CN104189047A - Medicinal composition for preventing and treating myocardial ischemia - Google Patents
Medicinal composition for preventing and treating myocardial ischemia Download PDFInfo
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- CN104189047A CN104189047A CN201410477081.4A CN201410477081A CN104189047A CN 104189047 A CN104189047 A CN 104189047A CN 201410477081 A CN201410477081 A CN 201410477081A CN 104189047 A CN104189047 A CN 104189047A
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Abstract
The invention relates to a medicinal composition for preventing and treating myocardial ischemia. The medicinal composition comprises the following raw materials in parts by weight: 250 parts of tanshinol, 20 parts of carthamin yellow, 80 parts of puerarin and 150 parts of glycyrrhizin. Through studies, an inventor discovers that the medicinal composition has an obvious prevention and treatment effect on the myocardial ischemia.
Description
Technical field
The present invention relates to a kind of for preventing and treat the pharmaceutical composition of myocardial ischemia.
Background technology
Myocardial ischemia refers to that the hemoperfusion of heart reduces, and causes the oxygen supply of heart to reduce, and energy metabolism of myocardial is undesired, can not support a kind of pathological state of the normal work of heart.Along with the raising of living standards of the people, myocardial ischemia is in the prevalence of China the trend rising year by year at present.Myocardial ischemia is commonly encountered diseases and the frequently-occurring disease of middle-aged and elderly people.
This disease clinical manifestation is mainly: 1. after there is breastbone when fatigue or psychentonia or precordial fullness pain, or tighten sample pain, and shoulder, left upper arm radiation left, continue 3～5 minutes, spontaneous remission person after having a rest, time with profuse sweating.2. there is uncomfortable in chest, cardiopalmus during physical exertion, breathe hard, spontaneous remission person during rest.3. there is the throat pain relevant with motion and burn feeling, constriction, toothache etc.Heavy meal, cold, there is chest pain, person uncomfortable in chest after drinking.5. when night, sleep pillow was low, feel chest distress, need high pillow clinostatism side to feel comfortable person; Sleep soundly or put down unexpected chest pain, cardiopalmus, dyspnea while crouching daytime, need sit up immediately or stand can alleviation person.6. sexual life or firmly occur nervous, uncomfortable in chest, out of breath during defecation or chest pain is uncomfortable.7. the bradycardia, Blood pressure drop or the person of fainting that happen suddenly.
Therapeutic Principle: because myocardial ischemia has the danger that myocardial infarction and sudden death occur, while therefore finding myocardial ischemia, and early treatment.The atherosclerotic generation of active prevention, as occurred, answers active treatment, prevents and treats pathological development and strives for reversing.Complications has occurred, should treat in time, control worsens, and extends patient's life-span.
Current conventional prophylactic agent: the medicine of the primary prevention of coronary heart disease comprises aspirin, beta-blocker, calcium ion antagonist, Statins lipid regulating agent and angiotensin converting enzyme inhibitor.Current conventional medicine: (1) antiplatelet drug is prevented and treated thrombosis, prevention coronary artery and cerebral artery thrombosis thromboembolism, as aspirin, clopidogrel.(2) receptor blocking agent decreased heart rate reduces myocardium Mao oxygen, and prevention sudden death, as metoprolol or its slow releasing tablet.(3) calcium ion antagonist.(4) statins reduces the cholesterol in blood plasma, stablize artery plaque, prevent the speckle formation thrombosis that comes off, as (5) RAS system blocking agent such as atorvastatin, Rosuvastatin can prevent remodeling ventricle, improve cardiac function, as benazepril and valsartan etc.(6) nitrate esters medicine coronary artery dilator, increases blood supply of cardiac muscle, as Isosorbide-5-Nitrae.(7) thrombolytic drug dissolves the thrombosis of acute formation, for acute myocardial infarction.
Can find out that at present, for prevention and the treatment of myocardial ischemia, common drug is substantially all western medicine composition, these medicines or monopolized by external pharmacy corporation, import drugs is expensive, or competes too fierceness, and market has not had profit space.Chinese Traditional Medicine, having much advantage aspect treatment cardiovascular and cerebrovascular disease, still, due to the complexity of Chinese crude drug composition, can not be approved by mainstream market Chinese medicine all the time in fact.Thereby develop the prevention according with the demands of the market and the medicine for the treatment of myocardial ischemia, and capture cardiovascular and cerebrovascular vessel New drug market, imperative.
Raw Materials Situation involved in the present invention is as follows:
Danshensu is the main water soluble ingredient of Chinese medicine labiate Radix Salviae Miltiorrhizae (Salviamiltiorriza Bunge), and chemical name is D-(+) β-(3,4-dihydroxy phenyl) lactic acid.Danshensu has the effect of dwindling myocardial infarct size and alleviating the course of disease, myocardial ischemia reperfusion injury is had to protective effect simultaneously.Danshensu suppresses the synthetic of cell endogenous cholesterol, also has the effect of lipotropism matter protein oxidation, reduces cholesterolemia, therefore has protection blood vessel barrier, prevents lipidosis and atherosclerosis (AS) effect.The function of promoting blood circulation to disperse blood clots of the research such as Yan Changkai danshensu, find that danshensu can obviously suppress the rat platelet aggregation in vitro activity of being induced by ADP, thrombus formation time after prolongation electricity irritation rat carotid artery, obviously reduce the whole blood viscosity of the basic, normal, high shear rate of rat's blood stasis model, blood viscosity, packed cell volume, Casson yield stress, erythrocyte electrophoretic time and erythrocyte aggregation index.
Carthamus yellow is the natural yellow pigment extracting from the petal of Flos Carthami, is Chalcone Compounds.Carthamus yellow is that China's approval allows the edible natural pigment using, listed in GB2760-1996, and be national new drug.Animal experiment study shows, Carthamus yellow has the Platelet Aggregation in Rabbits effect that suppresses very significantly ADP induction, and Carthamus yellow is by suppressing the platelet Ca due to platelet activating factor (PAF)
2+interior stream, and platelet activation is suppressed, suppress the increase of its gathering, release reaction and Intracellular Calcium Concentration, play the cardiovascular effect of protection, effect cruel in its effect is total to paf receptor antagonists Semen Ginkgo is similar.Platelet aggregation and the interior free calcium concentration of platelet that Food Red anthoxanthin can suppress due to PAF increase; its mechanism is that Carthamus yellow may be suppressed platelet activation by stream in platelet calcium due to inhibition PAF, plays the effect of protection cardiovascular and cerebrovascular vessel.
Puerarin (puerarin) belongs to flavonoid glycoside, and chemical constitution is 8-D-Glucopyranose .-4, the different ketoside of 7-dihydroxy; there is beta-2 adrenoceptor retardation, can strengthen myocardial contraction, blood vessel dilating; protecting myocardial cell, toxicity is little, safety range is wide.Puerarin has been widely used in diseases of cardiovascular and cerebrovascular systems clinically at present, and hypertension, angina pectoris, acute myocardial infarction, multiple arrhythmia, insulin resistant and hyperlipidemia etc. are all had to certain curative effect.
Glycyrrhizin, glycyrrhizin is again glycyrrhizic acid, glycyrrhizin, potenlin, molecular formula: C
42h
62o
16.Pharmacological research shows that these product can promote bile pigments metabolism, reduces transaminase, has the effects such as antiinflammatory, antiallergic and protecting film structure simultaneously.Clinical acute hepatitis, chronic hepatitis, liver poisoning and the early stage liver cirrhosis of being used for.Oral: each 150mg, every day 2 times.
Summary of the invention
The present invention aims to provide a kind of for preventing and treat the pharmaceutical composition of myocardial ischemia, by screening suitable crude drug and proportioning thereof, reaches the object of safe and effective prevention and treatment myocardial ischemia.
In order to achieve the above object, the present invention is by the following technical solutions:
For preventing and treat a pharmaceutical composition for myocardial ischemia, it is characterized in that, by the raw material of following weight proportion, formed: 250 parts of danshensus, 20 parts of Carthamus yellows, 80 parts of puerarins, 150 parts of glycyrrhizins.
Inventor can significantly reduce myocardial ischemia scope by pharmaceutical research proved invention medicine, reduces the activity of lactic acid dehydrogenase, obviously extends clotting time, and the platelet aggregation of ADP induction is also had stronger inhibitory action and is dose-dependence.
Below in conjunction with pharmacological experimental data, beneficial effect of the present invention is described:
1, material
1.1 medicines and reagent: danshensu, by Xi'an, Fei Dasan Bioisystech Co., Ltd provides, content >=98%, lot number 110604.Carthamus yellow, Zhejiang Yongning Pharmaceutical Co., Ltd produces, content >=98%, lot number 120809.Puerarin, by Xi'an, Fei Dasan Bioisystech Co., Ltd provides, content >=98%, lot number 090604.Glycyrrhizin, Wanrong, Wuhan development in science and technology company limited produces, content >=98%, lot number 120506.Aspirin, Qingdao Huanghai Pharmaceutical Co., Ltd. produces, lot number 12012141.The above sea blue season development in science and technology of adenosine diphosphate (ADP) (ADP) company limited, lot number 101101.Sodium citrate, Beijing Yili Fine Chemicals Co., Ltd., lot number 111211.Propranolol hydrochloride, Shijiazhuang three nine-day periods after the winter solstice Xun Li pharmaceutcal corporation, Ltd produces, lot number 050711.
1.2 instruments: LBY-NJ blood pool instrument Pulisheng Precision Instruments Research Center, Beijing.DL-4000B centrifuge Anting Scientific Instrument Factory, Shanghai.TDL-40B type centrifuge: Town in Shanghai booth instrument plant produces.Synexgy HT type microplate reader: Bio-TEK company produces.DS-671 electronic balance: Shanghai Shou Gang Electronics Co., Ltd. manufactures.XW-80A eddy mixer: go up Industrial Co., Ltd. of Nereid section.
1.3 laboratory animals: Sprague – Dawley rat, ♂; Kunming mice, ♂, body weight 20 ± 2 g, are provided by Shandong greenery drugmaker animal center.
1.4 Experimental agents by danshensu, Carthamus yellow, puerarin, glycyrrhizin according to the ratio mix homogeneously of (250:20:80:150), with sodium carboxymethyl cellulose (CMC-Na), be configured to respectively 2.5,5.0, a low middle Senior Three concentration of 10mg/mL, rat and mice according to every 100g body weight, give 1mL administering medical liquids, dosage is respectively 25,50,100mg/kg.
, method
2.1 Experimental agents are the impact on Acute Myocardial Ischemia in Rats on unit
Rat is divided into 6 groups at random by body weight, is respectively sham operated rats, model group, Experimental agents group (25,50,100mg/kg), Propranolol group.Coronary artery ligation is prepared myocardial infarction and ischemia model.Rat is with chloral hydrate anesthesia (300mg/kg), face upward position fixing, along left mid-clavicular line longitudinal incision skin approximately 2 cm, the 4th, five intercostal blunt separation flesh layers, in heart beating, beat and the most obviously locate, fracture rib is opened breast, cut off pericardium, expose heart, heart is extruded to breast chamber, with left hand middle finger, with medium dynamics top heart, by spinal column lateral root portion, left auricle root below is exposed clear, between pulmonary conus and left auricle, left auricle root is below 2～3 mm place Quick-threading following coronary artery occlusion left anterior descending branches tiltedly, after ligation, heart playbacks rapidly, extruding rib air-out, close rapidly breast chamber, a sham operated rats not ligation of threading.Sham operated rats, model group gavage give 0.5% CMCNa solution, 1mL/100 g; Experimental agents group respectively gavage gives 25,50,100 mg/kg drug suspensions; Propranolol group gavage gives 5 mg/kg Propranolol, each organizes equal successive administration 3d, 2 h modeling as stated above after last administration, postoperative 24 h, abdominal aortic blood, centrifuging and taking serum, carry out the detection of zymetology index, get after blood and take out rapidly heart, with ice normal saline, clean, remove trunk, connective tissue, filter paper blots.Along coronary sulcus excision atrium, leave ventricle, along coronary sulcus, from the apex of the heart, to the parallel ventricle by rat of heart base portion, be cut into the myocardium sheet that approximately 0.1 cm is thick, with 37 ℃ of dyeing 3～5 min of 0.5% nitro blue tetrazolium (NBT) solution, weighed undyed infarcted myocardium quality, calculates infarcted myocardium and accounts for the ratio of quality whole-heartedly.Myocardial infarct size=(infarct myocardial Mass Measured/whole-heartedly weight) * 100%.
The impact of 2.2 Experimental agents on clotting time of mice
Mice is divided into blank group at random by body weight, aspirin group, experimental group (25,50,100mg/kg).Blank group gives the aspirin that 0.5% CMCNa solution, aspirin group give 6.25 mg/kg, and experimental group gives respectively the medicinal liquid of 25,50,100 mg/kg.2h after gastric infusion, from mouse orbit venous plexus, get blood, in microscope slide two ends, each 1 is bled, diameter 5mm at the bottom of blood, with stopwatch, clock immediately, every 30 s, with clean pin, from drop of blood edge, to central authorities, provoke once gently, and observation has or not the blood streak to provoke, only, record clotting time when having the blood streak.
The impact of 2.2 Experimental agents on rat platelet aggregation function
2.2.1 dose-effect relationship
Get 50 of Sprague – Dawley rats, male, body weight (200-250) g, be divided at random 5 groups: blank group, aspirin group (50mg/kg), experimental group (25, 50, 100mg/kg), blank group gives 0.5% CMCNa solution (10ml/kg), each organizes gastric infusion, 2h after administration, with 3% pentobarbital sodium difference anesthetized rat (30mg/k), through ventral aorta, take a blood sample, with 3.8% liquor sodii citratis anticoagulant (blood: anticoagulant=9:1), the centrifugal 5min of 800r/min, separated platelet rich plasma (PRP), remainder is again with the centrifugal 15min of 3000r/min, separated platelet poor plasma (PPP), by turbidimetry, take ADP(2 μ mol/l) be derivant, with platelet aggregation rate after LBY-NJ blood pool instrument mensuration 5min, and calculate platelet aggregation inhibition rate=(blank pipe platelet aggregation %-delivery tube assemble %) * 100%/blank pipe platelet aggregation %.
2.2.2 time-effect relationship
50 male Sprague – Dawley rats, body weight (200-250) g, be divided at random 5 groups: blank group, aspirin group, experimental group (7d, 3d, 2h), blank group gives 0.5% CMCNa solution (10ml/kg), and aspirin group gives aspirin medicinal liquid 50mg/kg, for three days on end; Experimental group gives the medicinal liquid of 50mg/kg, is divided into 3 groups, and successive administration is 7 days, 3 days and 1 day respectively, gastric infusion, once a day, and 2h after last administration, same said method, records platelet aggregation rate, and calculates platelet aggregation inhibition rate.
The impact of 2.3 Experimental agents on hemorheology of rat
Select 30 male Sprague-Dawley rats else, body weight (300～350) g, be divided at random 3 groups: blank group, aspirin group, Experimental agents group, blank group gives 0.5% CMCNa solution (10ml/kg), aspirin group gives aspirin medicinal liquid 50mg/kg, experimental group gives 50mg/kg medicinal liquid, gastric infusion, 2h after administration, collect blood, get about 5ml blood anticoagulant heparin and carry out blood examination, measure respectively low, in, height is cut the whole blood viscosity of rate, erythrocyte sedimentation rate, packed cell volume, the index such as deformable index and erythrocyte electrophoretic time.
2.4 the date processing: (` of mean ± standard deviation for data
x ± s) represent, between data, significant difference is used
tcheck takes statistics to learn and processes.
3,
result
The impact of 3.1 Experimental agents on rats with myocardial ischemia myocardial infarct size
After rat coronary artery left anterior descending branch ligation 24 h, model group infarcted region accounts for and weighs whole-heartedly 35.8% left and right; Propranolol group infarcted region accounts for and weighs whole-heartedly 16.3% left and right; Each dosage group ischemic region of Experimental agents accounts for and is heavily respectively whole-heartedly 17.52%, 14.89%, 12.28% left and right.Propranolol group and the comparison of ischemia model group, infarcted region accounts for anharmonic ratio whole-heartedly and has reduced by 43.2% (P<0.05); Each dosage group of Experimental agents 25,50,100 mg/kg and the comparison of ischemia model group, infarcted region accounts for anharmonic ratio whole-heartedly and has reduced respectively by 38.84%, 48.02%, 57.13 % (P<0.01), the above results explanation, Experimental agents can dwindle myocardial ischemia infarct size after left anterior descending coronary artery ligation, significantly reduce myocardial ischemia scope, obviously reduce the activity of lactic acid dehydrogenase (LDH), and demonstrate certain dose-effect relationship.(table 1)
Impact (the ` of table 1. Experimental agents on rat myocardial infarction model scope and Serum LDH activity
x ± s, n=10)
| Group | Dosage (mg/kg) | Infarcted region/heart (%) | LDH active (U/L) |
| Sham operated rats | ? | 0 | 4098.5±398.6 |
| Model group | ? | ? 28.65±3.25 DDD | ?5933.2±403.5 DD |
| Propranolol group | 5 | ?16.28±2.98** | ?4836.9±473.2** |
| Experimental agents group | 25 | ?17.52±0.95** | ?4533.2±406.9** |
| ? | 50 | ?14.89±1.01** | ?4328.3±447.6** |
| ? | 100 | ?12.28±1.43** | ?4198.5±398.2** |
With sham operated rats comparison: DD
p <0.01, DDD
p <0.001; With model group comparison: * *
p <0.01, * * *
p <0.001
The impact of 3.2 Experimental agents on clotting time
The experimental result of measuring clotting time of mice with slide method shows, positive control drug aspirin can significant prolongation mice clotting time, test low middle dosage group and can make cruor time extending, have significance with blank group comparing difference, but high dose group effect not obvious (table 2).
Impact (the ` of table 2. Experimental agents on clotting time of mice
x ± s, n=10
)
With the comparison of blank group: * *
p <0.01 * * *
p <0.001
The impact of 3.2 Experimental agents on platelet aggregation
Experimental result shows, aspirin can obviously suppress platelet aggregation in body, the low middle high dose group of Experimental agents all has certain effect to platelet aggregation, and there is dose-effect relationship (table 3), give after 50mg/kg Experimental agents 2h, can suppress hematoblastic gathering, within 3 days, 7 days, compare hematoblastic inhibitory action without significant difference with successive administration.(in Table 4).
Table 3. various dose Experimental agents is on the impact of platelet aggregation (`x ± s, n=10)
With blank group comparison: *
p <0.05 * *
p <0.01
Table 4 different dosing time Experimental agents is on the impact of platelet aggregation (`x ± s, n=10)
With blank group comparison: *
p <0.05, * *
p <0.01.
3.3 Experimental agents are on hemorheological impact
Compare with blank group, experimental group can obviously improve hemorheology index, and basic, normal, high whole blood viscosity, erythrocyte sedimentation rate, packed cell volume, deformable index and the erythrocyte electrophoretic time of cutting rate all obviously reduces (in Table 5).
Table 5 Experimental agents is on the impact of hemorheology index (`x ± s, n=10)
*
p <0.05, * *
p <0.01 * * *
p <0.001 with the comparison of blank group.
The specific embodiment
In order to understand better and to implement the present invention, below in conjunction with specific embodiment, further illustrate the present invention.
Embodiment 1
Take: danshensu 250mg, Carthamus yellow 20mg, puerarin 80mg, glycyrrhizin 150mg, mix homogeneously, incapsulates shell, can make the capsule that is applicable to one day dosage of normal adult, and this medicine can be used in prevention and treatment myocardial ischemia.
Below in conjunction with small-scale clinical experiment, illustrate the present invention:
1, data and method
1.1 case selections: during in December, 2011 to 2014 year January, inventor collects person in middle and old age's Patients with Myocardial Ischemia 25 examples altogether, all from hypertension generaI investigation and senior health and fitness's health check-up, male 15 examples wherein, female's 10 examples; The oldest 72 years old, minimum 45 years old, average 64 years old.Wherein with arrhythmia 6 examples, angina pectoris 4 examples, old myocardial infarction 1 example; Merge hyperlipidemia 14 examples.Get rid of severe heart failure, have apoplexy history and the patient of medication in accordance with regulations not.
1.2 diagnosis basis: electrocardiogram has T ripple sT-T ripple changer, and T ripple is lower than 1/10 of R ripple, and ST section moves down >0.05 mV.
1.3 curative effect judgements:
Effective: ECG T wave or sT-T ripple recover normal; Clinical symptoms disappears substantially.Effective: ECG T wave or sT-T ripple make moderate progress, but do not reach normal, clinical symptoms is obviously improved.Invalid: electrocardiogram and clinical symptoms are improved not obvious or without improvement.
1.4 medications: the capsule that the oral the present invention of patient makes according to embodiment 1, every day 3 times, 4 weeks courses for the treatment of.In inquiry observed and recorded treatment front and back and therapeutic process, the change of patient clinical symptom and electrocardiogram change.
2, result
In tested patient one week, chest pain and asthma symptom improve at first; Two weeks uncomfortable in chest, weak symptoms of medication are improved; Three weeks rear electrocardiograms of medication change to some extent, and nervous symptom alleviates, and taking on a new look appears in dizzy, asthenia, and to the improvement of medication surrounding electrocardiogram obviously, tested crowd is substantially among steady statue afterwards.(statistical result is in Table 6).
Before and after the treatment of table 6 person in middle and old age Patients with Myocardial Ischemia, symptom and electrocardiogram improve situation
| n | Effective | Effectively | Invalid | Total effective rate |
| 25 | 8 | 16 | 1 | 96% |
Claims (1)
1. for preventing and treat a pharmaceutical composition for myocardial ischemia, it is characterized in that, by the raw material of following weight proportion, formed: 250 parts of danshensus, 20 parts of Carthamus yellows, 80 parts of puerarins, 150 parts of glycyrrhizins.
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| CN105616439A (en) * | 2016-03-11 | 2016-06-01 | 王巧玲 | Capsules for treating alcoholic cardiomyopathy and preparing method of capsules |
| CN108743654A (en) * | 2018-08-03 | 2018-11-06 | 哈尔滨医科大学 | It is a kind of to be used to treat Chinese medicine composition of ischemic heart disease and its preparation method and application |
| CN116492359A (en) * | 2023-04-12 | 2023-07-28 | 南方医科大学珠江医院 | Composition containing glycosylated puerarin and preparation method and application thereof |
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| CN1334121A (en) * | 2001-08-31 | 2002-02-06 | 石家庄以岭药业有限公司 | Medicinal composition for restoring cardiac collaterals and its application |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105616439A (en) * | 2016-03-11 | 2016-06-01 | 王巧玲 | Capsules for treating alcoholic cardiomyopathy and preparing method of capsules |
| CN108743654A (en) * | 2018-08-03 | 2018-11-06 | 哈尔滨医科大学 | It is a kind of to be used to treat Chinese medicine composition of ischemic heart disease and its preparation method and application |
| CN108743654B (en) * | 2018-08-03 | 2021-04-27 | 哈尔滨医科大学 | A kind of traditional Chinese medicine composition for treating ischemic heart disease and its preparation method and application |
| CN116492359A (en) * | 2023-04-12 | 2023-07-28 | 南方医科大学珠江医院 | Composition containing glycosylated puerarin and preparation method and application thereof |
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Application publication date: 20141210 |