CN1156281C - Application of ginsenoside Rg2 in preparing medicine for cardio-and cerebro-vascular disease - Google Patents

Application of ginsenoside Rg2 in preparing medicine for cardio-and cerebro-vascular disease Download PDF

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CN1156281C
CN1156281C CNB011021179A CN01102117A CN1156281C CN 1156281 C CN1156281 C CN 1156281C CN B011021179 A CNB011021179 A CN B011021179A CN 01102117 A CN01102117 A CN 01102117A CN 1156281 C CN1156281 C CN 1156281C
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panaxoside
group
shock
ginsenoside
ischemia
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CN1309969A (en
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李龙云
田建明
金毅
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Jilin Fusheng Pharmaceutical Co Ltd
Jilin Academy of Traditional Chinese Medicine
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Jilin Fusheng Pharmaceutical Co Ltd
Jilin Academy of Traditional Chinese Medicine
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Abstract

The present invention belongs to a new application of a medicament which contains effective components of Chinese medicines. Ginsenoside Rg2 is a compound extracted and separated from stems and leaves of ginseng, and in vivo and in vitro experiments prove that the ginsenoside Rg2 has obvious curative effects on various kinds of shock, heart failure, myocardial ischemia and cerebral ischemia, wherein the effects are superior to those of known shenmai injections. The ginsenoside Rg2 can be prepared into a plurality of compounds and various medical preparations comprising injections, tablets, capsules, microcapsules, aerosol agents, syrup agents, oral medicinal liquid, suppositories and the like for treating shock, heart failure, coronary heart disease, cerebral infarction, senile dementia and other diseases. The structural formula of the ginsenoside Rg2 is disclosed in the specification.

Description

Panaxoside Rg 2Application in the preparation treatment heart, cerebrovascular disease medicament
Pharmaceutically active ingredient new medical use field in the invention belongs to.Panaxoside Rg 2(GinsengnosideRg 2) be isolated chemical compound from Radix Ginseng the earliest, because of its content is very low, separation difficulty is not used by the world of medicine so far.According to report (1), the stripped cardiotonic of Radix Ginseng Rubra is better than Radix Ginseng, panaxoside Rg in the flushing ginseng 2Content apparently higher than Radix Ginseng.So tentatively think panaxoside Rg 2Main component for the Radix Ginseng cardiotonic.Isolate panaxoside Rg by traditional method 2After, we have carried out stripped preliminary examination again, and this chemical compound does not have obvious influence to normal isolated heart as a result, in the face of pentobarbital sodium is made the effect that the isolated heart that declines has increases the myocardial contraction amplitude (2)The experimental result of above-mentioned contradiction is difficult to confirm panaxoside Rg 2Therapeutical effect to the heart, cerebrovascular disease.So the present invention adopts whole animal, the multiple models such as papillary muscles and cultivation myocardial cell that exsomatize, and systematically studies and proved panaxoside Rg 2Treatment and preventive values to the heart, cerebrovascular disease.
Experiment showed, panaxoside Rg 2, exsomatize papillary muscles dirty in the body-centered hearfelt (under the low calcium condition) and cultivation myocardial cell (anoxia lacks under the sugared condition) are all had positive inotropic action, and its model of action is different with cardiotonic glycoside.Panaxoside Rg 2The main and myocardium myo fibril of above-mentioned effect to Ca 2+Sensitivity increases relevant.Experiment is proof also, and this chemical compound all has obvious treatment and preventive effect to dog hemorrhagic shock, cardiogenic shock, rabbit toxic shock.In addition, panaxoside Rg 2Myocardial ischemia and apoptosis of cardiac muscle due to chemical method and the coronary ligation method all there are obvious treatment and preventive effect.This chemical compound has significant protective effect to common carotid artery ligation apoptosis amount and external granule Neuron Apoptosis.Content the present invention that this chemical compound can also obviously reduce CK, LDH in animal broken end cerebral ischemia and the common carotid artery ligation cerebral ischemia cerebral tissue has confirmed panaxoside Rg 2As the using value of Chinese medicine one kind new medicine treatment shock, heart failure, coronary disease pain, cerebral infarction and alzheimer disease, above-mentioned research is all undertaken by Chinese medicine one kind new medicine requirements of customs declaration, is about to be developed to Chinese medicine one kind new medicine.
Panaxoside Rg 2Feature is as follows:
1. molecular formula C4 22H 72O 13
Figure C0110211700031
4, disjunctive path
Stem and leaf of Radix Ginseng-→ decoct-→ solvent extracts and separate-→ panaxoside Rg 2
Rg 2Can combine with corresponding pharmaceutical carrier and make various preparations and use, wherein said preparation can be various dosage forms such as injection (injectable powder and injection of solution agent), tablet (coated tablet and Film coated tablets), capsule (common and microencapsulation), aerosol, suppository (anus and vaginal suppository), oral mucous membrane patch, chewable tablet, syrup and other oral liquid.
5, panaxoside Rg 2Shock, anti-heart failure, resist myocardial ischemia and the anti-cerebral ischemia activity:
The shock experimental basis:
(1) panaxoside Rg 2Influence to the acute ischemic cardiogenic shock
Get 30 of healthy hybrid dogs, divide equally 6 groups, anaesthetize with sodium pentobarbital, separate trachea, carotid artery, femoral artery and femoral vein, connect artificial respirator and RM-6000 type polygraph respectively, and separate aortic root, by discharge magnetic flowmeter cassette probe.After anterior descending coronary (LAD) root, middle part, tip ligation, write down respectively BP, LVSP, LVEDP, ± dt/dpmax, HR, breathing rate, CO, and get blood by arteriovenous and survey AST, CK, LDH activity.Observing the iv various dose acted in different time by the reagent thing.Each administration group data and solvent matched group are organized a t check, represent to survey mean+SD and change percentage from (%) mean+SD with X ± SD, see Table 1.
A, to the influence of HR
Panaxoside Rg 21.0mgkg -110~30min heart rate obviously speeds after the group administration, compares P<0.05 with matched group, gives birth to arteries and veins heart rate is not had obvious influence.
B, to the influence of MAP
Panaxoside Rg 21.0mgkg -110~120minMAP obviously raises panaxoside Rg after the group administration 20.5mgkg -120~120minMAP obviously raises after the group administration.Give birth to the arteries and veins group only after the administration 30minMAP obviously raise, its effect is slowly.
C, to the influence of LVSP
Panaxoside Rg 2Each dosage group all has obvious rising effect to LVSP, holds time for a long time, all reaches 120min, gives birth to after the arteries and veins administration 10~60min LVSP that obviously raises.
The influence of d, right ± dp/dtmax
Panaxoside Rg 210min promptly raises+dp/dtmax after each dosage group administration, and keeps 120min, gives birth to arteries and veins group 30~60min and obviously raises+dp/dtmax.
Panaxoside Rg 2Each dosage group is obvious rising-dp/dtmax all, the 30~60min that holds time, and give birth to arteries and veins right-dp/dtmax do not have obvious influence.
In sum, panaxoside Rg 2Acute ischemic cardiogenic shock dog is had the obvious treatment effect, and its hemodynamic index etc. more all improves significantly with matched group.Panaxoside Rg 2Relatively onset is fast slightly with giving birth to arteries and veins, and it is also long than giving birth to arteries and veins to hold time.
(2) panaxoside Rg 2Influence to endotoxin shock:
A, panaxoside Rg 2Influence to the rabbit cardiac function
Get 42 of healthy rabbits, divide equally 7 groups, equal iv1.0mgkg except that sham operated rats -1Escherichia coli endotoxin behind the 10h, connects RM-6000 type polygraph as stated above, and iv is subjected to the reagent thing by dosage shown in the table 2, the equal iv equal-volume of sham operated rats and model group solvent.Different time MAP before and after the record administration, HR, LVSP, LVEDP, IP (wait and hold systolic pressure), ± dp/dtmax, VPm (maximum myocardial contraction speed) are with MAP<10KPa, and as the shock index, observation post's reagent thing is to the influence of cardiac function.
By shown in the table 2, be subjected to the reagent thing to influence as follows to endotoxin rabbit cardiac function:
1. to the influence of MAP, LVSP
Panaxoside Rg 2Each dosage group 15~120min after administration, to significantly increase effect of MAP, LVSP, Rhizoma Zingiberis Recens group 30~60min after administration has tangible increase effect to MAP, LVSP.
2. the influence of right ± dp/dt max
Panaxoside Rg 2Each dosage group is right in 15~120min after administration ± dp/dt max all is significantly increased effect, Rhizoma Zingiberis Recens group instrument after administration during 60min right ± dp/dt max tangible increase effect is arranged.
3. to VPm, influence
Panaxoside Rg 2Each dosage group all has tangible increase effect, Rg to VPm 2In 4.0mgkg -1Organize this acting duration 15~120min, Rg 22.0, mgkg -1Organize this acting duration 30~120min.Rhizoma Zingiberis Recens also has the increase effect to VPm, and the Rhizoma Zingiberis Recens group only is significantly increased effect when 60min.
4. to the influence of LVEDP
Panaxoside Rg 2Each dosage group all has tangible reduction effect to LVEDP, and effect onset time and action intensity speed with the increase of dosage and strengthen, and this acting duration all is maintained until 120min.The Rhizoma Zingiberis Recens group also has the effect that reduces LVEDP, but the persistent period is 30~60min.
Above result shows, panaxoside Rg 2The shock rabbit cardiac function that endotoxin is caused improves significantly.SHENMAI ZHUSHEYE and Rg 2Relatively onset is slow, and the persistent period is short.
B, endotoxin caused the influence of rabbit microcirculation disturbance
Get 29 of Japan large ear rabbits, divide equally 5 groups, slough the both sides tragus with depilatory before the experiment by table 3.Insert femoral artery and femoral venous catheter under the local anaesthesia, in order to observe arteriotony and iv medicine.Iv is subjected to the reagent thing by dosage shown in the table 3, and matched group iv equal-volume solvent is respectively organized equal iv endotoxin 5mgkg simultaneously -1, observe rabbit ear arteriole caliber and change of flow state, the results are shown in Table 3.
As a result, 2~3min behind the iv endotoxin, solvent treated animal have 71.4% I phase blood pressure drops to occur, and ginseng arteries and veins group has 50% I phase blood pressure drops to occur, panaxoside Rg 20.85,1.7mgkg -1Have 16.7%, 37.5% I phase blood pressure drops to occur respectively.Each treated animal ear edge arteries caliber of 20min all has obvious change behind the iv endotoxin, and model group is expansion earlier, and the back continues to shrink, and is shrunk to wire until some animal arteriole, and achroacyte passes through.And the administration group can suppress all that arteriole shrinks due to the endotoxin, and the blood fluidised form is had some improvement.
In a word, panaxoside Rg 2Animal microcirculation disturbance due to the endotoxin is improved significantly, and its effect strengthens with increase of dosage.
(3) panaxoside Rg 2To the hemodynamic influence of hemorrhagic dogs
Get healthy dogs, anesthesia, connection RM-6000 type polygraph.Blood-letting drops to below the 5.3KPa to MAP, stablized 10 minutes, by dosage shown in the table 4 respectively iv be subjected to the reagent thing, matched group iv equal-volume solvent, write down respectively MAP, LVSP, LVEDP, ± dp/dt max, IIR, breathing rate.4.5h gets blood after administration, surveys LDO and SOD.6h dog survival number after the record administration.
Table 4 shows:
1. to the influence of MAP
Panaxoside Rg 210~120min MAP that can obviously raise after each dosage group administration, 5~10min MAP that also obviously raises after the administration of Rhizoma Zingiberis Recens group.
2. to the influence of LVSP
Panaxoside Rg 2The effect of rising LVSP is all arranged, when removing 60min 0.5,1.0mgkg after each dosage group administration -10.5mgkg during with 120min -1Group compares outside P<0.05 with matched group, and all the other all have rising trend.
3. the influence of right ± dp/dt max
Panaxoside Rg 210~120min can obviously raise+dp/dt max after each dosage group administration, 0.5mgkg when right-dp/dt max removes 5min -11.0mgkg during with 120min -1Compare outside P<0.05 with matched group, all the other have rising trend.
Table 5,6 shows panaxoside Rg 2The effect that obvious reduction hemorrhagic dogs Serum LPO content, enhance SOD activity, prolongation time-to-live is arranged and improve survival rate.
More than show panaxoside Rg 2The dog hemorrhagic shock there is obvious protective effect, rising MAP, LVSP, ± dp/dtmax, its effect is slowly lasting.Panaxoside Rg in addition 2The respiratory frequency that can slow down reduces LPO content, and enhance SOD activity reduces the animal dead rate, prolongs the time-to-live.
Anti-heart failure experimental basis:
(1) panaxoside Rg 2To the hemodynamic influence of heart failure due to the pentobarbital sodium
Get 30 of healthy hybrid dogs, divide equally 6 groups, anaesthetize, open breast, press the observation index intubate, connect RM-6000 type polygraph, write down mean arterial pressure (MAP) respectively, left ventricular pressure (LVSP), end diastolic pressure (LVEDP), myocardial contraction maximum rate (± dp/dt max), heart rate indexs such as (HR).Cause heart failure and shock by femoral artery constant speed input pentobarbital sodium, with ± dp/dt max descend 80%, mean arterial pressure and cardiac output drop to 40%, be the heart failure index, be subjected to the reagent thing by intravenous injection, write down administration respectively before, the hemodynamic index of different time after the administration.With (heart failure) before the administration is 100%, and each index changes percentage rate after the calculating administration.
By table 7 as seen, cause the dog acute heart failure by pentobarbital sodium, the invention of its hemodynamics index shows and changes, and CO rate of descent 59.17 ± 14.96%, MAP rate of descent are 69.93 ± 9.854% etc., show this model success.Stable back iv is subjected to the reagent thing, and is as follows with the influence of every index:
1. to the influence of MAP
Ginsenoside 0.5mgkg -1And Rg 21.0mgkg -120~60min can obviously increase MAP after administration, Rhizoma Zingiberis Recens 1g crude drug kg -1Group also can obviously increase MAP, but and panaxoside Rg 2Relatively, the Rhizoma Zingiberis Recens onset is slow.
2. to the influence of LVSP, LVEDP
Panaxoside Rg 2Each dosage group LVSP that all can obviously raise obviously reduces LVEDP, and is more rapid-action with Rhizoma Zingiberis Recens.
3. the influence of right ± dp/dt max
Panaxoside Rg 2Each dosage group all can obviously raise ± dp/dt max, and action intensity continues to increase in 5~60min after administration, and Rhizoma Zingiberis Recens also has the effect of rising ± dp/dtmax, but and Rg 2Relatively, the Rhizoma Zingiberis Recens onset is slow.
4. to the influence of HR, CO
Panaxoside Rg 20.5mgkg -15~60min can obviously increase HR, panaxoside Rg after the group administration 210~60min all can obviously increase CO after each dosage group administration, and Rhizoma Zingiberis Recens also has the effect that increases HR, CO.
Above result shows, panaxoside Rg 2The dog acute heart failure that is brought out by pentobarbital sodium is had significant protective effect, can increase MAP, LVSP, ± dp/dt max, HR, CO, reduce LVEDP, thereby strengthen cardiac function.More rapid-action with Rhizoma Zingiberis Recens.
(2) panaxoside Rg 2Influence to the effect of guinea pig in vitro papillary muscles
Get Cavia porcellus with the wooden stick head of fiercelying attack, take out heart rapidly, with KH liquid flush away blood, take out papillary muscles, its bottom is fixed on the stimulating electrode, the chordae tendineae end is clamped to put into rapidly with frog heart clip and is bathed temperature control at the bath that 36 ℃ of 20ml fill KH liquid, passes to 95%O 2, 5%CO 2Mist is connected in two with frog heart clip by transducer again and leads on the physiograph, begins to test after stablizing 30~60min.After waiting to shrink constant amplitude after each dosing (4~5min), till shrinkage amplitude no longer increases even dwindles or autorhythmicity occurs, add second concentration again.
Solvent group, ouabain group and panaxoside Rg 2Normal KH liquid group (is joined Saponin Rg to call the normal person in the following text 2Group), treat papillary muscles shrink stable after, in bath, add same volume respectively, the ouabain of variable concentrations, ginsenoside and solvent with the preparation of KH liquid.
Panaxoside Rg 2Low calcium KH liquid group is (hereinafter to be referred as low calcium panaxoside Rg 2Group), treat papillary muscles in normal KH liquid stable after, change low calcium KH liquid, this moment, shrinkage amplitude dwindled gradually, stable back adds the same volume with low calcium KH liquid preparation, the panaxoside Rg of variable concentrations in bath 2, calculating tension force as follows increases percentage rate:
The rate of opening increases the preceding shrinkage amplitude of percentage rate=administration after-contraction amplitude/administration * 100%
From table 8, Fig. 1 as can be seen, panaxoside Rg 2Shrinkage amplitude to guinea pig papillary muscle in the normal KH liquid has certain potentiation, Rg 2Concentration is 2.11 * 10 -3MmolL -1Shi Zuoyong is the strongest, just no longer increases afterwards.Panaxoside Rg 2Can obviously increase the shrinkage amplitude of guinea pig papillary muscle in the low calcium KH liquid, and be dose-effect relationship preferably with the concentration increase.Low calcium panaxoside Rg 2The regression curve equation be: Y=32.32X+134.902, try to achieve Δ FC=(50% concentration) 2.37 * 10 -3MmolL -1, from Fig. 1 read Δ Fc max=188.7 ± 55.1%.The solvent group has the trend that reduces shrinkage amplitude.
From table 9, Fig. 2 as can be seen, ouabain can obviously strengthen the guinea pig papillary muscle contractility, and its shrinkage amplitude increases with the increase of drug level, and the regression curve equation of ouabain is Y=106.09X+762.679, tries to achieve Δ FC=(50% concentration) 1.91 * 10 -7MmolL -1, from Fig. 2 read Δ Fc max=235.7 ± 57.6%.
The result shows that in normal KH liquid, ouabain surpasses panaxoside Rg to the action intensity of papillary muscles 2In low calcium KH liquid, panaxoside Rg 2The papillary muscles shrinkage amplitude there is tangible increase effect.
(3) panaxoside Rg 2To cultivating the beat influence of amplitude of myocardial cell
Experiment is cultivated myocardial cell with reference to the method for foundation such as Harary, take out and give birth to 2~4 days rat neonatal rats in back, separate ventricular muscles, with trypsinization, separating myocardium cell, with Eagle medium preparation cell suspension, put in 37 ℃ of incubators and hatched 2 days, treat that experimentizing when synchronization is beaten appears in cell.
This experiment myocardial cell anoxia lacks sugared model, adopts sugar-free Hank ' s liquid culture medium nitrogen saturation, is subjected to the reagent substrate concentration to be respectively panaxoside Rg 20.05,0.025,0.0125mmolL -1Ouabain 1mmolL -1SHENMAI ZHUSHEYE 0.4g crude drug L -1Normal cultivation myocardial cell and medicine temperature are incubated time 4h, and anoxia lacks sugared myocardial cell and the medicine temperature is incubated time 6h, the amplitude of variation percentage rate (%) of beating before and after the record administration.
Radix Ginseng soap Rg as a result 2Under used concentration the normal cultivation myocardial cell amplitude of beating is not all had obvious influence, and SHENMAI ZHUSHEYE increases by 19.3%, ouabain increases by 30.4%; But panaxoside Rg 2Anoxia is lacked the effect that sugared myocardial cell is significantly increased the amplitude of beating, be respectively 72.8%, 48.2%, 32.4%, and Rhizoma Zingiberis Recens and ouabain increase by 18.1% and 32.4% respectively.
Above result shows, Radix Ginseng soap Rg 2Only anoxia is lacked the effect that sugared myocardial cell has increases the amplitude of beating, and not obvious to the normal myocardium effect, this point is different with ouabain.
(4) panaxoside Rg 2To striping myocardium myo fibril Ca 2+The influence of sensitivity
Preparation of striping myocardium myo fibril and Ca 2+Mg 2+-atpase activity is measured the method for setting up with reference to Alous (1988) and Pagen (1984) etc., gets the dog heart, and homogenate is centrifugal, and taking precipitate adds Buffer solution, and is centrifugal repeatedly, final taking precipitate, and adjusting protein content with Buffer liquid is 5mgL -1Get the fribrillin liquid for preparing and add reactant liquor and be subjected to the reagent thing, 30 ℃ of following incubation 10min, the ATP that adds 4mM starts reaction, adds the TAC cessation reaction of 1ml 15% behind the 10min.Centrifugal, get supernatant and survey Phos (Pi) content that discharges with the Bonting method.Unit is with umol Pimg -1H -1Expression.
Shown in Figure 3, panaxoside Rg 20.1mmolL -1Can make the active rising of striping myocardium myo fibril, enzymatic activity-pCa curve is shifted to the upper left side, think that promptly this medicine has Ca 2+Sensitization.
Prevention and treatment myocardial ischemia experimental basis:
(1) panaxoside Rg 2The influence of coronary ligation dog epicardial potential, serum cardiac muscle three enzymes and myocardial infarction area
Experimental technique is asked for an interview " to the hemodynamic influence of cardiogenic shock dog ", after the coronary ligation operation finishes, place multipoint electrode, record epicardial potential (EECG), measure each index of hemodynamics simultaneously, and get blood by artery and vein and survey AST (glutamic oxaloacetic transaminase, GOT), CK (creatine kinase), LDH (lactic acid dehydrogenase) activity.Experiment 6h cuts open and cores dirtyly, and press the NBT staining and measure myocardial infarction area, be degree of myocardial ischemia and scope with epicardial potential ST section total mv number (∑-ST) raise) 2mv electrodeplate (N-ST) that raises with the ST section.Observe iv and be subjected to of the effect of reagent thing at different time.
Shown in the table 10, panaxoside Rg 2And SHENGMAI ZHUSHEYE all can obviously reduce N-ST and alleviate ∑-ST.By table 11 as seen, panaxoside Rg 2Myocardium three enzymes and infarct size are had tangible reduction and reduce effect, but the action intensity of SHENGMAI ZHUSHEYE is not as good as Rg 2
(2) panaxoside Rg 2Influence to rat heart muscle ischemia due to the isoproterenol
Get rat, iv is subjected to the reagent thing by dosage shown in the table 12, and matched group iv equal-volume solvent is respectively organized the equal ip different third tight upper parathyrine 2mgkg-1 simultaneously, every day 1 time, continuous 3 times, survey before the administration respectively and the last administration after the different time electrocardiogram, and portion cores dirty, check its necrosis area, as the myocardial ischemia index, the effect of observation post's reagent thing the results are shown in Table 12 with J point skew and myocardial necrosis area.
The result shows, panaxoside Rg 2The anomalous ecg due to the isoproterenol can be obviously improved, the myocardial necrosis area can be obviously dwindled.
(3) panaxoside Rg 2Influence to rat heart muscle ischemia due to the pituitrin
Get rat, connect the II electrocardiograph that leads, iv is subjected to the reagent thing by dosage shown in the table 13, and matched group iv equal-volume solvent is respectively organized equal iv pituitrin 0.5ukg after 10 minutes -1, different time electrocardiogram before the record administration, after the administration as the myocardial ischemia index, the results are shown in Table 13 with the skew of J point.
Panaxoside Rg as a result 2Can obviously improve, show that this chemical compound has the effect of tangible anti-coronary vasospasm myocardial ischemia by electrocardiographic abnormality due to the pituitrin.
(4) ginseng Saponin Rg 2The rat coronary ligation is brought out the protective effect of apoptosis of cardiac muscle.
Get 25 of SD male rats, divide equally 5 groups: 1. sham operated rats (the not ligation of left coronary artery threading), 2. solvent matched group (3h iv 1mkg before the left coronary artery ligation -1Solvent), 3. ischemia filling group again (3h iv 1mlkg before the ligation -1Solvent unclamps ligature behind the 30min after the ligation, recover blood flow 20min), 4. panaxoside Rg 21.0mgkg -1, 2.0mgkg -1(3h difference iv Rg before the ligation 21.0mgkg -1, 2.0mgg -1All the other are same 3.).Experiment finishes the rapid heart that takes out in back, adopts TUNEL to detect, and fluidic cell detects and the observation of DNA agarose electrophoresis is subjected to the protective effect of reagent thing to apoptosis of cardiac muscle.
The TUNEL testing result shows that sham operated rats and solvent matched group apoptosis cell are about 6%, and ischemia filling group again apoptosis cell obviously increases, and reaches about 21%, panaxoside Rg 21.0mgkg -1Group and 2.0mgkg -1The group apoptotic cell is respectively 15% and 8%, and is remarkable with ischemia filling group again comparing difference, sees Fig. 4.
Fluidic cell detects and shows that after ischemia was irritated 2h again, ischemia filling group again was typical apoptotic peak (AP peak) and accounts for 41.5% on the DNA rectangular histogram, and sham operated rats AP peak only accounts for 9.2%, sees Fig. 5.
The agarose gel electrophoresis result shows, ischemia is irritated 2h again, the visible significantly dna ladder degree band (integral multiple that is equivalent to 180~200Dp) of ischemia filling group again, and prompting has dna break and apoptosis, and the genome band only appears in sham operated rats at the point sample place, panaxoside Rg 21.0mgkg -1And 2.0mgkg -1Group gradient tea band obviously weakens, and sees Fig. 6.
In a word, panaxoside Rg 2Apoptosis of cardiac muscle, dna break all have significant protective effect during to ischemia-reperfusion.
Treatment cerebral infarction experimental basis:
(1) panaxoside Rg 2The influence of mice global brain ischemia
1. panaxoside Rg 2To the dehisce influence of the time of breathing of mice broken end
Get 50 of Kunming mouses, divide equally 5 groups, iv is subjected to the reagent thing by dosage shown in the table 14, breaks end behind the 10min, breaks end to the dwell time of breathing of dehiscing by stopwatch record mice immediately, as the cerebral ischemia index, the results are shown in Table 14 with this time length.
The result shows, panaxoside Rg 2Can obviously prolong the mice broken end dehisces the time of breathing.
2. panaxoside Rg 2Influence to mice broken end cerebral tissue CK, LDH
Get 60 of Kunming mouses, divide equally 5 groups, be subjected to the reagent group by dosage shown in the table 15 to iv, break end behind the 10min, broken end back 15Sec gets brain immediately, weigh rapidly, with the cold saline homogenate of 10 times of amounts, the centrifugal 5min of 3000Pr/min gets supernatant, press creatine kinase (CK), lactic acid dehydrogenase (LDH-L) test kit description method with Dutch II type semi-automatic biochemical analyzer survey CK and LDH content, the results are shown in Table 15.
As a result, ischemic tissue of brain creatine kinase (CK) content there is tangible reduction effect, and to lactic acid dehydrogenase (LDH) content Rg only 22.0mgkg -1The reduction effect is arranged, show, panaxoside Rg 2The mice global brain ischemia there is significant protective effect.
(2) panaxoside Rg 2Influence to ischemic brain injury
Get 66 of the SD male rats of body weight 250~270g, divide equally following 11 groups: normal control group, solvent add 4 groups of ischemia 3h, 4h, 5h, 6h etc., Rg 22.0mgkg -1Add 4 groups of ischemia 3h, 4h, 5h, 6h etc., ischemia 6h adds Rg 21.0mgkg -16h adds Rg with ischemia 22.5mgkg -1Group.Solvent and Rg 2Equal 3h intravenously administrables in advance before cerebral ischemia.
Except that the normal control group, after all the other rats are anaesthetized with pentobarbital sodium, cut the cervical region median line, separate right carotid (CCA), external carotid artery (ECA) and internal carotid artery (ICA), the 3-0 bolt line (U.S.A) for preparing is inserted from the ECA stump, enter anterior cerebral artery through ICA, to block blood flow of middle cerebral artery.Postoperative is levied (the tremulous pulse body turns left, the left fore hemiplegia) typical Honer to occur be the sign of model success.Experiment is got brain rapidly after finishing, and does following processing respectively:
Adopt TTC dyeing to observe cerebral infarct size, the results are shown in Figure 7, Fig. 8.
Adopt the DNA sepharose electrophoresis to observe dna cleavage, the results are shown in Figure 9.
Adopt fluidic cell to detect (FCM) observing apoptosis peak (AP peak), the results are shown in Figure 10.
As a result, rat cerebral ischemia 6h shows through TTC dyeing: normal cerebral tissue is red, and right side middle cerebral artery infraction 6h hindbrain is organized as pale asphyxia, sees Fig. 7.
Different time cerebral ischemia (3h, 4h, 5h, 6h) infarct size in time prolongation and increase, if ivRg in advance 22.0mgkg -1, then above-mentioned infarct size is obviously dwindled, and sees Fig. 8 A.Various dose Rg 2(1.0,2.0,2.5mgkg -1) can obviously reduce the cerebral infarct size that ischemia 6h brings out, and with Rg 2The increase of dosage, infarct size reduces, and sees Fig. 8 B.
Sepharose electrophoresis result shows: cerebral ischemia 6h apoptosis gradient band is obvious, in advance ivRg 2(1.0,2.0mgkg -1) after, apoptosis gradient band disappears, and sees Fig. 9.
The fluidic cell testing result shows: behind the cerebral ischemia 6h, apoptosis (AP) peak is obvious, in advance Rg 2(1.0,2.0mgkg -1) AP peak, back obviously weakens, and the results are shown in Figure 10.
(3) panaxoside Rg 2Protective effect to the In vitro culture cerebellar granule neuron
1. granule neurons culture and apoptosis model
Get newborn 7 days SD rat neonatal rat, aseptic broken end is got cerebellum, remove blood vessel and meninges under the mirror, be cut into small pieces, with 0.06% trypsinization 15min, add pancreatin inhibitor and serum and stop digestion, the collecting cell suspension, it is centrifugal that (1500rpm 5min) abandons supernatant, precipitation adds BME and Eegle ' s culture fluid, adjusts 106 ml of cell density -1, be planted in the culture dish that is covered with poly-D-lysine in advance, add Ara-C behind 37 ℃ of cultivation 24h and suppress the glial cell growth, be used for experiment behind the 7d.
Anoxia lacks sugared inducing apoptosis model: get the neurocyte of cultivating 7d, culture fluid is used sugar-free Eagle culture medium instead, places to contain 95%N 2+ 5%CO 2CO2 gas incubator in, 37 ℃ are used for experiment as the apoptosis model after cultivating 6h.
The low apoptosis-induced model of potassium: get and cultivate 7d neurocyte (25mMKcl), lose culture fluid, adding contains in the DME/F12 culture fluid of 5mMKCl, behind 37 ℃ of cultivation 16h, is used for experiment as paper potassium inducing apoptosis model.
Hoechest 33258 fluorescence stainings:
The reference literature method is carried out, and Hoechest 33258 (8 μ g/ml), concrete grammar are slightly.
.DNA sepharose electrophoresis: method slightly
The result:
Light microscopic and phase contrast microscope show down: normal neurons cell space ellipse, and cell space dwindled after the clear anoxia of projection lacked sugared 6h, and axonotmesis or disappearance give panaxoside Rg 2Cellular morphology is clearly better after 20 μ g and the 40 μ g pretreatment, the results are shown in Figure 11,12.
Hoechast 33258 fluorescence stainings show: visible a large amount of apoptotic bodies behind the scarce sugared 6h of anoxia, nuclear splits the group, gives the variable concentrations panaxoside Rg 2The back transfers the corpusculum (white) of dying obviously to reduce, and this effect is proportional with dosage, the results are shown in Hoechest33258 colored graph 13.14.
The DNA electrophoresis result shows: the panaxoside Rg of variable concentrations 2Can obviously reduce oxygen and lack the DNA that sugared 6h brings out and split the group, apoptosis gradient band disappears after the administration.The results are shown in Figure 15,16.
Induce in the neural apoptosis model and must show at low potassium: the panaxoside Rg of variable concentrations 2Still but antagonism hangs down the neuronal damage that potassium brings out, and the results are shown in fluorescence staining and DNA electrophoresis.
Hemolytic test
With panaxoside Rg 2Be made into 0.5% solution, press official method preparation red cell suspension, application of sample, 37 ℃ of permanent baths, each Guan Junwu haemolysis in the 3h as a result.
Acute toxicity test
Get 60 of mices, 18~20g, male and female half and half, water 12h is can't help in fasting, 15~18 ℃ of room temperatures, iv panaxoside Rg 2, observe animal dead number in 7 days, press the Biss method and calculate LD50, panaxoside Rg as a result 2Mice LD50 is 330.06 ± 19.17mgkg -1
Fig. 1 is a panaxoside Rg 2And solvent is to the figure that influences of guinea pig in vitro papillary muscles shrinkage amplitude.
Fig. 2 is the influence figure of ouabain to guinea pig in vitro papillary muscles shrinkage amplitude.
Fig. 3 is a panaxoside Rg 2To pC aThe figure that influences with calcium, magnesium-atpase activity response curve.
Fig. 4 is a panaxoside Rg 2The rat coronary ligation is brought out the protective effect of apoptosis of cardiac muscle, adopt the detection figure of TUNEL detection method.
Fig. 5, be panaxoside Rg 2The rat coronary ligation is brought out the protective effect of apoptosis of cardiac muscle, adopt the detection figure of fluidic cell detection method.
Fig. 6 is a panaxoside Rg 2The rat coronary ligation is brought out the protective effect of apoptosis of cardiac muscle, adopt the detection figure of DNA sepharose electrophoresis detection method.
Fig. 7 is TTC stained brain cerebral infarction models figure.
Fig. 8 is a panaxoside Rg 2The figure that influences to cerebral infarct size.
Fig. 9 is a panaxoside Rg 2To the influence of ischemic brain injury, adopt the detection figure of DNA agarose electrophoresis.
Figure 10 is a panaxoside Rg 2To the influence of ischemic brain injury, adopt the detection figure of fluidic cell detection method.
Figure 11 is a panaxoside Rg 2To the neuronic protective effect of material of In vitro culture cerebellum, adopt the detection figure of phase contrast microscope detection method.
Figure 12 is a panaxoside Rg 2To the neuronic protective effect of material of In vitro culture cerebellum, adopt the detection figure of light microscope detection method.
Figure 13,14 is a panaxoside Rg 2To the neuronic protective effect of material of In vitro culture cerebellum, adopt the detection figure of Hoechest33258 fluorescence staining detection method.
Figure 15,16 is a panaxoside Rg 2To the neuronic protective effect of material of In vitro culture cerebellum, adopt the detection figure of DNA sepharose electrophoresis detection method.
6, the invention process method
Panaxoside Rg 2Can combine with corresponding pharmaceutical carrier and be prepared into various doses and be used for shock, myocardial ischemia and cerebral ischemia treatment.The following table of its implementation method
Dosage form Specification Adjuvant Route of administration Remarks
Injection tablet capsule agent suppository aerosol note agent microballoon 25mg/ piece 50mg/ piece 5mg/ml 25mg/ sheet of 10mg/ gram 20mg/ gram 25mg/ sheet 50mg/ sheet 25mg/ grain 50mg/ grain 25mg/ grain Water for injection or other solvent medical starches or other auxiliary material capsule for medicine fatties, water-soluble base propellant are stained with the mixture coating material Intramuscular injection intravenous injection anal respiration road for oral administration oral mucosa alimentary canal Comprise that powder-injection and injection of solution agent comprise that sugar coated tablet, Film coated tablets etc. comprise that common chamber capsule and microencapsulation comprise that pessary comprises alimentary canal microballoon and vein microballoon
Table 1 panaxoside Rg2To the hemodynamic impact of acute ischemic cardiogenic shock dog (n=5, X ± SD)
Group     HR                 MAP             LVSP              +dp/dtmax         -dp/dtmax (beats/min)            (Kpa)           (Kpa)              (Kpa/s)           (Kpa/s)
Control group is given birth to arteries and veins 140mgkg-1Normal Rg2 0.5mg·kg -1         Rg 2 1.0mg·kg -1 164.80±15.547     12.25±1.867    19.28±3.411       469.33±173.44    325.33±93.14.2 148.00±21.225     12.58±1.799    18.48±2.265       421.33±39.554    288.00±82.513 167.40±28.553     13.11±1.317    19.17±1.782       418.67±116.85    328.00±32.111 170.00±18.014     12.56±1.092    19.47±1.614       461.33±149.55    341.33±78.656
Control group is given birth to arteries and veins 140mgkg-1Shock Rg20.5mg·kg -1         Rg 21.0mg·kg -1 135.60±17.573     8.52±1.367     13.49±1.688       191.95±65.710    191.95±92.160 118.80±20.933     8.42±1.267     12.90±1.715       237.27±64.1194   159.96±61.609 145.80±49.610     8.55±1.224     14.05±0.890       218.61±60.794    194.62±41.730 135.80±19.942     8.08±1.392     14.10±2.919       191.95±39.543    167.96±48.613
Give birth to arteries and veins 140mgkg behind the control group medicine-1 5min    Rg 20.5mg·kg -1 %      Rg 21.0mg·k6 -1 -12.44±5.395      2.09±8.211     -2.59±14.204      2.54±12.233      1.67±12.983 -8.38±15.067      4.94±6.992     5.48±8.083        -0.37±14.796     2.09±16.658 -16.00±20.018     -5.40±13.245   …7.06±12.063     -7.14±25.436     -7.35±21.002  2.02±13.138      10.50±6.920    2.59±3.540        11.64±23.888     11.79±25.308
Give birth to arteries and veins 140mgkg behind the control group medicine-1 10min   Rg 20.5mg·kg -1  %     Rg 21.0mg·kg -1 -12.66±7.430      -0.64±7.363    -4.26±9.751       5.83±6.625       6.25±22.768 -7.60±9.701       7.75±16.555    10.36±8.713*      19.86±24.170     18.39±28.791 -4.06±19.756      9.70±8.248     …1.12±6.721      21.90±15.536     11.97±19.396 8.94±17.982*      23.92±10.777** 15.62±8.935**     28.48±31.024     45.51±31.973
Give birth to arteries and veins 140mgkg behind the control group medicine-1 30min   Rg 20.5mg·kg -1  %     Rg 21.0mg·kg -1 -11.12±9.363      -5.61±17.318   -2.70±12.509      3.57±22.490      1.97±25.642 -9.07±7.238       21.24±18.352*  23.96±9.705**     44.56±19.927*    28.48±24.684 -3.36±20.854      31.34±6.862**  18.88±12.611*     40.60±31.627     38.77±23.862* 6.49±11.732*      38.66±14.960** 27.68±8.516**     80.17±26.303**   49.02±35.889*
Give birth to arteries and veins 140mgkg behind the control group medicine-1 60min   Rg 20.5mg·kg -1  %     Rg 21.0mg·kg -1 -12.50±11.325     -5.33±15.629   -1.03±10.433      -2.06±23.601     -2.69±26.896 -9.33±4.326       20.17±2L 729   20.50±13.128*     21.63±8.088      8.74±33.330 0.50±20.936       31.00±16.924** 21.61±15.039*     55.12±49.208*    48.13±50.880 2.11±10.967       38.40±24.028** 24.85±16.068*     75.92±34.976**   44.36±30.879*
Give birth to arteries and veins 140mgkg behind the control group medicine-1 120min  Rg 20.5mg·kg -1   %    Rg 21.0mg·kg -1 -13.83±15.944     -6.24±14.204   -2.66±8.884       -18.96±42.972    -4.74±37.075 -13.81±4.186      9.69±18.956    10.87±14.590      15.75±22.819     0.22±29.349 -5.05±24.770      22.39±20.395*  15.39±15.918      41.55±33.520*    34.95±41.988  1.09±10.189      36.24±9.970*** 19.26±9.827**     59.71±25.900**   31.74±19.903
Compare * P<0.05, * * P<0.01, * * * P<0.001 with control group
Table 2 panaxoside Rg2The shadow noon of Endotoxic Shock Cardiac Function in Rabbits (n=6, X ± SD)
Group     MAP                LVSP             LVEDP           dp/dtmax          -dp/dtmax                  Vpm    (Kpa)               (Kpa)            (Kpa)            (Kpa/s)            (Kpa/s)                 (l/s)
Sham-operation group solvent group ginseng wheat 1g crude drug kg-1        Rg 2 2mg·kg -1        Rg 2 4mg·kg -1 14.07±0.99         18.64±2.01       0.20±0.08       992.3±129.4      814.3±85.2             10.26±1.34 7.24±1.23          11.09±1.32       0.97±0.14       640.1±74.2       398.4±77.7             6.14±1.01 8.02±1.30          12.18±1.12       0.93±0.06       657.1±89.4       427.3±98.6             6.65±1.08 9.40±1.11*         16.66±2.11**     0.94±0.06       789.4±106.2*     412.4±89.4             6.14±0.08 12.08±0.84**       18.60±3.04**     0.76±0.06*      892.1±128.3**    506.4±98.4*            7.24±0.09*
The sham-operation group is molten according to group ginseng wheat 1g crude drug kg-1        Rg 2 2mg·kg -1        Rg 2 4mg·kg -1 16.12±0.94         19.86±3.12       0.23±0.06       938.4±135.4      836.7±97.3             10.89±1.56 9.82±0.66          10.11±3.03       1.06±0.19       772.5±128.4      435.4±79.9             6.28±1.03 10.74±2.83*        14.94±2.02*      0.78±0.03*      799.2±114.0*     521.6±89.8             6.34±11.2 8.96±0.98          19.32±3.44**     0.54±0.02*      897.2±106.4**    748.8±87.4**           9.94±1.32** 13.21±0.98**       20.12±4.11**     0.33±0.04**     939.6±125.8**    792.3±77.6**           9.98±1.20**
Sham-operation group solvent group ginseng wheat 1g crude drug kg-1 60min  Rg 2 2mg·kg -1        Rg 2 4mg·kg -1 14.18±1.04         20.12±1.98       0.27±0.07       940.3±116.2      811.2±97.2             10.04±1.30 9.10±0.82          12.65±1.32       1.34±0.37       729.4±129.9      546.1±98.6             5.48±1.04 12.23±2.08**       16.20±3.01*      0.66±0.12*      876.2±98.4*      679.8±70.2*            8.87±10.8* 10.04±2.10*        19.92±2.04**     0.84±0.14*      902.6±104.3**    776.3±77.2**           8.16±1.21** 12.12±0.87**       20.18±2.04**     0.31±0.04**     899.3±106.4**    789.4±99.6**           9.94±1.26**
Sham-operation group solvent group ginseng wheat 1g crude drug kg-1 120min Rg 2 2mg·kg -1        Rg 2 4mg·kg -1 15.22±0.89         19.69±1.74       0.26±0.07       941.2±115.5      805.2±89.7             9.98±1.20 8.64±1.28          13.12±1.12       1.45±0.38       659.4±107.2      439.6±89.7             4.86±0.09 10.01±1.09         14.45±3.18       1.38±0.39       777.9±127.2*     538.4±92.5             6.94±9.8 13.25±3.14**       18.94±1.65*      0.70±0.04*      939.8±105.6**    794.2±101.3**          8.56±1.04** 13.26±2.56**       20.12±2.01*      0.29±0.03**     928.2±108.4**    799.6±111.4**          9.76±1.12**
Compare * P<0.05, * * P<0.01 with the solvent group
Table 3 panaxoside Rg2The impact of rabbit microcirculation disorder due to the induced by endotoxin
Arteriole caliber (μ the m) (fluidised form of X ± SD)
Group dosage number of animals
                                           0             2             5            10            0        10
Control group---6 42.8 ± 6.79 49.2 ± 6.79 38.0 ± 4.60 27.8 ± 7.83 line grains stream grain pendulum stream is stagnated
Shenmai injection 1.7g crude drug kg -16 43.7 ± 4.50 48.2 ± 5.23 44.8 ± 4.62*, 36.2 ± 4.02* line grains stream grain unhurried current grain stream
Panaxoside Rg2    0.85mg·kg -15 45.2 ± 5.54 47.8 ± 3.35 43.6 ± 4.62 38.6 ± 5.46* line grains stream grain unhurried current
Panaxoside Rg2    1.7mg·kg -16 41.8 ± 5.85 44.8 ± 7.88 40.5 ± 6.44 37.0 ± 5.44* line grains stream grain unhurried current
Compare * P<0.05 * * P<0.01 with control group
Table 4 panaxoside Rg2To the hemodynamic impact of hemorrhagic dogs (n=5, X ± SD)
Group HR MAP LVSP dp/dtmax-dp/dtmax breathe (beats/min) (Kpa) (Kpa) (Kpa/s) (Kpa/s) (beats/min)
Control group ginseng wheat 1g crude drug kg-1Normal Rg2 0.5mg·kg -1           Rg 2 1mg·kg- 1 191.20±15.834     15.54±1.606       20.77±2.042         498.54±106.89      541.20±219.76        13.80±5.310 203.80±32.453     16.54±3.674       23.27±5.282         565.19±190.30      557.19±155.85        20.00±4.000 222.40±51.413     17.97±2.380       24.77±3.157*        631.84±191.00      506.54±203.91        26.60±12.700 192.80±24.077     16.61±1.961       22.05±3.293         519.87±152.57      565.19±257.20        17.20±7.855
Control group ginseng wheat 1g crude drug kg-1Lose compensatory 0 Rg2 0.5mg·kg -1           Rg 2 1mg·kg -1 160.00±33.904     5.01±0.125        8.74±1.029          154.63±36.016      151.96±59.315        20.20±5.782 197.60±33.020     4.85±0.268        9.89±1.994          191.95±36.016      114.64±32.103        26.80±8.927 165.80±38.486     5.09±0.068        10.29±2.686         162.63±30.397      146.63±23.058        50.80±21.371* 163.20±27.225     5.04±0.129        9.44±1.645          146.63±23.088      131.97±52.563        33.00±10.654*
Control group ginseng wheat 1g crude drug kg-1 %5min    Rg 2 0.5mg.kg -1           Rg 2 1mg·kg -1 1.41±4.467        14.21±8.438       20.39±20.298        7.56±4.541         -0.91±32.987         37.55±51.367 0.32±3.603        51.17±31.454*     40.18±24.689        57.26±53.091       65.52±40.664*        13.68±19.653 18.26±16.592      42.23±12.611**    36.16±16.556        95.47±36.868***    55.87±18.150**       -15.10±10.032 0.64±4.021        23.63±11.894      34.02±17.304        70.34±65.599       53.66±43.780         9.07±8.205
Control group ginseng wheat 1g crude drug kg-1 %10min   Rg 2 0.5mg·kg -1           Rg 2 1mg·kg -1 11.69±22.703      18.72±16.402      20.67±25.436        13.46±19.357       14.02±70.606         62.83±35.903 1.87±4.650        51.14±25.678*     34.94±38.103        91.31±79.841       110.73±48.655*       6.29±21.304* 25.20±12.247      59.22±12.514**    42.37±18.923        122.57±70.603*     86.70±40.850         -19.98±10.423** 4.65±3.099        47.26±6.300**     53.77±23.325        116.29±88.304*     81.09±54.491         6.51±12.526*
Control group ginseng wheat 1g crude drug kg-1 %30min   Rg 2 0.5mg·kg -1           Rg 2 1mg·kg -1 23.80±32.248      48.50±23.199      41.58±33.550        90.10±21.932       69.66±58.187         59.03±45.001 3.17±15.090       71.61±38.623      60.13±38.331        125.64±79.879      188.61±100.30        0.98±29.367* 42.14±24.097      115.08±15.857***  80.73±18.963        213.45±81.256*     215.58±129.09        -20.00±17.897** 24.97±20.633      93.50±14.148**    90.96±47.076        189.12±77.969 *    182.89±130.83        10.13±16.043
Control group ginseng wheat 1g crude drug kg-1 %60min   Rg 2 0.5mg·kg -1           Rg 2 1mg·kg -1 24.47±33.938      44.72±25.238      30.46±23.233        68.16±33.736       65.66±77.647         73.90±45.804 5.12±14.933       88.16±36.311      79.85±47.776        156.51±64.444*     271.03±194.58        -3.07±22.943** 47.34±29.711      100.21±28.417*    79.78±25.707*       176.11±59.454**    206.16±156.97        -25.27±7.683** 30.79±21.121      111.14±19.557**   101.09±59.766*      248.68±84.912**    136.23±152.47        9.55±14.515*
Control group ginseng wheat lg crude drug kg-1 %120min  Rg 2 0.5mg·kg -1           Rg 21mg·kg -1 21.16±39.435      35.48±42.276      31.61±31.352        54.67±52.366       57.15±74.068         40.28±37.279 3.75±18.907       45.25±28.570      44.41±40.850        110.60±84.629      175.52±104.71        -7.27±12.210* 49.83±35.421      109.50±35.818*    75.70±19.011*       184.57±39.587**    206.10±151.70        -20.04±7.036** 38.11±19.921      123.56±22.711**   81.93±40.657        240.86±59.071***   239.42±123.68*       14.51±13.295
Compare * P<0.05 * * P<0.01 * * * P<0.001 with control group
Table 5. panaxoside Rg2To the impact of hemorrhagic dogs Serum LPO, SOD (n=5, X ± SD)
4.5h after the administration before the administration
Group dosage
                               LPO(nmol/ml)       SOD(nu/ml)      LPO(nmol/ml)    SOD(nu/ml)
Control group---5.38 ± 1.16 81.20 ± 7.79 8.10 ± 0.67 76.00 ± 9.92
Ginseng wheat 1g crude drug kg-1    5.58±0.58         81.60±4.04     6.02±1.24*     101.80±21.74*
Panaxoside Rg2  0.5mg·kg -1     5.68±1.11         80.00±2.45     6.70±0.90*     99.40±12.56*
Panaxoside Rg2  1.0mg·kg 1      5.32±1.21         84.60±10.02    6.86±0.92*     113.60±11.72***
Annotate: compare * P<0.05 * * P<0.01 * * * P<0.001 with control group
Table 6. panaxoside Rg2Impact to hemorrhagic dogs survival rate and total bloodletting amount
Group dosage surviving animals is counted the total bloodletting amount of time-to-live survival rate
                                   (n)          (min)         (%)        (ml)
Control group---1 224.00 ± 87.99 20 540.00 ± 29.155
Ginseng wheat 1g crude drug kg -1       2        297.00±57.62     40     636.00±119.71
Panaxoside Rg2    0.5mg·kg -1        5        360.00±0.00**    100    635.00±89.722
Panaxoside Rg2    1.0mg·kg -1        4        339.20±46.51*    80     596.00±57.706
Annotate: compare * P<0.05 * * P<0.01 with control group
Table 7 panaxoside Rg2To heart failure due to the yellow Jackets and the hemodynamic shadow of Shock Dogs noon (n=5, X ± SD)
Group     HR                  MAP                LVSP             LVEDP                  +dp/dtmax           -dp/dtmax                CO  (beats/min)           (Kpa)              (Kpa)             (Kpa)                    (Kpa/s)            (Kpa/s)               (L/min)
Contrast ginseng wheat 1g crude drug kg-1Normal Rg2 0.5mg·kg -1           Rg 2 1mg·kg -1 175.60±39.450     15.08±2.547        22.13±1.584        0.24±0.174           618.51±100.46       466.55±121.08        1.59±0.575 175.00±21.954     14.07±0.881        22.00±2.757        0.19±0.294           607.85±174.21       479.88±42.153        1.55±0.541 175.20±28.630     11.48±3.042        17.62±4.851        0.11±0.344           479.88±222.27       335.92±131.42        1.54±0.742 161.80±25.236     13.57±2.193        18.93±3.495        -0.08±0.657          419.90±123.26*      383.90±186.24        1.41±0.303
Contrast ginseng wheat 1g crude drug kg-1Heart failure Rg2 0.5mg·kg -1           Rg 2 1mg·kg -1 120.80±23.488     3.45±0.326         7.01±1.260         1.17±0.417           57.32±16.053        22.66±5.961          0.65±0.240 103.80±10.895     3.97±0.460         8.45±0.657         1.15±0.221           71.98±11.923        37.32±11.153*        0.50±0.180 113.00±29.043     4.05±0.729         7.86±0.718         1.23±0.455           62.65±11.152        61.32±56.239         0.82±0.280 110.60±35.444     4.83±1.120*        8.64±2.062         0.99±0.383           63.98±11.153        45.32±17.252*        0.54±0.248
Contrast ginseng wheat 1g crude drug kg-1 %5min    Rg 2 0.5mg·kg -1           Rg 2 1mg·kg -1 -20.00±15.712     2.66±24.371        2.53±29.932        5.80±46.602          -13.76±27.379       -16.00±20.735        -8.11±20.015 1.19±16.159       10.97±8.894        2.74±3.793         -40.00±20.325        15.67±11.093        -2.50±5.586          25.43±28.334 8.26±7.781**      20.75±22.683       18.36±16.784       -48.63±21.082*       52.33±48.155*       15.00±57.555         36.70±17.596** -10.00±10.446     18.44±11.359       10.25±5.414        -48.63±18.068*       29.33±10.314*       24.22±18.159*        35.27±44.711
Contrast ginseng wheat 1g crude drug kg-1 %10min   Rg 2 0.5mg·kg -1           Rg 2 1mg·kg -1 -21.61±17.505     -2.44±24.394       -1.66±27.732       3.14±57.232          -17.09±23.483       -18.67±22.187        -16.01±18.766 7.57±12.392*      7.54±6.921         3.60±3.488         -46.01±16.928        44.00±38.269*       33.34±51.375         48.27±27.993** 7.65±13.058*      22.41±19.190       23.19±20.015       62.82±11.633*        107.23±95.795*      35.00±57.855         52.87±45.485* -4.64±23.629      17.38±9.962        15.43±13.015       54.01±12.937         68.33±45.430**      50.22±23.131*        101.01±90.458*
Contrast ginseng wheat 1g crude drug kg-1 %20min   Rg 2 0.5mg·kg -1           Rg 2 1mg·kg -1 -30.85±16.259     -9.15±15.796       -7.69±19.993       -3.29±37.575         -20.24±25.576       -21.67±21.732        -22.56±23.611 5.84±8.426**      13.68±21.660       12.00±21.781       -48.12±13.016*       63.34±39.349**      60.00±41.832**       83.26±54.311** 8.22±18.826**     30.32±16.116**     25.33±18.45*       -66.07±10.814**      137.44±37.779***    84.17±91.874*        60.32±53.279* -3.62±24.187      25.21±5.924**      23.19±14.663*      -61.61±8.623**       149.67±99.166**     130.21±127.09*       150.50±143.740*
Contrast ginseng wheat 1g crude drug lg-1 %40min   Rg 2 0.5mg·kg -1           Rg 2 1mg·kg -1 -30.75±13.108     -21.83±18.483      -21.31±21.513      -3.35±36.494         -30.24±26.833       -21.67±21.732        -30.00±21.938 12.06±9.989***    27.47±22.714**     23.08±21.183*      -40.29±7.455         118.67±62.743**     101.67±85.473*       128.02±51.304*** 15.82±18.113**    39.85±13.817***    29.41±9.039**      -62.70±8.099**       138.39±36.185***    110.00±104.52*       80.37±75.473* 2.14±31.649       34.37±16.708***    41.58±37.014*      -54.01±12.937*       215.00±140.36**     140.20±176.54        179.03±138.39*
Contrast ginseng wheat 1g crude drug kg-1 %60min   Rg 20.5mg·kg -1           Rg 21mg·kg -1 -22.68±12.671     -21.13±14.894      -25.13±14.873      10.98±32.930         -37.58±23.593       -33.32±25.683        -35.95±22.034 1.87±15.356*      25.27±29.611*      23.25±24.665**     -39.38±9.915*        109.00±53.510***    108.33±140.44        105.40±51.842*** 2.14±13.611*      43.33±19.31****    27.68±7.967***     -62.68±10.994**      128.44±47.035***    81.67±105.15*        58.67±64.078* 2.65±33.403       47.74±39.903*      47.82±42.208**     -61.60±20.804**      267.00±174.84**     199.98±212.43*       189.16±134.910**
Compare * P<0.05, * * P<0.01, * * * * P<0.001 with control group
Table 8 panaxoside Rg2And solvent is to the impact (n=10) of guinea pig in vitro papillary muscle shrinkage amplitude
Figure C0110211700201
Table 9 ouabain is to the impact of guinea pig in vitro papillary muscle shrinkage amplitude (n=10, X ± SD)
Figure C0110211700202
Table 10 panaxoside Rg2To dogs with acute myocardial ischemia external membrane of heart the influence of peak current (n=5, X ± SD)
Group Ischemic scope degree of ischemia N-ST ε-ST (mv)
Control group is given birth to arteries and veins 140mgkg-1Normal Rg2 0.5mg·kg -1               Rg 2 1.0mg·g -1 20.80±4.147                  117.40±46.278 20.80±2.387                  123.40±27.844 21.20±2.168                  137.70±11.638 20.20±1.304                  159.40±63.545
Give birth to arteries and veins 140mgkg behind the control group medicine-1 10min         Rg 2 0.5mg·kg -1  %           Rg 2 1.0mg·kg -1 4.37±35.312                  22.64±98.041 -36.79±30.684                -41.82±26.789 -5.44±18.424                 -34.81±15.265 -35.75±22.697                -43.41±16.450
Give birth to arteries and veins 140mgkg behind the control group medicine-1 30min         Rg 2 0.5mg·kg -1  %           Rg 2 1.0mg·kg -1 3.53±11.035                  37.75±66.866 -25.48±13.204**              -41.01±26.434* -27.89±21.228*               -48.93±22.948* -43.06±18.266**              -56.74±15.150*
Give birth to arteries and veins 140mgkg behind the control group medicine-1 60min         Rg 2 0.5mg·kg -1  %           Rg 2 1.0mg·kg -1 2.57±18.925                  25.57±27.590 -24.38±34.579                -42.63±20.016** -36.13±29.193*               49.26±12.198*** -38.19±32.394*               -57.80±11.831***
Give birth to arteries and veins 140mgkg behind the control group medicine-1 120min        Rg 2 0.5mg·kg -1  %           Rg 2 1.0mg·kg -1 4.21±35.364                  34.41±84.792 -37.02±27.443                -52.79±14.903 -25.34±30.834                -48.77±6.332 -17.64±24.145                -44.61±37.053
Compare * P<0.05, * * P<0.01 * * * P<0.001 with control group
Table 11 panaxoside Rg2To the impact of acute ischemia dog serum cardiac muscle three enzymes and infarct size (n=5, X ± SD)
Group AST CK LDH infarct size infarct size (IU/L) is (IU/L) (accounting for whole-heartedly %) (accounting for ventricle %) (IU/L)
Control group is given birth to arteries and veins 140mgkg-1Shock Rg20.5mg·kg -1                 Rg 21.0mg·kg -1 56.40±21.031        122.40±34.588      169.00±103.45 29.00±2.345*        62.80±38.324*      274.60±32.470* 34.20±17.079        86.20±37.838       118.60±58.166 30.80±19.524        78.60±48.195       112.60±79.852
Give birth to arteries and veins 140mgkg behind the control group medicine-1 360min          Rg 2 0.5mg·kg -1                 Rg 2 1.0mg·kg -1 195.80±59.260       704.60±282.71      214.00±55.767      16.43±2.018            22.38±2.203 86.20±47.442*       274.60±157.78*     115.20±63.519*     11.27±3.191*           15.20±4.549* 45.60±18.022***     107.20±52.108**    119.80±44.690*     10.03±2.296**          13.46±3.674** 66.60±42.653**      122.20±72.947**    152.40±100.04      8.30±3.043**           11.63±4.860**
Compare * P<0.05, * * P<0.01, * * * P<0.001 with control group
Table 12. panaxoside Rg2Isoprel is caused the impact (X ± SD) of myocardial ischemia in rats
The eccentric myonecrosis heart rate of J point behind the medicine (inferior/minute)
The group number of animals
Moved before sum (mm) degree (%) administration after the administration 30 fens
Control group 11 9.41 ± 5.69 7.31 ± 2.92 247.7 ± 14.7 257.1 ± 12.5
Ginseng wheat 2g crude drug kg-1   11    5.14±1.76*    2.94±1.22***    264.4±16.6    265.1±14.1
Rg 2 2.5mg·kg -1   9     4.17±2.85*    2.52±1.52***    241.0±11.9    244.2±24.3
Rg 2 5.0mg·kg -1   11    5.00±2.52*    1.81±1.64***    248.2±17.9    246.4±20.1
Annotate: compare * P<0.05, * * P<0.01, * * * P<0.001 with control group
Table 13. panaxoside Rg2To the impact of myocardial ischemia in rats due to the pituitrin (X ± SD)
J point eccentricity behind the medicine (inferior/minute)
The group number of animals
Moved before sum (mm) administration after the administration 30 fens
Control group 10 15.75 ± 4.37 474.7 ± 36.8 452.9 ± 39.5
Ginseng wheat 2g crude drug kg-1  8      10.69±3.85*      461.9±41.5    425.2±60.1 
Rg 2 2.5mg·kg -1  11     7.77±3.81***     465.7±20.8    437.9±19.8
Rg 2 5.0mg·kg -1  10     7.10±2.88***     464.2±30.1    431.0±36.6
Annotate: compare * P<0.05 * * * P<0.01 * * * P<0.001 with control group
Table 14 panaxoside Rg2To the dehisce impact (X ± SD) of breathing time of mouse broken end
The group dosage number of animals breathing time of dehiscing
(only) (S)
Control group---10 19.0 ± 3.86
Nimotop 1mgkg-1    10    24.9±2.92**
Panaxoside Rg2   5mg·kg -1    10    22.5±2.51*
Panaxoside Rg2   10mg·kg -1   10    23.4±2.67**
Compare * P<0.05, * * P<0.01 with control group
Table 15 panaxoside Rg2Impact to mouse broken end brain tissue CK, LDH
Group dosage number of animals CK LDH
(only) (u/100g tissue) (u/100g tissue)
Control group---12 21415.3 ± 808.7 2843.7 ± 255.4
Nimotop 1mgkg-1     12    20594.8±640.0**     2711.7±261.9
Panaxoside Rg2   5mg·kg -1     12    21024.1±1162.8      2873.3±238.6
Panaxoside Rg2   10mg·kg -1    12    19447.1±1014.1***   2788.8±266.4
Compare * P<0.05, * * P<0.01, * * * P<0.001 with control group

Claims (3)

1. panaxoside Rg 2Application in the preparation treatment heart, cerebrovascular disease medicament is characterized in that, the application in preparation treatment shock, the medicaments for resisting myocardial ischemia.
2. application as claimed in claim 1, wherein said shock is selected from cardiogenic shock, hemorrhagic shock or endotoxin shock; Said cerebral ischemia is selected from apoplexy.
3. according to any described application in claim 1 or 2, it is characterized in that described medicine comprises pharmaceutically suitable carrier pharmaceutical preparation, can be injection, tablet, capsule, aerosol, suppository, oral mucous membrane patch, chewable tablet, syrup or other oral liquid formulation.
CNB011021179A 2000-01-31 2001-01-21 Application of ginsenoside Rg2 in preparing medicine for cardio-and cerebro-vascular disease Expired - Fee Related CN1156281C (en)

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CN100378119C (en) * 2004-10-20 2008-04-02 吉林省中医中药研究院 Gen-seng saponin Rg2 preparation method, its pharmaceutical composition and uses in pharmacy
JP4773512B2 (en) * 2005-04-26 2011-09-14 コ,ブン−キョン Extraction method of ginseng saponin Rg2, pharmaceutical composition containing the extract and use thereof
CN100337636C (en) * 2005-07-14 2007-09-19 中国医药研究开发中心有限公司 Medicinal composition contg. ginseng secondary glycosides, prepn. method and application thereof
CN101397327B (en) * 2007-09-29 2012-01-11 广州天安医药科技有限公司 Use of dihydro ginsenoside Rg2

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* Cited by examiner, † Cited by third party
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