CN101229197A - Uses of Huatuo reforger pill on preparing anemic heart disease preventing and curing medicine - Google Patents
Uses of Huatuo reforger pill on preparing anemic heart disease preventing and curing medicine Download PDFInfo
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Abstract
The invention provides an application of Huatuo reconstruction pill in preparing medicine for heart disease due to blood inefficiency. Huatuo reconstruction pill can also be replaced by other agents and can also combine with other medicine to make compound preparation.
Description
Technical field
The present invention relates to the new purposes of HUATUO ZAIZAO WAN aspect preparation control myocardial ischemia, myocardial infarction ischemic heart medicine.
Background technology
HUATUO ZAIZAO WAN is the same with YUNNAN BAIYAO, is the secret kind of Chinese medicine of China of producing without competition of applicant.Function with blood circulation promoting and blood stasis dispelling, eleminating phlegm and freeing channels, promoting the circulation of QI to relieve pain.Be used for the stroke in convalescent stage and the sequela of phlegm stagnation in collateral, disease is seen hemiplegia, contracture numbness, oral crooked, slurred speech.This medication is imitated definite, enjoys higher reputation in the associated patient at home and abroad.
But up to now, do not see that HUATUO ZAIZAO WAN is at the report of using aspect the ischemic heart medicines such as preparation control myocardial ischemia, myocardial infarction.
Summary of the invention
The present invention is exactly in order to provide HUATUO ZAIZAO WAN in the new purposes aspect the ischemic heart medicines such as preparation control myocardial ischemia, myocardial infarction.
Zoopery is found, with myocardial infarction model test due to the rat myocardial ischemia and reperfusion, the result shows that HUATUO ZAIZAO WAN obviously alleviates the myocardial infarction degree, infarct size reduces, infarcted region weight saving, infarcted region account for ventricle and heart percentage ratio reduces, and activity of SOD in serum raises simultaneously, MDA content reduces, and with model group significant difference is arranged more all.To the experimental period of anesthetized dog, HUATUO ZAIZAO WAN has the obvious effect that improves dog acute myocardial ischemia and myocardial infarction, obviously alleviates by the degree of myocardial ischemia of epicardial electrogram mapping (∑-ST); Reduce myocardial ischemia scope (N-ST) by epicardial electrogram mapping; Dwindle through the shown infarcted region of N-BT dyeing; Release, the creatine kinase (CK) of the serum lactate dehydrogenase (SLD) (LDH) that myocardial ischemia and myocardial infarction are caused be active to raise and the activity of endothelin level (ET) has obvious inhibitory action, blood plasma 6-ketone-prostacyclin F when raising myocardial ischemia simultaneously
1 α(6-Keto-PGF
1 α) and 6-Keto-PGF
1 α/ TXB
2Ratio.HUATUO ZAIZAO WAN is to the influence of normal anesthesiaing dog heart blood flowing dynamics, myocardial oxygen consumption, and experimental result shows: HUATUO ZAIZAO WAN does not all have obvious influence to parameters such as arteriotony, heart rate, standard I I ECG P R interval, QRS interval, QT interval and T ripples; Obvious coronary artery dilating, coronary blood flow increasing increases the blood supply of cardiac muscle ability; The heart left chamber work done be can increase, LVSP and dp/dt increased
Max, improve the cardiac activity ability, heart is had the positivity regulating action; Simultaneously can increase cardiac output and cardiac output, reduce total peripheral resistance; Can obviously increase myocardial oxygen consumption, this and medicine increase coronary blood flow, increase ventricular stroke work, regulate relevant to the positivity of heart.Adopt the BornShi turbidimetry, observe the influence of HUATUO ZAIZAO WAN the rabbit platelet aggregation.The result shows: gave the rabbit gastric infusion in continuous 7 days, HUATUO ZAIZAO WAN obviously reduces adenosine diphosphate (ADP) (ADP), arachidonic acid (AA) and collagen-induced rabbit platelet aggregation rate (P＜0.01～0.001).The prompting HUATUO ZAIZAO WAN has the effect of anticoagulant.HUATUO ZAIZAO WAN is to the influence of rats in vitro thrombosis and blood viscosity.The result shows, gives the rat oral gavage administration in continuous 7 days, and HUATUO ZAIZAO WAN obviously shortens thrombosis length (P＜0.05～0.001), alleviates wet weight of thrombus and dry weight (P＜0.05～0.001); Obviously reduce shear rate 60S
-1, 5S
-1Under whole blood viscosity (P＜0.05～0.01).Show that HUATUO ZAIZAO WAN has the effect that suppresses thrombosis and blood viscosity lowering.
In a word, multinomial pharmacological testing shows that HUATUO ZAIZAO WAN has multinomial pharmacological action at cardiovascular field, has clinical value at ischemic heart desease drug treatments such as preparation control myocardial ischemia, myocardial ischemia reperfusion injury, myocardial infarctions.
Experiment of the present invention shows that further other dosage forms of the HUATUO ZAIZAO WAN of same recipe have akin curative effect.
Experiment of the present invention shows that further HUATUO ZAIZAO WAN can be made compound preparation or use in conjunction with medicines such as Radix Notoginseng, Radix Salviae Miltiorrhizae, Fructus Crataegis.
The specific embodiment
The invention will be further described below in conjunction with embodiment.
[embodiment 1] HUATUO ZAIZAO WAN is to the influence of myocardial infarction due to the rat myocardial ischemia and reperfusion.
Test material
56 of animal Wistar kind rats, the II level, male, body weight 240～260g.
The medicine HUATUO ZAIZAO WAN, its extract use in experiment, the pitchy thick paste, every gram thick paste is equivalent to the 0.63g crude drug, lot number approximately: 060320, provide by Qixing Pharmaceutical Co., Ltd., Guangzhou, the pharmacodynamics dosage is with crude drug amount calculating (g crude drug/kg).HEXINSHUANGPIAN, the 30mg/ sheet, lot number 0501017, Tianjin Tanabe Seiyaku Co., Ltd. produces.TONGXINLUO JIAONANG, the 0.38g/ grain, 1.4g crude drug/g powder, lot number 060109, Shijiazhuang Yiling Pharmaceutical Co., Ltd produces.
The test method animal is divided into 7 groups: sham operated rats (not ligation behind the threading gives the equivalent normal saline), model group (giving the equivalent normal saline), diltiazem 10mg/kg group, Tongxinluo 1.2g crude drug/kg group, HUATUO ZAIZAO WAN 7,3.5,1.75g crude drug/kg group.Medicine is assigned to desired concn with normal saline, and route of administration is a duodenum, and the administration volume is 4.8ml, and wherein HUATUO ZAIZAO WAN is because former extraction extractum drug level is lower, and 7.0g/kg group administration volume is 9.6ml/kg (not diluted).
Animal faces upward the position and fixes with pentobarbital sodium intraperitoneal anesthesia (45mg/kg), and tracheostomize inserts tracheal intubation, meets respirator pedestrian worker and breathes (32 times/minute, breathed ratio 1: 3); Open breast, disconnected 3-4 rib is opened pericardium, exposes heart, in left anterior descending coronary artery root threading (No. 0 stitching thread), is equipped with ligation usefulness, opens abdomen, separates duodenum, is equipped with administrable; Stablize ligation in 10 minutes behind the threading, feed and be subjected to close abdomen behind the reagent thing; Cut off ligature after 40 minutes, realize perfusion again, sew up thoracic wall, animal recovers autonomous respiration.
Pour into and finish test after 120 minutes, abdominal aortic blood is measured activity of SOD in serum, MDA content; 5 of the following crosscuts of heart ligature, multi-media color pathology picture and text analytical system is adopted in N-BT dyeing (dyeing back mottle not obvious person eliminate), measures total myocardial area and infarcted myocardium area, observation myocardial infarction degree with fixing image distance; The result carries out statistical procedures (t check).
Result of the test
1. to the influence of myocardial infarction degree.The results are shown in Table 1.
Table 1. HUATUO ZAIZAO WAN is to the influence of myocardial infarction degree
| Grouping | Dosage crude drug/kg | n | Cardiac muscle gross area mm 2 | Infarcted myocardium area mm 2 | Infarcted region weight g | Infarcted region accounts for ventricle % | Infarcted region accounts for heart % |
| Model | 8 | 323.21±19.17 | 98.63±14.65 | 0.244±0.040 | 30.5±3.6 | 26.0±3.1 | |
| The diltiazem group | 10mg | 8 | 324.41±21.10 | 73.52±9.34** | 0.175±0.029** | 22.6±3.2** | 19.6±2.7** |
| The Tongxinluo group | 1.2g | 8 | 323.91±23.89 | 66.40±14.01** | 0.155±0.033** | 20.5±4.2** | 17.3±3.5*** |
| HUATUO ZAIZAO WAN | 1.75g | 8 | 328.25±15.40 | 79.73±13.94* | 0.187±0.038** | 24.2±3.9** | 20.8±3.3** |
| HUATUO ZAIZAO WAN | 3.5g | 8 | 332.65±24.12 | 75.83±12.23** | 0.174±0.027** | 22.8±3.1** | 19.5±2.7** |
| HUATUO ZAIZAO WAN | 7g | 8 | 319.39±12.11 | 59.42±12.88** | 0.143±0.036** | 18.7±4.4** | 15.8±3.7** |
Annotate: *, * * and model group compare, P＜0.05, P＜0.01.
Result of the test confirms that the model group infarcted region accounts for ventricle and heart percentage ratio is respectively 30.5 and 26.0%; Diltiazem 10mg/kg group and Tongxinluo 1.2g/kg group myocardial infarction degree alleviate, and infarct size reduces, infarcted region weight saving, and infarcted region accounts for ventricle and heart percentage ratio reduces, and with model group significant difference (P＜0.01) is arranged relatively; HUATUO ZAIZAO WAN 7,3.5,1.75g crude drug/kg group, myocardial infarction degree have obviously and alleviate, and infarct size reduces, infarcted region weight saving, and infarcted region accounts for ventricle and heart percentage ratio reduces, and with model group significant difference (P＜0.05～P＜0.01) is arranged relatively.
2. to the influence of activity of SOD in serum, MDA content
Experimental observation arrives, and the model group activity of SOD in serum reduces, and MDA content raises, and with sham operated rats significant difference (P＜0.05～P＜0.01) is arranged relatively; Diltiazem and Tongxinluo group SOD are active to raise, and MDA content reduces, and with model group significant difference (P＜0.05) is arranged relatively; HUATUO ZAIZAO WAN 1.75, the active rising of 3.5g/kg group SOD, MDA content reduces, and active rising of 7g/kg group SOD relatively has significant difference (P＜0.05) with model group.The results are shown in Table 2.
Table 2. HUATUO ZAIZAO WAN is to the influence of activity of SOD in serum, MDA content
| Grouping | Dosage/kg | n | SOD(NU/ml) | MDA(nmol/ml) |
| Sham operated rats model diltiazem group Tongxinluo HUATUO ZAIZAO WAN HUATUO ZAIZAO WAN HUATUO ZAIZAO WAN | 10mg 1.2g crude drug 1.75g crude drug 3.5g crude drug 7g crude drug | 8 8 8 8 8 8 8 | 238.2±9.9 203.4±12.0## 216.8±12.3* 214.6±8.3* 215.9±9.4* 215.8±9.1* 214.9±10.2* | 5.28±0.75 6.53±1.61# 5.41±0.30* 5.33±0.80* 5.00±0.70* 5.29±0.78* 6.18±1.19 |
Annotate: #, ## and sham operated rats compare, and P＜0.05, P＜0.01.* and model group compare, P＜0.05.
Conclusion
Reperfusion injury behind the myocardial ischemia, clinical often betide coronary artery bypass grafting postoperative and thrombolytic art treatment heart infarction after.Studies confirm that, after the myocardial ischemia certain hour causes myocardial damage, can cause the inhibition of cardiac function, perfusion not only is unprofitable to the recovery of cardiac function again, increases the weight of existing myocardial damage on the contrary, thereby causes the generation of myocardial infarction or further increase the weight of.It is relevant with the factors such as a large amount of generations, intracellular calcium overload and the excretory a series of endothelial factors of vascular endothelial cell of energy metabolism of myocardial obstacle, oxygen-derived free radicals that myocardial ischemia-reperfusion mechanism be it is generally acknowledged.SOD is body oxidation and the equilibrated key factor of antioxidation, MDA then reflects body inner lipid peroxidating degree, SOD is active to be reduced, MDA content increases, reflected the formation of oxygen-derived free radicals indirectly and to the participation of myocardial damage, the former reacts the ability that body is removed oxygen-derived free radicals, and the latter then reacts the order of severity that body cell is attacked by free radical.
This test is observed drug effect with the rat myocardial ischemia and reperfusion damage model, and experimental observation arrives, and myocardial ischemia reperfusion injury causes myocardial infarction to take place, and N-BT dyeing back heart infarction speckle is obvious, accounts for 30.5% and 26.0% of the ventricle and the heart gross area; HUATUO ZAIZAO WAN 7,3.5,1.75g crude drug/kg group myocardial infarction degree has obviously and alleviates, and infarct size reduces, infarcted region weight saving, infarcted region accounts for ventricle and heart percentage ratio reduces, activity of SOD in serum, MDA content reduces, and with model group significant difference (P＜0.05～P＜0.01) is arranged relatively
Result of the test shows, HUATUO ZAIZAO WAN has clear and definite protective effect to myocardial infarction due to the myocardial ischemia, and one of possible mechanism is removed the ability of oxygen-derived free radicals for increasing body.
[embodiment 2] HUATUO ZAIZAO WAN is to the influence of anesthetized dog myocardial ischemia, myocardial infarction and relevant coronary flow, myocardial oxygen consumption and blood parameters.
Experiment material
1. laboratory animal: 36 of healthy adult dogs, male and female dual-purpose, body weight 13.50 ± 2.19kg.
2. experiment medicine: HUATUO ZAIZAO WAN, with embodiment 1; Diltiazem (diltiazem), the 30mg/ sheet, Tianjin Tanabe Seiyaku Co., Ltd. produces (lot number: 0501017); TONGXINLUO JIAONANG, the 0.38g/ grain, 1.4g crude drug/g powder, lot number: 060109, Shijiazhuang Yiling Pharmaceutical Co., Ltd produces; 0.9% sodium chloride injection, the Beijing Double-Crane Pharmaceutical Co., Ltd produces (lot number: 0603141).
Experiment is divided into six groups: (1) blank group, normal saline 3ml/kg, n=6; (2) positive control drug diltiazem group, 5mg/kg, n=6; (3) Chinese medicine contrast medicine TONGXINLUO JIAONANG 0.24g crude drug/kg dosage group, n=6; (4) HUATUO ZAIZAO WAN 0.5g crude drug/kg dosage group, n=6; (5) HUATUO ZAIZAO WAN 1.0g crude drug/kg dosage group, n=6; (6) HUATUO ZAIZAO WAN 2.0g crude drug/kg dosage group, n=6.
Above-mentioned experiment medicine all is mixed with equal-volume (3ml/kg) with normal saline, through duodenal administration before experiment.
Experimental technique
Animal via pentobarbital sodium (30mg/kg) intravenous anesthesia, tracheal intubation connects SC-3 type electric pulmotor (Shanghai); Left side the 4th intercostal is opened breast, exposes heart, cuts off pericardium, makees the pericardium bed; Separate LCA, (Cuff-E, Φ=2.4mm 20MHz), measure heart coronary flow (CABF) to place SAGE-300 type Ultrasound Doppler Flowmeter (U.S. CBI company) probe; Separate the anterior descending coronary stage casing, threading causes the acute experiment myocardial infarction and ischemia model in order to ligation; Seam is put the fixed epicardial lead of multiple spot (30 mapping points), traces epicardial electrogram (EECG)
[1], outcome record is in MP-100 polygraph (U.S. BIOPAC).Ligation arteria coronaria 15 minutes, carry out record, as control value before the administration, test medicine or normal saline through duodenum, 15,30,45,60,90,120,180 minutes record EECG behind medicine, raising greater than 2mv with the S-T section is criterion, calculating myocardium degree of ischemia (∑-ST:S-T section raise total mv number) and myocardial ischemia scope (the N-ST:S-T section raises and always counts).Through the external jugular vein intubate to coronary sinus vein, parallel common carotid artery intubate was got artery and vein blood, blood oxygen analysis instrument (OMNI S2 in 15,30,60,120,180 minutes before ischemia, behind the ischemia 15 minutes (before the medicine), medicine, Roche, Germany) measure coronary sinus vein oxygen content (VO respectively
2) and arterial oxygen content (AO
2), and pass through coronary flow (CABF) calculating myocardium oxygen consumption (MOC): MOC=(AO
2-VO
2) * CABF/100.RA-1000 type automatic clinical chemistry analyzer (U.S. TECHNICON) is measured serum creatine kinase (CK), lactic acid dehydrogenase (LDH); Put the method for exempting from and measure endothelin level (ET), thromboxane (TXB
2) and 6-ketone-prostacyclin F
1 α(6-Keto-PGF
1 α) (GC-911-γ count instrument, Chinese University of Science and Technology's industry head office).
180 minutes records finish behind the medicine, take off heart immediately, and the flushing of NS liquid is weighed, and under the heart ligature, is parallel to coronary sulcus and equably ventricle partly is cut into 5, places nitro tetrazole orchid (N-BT) dye liquor, room temperature dyeing 15 minutes.HPIAS-1000 type medical images analytical system (Beijing).The infarcted region (the non-dyeing of N-BT district) of measuring every myocardium bilateral and non-infarcted region (N-BT dye district) are calculated area, the ventricle gross area and the infarcted region gross area of every cardiac muscle.Calculating infarcted region accounts for ventricle and accounts for dirty whole-heartedly percentage ratio.Experimental result is carried out statistical procedures, judges its significance with the t check.
Experimental result
(1). to the influence of dog myocardial ischemia (epicardial electrogram mapping)
1. to the (influence of ∑-ST) of dog degree of myocardial ischemia
The result shows, through duodenal administration, HUATUO ZAIZAO WAN 1.0 and 2.0g crude drug/kg dosage group all has and obviously alleviates degree of myocardial ischemia (effect of ∑-ST), wherein obviously effect of medicine performance in 60 minutes behind the 2.0g/kg group medicine, and continue to behind the medicine 180 minutes.Behind the medicine 120 minutes-180 minutes, animal ∑-ST by medicine before 514.00 ± 118.40mV reduce to 410.67 ± 160.34mV and 375.83 ± 168.75mV, descended 22.20% and 28.31% respectively, with before the medicine and with the relatively equal difference highly significant (P＜0.05) of matched group.
2. to the influence of dog myocardial ischemia scope (N-ST)
The result shows that after matched group fed normal saline, myocardial ischemia scope (N-ST) did not have obviously change.Three dosage groups of HUATUO ZAIZAO WAN have the effect that reduces myocardial ischemia scope (N-ST) in various degree, wherein behind the 2.0g/kg dosage group medicine 90,120 minutes, N-ST is respectively by 29.67 ± 0.82 mapping points before the medicine, reduce to 27.83 ± 1.94 and 26.67 ± 3.39 mapping points, compared notable difference (P＜0.05-0.01) with matched group.
Above result shows that HUATUO ZAIZAO WAN improves significantly to experimental acute dog myocardial ischemia, can significantly alleviate degree of myocardial ischemia and (∑-ST), dwindle myocardial ischemia scope (N-ST).
(2). to the influence of dog acute myocardial infarction scope (N-BT staining mensuration)
Each administration group of table 3. is to the influence of dog acute myocardial infarction scope (n=6, X ± SD)
| Group | Dosage crude drug/kg | Heart area mm 2 | Ventricle area mm 2 | Infarcted region area mm 2 | Infarcted region/heart | Infarcted region/ventricle |
| Normal saline | 3ml | 11848.8±5285.5 | 4731.7±1220.4 | 1020.00±258.6 | 9.99±5.11 | 21.26±7.10 |
| Diltiazem | 5mg | 11079.2±1493.0 | 3792.0±493.6 | 338.42±171.3** | 3.08±1.47** | 10.09±4.35** |
| Tongxinluo | 0.24g | 10820.2±2154.5 | 3947.7±550.1 | 474.00±282.2** | 4.40±2.21* | 9.73±6.00* |
| HUATUO ZAIZAO WAN | 0.5g | 10058.0±1504.7 | 3873.8±351.1 | 585.33±290.8* | 5.94±2.89 | 14.07±7.11 |
| HUATUO ZAIZAO WAN | 1.0g | 14463.3±2461.1 | 4767.8±1044.7 | 512.17±196.7** | 3.65±1.51* | 9.98±4.57** |
| HUATUO ZAIZAO WAN | 2.0g | 14739.3±4825.4 | 5316.4±776.1 | 572.17±375.7* | 4.08±2.49* | 9.42±6.08* |
Annotate: compare with matched group: * P＜0.05, * *: P＜0.01, * * *: P＜0.001.
The results are shown in Table 3, learn the N-BT staining with quantitative tissue and show myocardial infarct size, normal saline control animals myocardial infarction district accounts for 9.99 ± 5.11% and 21.26 ± 7.10% of heart and ventricle respectively; Three dosage groups of HUATUO ZAIZAO WAN can reduce animal cardiac muscle infarcted region area, with matched group significant difference (P＜0.05 or P＜0.01) is arranged more all, wherein 2.0g/kg group myocardial infarction district area accounts for 4.08 ± 2.49%, 9.42 ± 6.08% of heart and ventricle respectively, reduces by 59.16% and 55.69% (all P＜0.05) than the normal saline matched group respectively.
(3). to the influence of expeirmental myocardial ischemia dog coronary flow
The result shows that after ligation anesthetized dog coronary artery formed myocardial ischemia, coronary flow had the short time compensatory to increase increasing degree about 10%.The effect of remarkable increase Ischemic Heart coronary flow is arranged behind the diltiazem group medicine; The trend that increases the Ischemic Heart coronary flow is all arranged behind three dosage groups of HUATUO ZAIZAO WAN medicine, compare, no significant difference (all P＞0.05) with the normal saline group.
(4). to the influence of expeirmental myocardial ischemia dog artery and vein oxygen content and myocardial oxygen consumption
The result shows that tremulous pulse, coronary sinus vein oxygen content and myocardial oxygen consumption all do not have significant change before and after the administration of matched group normal saline; The venous sinus oxygen content can obviously raise 15-60 minute the time behind the diltiazem medicine; Myocardial oxygen consumption when reducing by 120 minutes.The coronary sinus vein oxygen content has rising trend after HUATUO ZAIZAO WAN 1.0g/kg and the administration of 2.0g/kg dosage group, but compares no significant difference with matched group.1.0g/kg animal cardiac muscle oxygen consumption 15-120 minute all obviously descends, and has wherein compared significant difference (P＜0.05) 120 minutes the time with matched group.
(5). expeirmental myocardial ischemia dog blood biochemical is learned the influence of index
1. dog serum creatine kinase (CK) and the active result of influence of lactic acid dehydrogenase (LDH) are shown, serum CK, LDH content are respectively 240.06 ± 75.76u/L and 53.70 ± 27.03u/L (n=36) before the myocardial ischemia, after the ligation arteria coronaria forms acute myocardial ischemia, CK, LDH content obviously raise in the blood, are respectively 333.69 ± 153.57u/L and 68.95 ± 38.25u/L.Increased by 39.00% with comparison CK content before the ischemia, LDH content has increased by 28.39%; The prolongation that CK, LDH discharged along with the coronary ligation time further increases, behind the normal saline group medicine 30,60,120,180 minutes with medicine before compare, CK increases by 68.22%, 123.37%, 248.54%, 344.07% respectively; LDH increases by 9.12%, 35.79%, 65.72% and 96.08% respectively; Diltiazem can obviously suppress active rising of CK, LDH that myocardial ischemia, myocardial infarction cause, with the matched group normal saline significant difference (P＜0.05) is arranged relatively.LDH discharged (P＜0.01) when HUATUO ZAIZAO WAN 1.0g/kg also can obviously suppress 120-180 minute; 2.0g/kg CK discharges (P＜0.05) in the time of can obviously suppressing 120 minutes, LDH discharges (P＜0.05) in the time of can obviously suppressing 120-180 minute simultaneously.
2. to dog plasma Endothelin (ET), thromboxane (TXB
2) and 6-ketone-prostacyclin (6-Keto-PGF
1A) active influence
The result shows, continues in the ligation dog coronary artery process normal saline control animals blood plasma 6-ketone-prostacyclin (6-Keto-PGF
1A) and 6-ketone-prostacyclin/thromboxance B
2Ratio obviously descends, and endothelin level discharges obviously to be increased.The endothelin level that the HUATUO ZAIZAO WAN group causes myocardial ischemia, myocardial infarction (ET) activity has obvious inhibitory action, can obviously suppress thromboxance B
2Release, 6-ketone-prostacyclin (6-Keto-PGF can obviously raise simultaneously
1A) and 6-ketone-prostacyclin/thromboxance B
2Ratio.
Conclusion
Epicardial electrogram mapping myocardial ischemia scope and degree are adopted in this experiment, and quantitative tissue is learned (N-BT staining) and measured myocardial infarct size, measures coronary flow, myocardial oxygen consumption and serum CK, LDH and blood plasma ET, TXB simultaneously
2, 6-Keto-PGF
1 αThe influence of HUATUO ZAIZAO WAN digestive tract administration to experimental dog acute myocardial ischemia, myocardial infarction and index of correlation studied in active variation.
Experimental result confirms that HUATUO ZAIZAO WAN has the obvious effect that improves dog acute myocardial ischemia and myocardial infarction, alleviates the degree of myocardial ischemia (∑-ST), reduce by the shown infarcted region of N-BT dyeing by epicardial electrogram mapping.
When causing local coronary stricture or coronary occlusion to form myocardial ischemia or myocardial infarction by the different causes of disease, other coronary arterial tree underwent compensatory enlargement and opening can make myocardial ischemia or myocardial infarction be eased.When myocardium occurrence of large-area ischemia and popularity infarction, this compensatory capacity is limited, causes myocardial necrosis and irreversible damage, and life danger takes place.Experiment shows that the coronary flow when HUATUO ZAIZAO WAN is to myocardial ischemia and myocardial infarction do not have obvious increase effect, may be too serious with the animal pattern myocardial damage, and due to the coronary dilation compensatory mechanism deficiency.
CK extensively is present in the cytoplasma membrane, is many with myocardial cell especially, and CK overflows when myocardial cell damages, and makes its active rising in blood, and activity of serum CK is high more, and the reflecting myocardium degree of injury is heavy more.This experiment shows with the index that is released to of CK, the ligation M-LAD, and the model that causes the anesthetized dog acute myocardial injury is successful.The CK of this laboratory observation when HUATUO ZAIZAO WAN can obviously suppress experimental acute myocardial ischemia dog myocardial damage overflows, and reduces activity of serum CK, the protecting myocardial cell film.LDH is released in histiocyte when myocardial infarction the body fluid in a large number, measures LDH activity in the coronary sinus vein blood, but the also degree of reflecting myocardium damage.Experimental results show that overflowing of serum CK, LDH when HUATUO ZAIZAO WAN can partly suppress the experimental myocardial damage of dog, reduce the activity of serum CK, LDH.
Modern medicine study thinks that the formation of syndrome of blood stasis and blood constituent, blood status and blood vessel wall factor are that pathological changes such as injury of vascular endothelial cells are closely related.When ligation dog coronary artery, because mechanical stimulus, lasting, serious ischemia, anoxia, all but hyperamization tube wall endotheliocyte is impaired, and endothelial injury can activate platelet and assemble mutually and adhere to the blood vessel part, and activates the thrombin system, promote a large amount of releases of fibrin formation and Endothelin, cause vasospasm, the blood coagulation increase, viscosity increases, be easy to form thrombosis, and hyperamization stream slowly, forms or increase the weight of myocardial ischemia, even myocardial infarction takes place.Therefore, Endothelin is important one of the stasis of blood factor that causes, and the release of inhibition Endothelin is the important judging quota of medicaments for resisting myocardial ischemia.This test shows that HUATUO ZAIZAO WAN has the effect that the obvious suppression Endothelin discharges, and this helps the expansion of blood vessel.
Prostacyclin (prostacyclin, PGI
2), thromboxane A2 (thromboxane A
2, TXA
2) be the excretory vaso-active substance of endotheliocyte, wherein PGI
2Be vasodilator material, TXA
2Be vaso-excitor material.This experiment is by measuring PGI
2The whole last reign of a dynasty thank to product 6-ketone-prostacyclin F
1 α(6-keto-PGF
1 α) and TXA
2Metabolite TXB
2The isoreactivity material, observing the variation and the observation medicine that continue in ligation dog coronary artery formation myocardial ischemia and the myocardial infarction process influences it.The result shows that active rising of the endothelin level that HUATUO ZAIZAO WAN causes myocardial ischemia, myocardial infarction (ET) has obvious inhibitory action, can improve blood plasma 6-ketone-prostacyclin (6-Keto-PGF simultaneously
1A) level.The used positive control drug diltiazem of this experiment is a calcium antagonist, good coronary dilating is arranged, increase coronary flow, reduce myocardial oxygen consumption, stop myocardium CPK under the acute cardiac ischemic condition, LDH, ET, thus alleviate and delayed the caused myocardial damage process of ischemia.
Above-mentioned experimental result shows that HUATUO ZAIZAO WAN has the obvious effect that improves dog acute myocardial ischemia and myocardial infarction, obviously alleviates by the degree of myocardial ischemia of epicardial electrogram mapping (∑-ST); Reduce myocardial ischemia scope (N-ST) by epicardial electrogram mapping; Dwindle through the shown infarcted region of N-BT dyeing; Release, the creatine kinase (CK) of the serum lactate dehydrogenase (SLD) (LDH) that myocardial ischemia and myocardial infarction are caused be active to raise and the activity of endothelin level (ET) has obvious inhibitory action, blood plasma 6-ketone-prostacyclin F when raising myocardial ischemia simultaneously
1 α(6-Keto-PGF
1 α) and 6-Keto-PGF
1 α/ TXB
2Ratio.
[embodiment 3] HUATUO ZAIZAO WAN is to the influence of cardiac hemodynamics of dogs and myocardial oxygen consumption.
Experiment material
1. medicine: HUATUO ZAIZAO WAN, with embodiment 1; Diltiazem (diltiazem), the 30mg/ sheet, Tianjin Tanabe Seiyaku Co., Ltd. produces (lot number: 0501017); TONGXINLUO JIAONANG, the 0.38g/ grain, 1.4g crude drug/g powder, lot number 060109, Shijiazhuang Yiling Pharmaceutical Co., Ltd produces; 0.9% sodium chloride injection, the Beijing Double-Crane Pharmaceutical Co., Ltd produces (lot number: 0603141).
2. animal: 36 of healthy adult hybrid dogs, body weight 15.22 ± 2.59kg, male and female dual-purpose.
Experimental technique
Laboratory animal pentobarbital sodium (30mg/kg) intravenous anesthesia, tracheal intubation connects phrenoton (SC-3 type, Shanghai).Execute left side the 4th intercostal thoracotomy, expose heart, cut off pericardium, make the pericardium bed, separate LCA, place SAGE-300 type Ultrasound Doppler Flowmeter (U.S. TRITON company) probe (Cuff-E, F=2.4mm 20MHz), measures heart coronary flow (CABF); Separate aortic root, place electromagnetic flowmeter (MF-1100 type, Japanese photoelectricity) probe, measure cardiac output.Cardiac output (CO); Left ventricle tip intubate connects pressure transducer (MPU-0.5A), measures left indoor pressure (LVSP) through carrier amplifier (AP-601G), calculates left indoor pressure rising maximum rate (dp/dt through differentiator (ED-601G) again
Max); The external jugular vein intubate is to coronary sinus vein, and the carotid artery intubate was got artery and vein blood in 15,30,60,120,180 minutes before the medicine, behind the medicine, and blood oxygen analysis instrument (OMNI S2, Roche, Germany) is measured coronary sinus vein oxygen content (VO respectively
2) and arterial oxygen content (AO
2), and pass through coronary flow (CABF) calculating myocardium oxygen consumption (MOC): MOC=(AO
2-VO
2) * CABF/100.Femoral arteriography is measured arteriotony (BP), leads electrocardiogram (ECG-II) with limb lead observation standard I I and calculates heart rate (HR) and relevant electrocardiogram parameter.Formula calculates other hemodynamic index: cardiac output (SO), left chamber work done (LVW), oxygen consumption index (MOCI), coronary resistance (CAVR), total peripheral resistance (PVR) and coefficient of oxygen utilization (MURO) etc.With above-mentioned every index synchronous recording in MP-100 type polygraph (U.S. BIOPAC company).
Execute abdominal operation, separate duodenum, intubate is in order to giving institute's reagent thing.
Experiment is divided into 6 groups: (1) blank group, normal saline 3ml/kg, n=6; (2) positive control drug diltiazem group, 5mg/kg, n=6; (3) Chinese medicine contrast medicine TONGXINLUO JIAONANG 0.24g crude drug/kg dosage group, n=6; (4) HUATUO ZAIZAO WAN 0.5g crude drug/kg dosage group, n=6; (5) HUATUO ZAIZAO WAN 1.0g crude drug/kg dosage group, n=6; (6) HUATUO ZAIZAO WAN 2.0g crude drug/kg dosage group, n=6.
Operation finishes, treat that observed index is stable after, value before the record medicine, 12 intestinal feed institute's reagent thing.And behind medicine, carried out record in 15,30,45,60,90,120,180 minutes.Every observation index and derivation parameter are carried out statistical procedures, carry out administration with the measured values of different observing times before and after self relatively, its change percentage rate organize between relatively, judge its significance with the t check.
Experimental result
1. to dog arteriotony (SP, DP), heart rate (HR) and Electrocardiographic influence
The result shows that the effect that obviously brings high blood pressure down with decreased heart rate is arranged behind the diltiazem medicine; Femoral artery systolic pressure (SP), diastolic pressure (DP) all do not have obviously change behind three dosage groups of HUATUO ZAIZAO WAN medicine; Each dosage group does not have obvious influence to heart rate.Parameters such as animal standard I I ECG P R interval behind each dosage group medicine of HUATUO ZAIZAO WAN, QRS interval, QT interval and T ripple all do not have obviously changing.
2. to the influence of dog coronary flow (CABF) and arteria coronaria resistance (CAVR)
The result shows that coronary flow, coronary resistance have no significant change before and after the normal saline administration.The calcium antagonist diltiazem is coronary blood flow increasing and reduction coronary resistance obviously; Tongxinluo also obvious coronary blood flow increasing in the time of 60 minutes; Three dosage groups of HUATUO ZAIZAO WAN all have the effect of tangible coronary blood flow increasing, and wherein 2.0g/kg dosage group was the most obvious to the coronary flow increase at 45-60 minute, and increasing degree has been compared notable difference (P＜0.05) with matched group about 20%.This explanation this product can be expanded the arteria coronaria blood vessel under the normal condition, increases the blood supply of cardiac muscle ability.Meanwhile, this product 2.0g/kg dosage group can obviously reduce coronary resistance, has wherein compared notable difference (P＜0.05) in 30-60 minute time period with before the medicine.
3. to the influence of left chamber contractility (LVCMT), left chamber work done (LVW)
The result shows that diltiazem can suppress the acting of ventricle at 45-60 minute.This product does not have influence significantly to myocardial contraction, and 2.0g/kg dosage group has the heart left chamber of increasing work done, the effect that improves the cardiac activity ability.
4. to dog left indoor pressure (LVSP), the maximum climbing speed (dp/dt of left indoor pressure
Max) influence
The result shows, LVSP and dp/dt
MaxAll be the important indicator of estimating myocardial contractility, be significantly increased LVSP and dp/dt behind the HUATUO ZAIZAO WAN 2.0g/kg dosage group medicine in 30 minutes
MaxEffect, illustrate that this product has the positivity regulating action to heart.
5. to the influence of dog cardiac output (CO), cardiac output (SO)
The result shows that diltiazem can obviously increase cardiac output and cardiac output, and Tongxinluo also is significantly increased effect to cardiac output and cardiac output.HUATUO ZAIZAO WAN 0.5g/kg and 2g/kg dosage group all can increase cardiac output and cardiac output, and (P＜0.05-0.01), to compare onset relatively slow with diltiazem, but acting duration is longer.
6. to the influence of total peripheral resistance (PVR)
The result shows that diltiazem can reduce the total peripheral resistance of animal, has compared notable difference with matched group.HUATUO ZAIZAO WAN 2g/kg had tangible reduction effect to total peripheral resistance in the time of 30-90 minute, compared notable difference (P＜0.05) with matched group.
7. to dog arterial oxygen content (AO
2), venous oxygen content (VO
2) influence
The result shows that each administration group does not have obvious influence to the animal arterial oxygen content, and diltiazem treated animal coronary sinus vein oxygen content all obviously increased in the time of 15-60 minute, with the normal saline matched group notable difference (P＜0.05) was arranged more all.30-120 minute coronary sinus vein oxygen content of HUATUO ZAIZAO WAN 1.0g/kg dosage group also obviously increases, and with the normal saline matched group notable difference (P＜0.05) arranged relatively.
8. to the influence of dog myocardial oxygen consumption (MOC), oxygen consumption index (MOCI) and coefficient of oxygen utilization (MURO)
The result shows that the positive control drug diltiazem is behind duodenal administration, and myocardial oxygen consumption, oxygen consumption index and coefficient of oxygen utilization all obviously reduce.The myocardial oxygen consumption of HUATUO ZAIZAO WAN 2.0g/kg dosage group raises, and has compared significant difference (P＜0.05) with matched group, and this may increase coronary blood flow with medicine, increases ventricular stroke work, regulates relevant to the positivity of heart.This product 1.0g/kg to the coefficient of oxygen utilization of heart, compared significant difference (P＜0.05) with matched group in 30 minutes, and the oxygen consumption index of cardiac muscle do not had influence significantly when can reduce 30-120 minute.
Embodiment 2 shows, the coronary flow of HUATUO ZAIZAO WAN during to myocardial ischemia and myocardial infarction do not have obvious increase effect, may be too serious with the animal pattern myocardial damage, due to the coronary dilation compensatory mechanism deficiency, but can reduce the oxygen consumption of Ischemic Heart.And this test shows that this product can increase the coronary blood flow of normal heart, increases ventricular stroke work, increases myocardial oxygen consumption, regulates relevant to the positivity of heart.The above results shows that HUATUO ZAIZAO WAN is different with the myocardial oxygen consumption effect to the supply of different conditions cardiac flow, and the oxygen consumption that reduces Ischemic Heart more has potential clinical value.
Conclusion
This laboratory observation the influence of HUATUO ZAIZAO WAN to normal anesthesiaing dog heart blood flowing dynamics, myocardial oxygen consumption, experimental result shows: HUATUO ZAIZAO WAN does not all have obvious influence to parameters such as arteriotony, heart rate, standard I I ECG P R interval, QRS interval, QT interval and T ripples; Obvious coronary artery dilating, coronary blood flow increasing increases the blood supply of cardiac muscle ability; The heart left chamber work done be can increase, LVSP and dp/dt increased
Max, improve the cardiac activity ability, heart is had the positivity regulating action; Simultaneously can increase cardiac output and cardiac output, reduce total peripheral resistance; Can obviously increase myocardial oxygen consumption, this and medicine increase coronary blood flow, increase ventricular stroke work, regulate relevant to the positivity of heart.
[embodiment 4] HUATUO ZAIZAO WAN is to the influence of rabbit platelet aggregation.
The BornShi turbidimetry is adopted in this test, observes the influence of HUATUO ZAIZAO WAN to the rabbit platelet aggregation.The result shows: gave the rabbit gastric infusion in continuous 7 days, HUATUO ZAIZAO WAN obviously reduces adenosine diphosphate (ADP) (ADP), arachidonic acid (AA) and collagen-induced rabbit platelet aggregation rate (P＜0.01～0.001).The prompting HUATUO ZAIZAO WAN has the effect of anticoagulant.The result shows: gave the rabbit gastric infusion in continuous 7 days, HUATUO ZAIZAO WAN obviously reduces adenosine diphosphate (ADP) (ADP), arachidonic acid (AA) and collagen-induced rabbit platelet aggregation rate (P＜0.01～0.001).The prompting HUATUO ZAIZAO WAN has the effect of anticoagulant.
[embodiment 5] HUATUO ZAIZAO WAN is to the influence of rats in vitro thrombosis and blood viscosity.
HUATUO ZAIZAO WAN is to the influence of rats in vitro thrombosis and blood viscosity.The result shows, gives the rat oral gavage administration in continuous 7 days, and HUATUO ZAIZAO WAN obviously shortens thrombosis length (P＜0.05～0.001), alleviates wet weight of thrombus and dry weight (P＜0.05～0.001); Obviously reduce shear rate 60S
-1, 5S
-1Under whole blood viscosity (P＜0.05～0.01).Show that HUATUO ZAIZAO WAN has the effect that suppresses thrombosis and blood viscosity lowering.
In a word, the present invention shows that by multiple animal species, multiple test HUATUO ZAIZAO WAN has the new purposes of the medicine aspect of ischemic heart desease such as preparation prevention, treatment myocardial ischemia, myocardial infarction as the curative of a kind of stroke in convalescent stage and sequela.
Claims (6)
1. the purposes of HUATUO ZAIZAO WAN aspect preparation control ischemic heart medicine.
2. the purposes of HUATUO ZAIZAO WAN according to claim 1 aspect preparation control ischemic heart medicine is characterized in that preparing the purposes of the medicine aspect that prevents and treats myocardial ischemia.
3. the purposes of HUATUO ZAIZAO WAN according to claim 1 aspect preparation control ischemic heart medicine is characterized in that preventing and treating the effect of the medicine aspect of myocardial ischemia reperfusion injury.
4. the purposes of HUATUO ZAIZAO WAN according to claim 1 aspect preparation control ischemic heart medicine is characterized in that the effect of the medicine aspect of myocardial infarction.
5. the purposes of HUATUO ZAIZAO WAN according to claim 1 aspect preparation control ischemic heart medicine is characterized in that HUATUO ZAIZAO WAN adopts other dosage forms of same recipe to replace.
6. the purposes of HUATUO ZAIZAO WAN according to claim 1 aspect preparation control ischemic heart medicine is characterized in that HUATUO ZAIZAO WAN and other drug make compound preparation jointly.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114668733A (en) * | 2022-03-18 | 2022-06-28 | 广州白云山奇星药业有限公司 | New application of Huatuo reforger pill |
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2008
- 2008-01-15 CN CNA2008100258060A patent/CN101229197A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114668733A (en) * | 2022-03-18 | 2022-06-28 | 广州白云山奇星药业有限公司 | New application of Huatuo reforger pill |
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