CN1985866A - Application of Chinese medicine composition in treating cardiac and cerebral vascular diseases - Google Patents
Application of Chinese medicine composition in treating cardiac and cerebral vascular diseases Download PDFInfo
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Abstract
The present invention discloses the application of one Chinese medicine composition in preparing medicine for preventing and treating apoplexy, cerebral ischemia causing dizziness and headache, memory disorder, thrombus and micro circulation disorder. The Chinese medicine composition is the supercritical extract and/or water extract of white tuckahoe, white atractylodes rhizome and angelica.
Description
Technical field
The present invention relates to a kind of purposes of Chinese medicine composition, particularly, relate to of the application of a kind of Chinese medicine composition, relate in particular to this Chinese medicine composition and prevent and treat application in the medicine of apoplexy, cerebral ischemia, dysmnesia, thrombosis and microcirculation disturbance in preparation at treating cardiac and cerebral vascular diseases.
Background technology
On November 2nd, 2005, the patent of invention description CN1225250C of bulletin disclosed a kind of Chinese medicine composition of preventing and treating senile dementia, it mainly is made up of Poria, the Rhizoma Atractylodis Macrocephalae and polysaccharide, n-butanol extract and/or volatile oil effective site in the crude drug that is grouped into, perhaps mainly is made up of the polysaccharide in one or both crude drug that are selected from Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis, n-butanol extract and/or volatile oil effective site.This Chinese medicine composition can adopt the method for supercritical extraction and water extraction to make.
Above-mentioned Chinese medicine composition has the purposes of control senile dementia.The present invention has excavated the new medical usage of this Chinese medicine composition.For known drug, find that it also has the performance of the another kind of disease of treatment, thereby can treat another kind of disease that this medical usage invention second time is for satisfying the medical clinical demand and the market demand, and is significant.
In view of the important function of the medical usage second time, the new purposes of researching and developing above-mentioned Chinese medicine composition is significant.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of new purposes of Chinese medicine composition, promptly prevents and treats application in the medicine of apoplexy, cerebral ischemia, dysmnesia, thrombosis and microcirculation disturbance in preparation.
The invention provides a kind of Chinese medicine composition and prevent and treat application in the medicine of apoplexy in preparation, this Chinese medicine composition is mainly by the supercritical extract and/or the water extract that are selected from a kind of, two or three crude drug in Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis, and perhaps supercritical extract and/or water extract effective site are formed.
The present invention also provides the application of a kind of Chinese medicine composition in the medicine of preparation control cerebral ischemia.
The present invention also provides a kind of Chinese medicine composition to prevent and treat dysmnesia in preparation, improves the application in the medicine of remembering.
The present invention also provides the application of a kind of Chinese medicine composition in the medicine of preparation control thrombosis.
The present invention also provides the application of a kind of Chinese medicine composition in the medicine of preparation control microcirculation disturbance.
For sake of convenience, with Poria of the present invention, the Rhizoma Atractylodis Macrocephalae, abbreviate FBD as when the Chinese medicine composition that is grouped into.Poria is called for short F, the Rhizoma Atractylodis Macrocephalae is called for short B, Radix Angelicae Sinensis abbreviation D.
FBD of the present invention can adopt following method to make: crude drug is ground into coarse powder, obtains supercritical extract through carbon dioxide supercritical fluid extraction, medicinal residues obtain water extract after with water extraction afterwards; Perhaps crude drug is after supercritical extraction obtains supercritical extract, medicinal residues with water extraction after, add ethanol and precipitate when containing determining alcohol for 45-95%, obtain polysaccharide, supernatant is used n-butanol extraction after reclaiming ethanol, obtains n-butanol extract; Perhaps, described crude drug water decocts, and after aqueous extract concentrates, adds ethanol and precipitates when containing determining alcohol for 45-95%, obtains polysaccharide, and supernatant is used n-butanol extraction after reclaiming ethanol, obtains n-butanol extract; Polysaccharide and n-butanol extract are water extract effective site.
In described supercritical extract and water extract effective site, can add pharmaceutical carrier or dressing, make Chinese medicine preparation.The common dosage forms adjuvant can be selected for use, and disintegrating agent is as hydroxypropyl starch, hyprolose, carboxymethyl starch sodium, carboxymethylcellulose calcium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose etc.; Filler is as lactose, sucrose, mannitol, microcrystalline Cellulose, dextrin, starch, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, cyclodextrin, micropowder cellulose etc.; Wetting agent and binding agent are as ethanol, pregelatinized Starch, polyvidone, sodium carboxymethyl cellulose, hypromellose; Lubricant is as Pulvis Talci, stearic acid, magnesium stearate, calcium stearate, micropowder silica gel, hydrogenated vegetable oil, Macrogol 4000 and 6000; Wetting agent is as sodium lauryl sulphate, Tween 80.
The consumption of FBD of the present invention and the course of treatment can be done suitably to adjust according to the light and heavy degree of dosage form, patient's age, disease, but are generally oral 3 times of every day, each 2, with 1 month be a course of treatment, can use 1 course of treatment or longer time continuously.
In order to understand essence of the present invention better, will its new purposes in pharmaceutical field be described with pharmacological testing and the result of FBD of the present invention below:
In pharmacodynamic study, find:
1, online bolt method causes after the focal cerebral ischemia in rats that in the reperfusion injury experiment, FBD group and positive drug nimodipine (2mg/kg) all have the obvious treatment effect to focal cerebral ischemia-reperfusion injury that line bolt method causes.The result shows that FBD can effectively prevent and treat apoplexy, cerebral ischemia.
2, in mice broken end global brain ischemia model, nimodipine (5mg/kg) can make the mice broken end global brain ischemia model mouth breathing time significantly increase (p＜0.05).FBD has certain prolongation effect to breathing time, but does not relatively have significant difference with the feminine gender group.Nimodipine and FBD can significantly improve the SOD vigor, and MDA content is not had obvious influence.The result shows that FBD can effectively prevent and treat apoplexy, cerebral ischemia.
3, in four artery occlusion rat whole brain ischemical reperfusion injuries experiments, FBD can the lengthening model rat ischemia after the electroencephalogram extinction time, shorten the back electroencephalogram recovery time of perfusion again and righting reflex recovery time, effect and dosage are proportionate.The result shows that FBD can effectively prevent and treat apoplexy, cerebral ischemia.
4, in the research of FBD to anesthetized dog periphery and cerebral blood flow influence, FBD has certain reduction cerebral vessels resistance to anesthetized dog, increase the effect of brain blood flow, and the periphery blood pressure of animal is also had the effect of similar nimodipine: reduce periphery blood pressure, particularly diastolic pressure; Decreased heart rate.But action intensity and action time are all less than nimodipine.30min was the most obvious after the FBD duodenal administration acted on administration to the improvement of brain blood flow.The result shows that FBD can effectively prevent and treat apoplexy, cerebral ischemia.
5, FBD consolidates in the bad influence research sodium nitrite induced mice memory, and FBD is to consolidating the bad good improvement effect that has by memory due to the sodium nitrite, and its action intensity is like stronger than huperzine A.The result shows that FBD can effectively prevent and treat dysmnesia, and improves memory, improves normal person's memory ability.
6, the positive drug Radix Salviae Miltiorrhizae Injection is counted (with comparing p＜0.05 before the administration) with the site that the FBD group can obviously increase the pia mater encephali microcirculatory vascular.The result shows effectively microcirculation improvement of FBD.
7, FBD can suppress rat arteriovenous shut thrombosis, reduces wet weight of thrombus; FBD and positive drug Radix Salviae Miltiorrhizae Injection (3000mg/kg) have in various degree improvement to the blood fluidised form of rat brain microcirculation disturbance, showing as the hemocyte aggregation extent alleviates to some extent, become granular as the blood fluidised form by the stasis shape, or by granular band shape or the wire of becoming, or become wire by the dotted line shape, meninges blood capillary site counting is obviously increased.FBD also has the obvious suppression effect to AA and the inductive platelet aggregation of ADP, and collagen-induced platelet aggregation is not then had the obvious suppression effect.The result shows that FBD can effectively improve thrombosis, reduces wet weight of thrombus.
In Its Mechanisms, find:
1, in the experiment of rat arteriovenous shut thrombosis, FBD has inhibitory action to thrombosis, with the feminine gender group significant difference (P＜0.05) is arranged relatively.But its suppression ratio is less than positive drug aspirin (25mg/kg).
2, in the research of FBD to the influence of rat meninges microcirculation disturbance, Radix Salviae Miltiorrhizae group (3000mg/kg) and FBD can obviously increase the site counting (with comparing p＜0.05 before the administration) of pia mater encephali microcirculatory vascular after administration; The blood fluidised form has improvement in various degree.
3, in the research of FBD to the platelet aggregation influence, FBD can have significance ground to suppress ADP and the inductive platelet aggregation of AA, and collagen-induced platelet aggregation is not had obvious effect, and its action intensity all is lower than aspirin (25mg/kg).
Through the above-mentioned FBD of studies show that locality and global brain ischemia-reperfusion injury had the obvious treatment effect.The mechanism of its ischemia resisting brain injury may with suppress thrombosis, antiplatelet aggregation and microcirculation improvement, it is relevant to increase the brain blood flow.
The invention has the advantages that: the present invention has excavated new medical application to known Chinese medicine composition FBD, has opened up a new application.FBD safety non-toxic of the present invention, pharmacological action is strong, is indicating well prospect in medicine.FBD preparation technology of the present invention is simple, and can be made into various peroral dosage forms, as tablet, capsule etc.FBD of the present invention has the obvious treatment effect to locality and global brain ischemia-reperfusion injury, the mechanism of its ischemia resisting brain injury may with suppress thrombosis, antiplatelet aggregation and microcirculation improvement, it is relevant to increase the brain blood flow, and it consolidates the bad good improvement effect that has to memory.These effects help preventing and treating apoplexy, cerebral ischemia, dysmnesia, thrombosis and microcirculation disturbance.
Description of drawings
Fig. 1 is the sketch map of FBD duodenal administration to anesthetized dog cerebral vascular resistance influence;
Fig. 2 is the sketch map of FBD duodenal administration to anesthetized dog internal carotid artery flow effect;
Fig. 3 is the sketch map of FBD duodenal administration to the influence of anesthetized dog periphery mean arterial pressure;
Fig. 4 is the sketch map of FBD duodenal administration to the influence of anesthetized dog heart rate.
The specific embodiment
Below by test the example beneficial effect of the present invention is further elaborated:
1 FBD is to the thrombotic influence of arteriovenous shut for the test example
1.1 experiment purpose: observe given the test agent to the thrombotic influence of rat arteriovenous shut.
1.2 animal
Strain: SD rat source: Shanghai Si Laike laboratory animal responsibility company limited
Sex: male and female half and half body weight: the 200-240g animal quality certification number: SCXK (Shanghai) 2003-0003
Raise: animal feeding in positive pressure purification ventilation Animal House, 25 ± 2 ℃ of room temperatures, ad lib and drinking-water.
1.3 medicine
1.3.1 given the test agent
Title: Guiling tablets (FBD) source: Shanghai Traditional Chinese Medicine Pharmaceutical Technology Co., Ltd
Character: peony tablet lot number: 040904
Specification: 0.48g/ sheet
1.3.2 positive control sample
Title: aspirin source: Shanghai XinYi BaiLuDa Medicine Co., Ltd
Specification: 25mg/ sheet character: white enteric coatel tablets lot number: 030503
1.4 animal grouping
30 female, 30 male rats respectively are divided into 6 groups by the random digit method, 10 every group (5 female Mus, 5 male Mus) animals.
1.5 medicinal liquid preparation
I. aspirin:
The preparation of II.FBD medicinal liquid:
The FBD amount:
1.6 experimental technique
The 1st treated animal gives 0.5% tragakanta, and all the other 5 treated animals are by the medicinal liquid oral administration gavage administration that should give, and the administration volume is 0.5ml/100g, administration every day 1 time, continuous 5 days.After the last administration 1 hour, rats by intraperitoneal injection 3% pentobarbital sodium 35mg/kg anesthesia, it is fixing that rat is lain on the back, and cuts skin of neck, separates left carotid artery and right side external jugular vein, connects with a shunt valve, manages 4 long trumpeter's art silk threads of a mid-7cm.Operation finishes the open blood flow in back 15 minutes, takes out silk thread and weighs, and deducts silk thread weight, is wet weight of thrombus.
1.7 result
As seen from Table 1, compare the formation (P＜0.05 or 0.01) that FBD various dose group energy dose dependent ground suppresses rat artery-vein bypass thrombosis with the feminine gender group; 4.60,2.30,1.15 and 0.56 g/kg administration group is respectively thrombotic suppression ratio: 19.95,16.77,11.62 and 8.17%.The positive drug aspirin can suppress the formation (P＜0.01) of rat arteriovenous shut thrombosis very significantly, and suppression ratio reaches 36.58% (table 1).
Data with mean+SD (
) expression, the data difference statistics adopts the t check, and group difference is judged with P＜0.05.
Table 1.FBD is to the thrombotic influence of rat arteriovenous shut
| Group | Number of animals (only) | Wet weight of thrombus (mg) | Suppression ratio (%) |
| Negative |
10 10 10 | 43.71±4.32 27.72±4.01 ** 34.99±8.52 * | / 36.58 19.95 |
* P＜0.05, * * P＜0.01,
aP=0.05034 compares with negative control group
Test example 2 FBD are to the therapeutical effect of rat line bolt method focal cerebral ischemia-reperfusion injury
2.1 experiment purpose: observe FBD causes reperfusion injury after the focal cerebral ischemia in rats to line bolt method therapeutical effect.
2.2 animal
Strain: Wistar rat sex: male body weight: 250～350 grams
Source: the Shanghai Si Laike laboratory animal responsibility company limited animal quality certification number: SCXK (Shanghai) 2003-0003
Raise: constant-temperature purification ventilation Animal House, ad lib and drinking-water, 25 ± 2 ℃.
2.3 medicine
2.3.1 the same 1.3.1 of test specimen
2.3.2 positive control sample
Title: nimodipine source: Zhengzhou Rui Kang pharmaceutical factory
Lot number: 20030106 content: 101.29% character: light yellow crystalline powder
2.4 animal grouping
By the grouping of random digit method, 10 every group.
2.5 medicinal liquid preparation
I. nimodipine: the injection that is mixed with 20mg/ml with 95% ethanol
The II.FBD given the test agent preparation with 1.5
2.6 experimental technique
Get healthy male Wistar rat, body weight 250-350g, totally 50, be divided into 3 groups at random, the FBD sample is in ischemia gastric infusion after 2 hours, and the administration volume is 0.5ml/100g; Positive controls nimodipine administration volume is 0.01ml/100g, behind ischemia 2 hours from the rat tail vein drug administration by injection.Negative control group is given 0.5% tragakanta of equal volume.
Rat (after 350～400mg/kg), is lain on the back and is fixed on the operating-table with 12% chloral hydrate intraperitoneal anesthesia.Room temperature maintains about 25 ℃.Cut the right side skin of neck, separation, ligation right carotid, external carotid artery and bifurcated artery thereof.Separate right side internal carotid artery (ICA), branch's arteria pterygopalatina to visible its cranium in bubbling place, this branch of root ligation.Be equipped with line, far-end placement bulldog clamp at the ICA near-end, common carotid artery crotch otch, inserting diameter is nylon wire 17～20mm of 0.26mm, and the bolt line enters ICA, (MCA) initiating terminal that passes middle cerebral artery is to the anterior cerebral artery near-end, all blood flows sources of blocking-up MCA.Tighten line fully, after 4 hours, extract nylon wire, make its blood flow logical again, ligation is equipped with line and skin suture, administration in 2 hours behind ischemia, and the rat of will performing the operation divides cage to put back to Animal House.
Behind the ischemia 24 hours, carry out the neurological handicap scoring, methods of marking is: (1) carries about 1 chi of Mus tail built on stilts, observes the forelimb situation.Normal rat two forelimbs stretch to ground symmetrically.If left side shoulder inward turning is arranged, to receive phenomenon in the left fore and send out the survivor, scoring is 4 minutes, otherwise is 0 minute.(2) check the resistance that opposing promotes with pushing away a left side (or right) shoulder on the sliding floor of animal horizontalization respectively to side shifting.Normal rat bilateral resistance is obvious and symmetrical.If push away right shoulder when mobile to the left, find the resistance descender, according to the difference of decline degree, marking is the 1-3 branch.(3) animal two forelimbs are put on the wire netting, observed the muscular tension of two forelimbs.Normal rat two forelimb tension force are obvious and symmetrical.And left fore tension force descender takes place, be chosen as the 0-3 branch according to the weight of decline degree.According to above standard marking, full marks 10 minutes.Scoring finishes, and broken end is got brain.Crownly be divided into 5 with brain is average, be put in the TTC solution 37 ℃ of incubation 10～15min dyeing.Infarcted region is not painted, and normal cerebral tissue dyes redness.With digital photographing behind the normal saline flushing, digital photograph utilizes every infarcted region sectional area of computer measurement and full brain sectional area, calculates infarct size percentage ratio.
2.7 result
FBD group and positive control drug nimodipine all have the obvious treatment effect to focal cerebral ischemia-reperfusion injury that rat line bolt method middle cerebral artery causes, compare with negative control group, brain necrosis percentage ratio is obviously reduced, and animal nerve is learned defective and is significantly improved.Effect and dosage that FBD organizes anti-locality ischemia reperfusion injury are tangible positive correlation (table 2).
Table 2.FBD is to the influence of rat line bolt method brain locality ischemia-reperfusion injury model
| Group | n | The neurological handicap scoring | Brain necrosis percentage ratio |
| Negative group nimodipine FBD | 9 9 9 | 7.9±1.9 5.6±1.7 * 4.2±0.4 ** | 21.98±9.50 10.77±9.14 * 1.42±1.00 ** |
*P＜0.05,
*Compare with negative group P＜0.01
The pharmacodynamic study of the anti-mice global brain ischemia of test example 3 FBD effect
3.1 experiment purpose: by the preventive effect of mice broken end global brain ischemia scale-model investigation FBD to global brain ischemia, and to the improvement effect of ischemia brain hypoxia-bearing capability.
3.2 animal
Strain: Kunming mouse sex: male and female half and half body weight: 20-22g
The source: Shanghai Institute of Pharmaceutical Industry's Animal House provides the animal quality certification number: SYXK (Shanghai) 2004-0015
Raise: animal feeding in positive pressure purification ventilation Animal House, 25 ± 2 ℃ of temperature, ad lib and drinking-water.
3.3 medicine
3.3.1 the same 1.3.1 of test specimen
3.3.2 the same 2.3.2 of control sample
3.3.3 other reagent
3.3.3.1 title: total protein is measured test kit
Source: Shanghai claim reagent company limited Shanghai Vaccine and Serum Institute lot number: 20040702
3.3.3.2 title: malonaldehyde (MDA) is measured test kit
The source: bio-engineering research institute lot number is built up in Nanjing: 20041013
3.3.3.3 title: superoxide dismutase (SOD) testing cassete
The source: bio-engineering research institute lot number is built up in Nanjing, Nanjing: 20041015
3.4 experimental apparatus
3.4.1 title: 3K30 high-speed low temperature refrigerated centrifuger source: German Sigma company
The ultrasonic cell pulverization machine of 3.4.2 title: JY92-II source: Ningbo Xin Zhike device institute
3.4.3 title: 80-2 type centrifuge source: Shanghai Surgical Operation Equipment Factory
3.4.4 title: 722 grating spectrophotometers source: Shanghai the 3rd analytical tool factory
3.5 animal grouping
Mice by the grouping of random digit method, is cooked totally 3 groups that SOD and MDA measure, every group of 10 animals; Survey broken end frequency of respiration, totally 3 groups, every group of 16 animals, all male and female half and half.
3.6 medicinal liquid preparation
The preparation of I.FBD medicinal liquid:
FBD：
II. nimodipine:
3.7 experimental technique
Each group all shifts to an earlier date 2 days gastric infusions, administration volume 0.2ml/10g body weight.Administration begins the back and gave laboratory sample the 3rd time on the 3rd day, and after administration 1 hour, with sharp shears the head of mice is cut in the lump together with the cerebellum brain stem, and is picked up counting in cutting at once, and record breaks end time of mouth breathing.The ice bath that will break end peels brain and cerebellum, weighs, and puts into the good centrifuge tube of ice bath in advance.According to the dilution ratio of 1.9ml ice normal saline/100mg brain,, two seconds, make 5% brain tissue homogenate, and also keep ice bath for 10 times in the ultransonic while with ultrasonic cell pulverization machine 140W.With tissue homogenate on refrigerated centrifuge with 4 ℃, centrifugal 30 minutes of 2700g.The careful supernatant of drawing is measured tissue homogenate total protein, SOD, MDA.Total protein is measured kit measurement with total protein, and 722 spectrophotometer 550nm measure absorbance, and the total protein computing formula is as follows:
SOD and MDA use SOD and MDA kit measurement respectively.It is a SOD unit of activity (U) that every milligram of histone SOD suppression ratio in the 1ml reactant liquor reaches 50% o'clock pairing SOD amount.The computing formula that 722 spectrophotometer 550nm measure absorbance SOD is as follows:
MDA measures according to measuring the description operation, and 722 spectrophotometer 532nm measure absorbance.The computing formula of MDA is as follows:
3.8 result
3.8.1 influence to the mouth breathing time
After each organizes mice broken end, all experience one from fierce mouth breathing to static relatively to the last for several times dead process of mouth breathing once more.Experimental result sees Table 3.
The negative group mouth breathing time is 20.6 ± 2.7 seconds; The positive controls nimodipine 5mg/kg mouth breathing time is 23.1 ± 3.4 seconds, relatively has significance to increase (p＜0.05) with the feminine gender group.The FBD low dose group mouth breathing time is 19.8 ± 1.9 seconds; In the dosage group mouth breathing time be with negative group prolongation to be arranged more slightly in 21.3 ± 3.6 seconds.The high dose group mouth breathing time is 22.9 ± 5.3 seconds, has relatively prolonged about 2 seconds with the feminine gender group.
Nimodipine can make the mice broken end global brain ischemia model mouth breathing time significantly increase.The FBD high dose has certain prolongation effect to the mice broken end global brain ischemia model mouth breathing time, but does not relatively have significant difference (table 3) with the feminine gender group.
Data with mean+SD (
) expression, the data difference statistics adopts the t check, and group difference is judged with P＜0.05.
Table 3.FBD is to the mice influence of broken end global brain ischemia model mouth breathing time
| Group | n | The mouth breathing time (s) |
| Negative group nimodipine | 16 16 | 20.4±2.7 23.0±3.3 * |
| FBD | 16 | 22.9±5.1 |
* p＜0.05, * * p＜0.01, with the feminine gender group relatively.
3.8.2 influence to SOD and MDA
Each is organized cerebral tissue and all handles according to experimental technique, and measures absorbance, measures total protein content and MDA content and SOD vigor respectively.Measurement result sees Table 4.
Negative group MDA content is 3.11 ± 0.43nmol/mgprot, with the relatively all not significantly rising and the reductions (relatively not having significant difference with the feminine gender group) of MDA value of each group of feminine gender group.Negative group SOD content is 59.48 ± 27.00U/mgprot, and the nimodipine group is 83.72 ± 17.08U/mgprot (P＜0.05), the significance nearly 23U/mgprot that raise.FBD group SOD content is 83.98 ± 21.25U/mgprot (P＜0.05), also the significance nearly 24U/mgprot that raise; Nimodipine does not obviously influence broken end MDA content, but the SOD vigor significance in the cerebral tissue is raise.(table 4).
Table 4.FBD is to the influence of mice broken end global brain ischemia model M DA content and SOD vigor.
| Group | n | Total protein content (mg/ml) | MDA content (nmol/mgprot) | SOD vigor (U/mgprot) |
| Negative |
10 10 10 | 1.87±0.53 1.53±0.63 1.42±0.71 | 3.11±0.43 3.57±0.85 3.06±0.56 | 59.48±27.00 83.72±12.08 * 83.98±21.25 * |
* p＜0.05, * * p＜0.01, with the feminine gender group relatively
The anti-four artery occlusion global brain ischemia reperfusion injury pharmacodynamic studies of test example 4 FBD
4.1 experiment purpose: observe the preventive effect of FBD to four artery occlusion rat whole brain ischemical reperfusion injuries.
4.2 animal
Strain: Wistar rat sex: male body weight: 250～270g
Source: the Shanghai Si Laike laboratory animal responsibility company limited animal quality certification number: SCXK (Shanghai) 2003-0003
Raise: constant-temperature purification ventilation Animal House, ad lib and drinking-water, 25 ± 2 ℃.
4.3 medicine
4.3.1 the same 1.3.1 of test specimen
4.3.2 the same 2.3.1 of positive control sample
4.4 experimental apparatus
4.4.1 title: SW-30 radio frequency bipolar coagulator source: detecting instrument factory of Shanghai Detecting Technology Inst.
Physiology monitor source, 4.4.2 title: SJ-42 four road: Shanghai Medical Electric Instrument Factory
4.5 animal grouping
50 male rats respectively are divided into 5 groups by the random digit method, 10 every group.
4.6 medicinal liquid preparation
I. nimodipine: the injection that is mixed with 10mg/ml with 0.5% tragakanta
The II.FBD given the test agent preparation with 1.5
4.7 experimental technique
Get healthy male Wistar rat, body weight 250-350g divides negative matched group, FBD group and positive nimodipine group.In preceding 1 hour gastric infusion of ischemia, volume is 0.5ml/100g.Animal with 12% chloral hydrate intraperitoneal anesthesia (350mg/kg), is exposed the atlas transverse foramen behind pillow, aim at transverse foramen with bipolar coagulation and fulgerize and solidify the bilateral vertebral artery.Make a kerf at cervical region then and expose bilateral carotid arteries, after the separation, put on No. 1 silk thread standby, sew up wound.In postoperative 24 hours, when rat regains consciousness, the bilateral carotid arteries folder is closed with the bulldog clamp of band silica gel tube, promptly cause the inaccessible global brain ischemia of 4 radicular arterieses, take out bulldog clamp and can make blood flow logical again, be perfusion phase again.This experiment ischemia is with the filling time is 1 hour again.Electroencephalogram does not disappear or severe inhibition occurs and rejects without exception in all ischemias 1 hour.Observation index is electroencephalogram extinction time behind the ischemia, irritates back electroencephalogram recovery time and righting reflex recovery time.All data are all used
Expression, statistical analysis is checked with t.
4.8 experimental result
As can be seen from Table 5, compare with the feminine gender group, FBD group can the lengthening model rat ischemia after the electroencephalogram extinction time, shorten the back electroencephalogram recovery time of perfusion again and righting reflex recovery time, effect and dosage are proportionate.Compare with the feminine gender group, the positive drug nimodipine also can make perfusion back electroencephalogram recovery time and righting reflex obviously shorten (P＜0.05 or P＜0.01) (table 5) recovery time.
Table 5.FBD to global brain ischemia pour into again the electroencephalogram of rat and behavioristics's influence (
)
| Group | n | Electroencephalogram extinction time (S) | Electroencephalogram recovery time (S) | Righting reflex recovery time (S) |
| Negative |
10 10 10 | 66±34 78±35 169±110 *△ | 1221±1359 173±143 * 104±86 * | 2376±1335 784±433 ** 292±176 ***△△ |
*P＜0.05,
*P＜0.01,
* *Compare with negative control group P＜0.001;
△P＜0.05,
△ △Compare with the nimodipine group P＜0.01;
Test example 5 FBD are to the research of anesthetized dog periphery and cerebral blood flow influence
5.1 experiment purpose: observe of the influence of FBD duodenal administration to anesthetized dog heart rate, peripheral arterial blood pressure, peripheral arterial and cerebral arteries flow and cerebral vascular resistance.
5.2 animal
Strain: hybrid dog sex: male and female dual-purpose
Body weight: 10.1 ± 0.7kg source: Shanghai Institute of Pharmaceutical Industry's Animal House
5.3 medicine
5.3.1 the same 1.3.1 of test specimen
5.3.2 the same 2.3.2 of control sample
5.3.3 other medicine
Heparin sodium: 140U/mg, Chinese Medicine (group) Shanghai chemical reagent head factory lot number: F20020930
5.4 key instrument
5.4.1 title: Elama Minogograf-82 type eight is led the physiograph source: Siemens Company
5.4.2 title: MFV-2100 electromagnetic flowmeter source: Japanese photoelectricity company
5.4.3 title: GPS-2 type high frequency electro surgical unit source: Wujin, Jiangsu radio factory
5.5 animal grouping
Every group 6.Convert out the dosage of dog according to the rat effective dose.
5.6 medicinal liquid preparation
The preparation of I.FBD medicinal liquid:
FBD：
II. nimodipine:
5.7 experimental technique
Dog is anaesthetized with 3% pentobarbital sodium 30mg/kg intravenous injection.The animal dorsal position is fixed on the operating-table, separates femoral vein in right side groin place, insert conduit and make transfusion usefulness, separate the right common femoral artery intubate, connect pressure transducer, measure the periphery blood pressure.Separate the left side femoral artery, in order to measuring the peripheral arterial blood flow.Separate the crotch of right carotid artery up to external carotid artery and internal carotid artery, the ligation external carotid artery, internal carotid artery is continued to employ, and electromagnetic flowmeter is hooked on the common carotid artery of homonymy in order to measuring the blood flow of internal carotid artery.Cut off the about 5cm of animal abdominal part from ventrimeson, find duodenum, and make pocket, intubate is in order to administration.Treat to stablize 30min behind the animal surgery, medicine gives from duodenum, and administration time is 1min.Observed after the administration 3 hours, respectively 5,10,15,30 and 60,90,120,180 minutes record animal electrocardiograms and peripheral arterial blood flow and ICAF amount and blood pressure before administration and after the administration.Negative control group in kind gives 0.5% tragakanta, 1ml/kg.Put to death dog in 180 minutes after the administration, get brain and weigh.Multiply by 2 representative full cerebral blood flows (CBF) with the right common carotid artery blood flow.The available following formula of cerebral vascular resistance (R) calculates:
R=MAP (kPa)/[CBF (ml/min) 100g brain].Test data measures from record.The MAP computing formula is 1mmHg=0.1333KPa
The experimental data mean+SD (
) expression.Experimental result statistics with after the administration with before the administration
Changing value and negative control group are carried out the t check with the changing value of time point
5.8 experimental result
The FBD duodenal administration sees Table 6-12 to the influence of anesthetized dog heart rate, blood pressure, periphery and cerebral blood flow and cerebral vascular resistance, Fig. 1-4.
Negative group, periphery blood pressure steady change is little, and As time goes on heart rate decreases, and peripheral blood flow and brain blood flow all reduce gradually, so the cerebral vessels resistance increases gradually.
Nimodipine group peripheral blood flow 12min and 120min significance after administration increase, after administration 30,60,90, the equal highly significant increase of 180min.And give carotid artery flow behind the nimodipine highly significant increase in the 10th, 15 minute, and increase at 30-180 minute significance.The 15-180 minute equal significance that the while peripheral blood is pressed in after the administration reduces, peripheral arterial diastolic pressure particularly, 15min significance after giving nimodipine reduces, in the equal highly significant reduction of 30-180min afterwards (rate of change of organizing same time point with feminine gender compares).Heart rate after administration 5,60,90min is that significance reduces, in the reduction of 15min highly significant.The 5min significance of cerebral vessels resistance after administration reduces, in the equal highly significant reduction of 10-180min.
The FBD duodenum gives behind the anesthetized dog periphery arterial flow and blood pressure and cerebral vessels resistance all less than significantly influence, the 30min after administration only, its brain blood flow has certain increase, 30min after administration, vascular resistance has the highly significant reduction, but the absolute value that reduces and few.
Therefore FBD has certain reduction cerebral vessels resistance to anesthetized dog, increases the effect of brain blood flow, and the periphery blood pressure of animal is also had the effect of similar nimodipine: reduce periphery blood pressure, particularly diastolic pressure; Decreased heart rate.But action intensity and action time are all less than nimodipine.30min was the most obvious after the FBD duodenal administration acted on administration to the improvement of brain blood flow.
Table 6.FBD duodenal administration to the influence of anesthetized dog peripheral arterial blood flow (n=6,
)
| Sample | The femoral artery flow | Before the administration | After the administration (min) |
| (ml/min) | 0 | 5 | 10 | 15 | 30 | 60 | 90 | 120 | 180 | |
| Negative control | Mean variation % | 26.3±17.6 - | 27.2± 22.9 -2.2± 12.5 | 24.7± 18.9 -10.1± 12.8 | 24.7± 19.9 -12.1± 14.7 | 22.7± 11.9 -9.1± 17.9 | 20.5± 9.7 -12.5± 28.0 | 23.5± 12.5 -4.4± 28.9 | 24.5± 11.3 5.4± 41.7 | 21.3± 10.8 -11.7± 25.9 |
| FBD | Mean variation % | 29.8±14.6 - | 28.5± 14.0 -2.1± 16.2 | 28.2± 14.0 -3.3± 15.6 | 29.7± 16.2 1.5± 24.6 | 29.2± 17.2 0.7± 28.5 | 24.0± 14.6 -15.8± 27.0 | 21.8± 9.5 -19.2± 28.4 | 22.2± 8.8 -16.4 ±31.5 | 20.7± 6.2 -20.6± 31.3 |
| Nimodipine | Mean variation % | 31.3±13.6 - | 25.5± 9.8 -14.8± 15.1 | 33.5± 18.5 5.1± 24.8 | 41.2± 21.3 26.3± 32.7 * | 54.7± 28.7 69.9± 56.0 ** | 57.5± 27.8 78.8± 35.5 ** | 57.5± 29.6 79.0± 57.7 ** | 56.2± 27.7 75.7± 53.7 * | 57.0± 27.5 79.7± 55.1 ** |
*P＜0.05,
*Compare with negative group P＜0.01
Table 7.FBD duodenal administration to the influence of anesthetized dog cerebral artery blood flow amount (n=6,
)
| Sample | Internal carotid artery flow (ml/min) | Before the administration | After the administration (min) | |||||||
| 0 | 5 | 10 | 15 | 30 | 60 | 90 | 120 | 180 | ||
| Negative control | Mean variation % | 31.0±13.1 - | 30.5± 12.5 -1.4± 2.3 | 30.0± 13.0 -3.7± 4.6 | 29.7± 13.6 -5.4± 5.8 | 27.7± 12.9 -12.0± 5.0 | 26.8± 13.5 -15.2± 7.3 | 25.7± 12.8 -18.6± 8.0 | 26.0± 12.8 -17.4± 9.1 | 24.5± 11.7 -22.0± 7.3 |
| FBD | Mean variation % | 38.0±20.9 - | 38.0± 20.9 -0.5± 1.3 | 38.7± 21.2 2.1± 5.3 | 38.3± 21.0 2.3± 9.8 | 39.2± 21.3 5.8± 13.5 * | 37.3± 21.2 -1.8± 7.3 * | 35.5± 19.9 -6.1± 7.7 * | 34.8± 20.6 -8.3± 11.0 | 33.8± 21.0 -11.1± 12.3 |
| Nimodipine | Mean variation % | 21.3±5.7 - | 25.3± 9.7 9.0± 17.7 | 39.3± 12.4 62.7± 42.69 ** | 40.5± 12.5 77.6± 55.5 ** | 33.0± 11.3 54.9± 62.9 * | 29.5± 13.5 42.5± 47.7 * | 28.7± 12.5 38.8± 44.8 * | 28.2± 13.2 36.8± 47.1 * | 26.7± 10.8 31.4± 49.0 * |
*P＜0.05,
*Compare with negative group P＜0.01
Table 8.FBD duodenal administration to the influence of anesthetized dog tremulous pulse mean pressure (n=6,
)
| Sample | Femoral blood pressure (mmHg) | Before the administration | After the administration (min) | |||||||
| 0 | 5 | 10 | 15 | 30 | 60 | 90 | 120 | 180 | ||
| Negative control | Mean variation % | 140.0±29.0 - | 141.7± 35.0 0.4± 5.2 | 140.8± 34.6 -0.2± 5.6 | 142.8± 31.5 1.8± 2.8 | 139.7± 28.5 -0.2± 1.7 | 139.2± 27.3 0.1± 9.7 | 139.5± 27.0 0.7± 12.9 | 140.3± 18.9 1.9± 0.9 | 44.2± 25.6 4.1± 10.6 |
| FBD | Mean variation % | 160.8±27.5 - | 160.8± 19.3 0.9± 6.6 | 166.7± 25.0 4.3± 7.6 | 160.8± 25.0 0.3± 4.1 | 164.2± 24.0 2.6± 5.0 | 62.5± 29.8 0.9± 5.5 | 161.2± 18.1 1.3± 8.8 | 160.0± 20.0 0.5± 9.3 | 156.7± 20.7 -1.5± 10.4 |
| Nimodipine | Mean variation % | 148.3±17.8 - | 141.7± 14.7 0.6± 5.0 | 120.8± 21.5 7.5± 11.0 | 110.0± 5.5 -15.2± 12.7 * | 96.7± 21.6 -26.1± 18.1 ** | 97.5± 22.1 -29.8± 14.2 ** | 97.5± 25.8 -30.6±1 8.0 ** | 100.8± 24.8 -27.1± 16.2 ** | 103.3± 27.5 -28.6± 17.6 ** |
*P＜0.05,
*Compare with negative group P＜0.01
Table 9.FBD duodenal administration to the influence of anesthetized dog systolic arterial pressure (n=6,
)
| Sample | Femoral blood pressure (mmHg) | Before the administration | After the administration (min) | |||||||
| 0 | 5 | 10 | 15 | 30 | 60 | 90 | 120 | 180 | ||
| Negative control | Mean variation % | 170.8±31.1 - | 167.5± 34.0 -2.2± 3 | 173.3± 34.9 1.2± 5.4 | 170.8± 31.7 0.0± 5.4 | 168.3± 29.1 -0.7± 4.7 | 168.3± 30.1 -1.1± 7.8 | 171.7± 27.3 0.9± 6.5 | 175.0± 23.7 3.5± 8.5 | 173.3± 20.4 2.7± 8.4 |
| FBD | Mean variation % | 203.3±20.2 - | 199.2± 15.0 -1.8± 4.0 | 220.8± 36.4 9.0± 18.5 | 198.3± 13.7 -2.2± 3.3 | 205.8± 15.0 1.6± 6.6 | 205.0± 15.5 1.1± 4.1 | 200.0± 8.4 -1.1± 7.5 | 198.3± 8.8 -1.8± 9.6 | 192.5± 13.3 -4.7± 10.5 |
| Nimodipine | Mean variation % | 185.8±19.3 - | 179.2± 17.7 -0.3± 4.0 | l71.7± 23.6 -2.4± 7.7 | 60.8± 20.8 -8.7± 7.0 * | 145.0± 27.6 -17.0± 11.1 ** | 44.2± 35.8 -18.6± 16.2 * | 153.3± 32.4 -16.3± 14.7 * | 154.2± 29.2 -13.5± 14.5 * | 51.7± 23.2 -16.5± 11.3 ** |
*P＜0.05,
*Compare with negative group P＜0.01
The influence that table 10FBD duodenal administration is pressed the anesthetized dog auterial diastole (n=6,
)
| Sample | Femoral artery | Before the administration | After the administration (min) |
| Blood pressure (mmHg) | 0 | 5 | 10 | 15 | 30 | 60 | 90 | 120 | 180 | |
| Negative control | Mean variation % | 128.3±27.9 - | 129.2± 33.2 -0.1± 5.2 | 126.7± 31.1 -1.9± 5.3 | 128.3± 32.8 -0.8± 6.0 | 123.3± 32.2 -4.8± 7.3 | 130.0± 32.1 0.8± 9.4 | 130.0± 30.3 0.9± 7.8 | 133.3± 25.2 4.6± 6.0 | 135.8± 26.7 6.5± 6.0 |
| FBD | Mean variation % | 143.3±29.1 - | 140.0± 24.1 -1.7± 3.7 | 150.0± 28.3 5.4± 8.2 | 143.3± 28.6 0.1± 2.4 | 145.8± 30.2 2.0± 10.1 | 141.7± 33.1 -1.6± 6.7 | 140.8± 25.4 -1.0± 6.8 | 143.3± 24.4 1.2± 11.1 | 141.7± 25.4 0.1± 12.4 |
| Nimodipine | Mean variation % | 129.2±20.8 - | 125.0± 17.6 0.6± 7.4 | 95.8± 25.2 -14.5± 15.9 | 85.0± 21.2 -22.0± 16.3 * | 73.3± 22.3 -32.2± 18.2 ** | 77.5± 21.4 -29.0± 15.5 ** | 72.5± 27.7 -34.2± 20.4 ** | 78.3± 25.4 -30.7± 19.5 ** | 82.5± 31.7 -29.4± 20.7 ** |
*P＜0.05,
*Compare with negative group P＜0.01
Table 11.FBD duodenal administration to the influence of anesthetized dog heart rate (n=6,
)
| Sample | Heart rate (inferior/minute) | Before the administration | After the administration (min) | |||||||
| 0 | 5 | 10 | 15 | 30 | 60 | 90 | 120 | 180 | ||
| Negative control | Mean variation % | 155.8±36.0 - | 155.0± 35.7 -0.5± 0.9 | 153.3± 36.5 -1.7± 3.8 | 155.7± 34.2 0.4± 6.5 | 157.3± 35.5 1.4± 8.5 | 153.5± 30.1 -0.3± 12.2 | 151.2± 29.1 -2.0± 9.7 | 152.8± 30.8 -1.0± 11.0 | 149.0± 32.8 -3.7± 10.6 |
| FBD | Mean variation % | 147.0±35.3 - | 147.2± 38.5 -0.3± 3.4 | 149.5± 36.1 1.8± 4.6 | 147.2± 36.1 0.2± 6.3 | 148.2± 35.6 1.0± 6.1 | 142.7± 40.4 -3.5± 7.9 | 137.3± 41.0 -7.1± 12.4 | 132.5± 43.7 -11.2± 13.3 | 133.0± 36.0 -9.6± 10.7 |
| Nimodipine | Mean variation % | 143.3±23.6 - | 145.7± 22.0 1.9± 1.9 * | 139.0± 27.4 -3.0± 8.1 | 130.8± 23.9 -8.5± 7.9 | 119.7± 20.2 -16.1± 8.5 ** | 116.5± 22.7 -18.4± 11.2 * | 116.8± 25.3 -18.2± 13.4 * | 117.5± 24.4 -17.5± 14.5 | 118.0± 22.7 -16.9± 14.6 |
*P＜0.05,
*Compare with negative group P＜0.01
Table 12.FBD duodenal administration to the influence of anesthetized dog cerebral vascular resistance (n=6,
)
| Sample | Cerebral vascular resistance kPa/ (the 100g of ml/min) | Before the administration | After the administration (min) | |||||||
| 0 | 5 | 10 | 15 | 30 | 60 | 90 | 120 | 180 | ||
| Negative control | Mean variation % | 0.42±0.10 - | 0.43± 0.10 2.0± 6.0 | 0.44± 0.11 3.7± 5.5 | 0.46± 0.11 7.9± 6.1 | 0.49± 0.13 13.7± 6.8 | 0.52± 0.18 19.5± 21.2 | 0.55± 0.19 25.4± 23.5 | 0.54± 0.16 25.0± 21.4 | 0.58± 0.17 35.2± 24.4 |
| FBD | Mean variation % | 0.48±0.28 - | 0.50± 0.33 0.9± 6.6 | 0.50± 0.31 1.6± 4.7 | 0.46± 0.24 -2.0± 6.1 | 0.46± 0.23 -2.1± 10.1 ** | 0.49± 0.27 2.7± 8.8 | 0.53± 0.34 7.9± 12.2 | 0.55± 0.35 10.5± 17.7 | 0.55± 0.34 12.6± 19.1 |
| Nimodipine | Mean variation % | 0.72±0.31 - | 0.64± 0.33 -14.0± 16.4 * | 0.35± 0.18 -52.5± 16.4 ** | 0.29± 0.15 -59.6± 11.2 ** | 0.30± 0.15 -56.8± 12.6 ** | 0.35± 0.19 -50.4± 16.4 ** | 0.34± 0.15 -49.4± 18.9 ** | 0.37± 0.18 -45.1± 22.5 ** | 0.40± 0.21 -40.6± 25.9 ** |
*P＜0.05,
*Compare with negative group P＜0.01
Test example 6 FBD are to the influence of cerebral microcirculation disturbance
6.1 experiment purpose: observe the influence of FBD, inquire into its treating cerebral ischemia mechanism to rat meninges microcirculation disturbance.
6.2 animal
Strain: SD rat sex: male body weight: 240～260g
Source: the Shanghai Si Laike laboratory animal responsibility company limited animal quality certification number: SCXK (Shanghai) 2003-0003
Raise: constant-temperature purification ventilation Animal House, ad lib and drinking-water, 25 ± 2 ℃.
6.3 medicine
6.3.1 the same 1.3.1 of test specimen
6.3.2 positive control sample
Title: Radix Salviae Miltiorrhizae Injection source: Shanghai Westen and Chinese Tranditional Medicine Pharamacentic Co., Ltd
Lot number: 030305 content: 3g/2ml character: weak yellow liquid
6.4 experimental apparatus
6.4.1 title: 307-6 table electric dental engine car source: Shanghai Dental Medical Apparatus and Instrument Factory
6.4.2 title: SXP-1B operating microscope source: Shanghai medical optical instrument factory
6.4.3 title: SQF-E anatomic microscope source: Shanghai Wanke Instrument Co., Ltd.
6.4 animal grouping
48 male rats respectively are divided into 6 groups by the random digit method, 8 every group.
6.6 medicinal liquid preparation
I. Radix Salviae Miltiorrhizae: stock solution is used
The II.FBD given the test agent preparation with 1.5
6.7 experimental technique
FBD injects back 20 minutes gastric infusions in macromolecule right rotary glycoside, and the administration volume is 0.5ml/kg.Radix Salviae Miltiorrhizae Injection is injected tail vein injection administration in back 20 minutes in macromolecule right rotary glycoside, and the administration volume is 2ml/kg.
With rat with 3% pentobarbital sodium 40mg/kg intraperitoneal anesthesia, make the skull windowing, cut off cerebral dura mater and expose the Interhemispheric E Ding of side district, observe the pia mater encephali microcirculation with anatomic microscope, after observing the pia mater encephali microcirculation, from macromolecule right rotary glycoside (the molecular weight 500,000) normal saline solution of vena femoralis injection 10%, dosage 15ml/kg, sham operated rats is given the normal saline of 15ml/kg, observes the pia mater encephali microcirculation in back 20 minutes in injection and changes.When confirming to have caused microcirculation disturbance (slow blood flow, hemocyte is assembled), again according to the grouping drug treatment, 60min after administration observes the microcirculation situation.Observation index is as follows:
1. fluidised form: erythrocytic fluidised form can be divided into 4 grades: 0 grade, and straight line (band) shape; The I level, the dotted line shape; The II level, granular; The III level, the stasis shape.
2. blood capillary site counting: get area and be about fixed area (this zone surrounds the border by blood vessel) about 1 square millimeter, calculate the number of hits of blood capillary and border (blood vessel) in this zone.The blood capillary that intersects with the border does not count.
3. color: observe color, divide scarlet, dark red, light red etc.
4. the variation around the blood capillary: mainly observe to have or not around the blood capillary and ooze out and bleeding.The site enumeration data is used
Expression, statistical analysis is checked with t.The credit that do not take statistics of other qualitative response data is analysed.
6.8 experimental result
Meninges microcirculation change of flow state: matched group and each treated animal of experiment are behind the injection macromolecule right rotary glycoside, and the blood fluidised form has abnormal change.The blood fluidised form becomes dotted line shape, granular by normal band shape, wire, even becomes the stasis shape, and the negative control treated animal is behind injecting normal saline, and the blood fluidised form is not seen improvement.And Radix Salviae Miltiorrhizae group and FBD various dose group are after administration, the blood fluidised form has improvement in various degree, shows as the hemocyte aggregation extent and alleviates to some extent, becomes granular as the blood fluidised form by the stasis shape, or by granular band shape or the wire of becoming, or become wire (table 14) by the dotted line shape.
Color changes: matched group and each treated animal of experiment are behind the injection macromolecule right rotary glycoside, and color changes with comparing originally not have obviously.
Variation around the blood capillary: test each treated animal behind injection macromolecule right rotary glycoside and sample, with compared blood capillary originally around do not see and ooze out with hemorrhage.
Capillary network changes before and after the administration: table 13 shows that the positive drug Radix Salviae Miltiorrhizae Injection is counted (with comparing p＜0.05 before the administration) with the site that the FBD group can obviously increase the pia mater encephali microcirculatory vascular.
The influence that table 13.FBD various dose group is counted meninges blood capillary site (
, n=10)
| Group | The preceding site of blood stasis counting | Treat preceding site counting | Site, treatment back counting |
| The negative group of normal group Radix Salviae Miltiorrhizae FBD | 5.10±0.74 5.00±0.47 5.20±0.63 5.00±0.67 | 5.10±0.74 3.60±0.70 ** 3.80±1.03 ** 3.70±0.67 ** | 5.10±0.74 3.60±0.70 4.80±0.92 △ 4.70±0.82 △ |
*P＜0.05,
*Compare before p＜0.01 and the blood stasis;
△P＜0.05,
△ △P＜0.01 with the treatment before compare
Table 14.FBD various dose group is to the influence of brain microcirculation fluidised form
| Group | 0 | I | II | III | ||||
| Before | After | Before | After | Before | After | Before | After | |
| |
10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 |
| |
0 | 0 | 0 | 0 | 5 | 5 | 5 | 5 |
| |
0 | 2 | 0 | 3 | 4 | 5 | 6 | 0 |
| |
0 | 4 | 0 | 3 | 5 | 3 | 5 | 0 |
Test example 7 FBD are to the influence of platelet aggregation
7.1 experiment purpose: observe the influence of FBD to platelet aggregation.
7.2 animal
Strain: SD rat sex: male body weight: 250～270 grams
Source: the Shanghai Si Laike laboratory animal responsibility company limited animal quality certification number: SCXK (Shanghai) 2003-0003
Raise: constant-temperature purification ventilation Animal House, ad lib and drinking-water, 25 ± 2 ℃.
7.3 medicine
7.3.1 the same 1.3.1 of test specimen
7.3.2 positive control sample
Title: Aspirin Enteric-coated Tablets source: Bayer HealthCare AG
Specification: 100mg/ sheet lot number: BTA4E31 character: white tablet
7.3.3 other reagent
7.3.3.1 title: ADP source: Sigma company lot number: 129F0496
7.3.3.2 title: AA (arachidonic acid) source: Fluka company lot number: 31,817,5/1 193
7.3.3.3 title: collagen
Source: Trinity Biotech Plc, Bray, Co.Wicklow, Treland. company
Lot number: 20050114
7.4 experimental apparatus
7.4.1 title: 80-2 type centrifuge source: Shanghai Surgical Operation Equipment Factory produces
7.4.2 title: MK4/HC platelet count instrument source: U.S. Baker Instruments company
7.4.3 title: Labor aggregometer-153 type two pass platelet aggregation instrument
Source: German Labor GmbH Hanburg company
7.5 animal grouping
Every group of 10-12 only.
7.6 medicinal liquid preparation
I. aspirin:
The II.FBD given the test agent preparation with 1.5
The III.ADP:pH7.4 phosphate buffer is made into 200 μ M concentration solution, and-20 ℃ of refrigerators are preserved standby.
AA:0.1M Na
2CO
3Buffer is made into 0.5mmol/L concentration solution, and-18 ℃ of refrigerators are preserved standby.
Collagen: preparation sign amount 2.0mg/ml, 2～8 ℃ of refrigerators are preserved, and white injectable powder faces with preceding and dissolves with distilled water, and 0.5ml/ props up, and is now with the current.
7.7 experimental technique
The trial drug single oral is irritated stomach, and volume is 5ml/kg, and negative control group gives with the volume tragakanta.Lumbar injection pentobarbital sodium 45mg/kg anesthesia in 1 hour after the oral administration gavage administration, it is fixing to lie on the back, the ventral aorta blood sampling,, with 500rpm centrifugal 5 minutes, get top blood plasma and be platelet rich plasma (PRP) in ratio anticoagulant in 1: 9 with 3.8% sodium citrate, remaining part centrifugal 15 minutes once more with 3000rpm, supernatant is platelet poor plasma (PPP), with platelet count instrument counting PRP platelet count, adjusts platelet count to 6 * 10 of PRP with PPP
5Individual/mm
3About.In testing tube, add PRP200 μ l, regulate monitor, put into instrument connection with a PPP pipe in addition to zero point, adjusting gain to the monitor stroke be 60 lattice, as 100%.37 ℃ of insulations of sample cell began to stir 1 minute after 2 minutes, and stirrer rotating speed 500rpm adds ADP 5 μ l or AA 4 μ l or collagen 8 μ l again, and making the ADP final concentration is 5 μ M; AA concentration is 4 μ M; Collagen concentration is 8 μ M; , record adds the stroke that the pen behind ADP or AA or the collagen moves, and is calculated as follows aggregation rate:
Calculate the average aggregation rate and the standard deviation of each test group, compare with the tragakanta group with the t-check.And be calculated as follows the gathering suppression ratio of each test group:
7.8 experimental result
Experimental result shows that positive drug aspirin (25mg/kg) all has the inhibitory action (P＜0.001) of highly significant to ADP, collagen, the inductive platelet aggregation of AA.
FBD all has inhibitory action to the inductive rat platelet aggregation of ADP, and inhibitory action and dosage positive correlation.
FBD all has inhibitory action to the inductive rat platelet aggregation of AA, and inhibitory action and dosage are proportionate.Experimental result sees Table 15～17.
Table 15.FBD is to the influence of the inductive rat platelet aggregation of ADP
| Group | n | Maximum agglutination rate (%) | Assemble suppression ratio (%) |
| Negative group aspirin | 12 10 | 87.4±9.6 60.8±13.1 *** | 30.5 |
| |
10 | 84.9±9.0 | 2.9 |
* P＜0.05, * * P＜0.01, * * * P＜0.001 and tragakanta group are relatively
Table 16.FBD is to the influence of collagen-induced rat platelet aggregation
| Group | n | Maximum agglutination rate (%) | Assemble suppression ratio (%) |
| Negative group aspirin FBD | 12 10 10 | 38.7±7.2 24.8±2.3 *** 36.6±9.4 | 35.8 5.4 |
* P＜0.05, #P＜0.01, * * * P＜0.001 and the comparison of tragakanta group
Table 17.FBD is to the influence of the inductive rat platelet aggregation of AA
| Group | n | Maximum agglutination rate (%) | Assemble suppression ratio (%) |
| Negative group aspirin FBD | 12 10 10 | 52.8±5.0 34.9±2.8 *** 47.9±11.3 | 33.8 9.3 |
* P＜0.05, * * P＜0.01, * * * P＜0.001 and the comparison of tragakanta group
Conclusion
Can see by above result of the test: FBD all has treatment or preventive effect to rat line bolt method focal cerebral ischemia and four artery occlusion global brain ischemia models, shows as to improve rat behavior scoring, reduces the brain necrosis area; Electroencephalogram extinction time behind the lengthening model rat ischemia, shorten the back electroencephalogram recovery time of perfusion again and righting reflex recovery time, its effect is better than nimodipine (2～5mg/kg).When the dosage of 9.2g/kg, also can prolong its mouth breathing time to mice broken end global brain ischemia model, improve the vigor of SOD, but effect is lower than nimodipine (5mg/kg).In addition, in the research of FBD to anesthetized dog periphery and cerebral blood flow influence, the FBD group has certain reduction cerebral vessels resistance to anesthetized dog, increases the effect of brain blood flow, and the periphery blood pressure of animal also there is the effect of similar nimodipine: reduce periphery blood pressure, particularly diastolic pressure; Decreased heart rate.But action intensity and action time are all less than nimodipine (5mg/kg).30min was the most obvious after its improvement to the brain blood flow acted on administration.
Find in the research aspect mechanism of action: FBD can suppress rat arteriovenous shut thrombosis, reduces wet weight of thrombus; FBD and positive drug Radix Salviae Miltiorrhizae Injection (3000mg/kg) have in various degree improvement to the blood fluidised form of rat brain microcirculation disturbance, showing as the hemocyte aggregation extent alleviates to some extent, become granular as the blood fluidised form by the stasis shape, or by granular band shape or the wire of becoming, or become wire by the dotted line shape, meninges blood capillary site counting is obviously increased.FBD also has the obvious suppression effect to AA and the inductive platelet aggregation of ADP, and collagen-induced platelet aggregation is not then had the obvious suppression effect.
Test example 8 FBD to the sodium nitrite induced mice memory consolidate bad influence
Principle: have the medicine that improves learning and memory can reduce the memory of sodium nitrite induced mice and consolidate the number of animals that bad mice was shocked by electricity after 24 hours, the wrong number in the 3min reduces, and shortening incubation period of jumping off platform for the first time.
8.1 experiment purpose: observe FBD to consolidate the bad not improvement effect that has by the memory of sodium nitrite induced mice.
8.2 animal strain, sex, body weight and source are all with 1.2
8.3 medicine
8.3.1 the same 1.3.1 of given the test agent
8.3.2 the same 1.3.2 of control sample
8.3.3 other reagent
Title: sodium nitrite (NaNO
2) character: white crystalline solid specification: analytical pure
Source: Chemical Reagent Co., Ltd., Sinopharm Group's lot number: 20040722
8.4 the animal grouping is by the grouping of random digit method, every group of 10 animals.
8.5 medicinal liquid preparation
FBD：
Huperzine A:
Sodium nitrite:
8.6 instrument
Title: mice diving tower monitor
Model: YLS-2T type
Source: Shandong Academy of Medical Sciences equipment station
8.7 experimental technique
1st, 2 groups of mice orally give N.S, the 3rd group of (positive drug group) orally give huperzine A 66.7 μ g/kg, fbd organizes oral administration.1 time/day, 0.2ml/10g body weight, one week of successive administration.After the last administration 1 hour, lumbar injection scopolamine 2mg/kg behind the 30min put into mice diving tower instrument endoadaptation 5min.Then the energising, the normal reaction after animal is shocked by electricity be the rebound platform to hide noxious stimulation, most animals may be once more or is repeatedly skipped on the copper grid, the platform that snaps back again after being shocked by electricity is so trained 5min, writes down the number of times that every Mus is shocked by electricity.Resurvey after 24 hours, the number of animals that record is shocked by electricity is jumped off the incubation period of platform and the wrong sum in the 3min for the first time.
8.8 result
Sodium nitrite causes anoxic dysmnesia, so the model group mice has obviously shortened the incubation period of jumping off platform for the first time; Huperzine A has prolonged the incubation period that mice jumps off platform for the first time, compares P＜0.05 with model group.The number of animals that is shocked by electricity also significantly reduces (compare with model group, the P value all＜0.01) with the interior errors number of 3min; FBD 4.6,2.3g/kg all significantly prolonged incubation period of jumping off platform for the first time, the number of animals that shocked by electricity (is compared with model group with the errors number in the 3min, the P value all＜0.01), and effect shows that like being eager to excel than huperzine A FBD can improve by the dysmnesia due to the cerebral anoxia.1.15g/kg FBD improve the effect not obvious (table 18) of above-mentioned two indexs.
Data with mean+SD (
) expression, the data difference statistics adopts one factor analysis of variance (ANOVA) or X
2Check, group difference is judged with P＜0.05 or P＜0.025.
Table 18.6 group mice to memory consolidate bad result of the test (n=10,
)
| Group | The animal sum is shocked by electricity | Wrong sum in the 3min | The incubation period (second) of jumping off platform for the first time |
| Negative control group model group huperzine A FBD | 8 10 6** 5** | 10 15 ## 6** 5** | 113.8±110.64 52.0±57.65 ## 166.9±136.82* 207.3±109.57** |
#P＜0.025##P＜0.01 is compared with negative control group;
* P＜0.05**P＜0.01 is compared with model group
8.9 conclusion
With above-mentioned two amnemonic result of the tests, FBD is to consolidating the bad good improvement effect that has by memory due to the sodium nitrite, and its action intensity is like stronger than huperzine A.The result shows that FBD can effectively prevent and treat dysmnesia.
In sum, FBD has the obvious treatment effect to locality and global brain ischemia-reperfusion injury.The mechanism of its ischemia resisting brain injury may with suppress thrombosis, antiplatelet aggregation and microcirculation improvement, it is relevant to increase the brain blood flow.And it consolidates the bad good improvement effect that has to memory.
The invention will be further elaborated by the following examples:
Embodiment 1
Get Poria 25g, Rhizoma Atractylodis Macrocephalae 12g, Radix Angelicae Sinensis 7g, after the mixing, water decocts, and after aqueous extract concentrates, adds ethanol precipitation, get polysaccharide (2.3g), supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion (0.71g), merges water extract effective site (polysaccharide and n-butanol extract), after adding appropriate amount of auxiliary materials, be pressed into tablet.
Embodiment 2
Get Poria 25g, Rhizoma Atractylodis Macrocephalae 12g, after the mixing, water decocts, after aqueous extract concentrates, add ethanol precipitation, get polysaccharide, supernatant is used n-butanol extraction after reclaiming ethanol, get n-butanol portion, merge water extract effective site (polysaccharide and n-butanol extract), after the adding appropriate amount of auxiliary materials, be pressed into tablet.
Embodiment 3
Get Rhizoma Atractylodis Macrocephalae 20g, Radix Angelicae Sinensis 10g, after the mixing, water decocts, after aqueous extract concentrates, add ethanol precipitation, get polysaccharide, supernatant is used n-butanol extraction after reclaiming ethanol, get n-butanol portion, merge water extract effective site (polysaccharide and n-butanol extract), after the adding appropriate amount of auxiliary materials, record capsule.
Embodiment 4
Get Rhizoma Atractylodis Macrocephalae 25g, water decocts, and after aqueous extract concentrates, adds ethanol precipitation, get polysaccharide, supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion, merge water extract effective site (polysaccharide and n-butanol extract), after the adding appropriate amount of auxiliary materials, make tablet.
Get Poria 50g, Rhizoma Atractylodis Macrocephalae 40g, Radix Angelicae Sinensis 20g, after the mixing, the CO2 supercritical extraction extracts volatile oil (2.5ml), and it is 10.0MP that extractor pressure is extracted in control, and temperature is 35 ℃, and extraction time is 2 hours.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 90%, precipitation obtains total polysaccharides (4.2g), supernatant use n-butanol extraction after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract (7.5g) add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 6
Get Poria 50g, Radix Angelicae Sinensis 20g, after the mixing, the entrainer hexane carries out the CO2 supercritical extraction, and control extractor pressure is 9.0MP, and temperature is 32 ℃, and extraction time is 3 hours, obtains supercritical extract.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 95%, precipitation, supernatant is used n-butanol extraction after reclaiming ethanol, obtains total polysaccharides and n-butanol extract, merges supercritical extract and total polysaccharides and n-butanol extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Embodiment 7
Get Rhizoma Atractylodis Macrocephalae 40g, Radix Angelicae Sinensis 20g, after the mixing, the CO2 supercritical extraction extracts volatile oil, and control extractor pressure is 14.0MP, and temperature is 32 ℃, and extraction time is 1 hour.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 75%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges volatile oil, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 8
Get Poria 50g, after Rhizoma Atractylodis Macrocephalae 40g mixes, the CO2 supercritical extraction, control extractor pressure is 12.0MP, and temperature is 35 ℃, and extraction time is 2 hours, obtains supercritical extract.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 85%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges supercritical extract, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 9
Get Radix Angelicae Sinensis 20g, as entrainer, carry out the CO2 supercritical extraction with ethyl acetate, control extractor pressure is 8.0MP, and temperature is 40 ℃, and extraction time is 3 hours, obtains supercritical extract.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 90%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges supercritical extract, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Get Poria 40g, Rhizoma Atractylodis Macrocephalae 20g, Radix Angelicae Sinensis 10g, after the mixing, the CO2 supercritical extraction, control extractor pressure is 12.0MP, and temperature is 35 ℃, and extraction time is 2 hours, obtains supercritical extract.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 85%, precipitation obtains total polysaccharides, supernatant use n-butanol extraction after reclaiming ethanol, merges supercritical extract, total polysaccharides and n-butanol extract add appropriate amount of auxiliary materials, capsule is recorded in granulation.
Embodiment 11
Get Poria 40g, the entrainer hexane carries out the CO2 supercritical extraction, and control extractor pressure is 9.0MP, and temperature is 32 ℃, and extraction time is 3 hours, obtains supercritical extract.Medicinal residues with water extraction after, adding ethanol to the alcohol amount of containing is 95%, precipitation, supernatant is used n-butanol extraction after reclaiming ethanol, obtains total polysaccharides and n-butanol extract, merges supercritical extract and total polysaccharides and n-butanol extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Embodiment 12
Get Poria 40g, Rhizoma Atractylodis Macrocephalae 20g, Radix Angelicae Sinensis 12g, after the mixing,, carry out the CO2 supercritical extraction and extract volatile oil (1.64ml) with the ethanol entrainer, medicinal residues with water extraction after, add ethanol precipitation, obtain total polysaccharides (2.74g), supernatant is used n-butanol extraction (4.9g) after reclaiming ethanol, merge volatile oil, total polysaccharides and n-butanol extract add appropriate amount of starch, granulate, record 16 of capsules.Taking dose: took 2 times each 2 on the 1st.
Embodiment 13
Get Poria 50g, Rhizoma Atractylodis Macrocephalae 25g, Radix Angelicae Sinensis 15g, after the mixing, water decocts, and after aqueous extract concentrates, adds ethanol precipitation, get polysaccharide (4.77g), supernatant is used n-butanol extraction after reclaiming ethanol, gets n-butanol portion (1.46g), merges polysaccharide and n-butanol extract, after adding appropriate amount of auxiliary materials, make 18 in tablet.Taking dose: took 2 times each 2 on the 1st.
Embodiment 14
Get Poria 50g, Rhizoma Atractylodis Macrocephalae 40g, Radix Angelicae Sinensis 20g, after the mixing, the CO2 supercritical extraction extracts volatile oil (2.5ml), and it is 10.0MP that extractor pressure is extracted in control, and temperature is 35 ℃, and extraction time is 2 hours.Medicinal residues with water extraction after, obtain water extract, merge volatile oil and water extract, add appropriate amount of auxiliary materials, compacting in flakes.
Get Poria 50g, after Rhizoma Atractylodis Macrocephalae 40g mixes, the CO2 supercritical extraction, control extractor pressure is 12.0MP, and temperature is 35 ℃, and extraction time is 2 hours, obtains supercritical extract.Medicinal residues with water extraction after, obtain water extract, merge supercritical extract and water extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Embodiment 16
Get Poria 50g, Radix Angelicae Sinensis 20g, after the mixing, entrainer ethanol carries out the CO2 supercritical extraction, and control extractor pressure is 9.0MP, and temperature is 32 ℃, and extraction time is 3 hours, obtains supercritical extract.Medicinal residues with water extraction after, obtain water extract, merge supercritical extract and water extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Embodiment 17
Get Rhizoma Atractylodis Macrocephalae 40g, after Radix Angelicae Sinensis 20g mixes, the CO2 supercritical extraction, control extractor pressure is 12.0MP, and temperature is 35 ℃, and extraction time is 2 hours, obtains supercritical extract.Medicinal residues with water extraction after, obtain water extract, merge supercritical extract and water extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Embodiment 18
Get Rhizoma Atractylodis Macrocephalae 40g, the CO2 supercritical extraction, control extractor pressure is 12.0MP, and temperature is 35 ℃, and extraction time is 2 hours, obtains supercritical extract.Medicinal residues with water extraction after, obtain water extract, merge supercritical extract and water extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Embodiment 19
Get Poria 50g, entrainer ethanol carries out the CO2 supercritical extraction, and control extractor pressure is 9.0MP, and temperature is 32 ℃, and extraction time is 3 hours, obtains supercritical extract.Medicinal residues with water extraction after, obtain water extract, merge supercritical extract and water extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Get Radix Angelicae Sinensis 20g, the entrainer hexane carries out the CO2 supercritical extraction, and control extractor pressure is 9.0MP, and temperature is 32 ℃, and extraction time is 3 hours, obtains supercritical extract.Medicinal residues with water extraction after, obtain water extract, merge supercritical extract and water extract, add appropriate amount of auxiliary materials, granulate, record capsule.
Claims (5)
1, a kind of Chinese medicine composition is prevented and treated application in the medicine of apoplexy in preparation, described Chinese medicine composition is mainly by the supercritical extract and/or the water extract that are selected from a kind of, two or three crude drug in Poria, the Rhizoma Atractylodis Macrocephalae and the Radix Angelicae Sinensis, and perhaps supercritical extract and/or water extract effective site are formed.
2, the application of the described Chinese medicine composition of claim 1 in the medicine of preparation control cerebral ischemia.
3, the described Chinese medicine composition of claim 1 is prevented and treated dysmnesia in preparation, improves the application in the medicine of remembering.
4, the application of the described Chinese medicine composition of claim 1 in the medicine of preparation control thrombosis.
5, the application of the described Chinese medicine composition of claim 1 in the medicine of preparation control microcirculation disturbance.
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| CN2008101890452A Division CN101439073B (en) | 2005-12-20 | 2005-12-20 | Application of Chinese medicinal composition in preparing medicament for preventing and treating dysmnesia and improving memory |
| CN200810188569XA Division CN101439072B (en) | 2005-12-20 | 2005-12-20 | Application of Chinese medicinal composition in preparing medicament for preventing and treating thrombus |
| CN2008101890503A Division CN101601710B (en) | 2005-12-20 | 2005-12-20 | Application of traditional Chinese medicine composition in preparation of medicament for preventing and treating cerebral ischemia |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101485695B (en) * | 2008-01-14 | 2012-05-02 | 上海中药制药技术有限公司 | Guiling dispersible tablets and preparation method thereof |
| CN104083707A (en) * | 2014-06-10 | 2014-10-08 | 凤台县中医院 | Traditional Chinese medicine composition for treating asthenia of qi and blood, palpitation and insomnia |
| CN105902613A (en) * | 2015-08-30 | 2016-08-31 | 王六生 | Preparation method and use of traditional Chinese medicine Lycopodium serratum Thunb. solution for improving memory |
| CN111202758A (en) * | 2018-11-20 | 2020-05-29 | 天津中医药大学 | Pharmaceutical composition for resisting cerebral ischemia injury and preparation method thereof |
-
2005
- 2005-12-20 CN CNB2005101116947A patent/CN100558371C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101485695B (en) * | 2008-01-14 | 2012-05-02 | 上海中药制药技术有限公司 | Guiling dispersible tablets and preparation method thereof |
| CN104083707A (en) * | 2014-06-10 | 2014-10-08 | 凤台县中医院 | Traditional Chinese medicine composition for treating asthenia of qi and blood, palpitation and insomnia |
| CN105902613A (en) * | 2015-08-30 | 2016-08-31 | 王六生 | Preparation method and use of traditional Chinese medicine Lycopodium serratum Thunb. solution for improving memory |
| CN111202758A (en) * | 2018-11-20 | 2020-05-29 | 天津中医药大学 | Pharmaceutical composition for resisting cerebral ischemia injury and preparation method thereof |
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