig. 6, after myocardial ischemia-reperfusion 14d, the Left Ventricular Ejection Fraction of cardiac systolic function is embodied
(LVEF) it is significantly reduced with left room short axis shortening rate (LVFS).Compared with model group, coronary heart disease side's intervention group, left room it is thinning by
(P < 0.01) is significantly increased to inhibition, LVEF, LVFS, it is suitable with the effect of positive drug Simvastatin, and the high agent in coronary heart disease side
Amount group effect is more preferable.
Influence of the embodiment coronary heart disease side 2.4.3 to parameters of left ventricular function LVSP, LVEDP, ± dp/dt, Tau value
As a result as shown in fig. 7, after myocardial ischemia-reperfusion 14d, the left ventricular systolic pressure (LVSP) of cardiac systolic function is embodied
It is significantly reduced with the maximum rate (+dp/dt) that isovolumic contraction period left ventricular pressure power rises, embodies the appearances such as cardiac diastolic function and relax
Time (Tau) is opened significantly to increase.Compared with model group, coronary heart disease side's intervention group ,+dp/dt significantly increases (P < 0.01), and is preced with
Heart red sage root formula high dose group acts on the effect for being better than positive drug Simvastatin；Tau significantly reduces (P < 0.001), there is dose-dependant
Property, and high dose group effect in coronary heart disease side's is better than the effect of positive drug Simvastatin.
Influence of the embodiment coronary heart disease side 2.4.4 to myocardial fibrosis
As a result as shown in figure 8, after myocardial ischemia-reperfusion 14d, compared with sham-operation, model group cardiac muscle occurs apparent fine
Dimensionization lesion, there were significant differences with sham-operation (P < 0.001) for fibrosis area, Simvastatin energy reverse myocardial fibrosis, equally
Coronary heart disease side also can significantly reduce myocardial fibrosis, reduce myocardial infarction area (P < 0.001).
The influence that myocardial fibrosis markers α-SMA expresses in the embodiment coronary heart disease side 2.4.5
As a result as shown in figure 9, Western blot is the results show that compared with sham-operation, model group cardiac muscular tissue Myocardial
The expression of Fibrosis Markers α-SMA significantly increases (P < 0.001).After coronary heart disease side intervenes, α-in cardiac muscular tissue
The protein expression level of SMA significantly reduces (P < 0.001).
Obviously, the above embodiment of the present invention is merely to illustrate examples made by the present invention, and be not to the present invention
Embodiment restriction.For those of ordinary skill in the art, it can also make on the basis of the above description
Other various forms of variations or variation.There is no necessity and possibility to exhaust all the enbodiments.And these belong to this
The spiritual changes and variations that derived from of invention are still in the protection scope of this invention.
Claims (3)
1. coronary heart disease compound preparation caused ventricle weight after preparation improves ST-Elevation Acute Myocardial Infarction Coronary recanalization
Application in the drug of structure, wherein coronary heart disease compound preparation is made of Radix Salviae Miltiorrhizae, Radix Notoginseng, dalbergia heartwood oil, and raw material proportioning is Dan Can ﹕ tri-
Qi ﹕ dalbergia heartwood oil=200g ﹕ 200g ﹕ 1.75mL.
2. application according to claim 1, wherein coronary heart disease compound preparation is oral preparation, it is selected from sugar coated tablet, mouth
Cavity disintegrating tablet, sublingual tablet, buccal tablet, effervescent tablet, hard capsule, pill, soft capsule, granule, suspension.
3. application according to claim 2, wherein the pill is pill.
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