CN102397281B - Ginsenoside composition for treating cardiovascular and cerebrovascular diseases - Google Patents
Ginsenoside composition for treating cardiovascular and cerebrovascular diseases Download PDFInfo
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Abstract
The present invention relates to the field of medicine, and discloses a pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, wherein the pharmaceutical composition comprises a ginsenoside monomer Rg1 and a ginsenoside monomer Rb1, a weight ratio of the Rg1 to the Rb1 is 1:4-4:1. The ginsenoside composition of the present invention has the following advantages that: the pharmaceutical composition of the present invention has effects of blood activating and stasis removing, blood circulation promoting and collateral activating, and can be applicable for obstruction of collaterals by blood stasis, apoplectic hemiplegia, chest stuffiness and pains, and central retinal vein occlusion; the efficacy of the pharmaceutical composition is definite; the adverse reaction rate is significantly reduced; when the weight ratio of the Rg1 to the Rb1 is 1:4, the LD50 of the ginsenoside composition is more than 1000 mg/kg, and is significantly higher than the LD50 of panax notoginsenosidum; the ginsenoside composition provides the significant inhibition effect for thrombosis, and the anticoagulant effect so as to essentially improve various damages of ischemic cardiovascular and cerebrovascular disease patients due to ischemia.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of by ginsenoside monomer Rg
1With ginsenoside monomer Rb
1The pharmaceutical composition of the treatment cardiovascular and cerebrovascular disease that forms.
Background technology
Cardiovascular and cerebrovascular disease is the primary disease that threatens human health, to cause dead and maximum disease that disables, regarded as " the No.1 killer " of harm humans health by World Health Organization (WHO) (WHO), the whole world has 1,500 ten thousand people to die from cardiovascular and cerebrovascular disease every year approximately, accounts for more than 50% of death toll.China has 4,000,000 people to die from this disease every year approximately, just has a people to die from this disease in per 24 seconds, accounts for 40% of the total cause of the death of China with regard to there being a people therefore to disable in per 13 seconds.According to World Health Organization's prediction, to the year two thousand twenty, noninfectious will account for 79% of China's cause of death, and wherein cardiovascular disease accounts for the first place.Cardiovascular and cerebrovascular disease has the low characteristics of three-hypers one: sickness rate is high, disability rate is high, mortality rate is high, cure rate is low.Cardiovascular and cerebrovascular disease sickness rate the highest countries and regions in the whole world are just in China, and China take in the north as high region of disease.The family that causes thus, medical treatment and financial burden have become the social problem that can not despise.
The cardiovascular and cerebrovascular diseases medicine that how evident in efficacy society need is more, safe.The diseases of cardiovascular and cerebrovascular systems medication is the focus of drug development research in the world wide, production application always.Therefore, Development and Production diseases of cardiovascular and cerebrovascular systems medication and realize that industrialization has extremely important social meaning and economic implications.
Radix Notoginseng total arasaponins has blood circulation promoting and blood stasis dispelling, the active effect of promoting blood circulation, at present Radix Notoginseng total arasaponins and preparation XUESAITONG series of products thereof are widely used in apoplectic hemiplegia, obstruction of collaterals by blood stasis and sequal of cerebrovascular diseases, obstruction of qi in the chest and cardialgia clinically, central retinal vein occlusion belongs to blood-stasis syndrome person.Complicated component in the Radix Notoginseng total arasaponins, at present known and mainly contain ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, ginsenoside Rd and arasaponin R1 as the composition of quality control index, other rare saponin are lower because of content, be difficult to measure its content, and because the difference of pseudo-ginseng and each preparation technology's of producer difference causes ginsenoside Rg1 in the different batches Radix Notoginseng total arasaponins, ginsenoside Rb1, ginsenoside Re, ginsenoside Rd, arasaponin R1 and other rare saponin contents in various degree difference and ratio different are arranged all.Because adverse reaction rate is rising year by year, along with consumption constantly increases and enlarges, safety issue has become important problem in the clinical application process.
Summary of the invention
The purpose of this invention is to provide a kind of pharmaceutical composition of safer treatment cardiovascular and cerebrovascular disease, it is definite to have drug effect, safe, the advantage that untoward reaction is low.
The pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease provided by the invention comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1, Rg wherein
1With Rb
1Part by weight is 1: 4～4: 1.
As preferably, described pharmaceutical composition is by ginsenoside monomer Rg
1With ginsenoside monomer Rb
1Form, wherein Rg
1With Rb
1Part by weight is 1: 4～4: 1; Described cardiovascular and cerebrovascular disease is hemorrhage or ischemic diseases.
More preferably, Rg in the described pharmaceutical composition
1With Rb
1Part by weight is 1: 4.
The present invention also provides a kind of pharmaceutical preparation for the treatment of cardiovascular and cerebrovascular disease, comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1And pharmaceutically acceptable adjuvant, wherein Rg
1With Rb
1Part by weight is 1: 4～4: 1.
More preferably, Rg in the described pharmaceutical preparation
1With Rb
1Part by weight is 1: 4.
As preferably, described pharmaceutical preparation is injection, freeze-dried powder injection or oral formulations.
Bibliographical information is arranged, and ginsenoside Rb1, ginsenoside Rg1 be at expeirmental myocardial ischemia, similar to Radix Notoginseng total arasaponins to aspects such as vascular smooth muscle effects, and both be the effective ingredient of blood vessel dilating smooth muscle.Therefore in early-stage Study, the inventor utilizes the cardiovascular and cerebrovascular disease model, the proportioning combination that the repeated screening checking is comprised of Ginsenoside Rg1 and Rb1.Along with going deep into of research, the inventor has found to have more the proportioning combination of the Ginsenoside Rg1 and Rb1 of therapeutic activity in the cardiovascular and cerebrovascular disease model take antiplatelet aggregation, antithrombotic and anti-anoxia enduring as index.Ginsenoside Rg1 in the tradition Radix Notoginseng: about 1: 1 of ginsenoside Rb1's proportioning, traditional knowledge thinks that Rg1 is the main component of activating blood circulation to dissipate blood stasis, the activity of Rb1 blood circulation promoting and blood stasis dispelling is very weak, therefore, the Ginsenoside Rg1 and Rb1 proportioning conforms to traditional Radix Notoginseng in the prior art, the ginsenoside Rg1: about 1: 1 of ginsenoside Rb1's proportioning, and think that the ginsenoside Rg1 has stronger haemolysis in the Radix Notoginseng, the ginsenoside Rb1 is then without haemolysis.
In arasaponin injection standard, hemolytic test is the important indicator of safety evaluatio always.The inventor furthers investigate unexpected discovery, and new proportioning ginsenoside Rg1's ratio of the present invention significantly reduces, and ginsenoside Rb1's ratio raises, Rg
1With Rb
1Part by weight is 1: 4, and its safety is more excellent than Radix Notoginseng and Radix Notoginseng total arasaponins preparation.
According to the present invention, described pharmaceutical composition has significant antiplatelet aggregative activity, but antithrombotic; The described pharmaceutical composition of specificity cardiac muscle anoxia enduring models show has the patient flesh anoxia functions of highly significant, and the time-to-live Rg1 of mice: Rb1 (1: 4) group exceeds nearly 10% than the Radix Notoginseng total arasaponins group.
Collagen protein-epinephrine brought out thrombotic impact studies show that in the Mice Body; the protective effect (P＜0.01) of pharmaceutical composition group tool highly significant of the present invention; and Rg1: Rb1 (1: 4) group and Rg1: Rb1 (1: 1) group compare mortality rate far below the Radix Notoginseng total arasaponins group with the Radix Notoginseng total arasaponins group; point out other composition influences in the possibility Radix Notoginseng total arasaponins and cause mortality rate to raise, and the ability that makes its antagonism collagen protein-epinephrine bring out the mice thrombus in vivo that increases of Rb1 ratio is strengthened.
Impact on the cerebral ischemia of head-breaking chmice acute studies show that, but panting the time of pharmaceutical composition significant prolongation decapitated mice of the present invention, the rate elongation of Rg1: Rb1 (1: 4,1: 5) group is than the Radix Notoginseng total arasaponins group leader, and the rate elongation of Rg1: Rb1 (1: 4) group is high than the rate elongation of Rg1: Rb1 (1: 5) group.
Pharmaceutical composition of the present invention can obviously prolong the clotting time of mice, and wherein, the rate elongation of Rg1: Rb1 (1: 4) group is high by 20% than the Radix Notoginseng total arasaponins group.
Hemolytic experiment shows that the Rg1 of same concentrations: Rb1 (1: 4) group, Rg1: Rb1 (1: 1) group and Rg1: Rb1 (4: 1) group are later than Rg1: Rb1 (5: 1) group and Radix Notoginseng total arasaponins group generation hemolytic reaction.
Ginsenoside Rg in the pharmaceutical composition of the present invention
1Or Rb
1Derive from crude drug Radix Notoginseng, Radix Ginseng, Radix Panacis Quinquefolii or semi-synthetic, can buy from the market, purity requirement is more than 90%.
Pharmaceutical composition of the present invention has blood circulation promoting and blood stasis dispelling, and the active effect of promoting blood circulation is used for obstruction of collaterals by blood stasis, apoplectic hemiplegia, obstruction of qi in the chest and cardialgia and central retinal vein occlusion disease, drug effect is definite, adverse reaction rate obviously reduces, and Rg1 and Rb1 part by weight are 1: 4 o'clock, its LD
50Greater than 1000mg/kg, be significantly higher than the LD of Radix Notoginseng total arasaponins
50(455mg/kg); Can obviously suppress thrombosis effect and anticoagulation, the various damages that can produce because of ischemia from improve ischemic cardiac disease of brain patient at all.
Pharmaceutical composition of the present invention has obvious antithrombotic, antiplatelet aggregation and anti-resisting oxygen lack, and finds that by the proportioning test research of different proportion its pharmacologically active is strong than the Radix Notoginseng total arasaponins effect.Tradition thinks that the ginsenoside Rg1 is the main component of invigorating blood circulation in the Radix Notoginseng, and have stronger haemolysis, and a little less than ginsenoside Rb1's effect of invigorating blood circulation, but the present invention confirms when compound recipe, tradition thinks that the composition Rg1 proportion of invigorating blood circulation is few, has on the contrary the effect of better invigorating blood circulation.And from acute toxicity test and hemolytic test, the present invention improves significantly aspect safety, and the present invention compares with Radix Notoginseng total arasaponins, and hemolytic obviously reduces, thereby more can ensure the safety of preparation.
The specific embodiment
The invention discloses a kind of pharmaceutical composition that comprises ginsenoside monomer Rg1 and Panaxadiol Saponins Monomer Rb1 for the treatment of cardiovascular and cerebrovascular disease, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described within not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
The ginsenoside monomer Rg1 that the present invention treats cardiovascular and cerebrovascular disease and Panaxadiol Saponins Monomer Rb1 compositions are compared the advantages such as to have drug effect suitable, and it is fixing to become to distinguish one from the other, quality controllable with other Radix Notoginseng total arasaponins ejection preparations, prove by following pharmacodynamic experiment.
Further details of the present invention can find in an embodiment, rather than protection domain is restricted to this embodiment.
Below in conjunction with embodiment, further set forth the present invention:
Test specimen
The ginsenoside Rg1, Kunming Medicine Group Stock Co., Ltd provides, purity 99.3%, lot number 20091011; The ginsenoside Rb1, Kunming Medicine Group Stock Co., Ltd provides, purity 98.6%, lot number 20091109; Radix Notoginseng total arasaponins, Kunming Medicine Group Stock Co., Ltd provides, content 93%, lot number 20080115.
Embodiment 1, ginsenoside Rg1, ginsenoside Rb1 and proportioning thereof are induced the impact of rabbit extracorporeal platelet aggregation on ADP
1 medicine
1.1 tested medicine preparation
The experiment before with distilled water be mixed with high concentration be 3.5700mg/ml, middle concentration be 1.7850mg/ml, low concentration be 0.8925mg/ml as the solution of final concentration, the ginsenoside Rg1 all forms by the different volumes proportioning mixing of ginsenoside Rg1 and the above-mentioned concentration of ginsenoside Rb1 from ginsenoside Rb1's different proportioning solution preparations.Normal group is selected normal saline, wherein adds tween 30 μ l in the tested medicine of each dosage and the normal saline among every 10ml.More than tested medicine before treated in vitro, all be mixed with clear and bright solution.
1.2 reagent
Adenosine diphosphate (ADP) (ADP): Sigma company product; Sodium citrate: Tianjin chemical reagent three factories, lot number: 061107; Sodium chloride injection: Kuming Nanjiang Pharmacy Co., Ltd, lot number: A08070412; Chloral hydrate (analytical pure): the special chemicals company limited in Rui Jin, Tianjin, lot number: 20060917; Tween 80 (chemical pure CP): Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20050324.
2 animals
Healthy rabbits, ♀
Dual-purpose, body weight 2-2.5kg, Sichuan Province's medical scientific institute Institute of Botany provides product batch number: Dossy-2009-10.
3 instruments
LBY-NJ2 blood pool instrument: Pulisheng Instruments Co., Ltd., Beijing; LG10-2.4A high speed centrifuge: Beijing high speed centrifuge factory.
4 statistical method
The measurement data one factor analysis of variance relatively adopts the Dunnett check between many groups.
Test method
1 test principle
Platelet rich plasma (platelet rich plasma, PRP) has certain turbidity, and platelets contained number directly has influence on the turbidity height among the PRP.After derivant adds PRP, under the condition that stirs, the integrated aggregation of platelet aggregation, the PRP turbidity descends, and light transmittance increases, and therefore changes to represent hematoblastic aggregation extent by the turbidity of measuring PRP.Be changed to the electric signal variation because the electro-optical system in the platelet aggregation instrument can change the turbidity of PRP dress, and trace with monitor.
2 drug level setting and foundations
2.1 ginsenoside Rg1 and ginsenoside Rb1 and Radix Notoginseng total arasaponins: the high concentration final concentration is that 3.57mg/ml arranges.This is tested the setting of high, medium and low concentration group dosage and is set to by geometric progression: (1) A medicine ginsenoside Rg1, B medicine ginsenoside Rb1 and Radix Notoginseng total arasaponins high dose group: 3.5700mg/ml; (2) concentration group: 1.7850mg/ml in ginsenoside Rg1 and ginsenoside Rb1 and the Radix Notoginseng total arasaponins; (3) ginsenoside Rg1 and ginsenoside Rb1 and Radix Notoginseng total arasaponins low concentration group: 0.8925mg/ml.
2.2 route of administration
Each medicine is external giving.
2.3 observation index
Platelet maximum agglutination rate and platelet aggregation inhibition rate.
3 test procedures
3.1 get blood
Chloral hydrate intraperitoneal injection of anesthesia rabbit with 10% is got blood from common carotid artery, is collected in the disposable plastic tube, adopts 3.2% sodium citrate anticoagulant, and blood and anticoagulant volumetric ratio are 9: 1, puts upside down immediately mixing (can not firmly rock) after getting.
3.2 the preparation of platelet rich plasma (platelet rich plasma, PRP) and platelet poor plasma (platelet poorplasma, PPP)
Blood adopts respectively the centrifugal 6min of 800r/min in room temperature, and the gained upper plasma is different rotating speeds PRP.With the centrifugal 15min of 3000r/min, upper strata liquid is PPP to residual blood again.In the process of the test, the platelet count among the PRP is controlled at and is about 500,000 mm-3.。
3.3 the mensuration of platelet maximum agglutination rate (MaxRate)
Adopt platelet aggregation instrument to measure by BornShi turbidimetry principle.Get respectively different rotating speeds PPP300 μ l in than zeroing in the turbid cup, get PRP 270 μ l and add solvent or tested medicinal liquid 30 μ l, incubation 5min in 37 ℃ of preheating gates in another in than turbid cup.During mensuration the PPP cup is inserted in the instrument connection and returns to zero, take out the PPP cup and insert the PRP cup, and add stirrer in PRP, then adding final concentration under the instrumentation prompting is the derivant ADP 10 μ l of 15 μ mol/L, induced platelet is assembled, and measures platelet maximum agglutination rate in the 5min.Platelet aggregation inhibition rate is calculated as follows: assemble suppression ratio (%)=(1-administration group aggregation rate/matched group aggregation rate) * 100%.
4 result of the tests
Ginsenoside Rg1 and each concentration of ginsenoside Rb1's Radix Notoginseng total arasaponins and ginsenoside Rg1, each proportioning of ginsenoside Rb1 are induced the impact of rabbit extracorporeal platelet aggregation effect on ADP, the results are shown in Table 1, as can be seen from Table 1: compare with Normal group, ginsenoside Rg1, ginsenoside Rb1's height, middle dosage group and the high, medium and low dosage group of Radix Notoginseng total arasaponins and Normal group compare, and difference all has significant (P＜0.05, P＜0.01 or P＜0.001); Rg1: Rb1=1: Isosorbide-5-Nitrae: 1,1: 4,2: 1,1: 2 high concentration and Rg1: Rb1=1: 4 middle concentration and Normal group compare, and difference all has significant (P＜0.05, P＜0.01 or P＜0.001).
5. conclusion
The ginsenoside Rg1, ginsenoside Rb1's height, middle concentration and the high, medium and low concentration of Radix Notoginseng total arasaponins, and Rg1: Rb1=1: Isosorbide-5-Nitrae: 1,1: 4,2: 1,1: 2 high concentration and Rg1: Rb1=1: 4 middle concentration has significant antiplatelet aggregative activity.Experimental result is as seen when senior middle school's dosage, and Rg1: Rb1=1: the 4 pairs of hematoblastic suppression ratio are identical with Radix Notoginseng total arasaponins, point out this proportioning that the effect of antithrombotic is arranged.
Table 1A, B medicine and the different proportionings of Radix Notoginseng total arasaponins and A: B on ADP induce rabbit extracorporeal platelet aggregation rate impact (
N=6)
Annotate: A is the ginsenoside Rg1, and B is the ginsenoside Rb1.Compare with Normal group:
*P＜0.05;
*P＜0.01;
* *P＜0.001
Embodiment 2 ginsenoside Rgs
1With Rb
1Different proportionings are on the impact of specificity cardiac muscle anoxia enduring model
1, test material:
Medicine: ginsenoside Rg
1With ginsenoside Rb
1Prepare respectively Rg1: Rb1=1: 4,4: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1
Reagent and equipment: isoproterenol hydrochloride inj (2ml:1mg Shanghai Hefeng Pharmaceutical Co., Ltd.), 250ml ground wide mouthed bottle, timer, sodica calx vaseline etc.
Laboratory animal: SPF level ICR mice, ♀
Dual-purpose, W:18～22g, laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods:
Mice is divided into 8 groups at random: Rg1: Rb1 (5: 1) group, Rg1: Rb1 (4: 1) group, Rg1: Rb1 (1: 1), Rg1: Rb1 (1: 4), Rg1: Rb1 (1: 5) group, Radix Notoginseng total arasaponins group, model group and blank group, every group 10, below respectively organize intraperitoneal injection 120mg/kg every day, administration volume 0.1ml/10g; Model group and blank group all give isometric normal saline, continuous 5 days.Each group is respectively at behind the last tail iv administration 10min, ip isoproterenol injection 0.4ml/10g (blank group is not given), behind the 15min mice is put into the ground wide mouthed bottle that fills the 20g sodica calx, immediately timing is to cease breathing as the index observing mouse survival time.
3 result of the tests:
Table 2 is on the impact of mouse survival time of specificity myocardial ischemia
| Group | Dosage (mg/kg) | Time-to-live (min) |
| Blank group | - | 22.31±3.59 |
| Model group | - | 18.23±2.45 ΔΔ |
| Rg1∶Rb1(5∶1) | 120 | 19.36±3.54* |
| Rg1∶Rb1(4∶1) | 120 | 19.87±4.22* |
| Rg1∶Rb1(1∶1) | 120 | 20.18±2.66* |
| Rg1∶Rb1(1∶4) | 120 | 22.08±4.27** |
| Rg1∶Rb1(1∶5) | 120 | 21.44±4.31* |
| Radix Notoginseng total arasaponins | 120 | 20.77±4.21* |
The Δ ΔP＜0.01, model group relatively has significant differences with blank group;
*P＜0.01, administration group and model group relatively have significant differences;
*P＜0.05, administration group and model group relatively have significant difference;
As shown in Table 2, Rg1: Rb1 (1: 4) group has the patient flesh anoxia functions (p＜0.01) of highly significant, and the Radix Notoginseng total arasaponins group has significant patient flesh anoxia functions (p＜0.05).From result of the test, under same dosage condition, the time-to-live Rg1 of mice: Rb1 (1: 4) group exceeds nearly 10% than the Radix Notoginseng total arasaponins group.And the time-to-live of Rg1: Rb1 (1: 1) group is compared no significant difference with the Radix Notoginseng total arasaponins group, illustrates that the main component of the anti-myocardial ischemia of Radix Notoginseng total arasaponins is ginsenoside Rg1 and ginsenoside Rb1.
Embodiment 3: collagen protein-epinephrine is brought out thrombotic impact in the Mice Body
1 test material
Medicine: ginsenoside Rg
1With ginsenoside Rb
1Prepare respectively Rg1: Rb1=1: 4,4: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1Visit aspirin, U.S. Beyer Co., Ltd produces.
Reagent: collagen protein, epinephrine etc.
Laboratory animal: SPF level ICR mice, ♀
Dual-purpose, W:18～22g, laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods:
Get 60 of mices, be divided at random 8 groups: Rg1: Rb1 (5: 1) group, Rg1: Rb1 (4: 1) group, Rg1: Rb1 (1: 1), Rg1: Rb1 (1: 4), Rg1: Rb1 (1: 5) group, Radix Notoginseng total arasaponins group, positive group and blank group, every group 10, below respectively organize intraperitoneal injection 120mg/kg every day, administration volume 0.1ml/10g; Positive group gavage is visitd aspirin 20mg/kg; Blank group gavage gives isometric normal saline, continuous 5 days.15min after the last administration (positive group and blank the group are 45min after the administration) gives derivant by tail iv; observe and record dead mouse number in 5 minutes or the recovery number of mice hemiplegia in 15 minutes; calculate each medicine to mouse brain thrombosis protective rate, the results are shown in Table 3.
Table 3 brings out thrombotic impact in the Mice Body to collagen protein-epinephrine
Compare with the blank group:
*P＜0.05;
*P＜0.01
Experimental result shows; whole hemiplegia in 5 minutes behind the blank treated animal injection derivant; dead in 15 minutes; the positive controls aspirin has the protective effect (P＜0.01) of highly significant; Rg1: Rb1 (1: 1) group and Rg1: Rb1 (1: 4,1: 5) organize also has a protective effect (P＜0.01) of highly significant, Rg1: Rb1 (1: 4) group and Radix Notoginseng total arasaponins group relatively mortality rate far below the Radix Notoginseng total arasaponins group.And Rg1: Rb1 (1: 1) group mortality rate is low than the Radix Notoginseng total arasaponins group, point out other composition influences in the possibility Radix Notoginseng total arasaponins and cause mortality rate to raise, and the ability that makes its antagonism collagen protein-epinephrine bring out the mice thrombus in vivo that increases of Rb1 ratio is strengthened.
Embodiment 4: on the impact of head-breaking chmice acute cerebral ischemia
1 test material
Medicine: ginsenoside Rg
1With ginsenoside Rb
1Prepare respectively Rg1: Rb1=1: 4,4: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h1.Naodesheng capsules, (97) are defended the accurate word Z-121 of medicine number, the 0.28g/ grain, and Guizhou really refreshing pharmaceutcal corporation, Ltd produces lot number 20081201.
Laboratory animal: SPF level ICR mice, ♀
Dual-purpose, W:19～22g, laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods
Get 72 of mices, male and female half and half are divided into 8 groups at random by table 4,12 every group.Each treated animal according to dosage in every day intraperitoneal administration once, blank group gavage gives sodium chloride injection 20ml/kg, the positive controls gavage gives NAODESHENG 1.68g/kg, continuous 7 times.30min after the last administration cuts after mouse ear fast broken end with profit, and record begins to the last snorting time from broken end.The results are shown in Table 4.
Table 4. is on the impact of head-breaking chmice acute cerebral ischemia
Compare with the blank group:
*P＜0.05;
*P＜0.01
Experimental result shows, but panting the time of administration group significant prolongation decapitated mice, the rate elongation of Rg1: Rb1 (1: 4,1: 5) group is than the Radix Notoginseng total arasaponins group leader, and the rate elongation of Rg1: Rb1 (1: 4) group is high than the rate elongation of Rg1: Rb1 (1: 5) group.
Embodiment 5: on the impact of clotting time of mice
1 test material
Medicine: ginsenoside Rg1 and ginsenoside Rb1 prepare respectively Rg1: Rb1=1: 4,1: 5,5: Isosorbide-5-Nitrae: 1,1: 1 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1Visit aspirin, U.S. Beyer Co., Ltd produces.
Laboratory animal: SPF level ICR mice, ♀
Dual-purpose, W:18～20g, laboratory animal room of Kunming Medicine Group Stock Co., Ltd produces, production licence number: SCXK (Yunnan) 2009-0001; Occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods
Get 60 of mices, male and female half and half are pressed table 5 and are divided into groups immediately, 10 every group.Each treated animal according to dosage in every day intraperitoneal administration once, blank group gavage gives sodium chloride injection 20ml/kg, the positive controls gavage gives aspirin 20g/kg, continuous 7 days.30min after the last administration plucks eyeball and gets blood, and slide method is measured the clotting time of respectively organizing mice.The results are shown in Table 5.
Table 5 is on the impact of clotting time of mice
Compare with the blank group:
*P＜0.05;
*P＜0.01
Experimental result shows that the administration group all can obviously prolong the clotting time of mice, and wherein, the rate elongation of Rg1: Rb1 (1: 4) group is high by 20% than the Radix Notoginseng total arasaponins group.
Embodiment 6: compositions of the present invention and the comparative study of Radix Notoginseng total arasaponins toxicity
With reference to version in 2005 " Chinese pharmacopoeia abnormal toxicity tests method and the present invention and relevant Radix Notoginseng total arasaponins are carried out toxicity test relatively with reference to the acute toxicity test method.
Table 6. the acute toxicity tests (LD
50)
Embodiment 7: compositions of the present invention and the comparative study of Radix Notoginseng total arasaponins ejection preparation hemolytic test
As the saponins Chinese medicine, hemolytic test is the important indicator as its safety evaluation always, carries out molten according to the test method of " Chinese medicine, natural drug zest and hemolytic investigative technique guideline "
Blood test is observed the present invention and haemolysis and the cohesion situation of Radix Notoginseng total arasaponins under variable concentrations.
1 test material
Medicine: ginsenoside Rg1 and ginsenoside Rb1 prepare Rg1: Rb1=1: 4 (W/W) mixture; Radix Notoginseng total arasaponins is produced content 93%, lot number: 20080115 by Kunming Medicine Group Stock Co., Ltd; 0.9% sodium chloride injection, Kuming Nanjiang Pharmacy Co., Ltd produces, lot number: 080530h
1
Laboratory animal: regular grade large ear rabbit, ♀
Dual-purpose is provided by unming Medical College's Experimental Animal Center, laboratory animal production licence card SCXK (Yunnan) 2005-2008, occupancy permit number: SYXK (Yunnan) 2009-0001.
2 test methods
The preparation of 2% red blood cell suspension: get Sanguis Leporis seu oryctolagi 20～30ml, remove Fibrinogen, add the about 10 times of amount washings of chlorination sodium injection, the centrifugal 15min of 1500r/min abandons supernatant, repeats 2～3 times, until till the not aobvious redness of supernatant, abandon supernatant, the gained erythrocyte is prepared 2% red blood cell suspension with sodium chloride injection, be for experiment.
The preparation of test liquid: precision takes by weighing this product, adds the chlorination sodium injection and is dissolved as every 1ml and contains the solution of 15mg and 25mg as test liquid.
The method of inspection:
Get respectively 7 in test tube, wherein 1～No. 5 pipe is for tested medication tube, manages negative control tube No. 6, manages positive control tube No. 7.Add 2% red cell suspension, sodium chloride injection, distilled water shown in the according to the form below, place immediately 37 ℃ ± 0.5 ℃ thermostatic water tank to carry out incubation behind the mixing.Beginning was observed once every 15 minutes, and the interval was observed once continuous 24 hours in 1 hour behind the 1h.
Be clear and bright redness such as the solution in the test, the pipe end, is acellular residual or have a small amount of erythrocyte residual, and showing has haemolysis to occur; All sink such as erythrocyte, the supernatant achromatism and clarity shows without haemolysis to occur.
If brownish red or rufous flocculent deposit are arranged in the solution, do not disperse after the jolting, showing has red blood cell condensation to occur.If any the phenomenon of red blood cell condensation, can further judge by the following method cohesion or pseudo agglutination.If condensation product again can Uniform Dispersion after test tube vibration, or condensation product placed on the microscope slide, drip 2 sodium chloride injections at the microscope slide edge, put microscopically and observe, the cohesion erythrocyte can be pseudo agglutination by the person of breaking up, if condensation product is not shaken loose or be not cohesion by the person of breaking up on slide.
The result judges:
When the negative control pipe occurs without haemolysis and cohesion, when the positive control pipe had haemolysis to occur, if haemolysis and cohesion did not occur in 3 hours the solution in test sample the 3rd pipe (0.3ml), it was up to specification to declare test sample; If haemolysis and cohesion occured in 3 hours the solution in test sample pipe the 3rd pipe (0.3ml), it is against regulation to declare test sample.
3 result of the tests:
Rg1: Rb1 (1: 4) group is when concentration reaches 25mg/ml, haemolysis and cohesion did not occur in the solution in the 3rd pipe (0.3ml) in 5 hours, the 5th pipe (0.5ml) began to occur hemolytic reaction in 4 hours, and the 4th pipe (0.4ml) began to occur hemolytic reaction in 6 hours; Hemolytic reaction does not occur under the 15mg/ml concentration.Rg1: Rb1 (1: 5) group is when concentration reaches 25mg/ml, haemolysis and cohesion did not occur in the solution in the 3rd pipe (0.3ml) in 5 hours, the 5th pipe (0.5ml) began to occur hemolytic reaction in 4 hours, and the 4th pipe (0.4ml) began to occur hemolytic reaction in 5 hours; Hemolytic reaction does not occur under the 15mg/ml concentration.Rg1: Rb1 (4: 1) group is when concentration reaches 15mg/ml, and hemolytic reaction did not occur at 3 hours the solution in the 3rd pipe (0.3ml).Rg1: Rb1 (5: 1) group is when concentration reaches 15mg/ml, and hemolytic reaction occured at 3 hours the solution in the 3rd pipe (0.3ml).Rg1: Rb1 (1: 1) group is when concentration reaches 25mg/ml concentration, haemolysis and cohesion did not occur in the solution in the 3rd pipe (0.3ml) in 3 hours, the 4th pipe (0.4ml) began to occur hemolytic reaction in 5 hours, the 5th pipe (0.5ml) began to occur hemolytic reaction in 4 hours, under the 15mg/ml concentration hemolytic reaction did not occur.When the Radix Notoginseng total arasaponins group reached 15mg/ml concentration in concentration, hemolytic reaction occured in solution in the 3rd pipe (0.3ml) at 3 hours.
Embodiment 8: the preparation of medicine composition injection of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 and be by weight and carry out proportioning at 1: 4, add an amount of water for injection dissolving, ultrafiltration, fill, the injection injection is made in sterilization.
Embodiment 9: the preparation of lyophilized injection of pharmaceutical composition of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 and be by weight and carry out proportioning at 4: 1, add an amount of water for injection dissolving, filter, fill, freeze-dried powder injection is made in lyophilization.
Embodiment 10: the preparation of medicinal composition tablets of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 and be by weight and carry out proportioning at 1: 4, be prepared into tablet according to the conventional formulation method.
Embodiment 11: the preparation of medicament composition capsule agent of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 and be by weight and carry out proportioning at 1: 4, prepare capsule in blocks according to the conventional formulation method.
Embodiment 12: the preparation of medicament composition granule agent of the present invention
Get ginsenoside Rg1, ginsenoside Rb1 and be by weight and carry out proportioning at 1: 4, prepare granule in blocks according to the conventional formulation method.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1, Rg wherein
1With Rb
1Part by weight is 1:4.
2. pharmaceutical composition according to claim 1 is characterized in that, by ginsenoside monomer Rg
1With ginsenoside monomer Rb
1Form, wherein Rg
1With Rb
1Part by weight is 1:4.
3. pharmaceutical composition according to claim 1 and 2 is characterized in that, described cardiovascular and cerebrovascular disease is hemorrhage or ischemic diseases.
4. a pharmaceutical preparation for the treatment of cardiovascular and cerebrovascular disease comprises ginsenoside monomer Rg
1With ginsenoside monomer Rb
1And pharmaceutically acceptable adjuvant, wherein Rg
1With Rb
1Part by weight is 1:4.
5. pharmaceutical preparation according to claim 4 is characterized in that, it is injection or freeze-dried powder injection.
6. according to claim 4 described pharmaceutical preparation is characterized in that, it is oral formulations.
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| CN101428050A (en) * | 2008-12-15 | 2009-05-13 | 云南白药集团股份有限公司 | Active composition for treating thrombus, cardio-cerebrovascular system diseases |
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| CN101129395A (en) * | 2007-09-10 | 2008-02-27 | 中国药科大学 | Traditional Chinese medicine active ingredient composition for treating cardiovascular disease and use thereof |
| CN101428050A (en) * | 2008-12-15 | 2009-05-13 | 云南白药集团股份有限公司 | Active composition for treating thrombus, cardio-cerebrovascular system diseases |
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