CN106511462A - Application of Guanxin salvia miltiorrhiza compound preparation in preparing medicine for improving ventricular remodeling - Google Patents
Application of Guanxin salvia miltiorrhiza compound preparation in preparing medicine for improving ventricular remodeling Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
- A61K36/258—Panax (ginseng)
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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Abstract
The invention discloses an application of a Guanxin salvia miltiorrhiza compound preparation in preparing a medicine for improving ventricular remodeling. The Guanxin salvia miltiorrhiza compound preparation is composed of 200 g of salvia miltiorrhiza, 200 g of pseudo-ginseng and 1.75 mL of dalbergiae odoriferae oil. The application comprises that for ventricular remodeling generated after acute ST-segment elevation myocardial infarction (STEMI) coronary artery recanalization, the Guanxin salvia miltiorrhiza compound preparation can effectively reduce levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CKMB) after STEMI coronary artery recanalization, improves systolic functions, reduces the area of myocardial fibrosis, and plays a major role in effectively improving ventricular remodeling.
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 medicine in preparation
Application.
Background technology
Coronary heart disease is death rate highest disease in angiocardiopathy, and its death toll is from 573.7 ten thousand increasings 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 raised with serum cardiac zymetology index and electrocardiogram, hemodynamic
Progressive deteriorates；Pathological characters are myocardium cell necrosis, and are divided into coagulating type necrosis and/or shrink band necrosis.Clinically, emphasize
Classified so that whether ST sections are raised in hunchbacked sample, that is, be divided into ST section 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, the available strategy for STEMI treatments is that thrombolysis is lasting with abundant
Blood vessel Reperfu- sion, and general revascularization surgical operation is better than medicine thromboembolism treatment, therefore adopt cardiovascular surgical procedure such as more
PCI (percutaneous coronary intervention, PCI) and CBG
Art (coronary artery bypass grafting, CABG) is treated.But, the hemoperfusion of continuous and effective is easily made
Into myocardial tissue damage, such as oxidative stress, calcium overload, fibrillatable etc., its whole latter stage is characterized as remodeling ventricle, and then develops into the heart
Force failure, causes death, and this is that clinically the key factor of myocardial infarction treatment effect on driving birds is not good is located at present.It can be seen that prevention ventricle
The generation of reconstruct or the process for reversing remodeling ventricle are the keys for reducing the death rate.
Coronary heart disease side is the classical blood-activating and stasis-removing compound recorded in 2005 and 2010 editions pharmacopeia, by the red sage root, three
7th, dalbergia heartwood oil is made.The compound contains tanshin polyphenolic acid B, tanshinone IIA, three ginseng saponin(e R1, ginsenoside Rg1, ginsenoside Rb1
Etc. various active composition, be adjuvant from the dalbergia heartwood oil with promoting qi circulation and relieving pain effect in side, coordinate the red sage root promoting blood circulation and removing blood stasis and
The pseudo-ginseng of scattered blood analgesic therapy, has significant curative effect to the coronary heart disease with qi depression to blood stasis as main pathogenesis.Pharmacology activity research shows, is preced with
Heart red sage formulation have anti-inflammatory, it is anti-oxidant, resist myocardial ischemia, anti-arrhythmia, the cardiovascular correlation diseases of the various treatments such as hypotensive
The effect of disease.Based on traditional effect, coronary heart disease compound preparation is mainly used in treating the obstruction of qi in the chest, shouting pain uncomfortable in chest, palpitation, coronary disease
The symptoms such as sick angina pectoris；Based on modern study, coronary heart disease compound preparation is mainly used in the protection of the diseases such as myocardial ischemia, anoxic
Effect.But, currently without with regard to the compound preparation and its prevention of the simple red sage root, pseudo-ginseng and dalbergia heartwood oil or treatment STEMI hats
Arteries and veins leads to the basic research of rear remodeling ventricle and clinical practice report again.The present invention is after setting up the STEMI Coronary recanalizations generally acknowledged
Remodeling ventricle animal model, studies coronary heart disease compound preparation heart after ST-Elevation Acute Myocardial Infarction Coronary recanalization is improved
The effect of room reconstruct, the secondary development for Chinese herbal medicine and its compound provide research example, are also ventricle weight after exploitation treatment STEMI
The new Chinese medicine of structure provides scientific basic.
The content of the invention
The invention discloses coronary heart disease compound preparation is being prepared for improving the application in cardiac-related diseases medicine.
More specifically, the invention discloses coronary heart disease compound preparation is being prepared for improving ST-Elevation Acute cardiac muscle
Application after infarct Coronary recanalization in the medicine of remodeling ventricle.
The coronary heart disease compound preparation that the present invention is used is made up of the red sage root, pseudo-ginseng, dalbergia heartwood oil, and proportioning is dropped for Salvia miltiorrhiza and Panax notoginseng
Sesame oil=200g 200g 1.75mL, each index composition contained by single medicinal material meet 2015 editions《Chinese Pharmacopoeia》Rule
It is fixed, can be by commercially available, it is also possible to obtain active component according to said ratio in method specified in pharmacopeia, and then be prepared into
Other commonly used in the art formulation.
The present invention establishes remodeling ventricle Animal diseases mould after generally acknowledged ST-Elevation Acute Myocardial Infarction Coronary recanalization
Type, i.e., carry out ramus descendens anterior arteriae coronariae sinistrae ligation operation to SD rats, cause 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
Fraction LVEF, left LVSF LVFS), the multi objective checking model such as cardiac muscular tissue HE dyeing and horse pine dyeing is created as
Work(.
By setting up the animal disease model generally acknowledged, from myocardium three enzyme, (glutamic-oxalacetic transaminease AST, lactic acid take off the present invention respectively
Hydrogen enzyme LDH, creatine kinase isozyme CK-MB), ultrasonic cardiography index (Left Ventricular Ejection Fraction LVEF, left LVSF
LVFS), the multi objectives such as the expression of infarct size, the dyeing of horse pine and myocardial fibrosis mark α-SMA, fully research hat
Heart red sage compound preparation improves the effect of remodeling ventricle after ST-Elevation Acute Myocardial Infarction Coronary recanalization, is the upper of the compound
Behind city, secondary development provides solid scientific basic.
Coronary heart disease compound preparation of the present invention can significantly inhibit glutamic-oxalacetic transaminease (AST), lactic acid after STEMI Coronary recanalizations
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 LVEF (LVEF), left LVSF (LVFS) and isovolumic contraction period left ventricular pressure power rise (+
Dp/dt), dose dependent reduces the IVRT (Tau) of reflection cardiac diastolic function, effectively improves the heart after Coronary recanalization
Functional level；Simultaneously coronary heart disease compound preparation can suppress the expression of the smooth muscle actin (α-SMA) in cardiac muscular tissue, show
Writing reduces the area of myocardial fibrosis, plays the significant role of anti-remodeling ventricle.
The invention has the advantages that：
1. remodeling ventricle animal disease model after the ST-Elevation Acute Myocardial Infarction Coronary recanalization of maturation is established, is
Follow-up drug development provides solid foundation.
2. based on the animal disease model set up, it was found that one kind improves ST-Elevation Acute Myocardial Infarction Coronary recanalization
The compound Chinese medicinal preparation of remodeling ventricle afterwards.
3. effect of the compound preparation after ST-Elevation Acute Myocardial Infarction Coronary recanalization is improved in remodeling ventricle shows
Write, be the new clinical research of the compound and application solid pharmacodynamic basis are provided, wide market after system development, also for
After the listing of Chinese herbal medicine and its compound, secondary development provides example.
4. the compound preparation can significantly inhibit the level of AST, LDH and CK-MB after STEMI Coronary recanalizations, protection cardiac muscle
Tissue；LVEF, LVFS and+dp/dt values is significantly improved, dose dependent reduces Tau values；After effectively improving cardiac muscular tissue's Reperfu- sion
Heart function level；The compound preparation significantly reduces the face of myocardial fibrosis by suppressing α-SMA expression in cardiac muscular tissue simultaneously
Product, plays the effect of anti-remodeling ventricle.
Description of the drawings
Fig. 1 is different fill again impact of the time to myocardium three enzymes AST, LDH, CK-MB index (N=8), note：With do evil through another person
Art group compares, * P<0.05, * * P<0.01, * * * P<0.001.
The result of the different cardiac muscular tissue HE dyeing for filling the time again of Fig. 2
The result of the different cardiac muscular tissue's horse pine dyeing for filling the time again of Fig. 3
Fig. 4 differences result that cardiac muscular tissue's ultrasonic cardiography index LVEF of filling time and LVFS are detected again ( N=8),
Note：Compare with sham-operation group, * * P<0.01, * * * P<0.001.
Fig. 5 coronary heart disease sides to blood plasma cardiac muscle three enzyme AST, LDH, CK-MB indexs impact (N=10), note：With
Sham-operation group compares,###P<0.001；Compare with model group, * * * P<0.001.
Impact of Fig. 6 coronary heart disease sides to cardiac function LVEF and LVFS (N=10), note：With sham-operation group ratio
Compared with,###P<0.001；Compare with model group, * P<0.05, * * P<0.01.
Fig. 7 coronary heart disease sides to cardiac function LVSP, LVEDP, ± dp/dt, Tau value impact (N=10), note：
Compare with sham-operation group,#P<0.05；Compare with model group, * P<0.05, * * P<0.01, * * * P<0.001.
Impact of Fig. 8 coronary heart disease sides to myocardial fibrosis (N=3), note：Compare with sham-operation group,###P<
0.001；Compare with model group, * * P<0.01.
Fig. 9 coronary heart disease sides to the improvement result of remodeling ventricle caused by myocardial ischemia-reperfusion (N=3), note：With
Sham-operation group compares,###P<0.001；Compare with model group, * * * P<0.001.
Specific embodiment
The present invention is described in further details with reference to specific embodiment, is not constituted to the further of the present invention
Limit.
Embodiment 1：The foundation of remodeling ventricle animal disease model after ST-Elevation Acute Myocardial Infarction Coronary recanalization
1.1 animal used as test of embodiment
Healthy adult male SD rat 90, SPF levels, 300～330g of body weight, by Beijing dimension tonneau China animal used as test technology
Co., Ltd provides.
1.2 experiment material of embodiment and instrument
Yellow Jackets, physiological saline, AD Instruments polygraphs, the breathing of ALC-V8S types toy
Machine (Shanghai Alcott bio tech ltd), surgery hand speed apparatus are quickly (beautiful according to sterilizer Germinator 500
State Harvard apparatus), animal heat-preservation blanket ALC-HTP (Shanghai Alcott bio tech 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, absorbable
Property surgical sutures PGA are purchased from Shanghai Pudong Jinhuan Medical Products Co., Ltd..
1.3 modelling of embodiment
After 8～12h of Rat Fast, with yellow Jackets (by body weight 40mg/kg) intraperitoneal injection of anesthesia (buttocks thing after stimulation
Contractile response, absent corneal reflex), take dorsal position and be fixed on mouse plate.After the mouth intubation of footpath, connect toy lung ventilator, breathing frequency
70 beats/min of rate, breathes ratio 1:1, tidal volume 1mL.Using AD Instruments polygraph real time record rats
Electrocardiogram.After rat neck and its skin of chest depilation, row thoracotomy, at about 0.5cm on the left of breastbone, 3 to 4 intercostals
About 2～3cm is cut off, rib is strutted with chest expander, cut off pericardium during expiration, expose heart.With great cardiac vein trunk as mark
Will, between pulmonary conus and left auricle of heart, about below left auricle of heart at 2mm, with 6-0 silk threads inserting needle through myocardium top layer about 1～
1.5mm, span are 2～3mm.It is after 5min to be stablized, silk thread is soft through a single intravenous infusion for being about 3.5cm
Pipe, line gently carry the end of a thread after passing, push down on flexible pipe, fixed after being clamped with haemostatic clamp.After ischemic 30min, haemostatic clamp is unclamped, removed
Fill 1d, 3d, 7d and 14d after ligature again, set up Model of Myocardial Ischemia-Reperfusion Injury.Judge that the successful standard of ligation is：
In electrocardiogram, ST sections are raised, and local myocardial tissue color is greyish white by red change；After Reperfu- sion 30min, ST sections fall more than 50% 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 by body weight, 10 per group；According to the different distribution groups of multiple filling time：
Sham-operation group, again fill 1d groups, again fill 3d groups, 7d sham-operation groups, again fill 7d groups, 14d sham-operation groups and again fill 14d groups.
1.5 model evaluation of embodiment
Embodiment 1.5.1 three enzyme Indexs measures of cardiac muscle
After multiple filling terminates, abdominal aortic blood.With full automatic biochemical apparatus detect blood plasma in three enzyme of cardiac muscle (AST, LDH,
CKMB) level.
As a result as shown in figure 1, myocardial ischemia-reperfusion causes acute myocardial injury, peak value is reached in multiple filling 14d, react
The optimum time point of heart pathology damage.
Embodiment 1.5.2 histopathological examination
Rat heart is taken, 10% neutral buffered formalin (fixation >=24h) is soaked in, the tissue Jing after fixing is repaiied
Block is drawn materials, step by step dehydration of alcohol, FFPE, sliding microtome section, and Jing Hematoxylin-eosins (HE) dyeing is carried out under light microscopic
Check.
As a result as shown in Fig. 2 sham-operation group, left ventricle shows 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 is filled again
Shape fibr tissue and blood vessel hyperplasia, cell infiltration, and visible left ventricular wall thin down portions.
The pine dyeing of embodiment 1.5.3 horse
Rat heart is taken, 10% neutral buffered formalin (fixation >=24h) is soaked in, the tissue Jing after fixing is repaiied
Block is drawn materials, step by step dehydration of alcohol, FFPE, sliding microtome section, and Jing Ma Song (Masson) dyeing is examined under light microscopic
Look 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
Dimensional tissue hyperplasia；3d is filled again, visible fibr tissue around blood vessel, a small amount of proliferation of fibrous tissue in infarcted region；7d, left ventricular wall is filled again
It is thinning, infarcted region proliferation of fibrous tissue；14d is filled again, left ventricle low portion cardiac muscle cell disappears, fibr tissue and blood vessel increase
It is raw.
Embodiment 1.5.4 ultrasonic cardiography index LVEF and LVFS detections
Using ultrahigh resolution toy ultrasonic image system, to multiple filling 7d, filling 14d, 7d sham-operation group and 14d are false again
Operation group, detection rat left chamber LVEF LVEF and rat left chamber's shortening fraction LVFS two indices.
As a result as shown in figure 4, M-mode ultrasonic cardiography results show, compare with 14d sham-operations, before 14d model group hearts
Wall is significantly thinning；And cardiac function index of correlation LVEF and LVFS significantly decline (7d vs 7d sham-operation groups；14d vs
14d sham-operation groups).
Embodiment 2：Coronary heart disease side improves the protection of remodeling ventricle after ST-Elevation Acute Myocardial Infarction Coronary recanalization
Effect
2.1 animal used as test of embodiment
Healthy adult male SD rat 60, SPF levels, 300～330g of body weight, by Beijing dimension tonneau China animal used as test technology
Co., Ltd provides.
Embodiment 2.2 is grouped and is administered
60 SD rats are randomly divided into 6 groups by body weight, 10 per group：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 set up, choose
Remodeling ventricle model caused by after elevation myocardial infarction Coronary recanalization, it is postoperative continuously to give gentamicin sulphate prevention infection.Art
Afterwards after 24h, above each group is administered (by body weight 10mL/kg) in gavage mode, continuous 14d.After last dose, the rat heart is detected
Dirty changes of function, myocardium three enzyme level, heart pathological change and fibrillatable situation, while investigate the table of fibrosis indices in hepatic α-SMA
Up to situation.
2.3 statistical method of embodiment
With 19.0 softwares of SPSS, using mean ± standard deviation (x ± s) expression, multigroup mean compares each group experimental data
Using variance analysis, P<0.05 is statistically significant.
2.4 experimental result of embodiment
Impact of the embodiment 2.4.1 coronary heart disease side to myocardium three enzymes index
As a result as shown in figure 5, comparing with sham-operation group, blood plasma three enzyme AST, LDH and CKMB levels of cardiac muscle of model group
Significantly raise, positive drug Simvastatin can significantly reduce myocardium three enzyme level, and basic, normal, high three dosage in coronary heart disease side can show
Writing reduces the level of myocardium three enzyme.Wherein, the dose-dependent relationship of LDH and CK-MB indexs is more apparent.
Impact of the embodiment 2.4.2 coronary heart disease side to parameters of left ventricular function LVEF and LVFS
As a result as shown in fig. 6, after myocardial ischemia-reperfusion 14d, embodying the Left Ventricular Ejection Fraction of cardiac systolic function
(LVEF) significantly reduce with left LVSF (LVFS).Compare with model group, coronary heart disease side's intervention group, left room is thinning to be received
(P is raised significantly to suppression, LVEF, LVFS<0.01) 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.
Embodiment 2.4.3 coronary heart disease side is to parameters of left ventricular function LVSP, LVEDP, the impact of ± dp/dt, Tau value
As a result as shown in fig. 7, after myocardial ischemia-reperfusion 14d, embodying the left ventricular systolic pressure (LVSP) of cardiac systolic function
The maximum rate (+dp/dt) risen with isovolumic contraction period left ventricular pressure power is significantly reduced, and is embodied the appearance such as cardiac diastolic function and is relaxed
Open time (Tau) significantly rising.Compare with model group, coronary heart disease side's intervention group ,+dp/dt significantly raise (P<0.01), and be preced with
The effect of heart red sage root formula high dose group is better than the effect of 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.
Impact of the embodiment 2.4.4 coronary heart disease side 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 significantly fine
Dimensionization pathology, fibrosis area and sham-operation there were significant differences (P<0.001), Simvastatin energy reverse myocardial fibrosis, equally
Coronary heart disease side can also significantly reduce myocardial fibrosis, reduce myocardial infarction area (P<0.001).
The impact that embodiment 2.4.5 coronary heart disease side is expressed to myocardial fibrosis markers α-SMA
As a result as shown in figure 9, Western blot results show, compare with sham-operation, model group cardiac muscular tissue Myocardial
The expression of Fibrosis Markers α-SMA significantly raises (P<0.001).After intervening Jing coronary heart disease side, 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 example of the present invention, and be not to the present invention
Embodiment restriction.For those of ordinary skill in the field, can also make on the basis of the above description
The change or variation of other multi-forms.There is no need to be exhaustive to all of embodiment.And these belong to this
The spirit of invention it is amplified obvious change or among changing still in protection scope of the present invention.
Claims (9)
1. coronary heart disease compound preparation is preparing the application improved in cardiac-related diseases.
2. application according to claim 1, is characterised by, described cardiac-related diseases are remodeling ventricle class disease.
3. application according to claim 2, it is characterised in that described remodeling ventricle is ST-Elevation Acute cardiac muscle stalk
The remodeling ventricle caused after dead Coronary recanalization.
4. the application according to claim 1-3, the medicinal raw material of wherein coronary heart disease compound preparation include the red sage root, pseudo-ginseng,
Dalbergia heartwood oil.
5. application according to claim 4, wherein coronary heart disease compound preparation is by from the red sage root, pseudo-ginseng, dalbergia heartwood oil and medicine
On, acceptable auxiliary material is made, and the red sage root is monarch drug in a prescription, and pseudo-ginseng is ministerial drug, plays main pharmacodynamics effect；Dalbergia heartwood oil is adjuvant, auxiliary
The drug action for improving the red sage root and pseudo-ginseng is helped, the effect of Synergistic is played.
6. application according to claim 5, wherein coronary heart disease compound preparation be oral formulations, including GUANXIN DANSHEN PIAN,
GUANXIN DANSHEN JIAONANG, coronary heart disease drop pill.
7. in the application according to claim 1-3, wherein coronary heart disease compound preparation, raw material proportioning is dropped for Salvia miltiorrhiza and Panax notoginseng
Sesame oil=200g 200g 1.75mL.
8. application according to claim 7, wherein coronary heart disease compound preparation are oral formulations, selected from sugar coated tablet, mouth
Cavity disintegrating tablet, sublingual tablet, buccal tablet, effervescent tablet, hard capsule, pill, soft capsule, granule, pill, supensoid agent.
9. application according to claim 7, wherein coronary heart disease compound preparation are non-oral formulation, selected from injection, defeated
Liquor, patch.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115364142A (en) * | 2022-06-06 | 2022-11-22 | 中国医学科学院药用植物研究所 | Application of Qidong Yixin oral liquid in preparation of medicine for treating diabetic cardiomyopathy |
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| CN115364142B (en) * | 2022-06-06 | 2023-05-12 | 中国医学科学院药用植物研究所 | Application of Qihuangyi heart oral liquid in preparation of medicine for treating diabetic cardiomyopathy |
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