CN101658567A - Medicament for treating coronary heart disease and angina and preparation method of granular formulation thereof - Google Patents
Medicament for treating coronary heart disease and angina and preparation method of granular formulation thereof Download PDFInfo
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Abstract
The invention relates to a medicament for treating coronary heart disease and angina and a preparation method of granular formulation thereof. The medicament takes traditional Chinese medical scienceprinciple as a basis, adopts a pure traditional Chinese medicine formaula, is reasonably prepared from raw material medicines such as milk veteh, Pueraria lobata, mistletoe, Salvia Miltiorrhiza, hawthorn, rhizoma ligustici wallichii, and the like by weight, and is prepared and processed by extracting effective components combining with modern technology. The invention has the effects of nourishingQi, invigorating the circulation of blood, invigorating pulse and tonifying the kidney. The medicine provided by the invention combines various kinds of medicine for treating patients with the deficiency of vital energy or patients suffered from the deficiency of the kidney with the symptom of chest distress, palpitation, hypodynamia, giddiness, lassitude in loin and legs, and the like caused bycoronary heart disease and angina. The medicament provided by the invention can obviously reduce the whole blood viscosity, plasma viscosity, fibrinogen viscosity and hematokrit of rats with blood stasis by pharmacodynamic experiment, and can obviously accelerate RBC electrophoresis, which indicate that the medicament can obviously recover the stickiness, concentration, coagulation and gathering of blood stasis type and has the function of blood circulation invigoration.
Description
One, technical field
Content of the present invention belongs to the preparation method of medicine and medicine thereof, and it relates to a kind of preparation method for the treatment of coronary heart disease, anginal medicine and granule thereof.
Two, background technology
Coronary heart disease also claims ischemic heart desease, since its sickness rate height, the mortality rate height, and the healthy of the mankind in serious harm, thereby b referred to as " human first killer ".Angina pectoris is lipidosiss such as coronary endometrium cholesterol, form atheromatous plaque to the lumen of vessels internal projection, and with fibrosis and calcification, cause coronary atherosclerosis, narrow even entirely shut, the traditional Chinese medical science thinks that this disease belongs to " thoracic obstruction ", " pained " category is by qi depression to blood stasis, blood-vessel obstructive and cause stagnation of QI and blood may bring about pain, six climate exopathogens cold-evil invades, so that cold coagulation is in arteries and veins, the contracture spasm, and diet is careless, rich and fatty diet, become and give birth to phlegm-damp, phlegm-damp is invaded, and occupies peaceful and spacious district, or the bright network of expectorant heat, scorching on the bad temper, or qi-blood-body fluid negative and positive deficiency, so that void and blood is capable slowly causes a disease.Being used for the treatment of coronary heart disease, anginal medicine now also has a variety ofly, but its most drug composition amount is big, and active component is clear and definite inadequately, and dose is big, takes inconvenience, and onset waits shortcoming slowly, not satisfactory to coronary heart disease, anginal therapeutic effect.Chinese patent literature and relevant documents and materials by retrieval.
Three, summary of the invention
It is little to the purpose of this invention is to provide a kind of medicine composition amount, and active component is clear and definite, and taking convenience is rapid-action, thereby it is better to reach curative effect, with low cost, can play better treatment and medicine without any side effects to coronary heart disease, angina pectoris.
Another object of the present invention provides a kind of preparation method of granule of this medicine.
Four, implementation
The object of the present invention is achieved like this: it is with pure Chinese prescription.
Medicine of the present invention be by crude drug by weight ratio (part) make:
The Radix Astragali 144 Radix Puerariaes 108 Herba Viscis 96
Radix Salviae Miltiorrhizae 108 Fructus Crataegis 108 Rhizoma Chuanxiongs 36
Treatment coronary heart disease provided by the invention, anginal medicine, its said medicament is a granule.
The preparation method of the granule of treatment coronary heart disease provided by the invention, anginal medicine:
(1), gets Rhizoma Chuanxiong power and be broken to 120 order fine powders;
(2), Radix Puerariae extracts three times merge extractive liquid,, decompression filtrate recycling ethanol with 85% alcohol heating reflux;
(3), Fructus Crataegi, Radix Salviae Miltiorrhizae extract once with alcohol heating reflux respectively, decompression filtrate recycling ethanol, the residue after all the other Radixs Astragali, Herba Visci, Rhizoma Chuanxiong three flavors extract with above-mentioned Fructus Crataegi, tanshinol decocts with water three times in the lump, filtrate merges, and concentrates;
(4), above-mentioned concentrated filtrate is merged, being concentrated into relative density is the clear paste of 1.30 (80 ℃), adds the 70-90% Icing Sugar of Rhizoma Chuanxiong fine powder and total amount, and mixing is used alcohol granulation, drying, and granulate is made 1000 parts, has promptly got sugared type; Or the 70-90% dextrin and the correctives of adding Rhizoma Chuanxiong fine powder and total amount, mixing is used alcohol granulation, drying, and granulate is made 1000 parts, promptly gets Sugarless type.
Treatment coronary heart disease provided by the invention, anginal medicine, it is with inrigorating qi and promoting blood circulation, and the kidney tonifying of promoting blood circulation is selected 6 flavor Chinese crude drugs for use for basic in the side, according to the theoretical next theoretical prescription of traditional Chinese medical science QI and blood, rationally preparation has blood viscosity lowering, improves blood " Gao Ning " state, the effect of blood lipid reducing content, be used for the treatment of coronary heart disease, angina pectoris shows as blood stasis due to qi deficiency or the double disease person of suffering from a deficiency of the kidney, card is seen uncomfortable in chest, cardiopalmus, weak dizzy, soreness of the waist and knees etc.
The Radix Astragali in the side, sweet in the mouth, warm in nature, return lung, spleen channel.Has invigorating QI to consolidate the body surface resistance, diuresis poison holding, evacuation of pus, expelling pus and promoting granulation." book on Chinese herbal medicine converges and says " carry " real arresting sweating is defended in the Radix Astragali, tonifying the lung spleen invigorating, and the medicine of wind dispelling fortune poison also ... "" book on Chinese herbal medicine meets former " carries that " Radix Astragali can all void of tonifying five ZANG-organs, controls the stringy pulse spontaneous perspiration, rushes down YIN-fire, removes lung-heat, losslessly then sends out, and has antiperspirant then to end.”。The Radix Astragali is the panacea of QI invigorating, how to enrich blood solely to imitate.Lid gas is invisible, and blood is then tangible.Tangible can not speed giving birth to, gas that must be invisible are with life.The capable then blood of gas is capable, and the stagnation of QI is blood stasis then, and this product is with reinforce functional activities of the heart, and the power of the motive of breaking out fortune blood is the guiding principle of the first medicine of we.
" stagnation of QI and blood may bring about pain, general rule are not bitterly ", " Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong " is the product of blood circulation promoting and blood stasis dispelling in the side.Radix Salviae Miltiorrhizae, bitter in the mouth is slightly cold.GUIXIN, pericardium, Liver Channel have promoting blood flow to regulate menstruation, stasis-dispelling and pain-killing, removing heat from blood eliminating carbuncle, the effect that relieving restlessness is calmed the nerves." book on Chinese herbal medicine is just read ": " Radix Salviae Miltiorrhizae, merit be with four things, can blood stasis dispelling with tissue regeneration promoting, kindly treat wind and eliminating stagnation, property is gentle and walk blood ... sweet-bitter flavor is with regulating menstruation, but specially logical battalion divides.Though Radix Salviae Miltiorrhizae has ginseng name, the power deficiency of enriching blood, the power of invigorating blood circulation is had a surplus, and is medicine first of the conditioning blood system.So it is treated migratory arthralgia and goes to tie long-pending person, also the blood sector-style is from going out the capable then long-pending ear voluntarily of blood.”。Rhizoma Chuanxiong, suffering, temperature.Return liver, gallbladder, pericardium channel.Blood-activating and qi-promoting, wind-expelling pain-stopping.The hot temperature of loosing of this product is logical, can blood circulation promoting and blood stasis dispelling, again can promoting the circulation of QI to relieve pain, and be " the gas medicine in the blood " effect of the sensible QI and blood of tool.Radix Puerariae, cool in nature, sweet in the mouth, suffering are returned spleen, stomach warp, have the expelling pathogenic factors from muscles effect.This three flavor share, and plays blood circulation and channel invigorating altogether, promoting the circulation of QI to relieve pain, falls the effect of numbness.
Fructus Crataegi in the side, sour in the mouth, sweet, warm in nature.Return spleen, stomach, Liver Channel, promoting digestion and removing stagnation, circulation of qi promoting dissipating blood stasis.Go into the Liver Channel blood system, the QI and blood of passing through has the merit of promoting blood circulation to disperse blood clots and relieves pain.Herba Visci, the flat and sweet in the mouth of property, hardship are returned liver, kidney channel, have wind-damp dispelling, invigorating the liver and kidney, the effect of bone and muscle strengthening.
Make a general survey of full side, QI invigorating, invigorate blood circulation, tonify deficiency and usefulness, the deficiency of vital energy and blood stasis, gas foot and congestion looses.The Radix Astragali is the product of QI invigorating in the side, can mend greatly and defend gas with fortune blood; Be equipped with Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong, Radix Puerariae etc. simultaneously, blood circulation promoting and blood stasis dispelling, promoting the circulation of QI to relieve pain, hard masses softening and resolving.Be equipped with Fructus Crataegi, spleen invigorating, venting QI-blood.Herba Visci, kidney-replenishing, bone and muscle strengthening.We's compatibility of drugs is rigorous, and none is free, sets upright at all with tonify deficiency, and body is filled, and is equipped with the product of promoting flow of QI and blood again, reaches the unimpeded purpose of QI-blood circulation.
Clinical observation, pharmacodynamics test, animal acute toxicity test:
The clinical observation of the safe granule therapy thoracic obstruction of the positive heart
1, physical data
By the standard of testing program, through screening qualified case 140 examples, arrange grouping by random alignment district group method, patient age 38-65 year, the mean age be (59.5 ± 2.18) year old; Male's 87 examples, women's 53 examples; Angina pectoris type: first hair style 28 examples, stable type 112 examples; Severity extent distributes: slight person's 60 examples, moderate person's 80 examples.Learn the processing there was no significant difference by statistics at aspects such as age, sex, angina pectoris type, severity extent distributions for two groups.
2, study subject is selected
2.1 diagnostic criteria: the tcm diagnosis standard, carry out according to " new Chinese medicine clinical guidance principle " that Ministry of Health of the People's Republic of China in 1997 develops and publishes.
1. suffocating pain over the chest, very then chest pain radiating to the back.
2. the lighter only feels chest distress, hypopnea.
3. Electrocardioscopy suffers from the ischemic change or the exercise test positive.
2.2 differential diagnosis in tcm
The mutual YIN syndrome of the expectorant stasis of blood: uncomfortable in chest as stifled, ambition dull pain or angor are a burst of, and pain is drawn the shoulder back of the body, cardiopalmus, and shortness of breath and fatigue, purplish tongue is dark or have ecchymosis, fat to moisten sliding or stringy and rolling pulse or puckery.
2.3 Western medicine diagnose standard
With reference to International Society of Cardiology and association and World Health Organization's clinical name standard through associating specialist paper " name of ischemic heart desease and diagnostic criteria ".Select the fatigue angina pectoris.
2.4 case is included standard in
Have thoracic obstruction main symptom, diagnosis is clear and definite, and traditional Chinese medical science classification belongs to through, moderate, and dialectical be that the mutual resistance of the expectorant stasis of blood is demonstrate,proved, and Western medicine diagnose is the fatigue angina pectoris, and the age is between 18-65 year, and angina pectoris patient more than 2 times shows effect weekly.
2.5 get rid of the case standard:
1. turn out to be coronary heart disease unstable angina, myocardial infarction and other heart disease on inspection, chest pain person due to severe neurosis, climacteric syndrome, the cervical spondylosis.
2. merge medium above hypertension, the severe pulmonary insufficiency.
3. life-time service coronary dilating medicine can cause serious consequence after the drug withdrawal.
4. under-18s, gestation or women breast-feeding their children.
3 observational techniques
3.1 tcm symptom point system
Clinical symptoms to the patient adopts the method for score to compare analysis (" new Chinese medicine clinical research guideline " with reference to Ministry of Public Health formulation in 1993 judged).
1. pain degree: slightly counted 1 fen; Moderate meter 2 minutes.
2. attack times: 2-6 meter is 1 minute weekly; Show effect every day and counted 2 fens for 1-3 time; Show effect every day and counted 3 fens more than 4 times.
3. persistent period: each pain continues 1-3min meter 1 minute; Each pain continues 4-6min meter 2 minutes; Each pain continues the above meter of 7min 3 minutes.
4. uncomfortable in chest as blocking up: uncomfortable in chest as blocking up the idol work, obvious after the activity, but do not influence the daily life meter 1 minute; Activity is then uncomfortable in chest as stifled slightly, needs to have a rest just to alleviate meter 2 minutes; Uncomfortable in chest as stifled heavier, influenced the daily life meter 3 minutes.
5. shortness of breath and fatigue: the shortness of breath and fatigue idol is done, and movable back obviously but did not influence the daily life meter 1 minute; The shortness of breath and fatigue hair is obvious, needs to have a rest to alleviate meter 2 minutes; Shortness of breath and fatigue is heavier, influences the daily life meter 3 minutes.
3.2 Therapeutic Method
Just the safe granule test group of the heart 80 examples adopt single blind randomized, remove and take nitroglycerin in case of necessity, withdraw other and treat relevant medicine and write down the nitroglycerin consumption.
The safe granule (provided by Shaanxi Hualong Pharmaceutical Co., Ltd., lot number is 020318) each a bag (10g) of the oral positive heart, every day 3 times are provided in treatment; Matched group oral administered compound Radix Salviae Miltiorrhizae Tabellae, each 3, every day 3 times.Two groups were for 4 weeks is a course of treatment, conscientiously fills in unified observation table on request.1 change of illness state of observed and recorded weekly.
4 efficacy assessment standards
4.1 efficacy evaluation project
Main summary angina pectoris, electrocardiogram, clinical symptoms, total effects, nitroglycerin stop lapse rate.
4.2 total effects evaluation
The main result who sums up angina pectoris, electrocardiogram, doing well,improving.1. produce effects: a, above-mentioned 3 all reach produce effects; B, 2 produce effects, 1 invalid.
2. effective: a, 1 produce effects, 2 are effectively; B, 2 produce effects, 1 is invalid; C, 3 are effectively; D, 1 produce effects, 1 is effectively, and 1 is invalid.3. invalid: as not reach above-mentioned produce effects, effective standard.
4. increase the weight of: have 2 to increase the weight of in above-mentioned 3.
5, observed result
Blood, urine, the just all no abnormal variation of routine have no adverse effects to leukocyte, platelet before and after the 140 routine patient treatments.The treatment group is at viewing duration, and xerostomia appears in 2 examples, stool is dried partially, and continuing to take medicine does not occur obviously increasing the weight of.
Angina pectoris changes before and after table 1 treatment
Annotate: all do not have the case of increasing the weight of, two groups relatively, p＜0.05
Angina pectoris attacks situation contrast before and after table 2 treatment
Annotate: relatively preceding with the treatment of this group, * p＜0.01
Electrocardiogram situation of change before and after table 3 treatment
Annotate: all do not have the case of increasing the weight of, two groups relatively, p＞0.05
Cardinal symptom is improved situation before and after table 4 treatment
Annotate: all do not have the case of increasing the weight of, two groups relatively, p＞0.05
Table 5 nitroglycerin class medicine stops lapse rate statistical table [example, (%)]
The relation of table 6 curative effect and severity extent
Annotate: all do not have the case of increasing the weight of, two groups relatively, p＞0.05
6, brief summary
(inpatient's 140 examples are observed in heart blood silt patient's clinical trial to the safe granule treatment of the positive heart thoracic obstruction altogether, and wherein 80 examples are organized in treatment, and in 60 example 4 weeks of the course of treatment of matched group, its result shows: treatment group produce effects 24 examples, effective 51 examples, total effective rate 93.75%; Matched group produce effects 17 examples, effective 38 examples, 91.67%, two group of no significant difference of contrast of total effective rate.Two groups all can be reduced the angina pectoris attacks frequency, shorten the outbreak persistent period.ECG curative effect, treatment group produce effects 16 examples, effective 56 examples, total effective rate 90%; Matched group produce effects 10 examples, effective 43 examples, total effective rate 88.34%.Two groups of contrast there was no significant differences.Improving for cardinal symptom such as uncomfortable in chest as stifled has certain curative effect, treatment group produce effects 29 examples, total effective rate 93.75%; Matched group produce effects 24 examples, total effective rate 90.00%.Two groups of contrast there was no significant differences.Observe when just using the safe granule of the positive heart, have 19 examples to suffer from just to stop using or reduce by half and use the nitroglycerin analgesic, all there are different improvement two groups of treatment backs to the picture of the tongue pulse condition.
Show by aligning the safe granule treatment of heart numbness (angina pectoris) clinical observation result: the safe granule of the positive heart can improve the dirty ischemia of the people, and alleviating angina pectoris symptom has better curative effect, and determined curative effect is not found untoward reaction.
" the safe granule of the positive heart " 182 routine clinical observation on the therapeutic effect data
1, case selection standard
1. physical data
All cases are inpatient, and the anginal diagnosis of CHD meets selects case standard, selected object to be the while in hospital person that has the angina pectoris attacks.According to principle at random, select treatment to organize 182 examples, male 102 examples, women 80 examples, the man: woman=1.27: 1,61.5 ± 16.1 years old mean age, wherein minor angina patient 81 examples are matched group, male 53 examples, women 28 examples, 60.2 ± 15.1 years old mean age.Matched group is not except that using the safe granule of the positive heart, and all the other treatments are all same with the treatment group.
2. clinical verification method
2.1.1 the each 10g/ bag of the safe granule of the oral positive heart/time, every day 3 times, the 10-14 days course of treatment.
2.1.2 chest pain grading standard (with reference to therapy of combining Chinese and Western medicine angina pectoris in 1979 and arrhythmia forum) " angina pectoris and ECG curative effect evaluation criteria "
2.1.3 continue 25 minutes, pain is shown effect 2-3 time at least weekly, or shows effect 1-3 time, but degree is heavy, need suck nitroglycerin sometimes at every turn.
2.1.4 moderate: have every day for several times and show effect than classical angina, continue several minutes to 10 minutes at every turn, degree is heavier, generally all needs to suck nitroglycerin.
2.2 electrocardiogram situation of change: the recovery that the ST section moves down, the low flat or inverted recovery of T ripple.
3. observation of curative effect
3.1 general index
Blood, urine, just routine test; The heart, liver, kidney function test; Myocardial enzymes is checked in blood glucose, blood fat, hemorheology etc.
3.2 curative effect is judged
3.2.1 treat anginal effect
Slightly:
(1) produce effects: transference cure or basic the disappearance.
(2) effective: painful can attack times, degree and persistent period have obviously and alleviate.
(3) invalid: symptom is preceding identical with treatment.
Moderate:
(1) produce effects: transference cure or basic the disappearance.
(2) effective: sx is to the standard of " slightly ".
(3) invalid: symptom is preceding identical with treatment substantially.
4.2.2 ECG curative effect evaluation criteria
(1) produce effects: electrocardiogram returns to " roughly normal " or reaches " normal ECG ".
(2) effective: the reduction of ST section, treating more than the back rise 0.05mV, but do not reach normal level, put the T ripple and shoal (reaching 25% above person) mainly leading: or the T ripple becomes uprightly chamber or intraventricular block improver by smooth.
(3) invalid: electrocardiogram is preceding identical with treatment substantially.
3.3 untoward reaction is seen and is looked into
Blood, urine, just routine test, liver, renal function, myocardial enzymes, subjective symptoms etc.
4. statistical analysis
The data X2 (card side) checks P＜0.05 * * P＜0.01 * * * significant difference
5. result
Give average 12 ± 1.5 days of patient's medication clinically, treatment group at last matched group as a result compares.The result shows: aspect allevating angina pectoris, the positive heart is safe particulate clinical effectively apparently higher than matched group: the treatment group also obviously is better than matched group aspect the electrocardiogram myocardial ischemia improving, and this medical instrument has the significantly effect of blood fat reducing and blood viscosity lowering simultaneously.Blood, urine, just conventional before and after two groups of treatments, indexs such as liver function, kidney merit, blood glucose, myocardial enzymes do not have significant difference.Do not find tangible clinical side effects in the treatment group.
Clinical effectiveness shows: the safe granule of the positive heart has the good curing effect in the treatment angina pectoris.It is very effective clinically adjuvant drug.
The safe granule therapy minor angina of subordinate list 1 positive heart observation of curative effect
The safe granule of the subordinate list 2 positive hearts is controlled the moderate curative effect to treat angina pectoris and is observed
Electrocardiogram improved the result after the safe granule of the subordinate list 3 positive hearts was controlled CHD
6. discuss
The CHD angina pectoris is because due to the heart oxygen supply weighing apparatus, and causes myocardial ischemia, anoxybiotic basic reason to be this three big principal element of spasm of narrow, thrombosis coronarius and arteria coronaria.Its initiating agent is the damage of arteria coronaria tunica intima in the generation of CHD, evolution, the collagen fiber of its deep layer are exposed in the blood Huaihe River, cause platelet adhesion and accumulate in damage location, discharge multiple vaso-active substance simultaneously, stimulate vascular endothelial cell and vascular smooth muscle cell proliferation and migration to cause luminal stenosis.These cytokines also stimulate simultaneously and form the thrombus obstruction blood vessel or stimulate vasospasm to cause tube chamber further narrow.Confirm through clinical observation and crown angiography, in above-mentioned factor separately or under the synergy, cause myocardial ischemia or can bring out anginal outbreak during simultaneously with the factor that increases myocardial oxygen consumption (as motion or excited).
The traditional Chinese medical science is thought: " the capable then blood of gas is capable, and the stagnation of QI is blood stasis then ".The most of patient with angina pectoris of clinical observation have the characteristics of bringing out or increasing the weight of because of depressed emotion, we use the gas of the safe granule reason of positive heart liver, spleen, heart channel and blood circulation promoting and blood stasis dispelling in view of the above, the patient with angina pectoris clinical symptoms is obviously alleviated, and obviously reduce the syndrome of blood stasis integrated value, the safe granule of the positive heart is to use the theory of Chinese medical science basis, and in conjunction with modern technologies, selects active drug for use, it is synthetic through science processing combination to extract its active ingredient, treats clinically in the CHD angina pectoris and brings into play enormous function.This clinical observation result shows, it treats anginal effective percentage apparently higher than matched group and inefficiency is lower than matched group.Also obviously be better than matched group aspect the electrocardiogram myocardial ischemia improving.Above result shows that the safe granule of the positive heart has the anginal effect of good curing CHD.
The safe particulate Main Ingredients and Appearance of the positive heart is: the active ingredient of extracting in the Chinese medicines such as the Radix Astragali, Radix Puerariae, Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong, and its comprehensive function is when treatment CHD:
1. coronary artery dilating is removed coronary spasm, significantly increases the blood flow of cardiac muscular tissue.
2. reduction myocardial oxygen consumption strengthens the ability of myocardium anoxia enduring ischemia.
3. have antiplatelet aggregation and thrombolytic effect.
4. improve myocardium microcirculation, repair the injury of myocardium cell.
5. it is synthetic in vivo to suppress cholesterol, suppresses its absorption and promotes its row to rush down, and eliminates the effect of sedimentary lipid in the blood vessel.
In the treatment of CHD, the Chinese medicine tool has certain effect, and therefore developing herbal species has profound significance, and the safe granule of the positive heart has a good application prospect in the treatment of CHD.
Pharmacodynamics test:
One. to the influence of Acute Myocardial Ischemia in Rats due to the pituitrin
Materials and methods
Laboratory animal: the wistar rat, body weight 180～220g, the male and female dual-purpose is provided by animal housing of Chinese Medical Sciences University, for obtaining laboratory animal quality certification unit.
Medicine: the safe sheet of the positive heart of positive control drug, Guizhou Shenqi Pharmaceutical Co., Ltd provides, lot number: the safe granule of the 960512 positive hearts, Liaoyang City's natural drug institute provides, lot number: 980103 pituitrin injection, Shenyang Biochemistyr Pharmaceutical Factory produces, lot number: 950611 are diluted to 1 μ/ml with Ns, iv0.1ml/100g, dosage are 1 μ/kg.
Anesthetis: urethane, the Beijing Chemical Plant produces, lot number: 921104
Method: according to literature method
(1)Select 60 of the normal rats of electrocardiogram for use, the male and female dual-purpose, divide equally 4 groups at random, irritate stomach for the 1st group and give distilled water 2ml/100g, irritate the stomach group respectively for the 2nd, 3 group and give the safe granule of the positive heart of 5.4g/kg, 2.7g/kg and (be made into 27.0% and 13.5% and suspension with distilled water respectively.) the 4th group irritate the safe sheet suspension of the positive heart that stomach gives 0.5g/kg (2.5%), the administration volume is 2ml/100g, successive administration 3 days, 1hr after the last administration, urethane 1.2g/kg intraperitoneal injection of anesthesia, it is fixing to face upward the position, connect electrocardiograph, trace the II lead electrocardiogram, annotated in the tongue intravenous injection pituitrin, 15s, immediate record 15s, 30s, 1min, 3min, 5min, the 15min electrocardiogram changes, with J point rising 1.5mv, the T ripple is low flat, two-way, be inverted, the ST section moves down 0.5mv, arrhythmia is the myocardial ischemia index, calculates each treated animal myocardial ischemia percentage rate, X
2The significance of difference between administration group and the matched group is compared in check, the results are shown in Table 1.
The safe granule of the positive heart of table 1 causes the anxious influence of giving birth to myocardial ischemia of rat to pituitrin
Compare * P＜0.01 with matched group
Conclusion: relatively there were significant differences (P＜0.01) that the positive heart of prompting Thailand granule has the antagonism pituitrin causes the effect of rat heart muscle ischemia for the safe sheet group of safe high and low two the dosage groups of granule of the positive heart and the positive heart and blank group.
Two, isoproterenol (ISO) is caused the protective effect of rat acute myocardial ischemia
Animal and medicine are the same, ISO:0.5mg/ml, and Shanghai Hefeng Pharmaceutical Co., Ltd. produces, lot number: 960802
Method: select 60 of the normal rat of electrocardiogram for use, male and female half and half, grouping and administration master method are the same, 1hr after the last administration, urethane 1.2g/kg intraperitoneal anesthesia is faced upward the position and is fixed, and connects electrocardiograph, trace normal II lead electrocardiogram, lumbar injection ISO2mg/kg, record 30s, 1,3,5,10,20,30, the 45min electrocardiogram, with ST field offset meansigma methods (ST), as the index of degree of myocardial ischemia and evaluation curative effect of medication
(2,3), the significance of difference between each administration group and the matched group is compared in t one check,
The safe granule of the positive heart of table 2 causes the anxious influence of giving birth to myocardial ischemia, ECG ST field offset of rat to ISO
Compare * P＜0.05, * * P＜0.01 with matched group
The result; by table 2 as seen, with matched group relatively, the ST field offset meansigma methods that the safe sheet group of the safe granule high and low dose group of the positive heart and the positive heart causes after to lumbar injection ISO obviously reduces (P＜0.05; P＜0.01), the myocardial ischemia of pointing out medicine that ISO is caused has the certain protection effect.
Three, to the influence of normal mouse normal pressure hypoxia-bearing capability
Material: animal: Kunming kind white mice, body weight 22～26g, the male and female dual-purpose is provided by animal housing of Chinese Medical Sciences University.
Get 40 of mices, male and female half and half, divide equally 4 groups at random, the normal control group gavages the normal saline of 0.2ml/10g, the safe granule high dose group of positive heart 7.8g/kg, low dose group 3.9g/kg, the safe sheet 0.6g/kg of the positive heart of positive controls, the gastric infusion volume is 0.2ml/10g, successive administration 3 days, 30min after the last administration is equipped with the 10g sodica calx with the Mus input, and volume is the wide mouthed bottle interior (every bottle of 1 mice) of 250ml, and seal bottleneck with vaseline, with anti-gas-leak, stopping with mouse breathing is index, and the record mice is because of the dead time (time-to-live) of anoxia, the t-check is compared each administration group and to returning according to the significance of difference between the group, be the results are shown in Table 3.
The safe granule of the positive heart of table 3 is to normal mouse influence of pressing the anoxia ability commonly used
Compare * * P＜0.01 with matched group
The result: compare with matched group, the safe tablet group of the safe granule high and low dose group of the positive heart and the positive heart all obviously prolongs the mice time-to-live, and (P＜0.01) shows that this medicine has the effect that strengthens mice normal pressure resistant anoxia ability.
Four, the positive safe granule analgesic activity experiment of the heart (mouse writhing method)
Animal: the same, medicine: with 1.Acetic acid: Zhengzhou City's chemical reagent three factories, lot number: 960812, be mixed with 0.6% solution through distilled water.
According to literature method
(4)Get 40 of white mice, male and female half and half are divided equally 4 groups at random, and group is irritated the stomach group and given normal saline 0.2ml/10g on the; 2nd, the .3 group is irritated the stomach group respectively and is given the safe granule 7.8g/kg of the positive heart, 3.9g/kg; Irritating stomach for the 4th group gives the positive heart safe sheet 0.6g/kg, successive administration 3 days, 30min after the last administration, every Mus lumbar injection 0.6% acetic acid 0.1ml/10g, behind the record injection algogen in 10 minutes each Mus turn round the body number of times, the significance of difference between each administration group and the matched group is compared in t～check, the results are shown in Table 4.The safe granule Dichlorodiphenyl Acetate of the positive heart of table 4 causes the influence of mouse writhing reaction
Compare * * P＜0.01 with matched group
The result: after giving algogen 0.6% acetic acid, each administration group and blank treated animal all go out out writhing response in 10min.But each administration group is turned round the body number of times and obviously is less than the blank group, and there were significant differences (P＜0.01), points out the safe granule of the positive heart to have analgesic activity.
Five, the safe granule of the positive heart influences stasis syndrome rat model hemorheological property
Experiment material
Animal: the wistar rat, the male and female dual-purpose, body weight 280～300g,, provide by animal housing of Chinese Medical Sciences University.
Medicine and reagent: the safe tablet of the safe granule of the positive heart and the positive heart is with 1; The heparin sodium powder, adrenalin hydrochloride (Adr) injection 1mg/ml, Shanghai Hefeng Pharmaceutical Co., Ltd. produces, lot number: 960502
Equipment: MVIS-2000 fully automatic blood rheological analysis instrument, cell electrophoresis instrument, erythrocyte (RBC) hematocrit pipe, ice cube, centrifuge.
Experimental technique
According to document
(5)Method is got 80 of rats, and male and female half and half are divided equally 5 groups at random, and the 1st group of blank group irritated stomach distilled water 2ml/100g every day; The 2nd group, the blood stasis model matched group, irritate stomach distilled water 2ml/100g every day, 3rd, 4 groups are respectively the safe high dose group 5.4g/kg of the positive heart, low dose group 2.7g/kg, the 5th group is the safe tablet group of positive heart 0.5g/kg, each administration group is irritated the stomach relative medicine every day, the administration volume is 2ml/100g, successive administration 7 days, 1hr2 after the last administration～5 group equal adrenaline subcutaneous injection 0.08ml/100g, inject altogether 2 times, at interval 4hr, between double injection Adr (front and back each 2 hours at interval), rat is immersed 5min in the frozen water.The 24hr that stops eating after the disposal, carotid artery is got blood under the waking state, the anticoagulant of part blood heparin sodium, part blood natural coagulation (respectively getting 2ml) is got serum, blood plasma after centrifugal, detects hemorheology index with corresponding instrument.T～check is each group difference significance relatively, the results are shown in Table 5.
The safe granule Dichlorodiphenyl Acetate of the positive heart of table 5 causes the influence (X ± SD) of mouse writhing reaction
Relatively compare * P＜0.05 * * P＜0.01 with the blood stasis model group in △ P＜0.0 5 △ △ P＜0.01 with the blank group
Result: as seen by table 5, the safe tablet group of the safe granule high and low dose group of the positive heart and the positive heart all reduces blood stasis rat whole blood contrast viscosity, plasma viscosity, Fibrinogen specific viscosity and packed cell volume, and the RBC electrophoresis is obviously quickened, with blood stasis model group comparing difference remarkable (P＜0.05P＜0.01), show that the safe granule of the positive heart can make the viscosity of blood stasis model dense, coagulates, gather obviously and recover, the prompting effect of invigorating blood circulation.
Three months toxicity tests of the safe granule rat of the positive heart
Summary: irritate stomach for rat (20 every group) with the safe granule 24g of the positive heart, 12g and three dosage of 6g/kg, every day secondary, 6 times weekly, three totally months.After the administration three months, each treated animal is put to death half, all the other half stop administration continuing to raise 2 week the back put to death, carry out coherence check, as a result animal generally in order, the every index of hematological examination and blood biochemistry checking is all in normal range; Each important organ index is normal, does not relatively have significant difference with matched group; Each important organ histological examination finds no obvious pathological change.Convalescent period, each treated animal was not also found the reaction of retardance toxicity.In view of the above, in the trimestral long term toxicity test of rat administration, do not find that the safe granule of the positive heart has overt toxicity reaction and the reaction of retardance toxicity.The animal safety consumption that test provides is 24g/kg, is equivalent to 48 times of clinical people's consumption.
Test objective: observe the safe granule of the positive heart of prolonged application, the toxic reaction that is produced and the symptom of appearance and the order of severity, the target organ of toxic reaction and recovery and development.Determine nontoxic amounts of reactants, for clinical application provides reference.
Test specimen: the safe granule of the positive heart, specification 10g/ bag, every day three times, each one bag.Lot number: 20020505, heavy dose is made into the aqueous suspensions of 80% concentration during test, and middle low dose is diluted in proportion, and the administration volume is every 15ml/kg.
Censorship unit: Shaanxi Hualong Pharmaceutical Co., Ltd.
Experimental animal: the SD rat, body weight 105g ± 5g, the Traditional Chinese Medicine Research Institute, Shanxi Province Experimental Animal Center provides, the quality certification: moving word 08-25 number of doctor.
The raising condition: 20～24 ℃ of temperature, relative humidity 40～50% ventilates 2 times/day, changes 2 times/week of bedding and padding, and water (tap water) freely absorbs, and meets GB14925-94, the quality certification: moving word 08-23 number of doctor.Raise and be full nutrition feed, the quality certification: moving word 08-22 number of doctor.
Dosage is provided with: according to clinical consumption and animal acute toxicity test, the used dosage of the test of pesticide effectiveness, establish large, medium and small three dosage: 24g 3., 12g and 6g/kg are equivalent to 48 times of clinical people's consumption respectively, 24 times and 12 times.
Route of administration: adopt and the corresponding to approach gastric infusion of clinical people's medication, noon and afternoon respectively are administered once, each 15ml/kg.
Test method: 80 of healthy SD rats are selected in test, and animal is divided equally 4 groups by body weight, and 20 every group, matched group (giving pure water) and three administration groups, each organizes equal gastric infusion, and the administration volume is 15ml/kg.Water and feedstuff freely absorb, perfusion every day 2 times, successive administration three months.Weigh weekly 1 time, and write down each feed consumption of water each 2 times.Note observing the general situation of animal, have poisoning manifestations to raise separately, and itemized record.Fasting after month last administration for the third time, second day every group get 10, after 0.35% sodium pentobarbital intraperitoneal anesthesia, 1. carotid artery is got blood, checks routine blood test, 10 indexs of blood biochemical; 2. dissect each important organ, weigh and calculate organ index; 3. important organ histological examination.10 animals of every group of residue stop administration, continue to raise 2 all backs and put to death, and inspection item is identical.
Result of the test: 1, animal is produced the influence of growing: do not find in the process of the test that each treated animal drinking-water of administration, feed reduce, defecating is the normal granules shape, does not have constipation and loose stool, animal activity is normal, fur is bright and clean, weekly weight increase and the matched group no significant difference of comparing.See for details table 1,
Three months body weight change of table 1 administration (g, x ± s)
Table 2 drinking-water and food consumption situation (ml, 10 of g/ days)
2, to the influence of routine blood test and blood biochemical: administration three months are respectively organized in administration and drug withdrawal recovers two weekly checks, hemoglobin, and RBC number, leukocyte count and differential counting, 10 biochemical indicators are all in range of normal value.See Table 3, table 4.
Three months rat serum routines of table 3 administration and the blood biochemistry checking (n=10 of x ± s)
Table 4 drug withdrawal recovers two all routine blood tests and the biochemical analysis (n=10 of x ± s)
The amount group is organized in a small amount in a large amount of groups of project unit's matched group (water)
RBC ×10
12/L 7.43±0.24 7.45±0.29 7.55±0.35 7.53±0.37
Hb g/L 124.50±5.24 126.30±5.57 124.58±5.73 125.08±5.67
WBC ×10
9/L 11.79±2.86 11.84±2.93 11.64±2.56 11.84±3.25
Neutral % 21.41 ± 6.33 20.78 ± 4.25 20.17 ± 4.74 21.34 ± 3.87
Lymph % 78.67 ± 6.39 79.22 ± 4.25 79.83 ± 4.75 78.67 ± 3.86
PLT ×10
9/L 159.04±30.78 159.66±26.18 158.86±29.83 157.58±31.68
TBIL μmol/L 2.62±0.71 2.98±0.57 2.48±0.65 2.18±0.55
TP g/L 66.17±4.56 68.54±4.46 62.65±6.36 61.88±6.36
ALB g/L 36.77±0.73 37.78±0.84 36.32±1.24 35.67±1.18
ALT U/L 45.34±6.57 46.33±6.18 46.12±6.76 43.54±7.57
GIU mmol/L 4.22±1.07 4.40±0.89 4.17±0.92 3.74±0.75
BUN mmol/L 5.15±0.98 5.42±1.01 4.89±0.92 4.97±0.96
Crea μmol/L 45.54±6.92 45.67±6.82 45.10±6.54 41.89±7.73
ALP U/L 159.33±43.36 162.65±39.73 171.12±63.18 153.76±69.38
TCHO mmol/L 1.58±0.31 1.66±0.37 1.49±0.31 1.48±0.28
AST U/L 145.32±27.65 136.78±18.55 150.33±25.79 148.11±22.46
3. to the influence of important organ index: each administration group and control animals important organ index are no abnormal.See Table 5, table 6.
Three months toxicity test important organs of the safe granule rat of the positive heart of table 5 index (n=10 of x ± s)
Table 6 drug withdrawal recovers 2 all important organ indexes (n=10 of x ± s)
4, important organ tissue examination: dissect animal, core respectively, liver, spleen, lung, kidney, adrenal gland, hypophysis, thymus, ovary, rectum, mesenteric lymph node, prostate, testis, 14 internal organs of epididymis, 10% formaldehyde fixed, specimens paraffin embedding slices, the dyeing of haematoxylin Yihong, observation by light microscope is also taken pictures.As a result, three months heavy doses of administration and matched group, each layer of cardiac muscle clear in structure, no cell infiltration in the cardiac muscle, myocyte and vascular morphology are no abnormal; Lobules of liver clear in structure, hepatocyte do not have pathological changes such as edema, degeneration; That spleen is organized is red, white pulp as seen, visible arterial sheath is dispersed in lymphocyte and erythrocyte in the white pulp in the red pulp; No obvious cell infiltration in the lung tissue, alveolar septum do not have obviously and thicken; Renal cortex and medullary substance layering are clear, and cortical areas's glomerule, renal tubules and medullary substance district Distal convoluted tubule cell are no abnormal; It is clear that adrenal cortex district and medullary substance are distinguished the boundary, and cortical areas's glomerular zone, reticular zone are all as seen; Bears gland cortex, medullary substance as seen, cellular morphology is no abnormal; Mucous membrane of rectum epithelial cell no abnormality seen, enteraden is normal, proper mucous membrane, the no abnormal change of flesh layer, serous coat is normal; Capsule of prostate does not have and thickens, and the glandular substance of prostate inner cell is monolayer alignment, and smooth muscle and fibrous tissue are no abnormal; Albuginea testis does not have and thickens, visible each phase spermatogenic epithelium cell in the seminiferous tubule, visible mature sperm in the tube chamber, the no abnormal change of interstitial cell; Epididymis tube wall rule, tube wall epithelium are pseudostratified ciliated columnar epithelium, no hypertrophy, degeneration; Visible each the phase follicle of ovary and each phase degeneration corpus luteum, the histiocyte no abnormality seen changes.The hypophysis tunicle does not have and thickens, adenohypophysis and neurohypophysis all as seen, no abnormality seen changes; The mesenteric lymph node tunicle does not have and thickens, and cortical areas's lymph follicle clear in structure, the lymphoid tissue of disperse do not have hypertrophy and change, and heavy dose of group is respectively organized and do not found that pathologic changes.Two weeks of drug withdrawal, dissect animal, core respectively, liver, spleen, lung, kidney, ovary, rectum, mesenteric lymph node, prostate, 10 internal organs of testis, do pathologic finding, also do not find pathological change.
Conclusion: the safe granule 24g of the positive heart, 12g and three dosage of 6g/kg are given rat oral gavage three months continuously, animal generally in order as a result, movable normal, fur is bright and clean, the drinking-water feed is no abnormal, weight increase, and the every index of blood picture inspection and blood biochemistry checking is all in range of normal value, each important organ index is normal, and each important organ histological examination does not see that obvious pathologic changes.In view of the above, do not find tangible toxic reaction and retardance toxic reaction in the trimestral test of rat oral gavage administration, used three dosage are distinguished 48 times of suitable clinical application, 24 times and 12 times.It is 24g/kg that the animal safety consumption is provided, 48 times of quite clinical consumption.
Claims (3)
1, a kind of treatment coronary heart disease, anginal medicine, it is characterized in that it by crude drug by weight ratio (part) make:
The Radix Astragali 144 Radix Puerariaes 108 Herba Viscis 96
Radix Salviae Miltiorrhizae 108 Fructus Crataegis 108 Rhizoma Chuanxiongs 36
2, treatment coronary heart disease as claimed in claim 1, anginal medicine is characterized in that said medicament is a granule.
3, as the process for producing granula of claim 1,2 described treatment coronary heart disease, anginal medicine, it is characterized in that:
(1), gets Rhizoma Chuanxiong power and be broken to 120 order fine powders;
(2), Radix Puerariae extracts three times merge extractive liquid,, decompression filtrate recycling ethanol with 85% alcohol heating reflux;
(3), Fructus Crataegi, Radix Salviae Miltiorrhizae extract once with alcohol heating reflux respectively, decompression filtrate recycling ethanol, the residue after all the other Radixs Astragali, Herba Visci, Rhizoma Chuanxiong three flavors extract with above-mentioned Fructus Crataegi, tanshinol decocts with water three times in the lump, filtrate merges, and concentrates;
(4), above-mentioned concentrated filtrate is merged, being concentrated into relative density is the clear paste of 1.30 (80 ℃), adds the 70-90% Icing Sugar of Rhizoma Chuanxiong fine powder and total amount, and mixing is used alcohol granulation, drying, and granulate is made 1000 parts, promptly gets sugar-containing type; Or the 70-90% dextrin and the correctives of adding Rhizoma Chuanxiong fine powder and total amount, mixing is used alcohol granulation, drying, and granulate is made 1000 parts, promptly gets Sugarless type.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102600422A (en) * | 2011-11-28 | 2012-07-25 | 王国荣 | Traditional Chinese mixture for treating angina pectoris at catabatic period |
| CN115252562A (en) * | 2022-08-17 | 2022-11-01 | 陕西方浩生物科技有限公司 | Preparation method of Zhengxintai granular traditional Chinese medicine composition |
| CN115282195A (en) * | 2022-08-17 | 2022-11-04 | 陕西方浩生物科技有限公司 | A Chinese medicinal composition for treating coronary heart disease and angina pectoris, and its preparation method |
-
2009
- 2009-09-18 CN CN200910023964A patent/CN101658567A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102600422A (en) * | 2011-11-28 | 2012-07-25 | 王国荣 | Traditional Chinese mixture for treating angina pectoris at catabatic period |
| CN115252562A (en) * | 2022-08-17 | 2022-11-01 | 陕西方浩生物科技有限公司 | Preparation method of Zhengxintai granular traditional Chinese medicine composition |
| CN115282195A (en) * | 2022-08-17 | 2022-11-04 | 陕西方浩生物科技有限公司 | A Chinese medicinal composition for treating coronary heart disease and angina pectoris, and its preparation method |
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