CN100522196C - Medicine or foods for prevention and treatment of microcirculation disorder and disease of live habits - Google Patents
Medicine or foods for prevention and treatment of microcirculation disorder and disease of live habits Download PDFInfo
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- CN100522196C CN100522196C CNB2005100694507A CN200510069450A CN100522196C CN 100522196 C CN100522196 C CN 100522196C CN B2005100694507 A CNB2005100694507 A CN B2005100694507A CN 200510069450 A CN200510069450 A CN 200510069450A CN 100522196 C CN100522196 C CN 100522196C
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Abstract
PROBLEM TO BE SOLVED: To obtain a drug or food which is effective for prophylaxis and treatment of circulatory disorders and lifestyle-related diseases.
Description
[technical field]
The invention relates to the medicine or the food of living habit diseases such as prevention and treatment microcirculation disturbance, hyperlipemia, fatty liver, hypertension, apoplexy.
[background technology]
1. microcirculation disturbance
Microcirculation is the vascular bed that is made of arteriole, blood capillary, thin vein, accounts for 90% of organism vascular system, is metabolic important place.Microcirculation disturbance is the common pathology link of obstacle behind hypertension, ischemic heart desease, cerebrovascular disease, diabetic vascular complication, hepatic renal dysfunction, the surgical operation.In this year day medical expense of 31,000,000 yen, with the medical expense of microcirculation disturbance dependency illness above 5,000,000 yen.So, the therapy of microcirculation improvement obstacle and the exploitation of medicine not only can solve the common people's health problem, can also be of value to compression medical treatment finance.
As everyone knows, after the tissue reperfusion of ischemia, by vascular endothelial injury, plasma albumin leak outside, leukocyte and back blood capillary thin vein adhere to, swim out of outside blood vessel etc. causes microcirculation disturbance.Various active materials such as ischemia-reperfusion obstacle and cell adhesion factor, peroxide, lipid peroxidation, nitric oxide, and blood cell compositions such as platelet, mastocyte, granulocyte are relevant.
Peroxide that is produced by the xanthine oxidase of vascular endothelial cell and the peroxide that is produced by granulocyte can aggravate microcirculation disturbance, leukocytic migration and adhesion, injury of vascular endothelial cells.The generation and the microcirculation disturbance of leukocyte adhesion after the perfusion and peroxide are closely related again.
The superoxide dismutase superoxide dismutase=SOD of the negative oxygen anion of removing, removing are through H
2O
2Though catalase catalase=CAT have the removing peroxidation,, because action target spot is single, be not enough to the microcirculation improvement obstacle, lack definite clinical efficacy, and its reason such as cost an arm and a leg so far can not be in clinical practice.
On the other hand, since ancient times, the Chinese medicine that Radix Notoginseng, Folium Ginkgo, Fructus Crataegi etc. have the microcirculation improvement obstacle is widely used in China.Radix Notoginseng was used for traumatic injury in the past, was used for the treatment of the microcirculation disturbance relevant heart, brain, liver illness in recent years.The existing report of drug efficacy study (non-patent literature 1-3) about Radix Notoginseng Main Ingredients and Appearance Radix Notoginseng total arasaponins.But, because the antiperoxide of Radix Notoginseng, a little less than the effect of inhibition albumin, so, use Radix Notoginseng microcirculation improvement obstacle separately, the effect that improves the diseases due to habit disturbance relevant with microcirculation disturbance is undesirable.
Negative oxygen anion of the removing of Folium Ginkgo extract and hydrogen peroxide, improve blood flow speed, suppress leukocyte and be identified (non-patent literature 4-14) with the adhesion of blood vessel endothelium, the effects such as lipid peroxidation, inhibition internal organs obstacle that suppress, but, Ginkgo Leaf has and brings out anaphylactoid side effect, has limited the clinical use of Folium Ginkgo.Partial peroxide produces dynamically Folium Ginkgo extract to obstacle in early days, whether mast cell degranulation has effect still without affirmation outside the blood vessel at microcirculation disturbance.
Fructus Crataegi has blood fat, cause again because of it cheap and tasty, very popular in China.Fructus Crataegi has the effect of removing negative oxygen anion and OH (non-patent literature 15), and still, whether Fructus Crataegi has the improvement effect to microcirculation disturbance, still unofficial.
The used ischemia of the present invention is paid close attention to the ideal model that the rat mesentery model of microcirculation obstacle that causes is the microcirculation disturbance of too many levels such as the excessive generation, leukocyte and the vascular endothelial cell adhesion that comprise vascular endothelial injury, peroxide, mast cell degranulation again.
2. high blood triglyceride and fatty liver
In addition, in recent years, hyperlipidemia fat, fatty liver receive publicity as the living habit sexually transmitted disease (STD).Fatty liver is many to cause that by fat and diabetes etc. the fatty liver that causes by drinking for a long time is also common.Drink for a long time and can increase the weight of Liver Microcirculation, hepatocyte injury (non-patent literature 16).
At present, the fatty liver that causes for drinking mainly with dietary restriction, improve the method treatment of alcohol drinking patterns, ancillary drug.But many Patients with Fatty Liver are difficult to keep dietary restriction and limit the treatment of drinking.
40% of the present dead sum of Japan is by due to the cardio-cerebrovascular disorder.The main high risk factor of cerebrovascular disease is a hypertension.The medical care expenses that is used for the treatment of hypertension and cerebrovascular disease every year is above 3,000,000 yen.Simultaneously, the hemiplegia sequela of last cerebrovascular disease needs to nurse, the burden of increase family numbers of patients and society etc., and prophylaxis of hypertension patient's secondary apoplexy also relates to financial, social, the healthy important topic of medical treatment.
Because cerebral vasospasm, arteriosclerosis, thrombosis, hemorrhage etc. is the main cause (cerebral thrombosis, cerebral hemorrhage etc.) of hyperpietic's secondary apoplexy.Though the medicine of controlling blood pressure can bring high blood pressure down,, also be not enough to suppress the morbidity of apoplexy.Though suppressing the antithrombotic medicine of platelet aggregation class also has been used for clinical, but, hemorrhage side effect easily takes place in long-term clothes, add and merely suppress the platelet aggregation medicine, can not improve vascular endothelial injury effectively, leukocyte and blood vessel endothelium adhere to, microcirculation disturbance links such as peroxide generation, be necessary that exploitation has too many levels microcirculation improvement obstacle, the medicine of prevention of brain apoplexy morbidity.
Apoplexy liability hypertension spontaneous generation rat (SHR-SP) is the hypertension model that caused by inherited genetic factors, cerebrovascular disorders takes place and death with few exceptions.As hypertension, apoplexy research and prevention, medicine exploitation model (non-patent literature 17-18) commonly used.
For above problem, have former medicine with Chinese medicines such as Radix Notoginseng, Semen Ginkgo, Fructus Crataegis be processed into powder and the former medicine of other Chinese medicine mix up for health food by patent application (patent documentation 1).But because its used Chinese medicine is Chinese drugs powder, its Main Ingredients and Appearance is difficult to guarantee.
[patent documentation 1] spy opens the 2002-233331 communique.
[non-patent literature 1] Zhan WJ, Wojta J, Binder BR:Effect ofnotoginsenoside R1 on the synthesis of tissue-type plasminogenactivator and plasminogen activator inhibitor-1 in culturedhuman umbilical vein endothelial cell.Arteriosclerosis andThrombosis 14:1040-1046,1994
[non-patent document 2] Chan P, Thomas GN, Tomlison B:Protectiveeffects of trilinolein extracted from Panax notoginseng againstcardiovascular disease.Acta Pharmacol Sin 23:1157-1162,2002
[non-patent literature 2] Liu JC, Chan P, Chen JJ, Lee HM, Lee WS, AhihNL, Chen YL, Hong HJ, Cheng TH.The inhibitory effect ofTrilinolei no nnorepinephrine-induced b-myosin heavy chainpromoter, and extracellular signal-regulated kinasephosphorylation in neonatal rt cardiomyocytes.J Biomed Sci11:11-18,2004
[non-patent literature 4] Jung F, mrowietz C, Kiesewetter H and WenzelE:Effect of Ginkgo biloba on fluidity of blood and peripheralmicrocirculation in volunteers.Arzneim.-Forsch.Drug Res.40:5589-593,1990
[non-patent literature 5] Zhang J, Fu S, Liu A, Mao T and Xiu RJ:Thetherapeutic effect of Ginkgo biloba extract in SHR rats and itspossible mechanisms based on cerebeal microvascular flow andvasomotion.Clinical Hemorheology and Micrccirculation 23:133-138,2000
[non-patent literature 6] Arnould T, Michiels C, Janssens D, Berna N andRemacle J:Effect Of Ginkgo fdrt on hypoxia-induced neutrophiladherence to human saphenous vein endothelium.Jouenal ofCardiovascular Pharmacology.31:456-463,1998
[non-patent literature 7] Szabo ME, Droy-Lefaix MT, Doly M, Braque P:Free radical-mediated effects in reperfusion injury:ahistologic study with superoxide dismutase and EGb 761 in ratretina.Ophthalmic Res.23:225-234,1991
[non-patent literature 8] Szabo ME, Droy-Lefaix MT, Doly M, Carre C andBraque P:ischemia and reperfusion-induced histologic changesin the rat retina.Investigative Ophthalmology and VisualScience.32:51471-1478,1991
[non-patent literature 9] Welt K, Fitzl G and Schaffranietz L:Myocardium-protective effects of Ginkgo biloba extract (EGb 761) in old rats against acute isobaric hypoxia.An electronmicroscopic morphometric study.Exp Toxic Pathol 48:81-86,1996
[non-patent literature 10] Pierre S, Jamme I, Droy-Lefaix MT, NouvelotA and Maixent JM:Ginkgo biloba extract (EGb 761) protecteNa, K-ATPase activiy during cerebral ischemia in mice.NeuroReport 10:47-51,1999
[non-patent literature 11] Welt K, Fitzl G and Schepper A:Experimentalhypoxia of STZ-diabetic rat myocardium and protective effectsof Ginkgo biloba extract.Exp Toxic Pathol 52:503-512,2001
[non-patent literature 12] Chandraskaran K, Mehrabian Z, Spinnewyn B, Drieu K, Fiskum G:Neuroprotective effects of bilobalide, acomponent of the Ginkgo biloba extract (EGb 761), in gerbilglobal brain ischemia.Brain Research 922:282-292,2001
[non-patent literature 13] Lee EJ, Chen HY, Wu TS, Chen TY, Ayoub IA andMaynard KI:Acute adminidtration of Ginkgo biloba extract (EGb761) affords Neuroprotection against permanent and transientfocal cerebral Ischemia in Sprague-Dawley rats.Journal ofNeuroscience Research 68:636-645,2002
[non-patent literature 14] Lenoir M, Pedruzzi E, Rais S, Drieu K, PerianinA:Sensitization of human neutrophil defense activities throughactivation of platelet-activating factor receptors byginkgolide B, a bioactive component of the Ginkgo biloba extractEGb761.Biochemical Pharmacology 63:1241-1249,2002
[non-patent literature 15] Bahorun T, Gressier B, Trotin F, Brunet C, Dine T, Luyckx M, Vasseur J, Cazun M, Cazin JC and Pinkas M:Oxygen species scavenging activity of phenolic extracts fromhawthorn fresh plant prgans and pharmaceutical preparations.Arzneim.-Forsch.Drug Res.46:11 1086-1089,1996
[non-patent literature 16] Horie H, Kimura H, Kato S, Ohki E, Tamai H, Yamagishi Y, Ishii H, Tsuchiya M.Role of nitric oxide inendotoxin-induced hepatic microvascular dysfunction in ratschronically fed ethanol.Alcohol Clin Exp Res 24:845-851,2000.
[non-patent literature 17] Yamori Y, Nagaoka A and Okamoto K.Importanceof genetic factorsIn hypertensive cerebrovascularlesions:an evidence obtainedby successive selective breeding of stroke-prone and resistantSHR.Jpn.Circ.J 38:1095-1100.1974.
[non-patent literature 18] Yamori Y, Horie R, Nara Y, Tagami S, KiharaM, Wano M, Isho H.Prevention of Cardiovascular diseases:Anapproach to active long life.163,1987, Elsevier (Amsterdam)
[summary of the invention]
As mentioned above, no matter be to consider from the common people are healthy, still consider that from compressing country's medical treatment finance the microcirculation improvement obstacle all is an important problem.Aspect the microcirculation improvement obstacle, anti-peroxidation agent SOD, CAT is the medical treatment cost height not only, and clinical efficacy is also unofficial, so, be not used as yet clinically.
Since ancient times, be used as Chinese medicine or food, can remove peroxide though the Fructus Crataegi of no safety hazard and Folium Ginkgo use separately,, because mast cell degranulation does not suppress ability, the effect of microcirculation improvement obstacle is limited in vivo.Though Radix Notoginseng is used the adhesion that can suppress leukocyte and blood vessel endothelium separately, suppresses mast cell degranulation,, a little less than the scavenging action to peroxide, the effect of using the microcirculation improvement obstacle separately also is limited.
In addition, the extract of Radix Notoginseng and Folium Ginkgo is relatively expensive, uses in the medicine of microcirculation improvement obstacle and food heavy dose ofly, will be difficult to be widely accepted because of its price is higher.
The food of patent documentation 1 is with Radix Notoginseng, Folium Ginkgo, the crude drug in whole of Fructus Crataegi is pulverized and is mixed use with other plurality of Chinese, but, the Chinese medicine compound made from this method is difficult to guarantee the Fructus Crataegi flavone of Fructus Crataegi active ingredient, the Radix Notoginseng total arasaponins of Radix Notoginseng active ingredient, the ginkgetin of Folium Ginkgo active ingredient, bilobalide, the content of ginkgoic acid and the stability of active ingredient.On the other hand, because ginkgoic acid content is higher in the Folium Ginkgo crude drug in whole, take the side effect that the Folium Ginkgo crude drug in whole can cause allergic reaction.
In view of above-mentioned reason, the present invention will be respectively has the extract of Radix Notoginseng, Fructus Crataegi, the Folium Ginkgo of improvement effect to mix to the different links of microcirculation disturbance to use (to call intermixture in the following text), study with the rat mesentery model of microcirculation obstacle, according to microcirculatory result of study, provide safety higher, its effect is used to some extent than the independent composition of its contained Chinese medicine to be increased, and has the medicine and the health food of resultant effect.
The present inventor has proved further that with the research of rat intermixture has prevention and therapeutical effect as medicine or food to hyperlipidemia, fatty liver, hypertension, apoplexy.For this reason, the present invention also intends being applicable to medicine or the food that prevents and treat above-mentioned disease.
For solving above-mentioned problem, the 1st characteristics of the present invention are that Fructus Crataegi extract, Radix Notoginseng extract, Folium Ginkgo extract are mixed the intermixture of formation.
The 2nd characteristic are that Fructus Crataegi extract is more than 30% in each 3-50% with Radix Notoginseng extract and Folium Ginkgo extract.With its minimum amount and maximum drug effect of performance that reaches Radix Notoginseng extract and Folium Ginkgo extract, reduce the purpose of the cost of material of this intermixture.
The 3rd characteristics are that this intermixture is Main Ingredients and Appearance with the Fructus Crataegi extract.
The content that the 4th characteristic are Radix Notoginseng extract and Folium Ginkgo extract is respectively at 3-10%, and the proportioning of the content of Fructus Crataegi extract between 80-90% is best performance drug effect, reduces the proportion compatibility of the cost of raw material.
The content that the 5th characteristic are Radix Notoginseng total arasaponinss in the Radix Notoginseng extract is 10-50%, and Fructus Crataegi flavone content is 3-10% in the Fructus Crataegi extract.
The 6th characteristic are that the flavonoid of ginkgo biloba in the Folium Ginkgo extract is about 24%, and bilobalide content is about 6%, and ginkgoic acid is below 5ppm.
[effect of invention]
According to preceding described, formed medicament of the present invention and food remove and have kept Fructus Crataegi extract, Radix Notoginseng extract, Folium Ginkgo extract separately prevention and the treatment microcirculation disturbance effect outside, because it is the Fructus Crataegi extract that has improved active ingredient that the present invention uses, Radix Notoginseng extract, the mixing of Folium Ginkgo extract, not only overcome the difficult absorbability of taking Radix Notoginseng powder in a large number, take the side effect of the easy anaphylaxis etc. of Folium Ginkgo separately, it is not strong that also You has mended the effect of simple use Radix Notoginseng extract antiperoxide, use Folium Ginkgo can not suppress the deficiency of effect aspects such as mast cell degranulation separately, this intermixture suppresses leukocyte and the thin vein endothelium adheres to, and the effect that suppresses mast cell degranulation is than taking Fructus Crataegi extract separately, Radix Notoginseng extract, the curative effect of Folium Ginkgo extract increases.And, to fatty liver, hypertension, apoplexy has prevention and therapeutical effect.
When keeping and having improved drug effect, reducing the higher Radix Notoginseng extract of price and the proportioning of Folium Ginkgo extract aspect the cost of material, improved the proportioning of cheap Fructus Crataegi extract.The invention provides the prevention of low cost, high curative effect and the medicine or the food of treatment microcirculation disturbance and living habit sexually transmitted disease (STD).
[description of drawings]
[Fig. 1] intermixture of the present invention and other medicaments are to the experimental technique key diagram of rat microcirculation disturbance improvement effect research.
[Fig. 2] (A) represents the variation in the rat mesentery thin vein blood vessel footpath that ischemia-reperfusion (I/R) causes, and SOD, CAT, intermixture are to the influence in thin vein blood vessel footpath.(B) expression SOD, CAT, Radix Notoginseng extract, Folium Ginkgo extract, Fructus Crataegi extract, intermixture are to pouring into the influence in mesentery thin vein blood vessel footpath after 30 minutes again.
What [Fig. 3] (A) represented that ischemia-reperfusion causes adheres to the variation of leukocyte count with the mesentery thin vein, and SOD, CAT, intermixture are to the influence of leukocyte adhesion.(B) expression SOD, CAT, Radix Notoginseng extract, Folium Ginkgo extract, Fructus Crataegi extract, intermixture are to pouring into the influence that adheres to leukocyte count after 30 minutes again.
The variation of thin vein blood vessel wall DHR fluorescence intensity before and after [Fig. 4] expression ischemia-reperfusion, and intermixture suppresses effect.(A) image before the ischemia (B) is the image that pours into again after 30 minutes, (C) is the image before the intermixture administration rat ischemia, is that intermixture administration rat is poured into the image after 30 minutes again (D).Be the image of 20 times of object lens.
[Fig. 5] (A) represents the variation of the rat mesentery thin vein wall DHR fluorescence intensity that ischemia-reperfusion (I/R) causes, and and the influence of SOD, CAT, intermixture.(B) expression SOD, CAT, Radix Notoginseng extract, Folium Ginkgo extract, Fructus Crataegi extract, intermixture are to pouring into the influence of mesentery thin vein wall DHR fluorescence intensity after 30 minutes again.
The image of mast cell degranulation behind [Fig. 6] expression ischemia-reperfusion.(A) being the image that pours into again after 30 minutes, (B) is that intermixture administration rat is poured into the image after 30 minutes again.
[Fig. 7] SOD, CAT, Radix Notoginseng extract, Folium Ginkgo extract, Fructus Crataegi extract, intermixture be to after pouring into 30 fens again, the influence of mesentery mast cell degranulation rate.
The rat mesentery microcirculation disturbance that [Fig. 8] intermixture causes ischemia-reperfusion improves the sketch map of action principle.
[Fig. 9] intermixture of the present invention is to the research method sketch map of high triglyceride, fatty liver improvement effect.
[Figure 10] is the content of tip blood triglyceride (A), (B) is the content of tip blood T-CHOL.Intermixture of the present invention can suppress the tip blood triglyceride rising that the long term alcohol picked-up causes.
[Figure 11] intermixture of the present invention is to the image of long term alcohol picked-up rat fat liver improvement effect.(A) be liver, (B) of long term alcohol picked-up rat be through 2 week of intermixture treatment of the present invention the back long term alcohol absorb the liver of rat.
[Figure 12] expression intermixture of the present invention is that systolic pressure, (B) are diastolic pressures to SHR-SP rat blood pressure improvement effect (A)
[Figure 13] intermixture of the present invention is to the influence (image that the laser dopper flowmeter scanner is measured) of SHR-SP rat brain blood flow
(A) the rheoencephalogram picture of the rheoencephalogram picture of SHR-SP rat, (B) SHR-SP rat+intermixture
[Figure 14] intermixture of the present invention is to the influence of SHR-SP rat survival rate
[specific embodiment]
Based on aforementioned reason, in order to have inquired into the effect to each pathology link of microcirculation disturbance of Fructus Crataegi extract, Radix Notoginseng extract, Folium Ginkgo extract, the intermixture of the present invention that forms (to call intermixture in the following text) after relatively rationally being cooperated by Fructus Crataegi extract, Radix Notoginseng extract, Folium Ginkgo extract and above-mentioned each single medicinal material extract use separately and compare, whether the effect of its microcirculation improvement obstacle strengthens.For this reason, the present invention studies with handstand type biological microscope, and it is dynamic to observe microcirculation continuously, and peroxide produces dynamically, and leukocyte and blood vessel endothelium adhere to dynamically, and the outer mast cell degranulation of blood vessel changes.Intermixture and Fructus Crataegi extract Radix Notoginseng extract, Folium Ginkgo extract, superoxide dismutase SOD, cat catalase etc. are compared microcirculation disturbance improvement effect behind the ischemia-reperfusion.
Below concrete research of the present invention is implemented in explanation.
＜to the improvement effect of microcirculation disturbance 〉
I. research method
1. zoologize
By celebrating answer university of private school charging no tuition Experimental Animal Center management of laboratory animal regulation, to get body weight be that the Wistar of 200-230g is male rat (the beautiful Experimental Animal Center supply of Saitama).
2. the foundation of ischemia-reperfusion model
Rat is used the use amount of sodium phenobarbital liquid (sodium pentobarbital) by (30mg/kg body weight), the row intraperitoneal injection of anesthesia.With No. 3 capable right venous cannulations of polyethylene tube.Open abdomen at the abdominal part median line, be about the 20-30mm abdominal part, gently take out the nearly mesentery ileocecus that returns cecum, be expanded on the thin slice observation port support board.Krebs-Ringer buffer with 37 degree drips on the mesentery surface.With subsidiary camera, the handstand biological microscope (Diaphot TMD-2S, Nikon, Tokyo) of 37 degree temperature chambers is observed under the white light of 12V, 100W.With 20 take advantage of composition lens is observed, with the camera photography that is connected on the biological microscope, direct observation on monitor.Video camera is preserved observed image with the time representation device with the S-VHS video-recorder recording.
Choosing contains diameter between 25-40um, and the long no obvious branch of 200um does not have the vascular bed that thin vein is touched by obviously crooked intestinal system.After the basis of carrying out 10 minutes is observed,, then, remove ligation (perfusion again), will transfer to the time 0 fen, observed continuously 30 minutes with the preceding mesentery arteriovenous ligation 10 minutes (ischemia) of polyethylene tube at look-out station circulation.
When the ligation tremulous pulse, blood flow rate slows down, but does not stop fully.Consider to have the existence of collateral circulation, with arteriovenous ligation simultaneously, blocking-up vein circulation is to guarantee ischemia.Ligation is poured into after 10 minutes again and has been caused enough that mesenteric mesaraic microcirculation disturbance guarantees that again the damage of intestinal tube self is in Min..Behind the part rat laparotomy, do not make ischemia and pay close attention to processing again, be the normal control group.Method of this research and medication are as shown in Figure 1.
3. microcirculation is observed dynamically
Observe microcirculatory dynamic change continuously.
At first, see through light image with high sensitivity ccd video camera system (CC-090, Flovel, the Tokyo) picked-up that is connected in biological microscope.On the video-tape of resetting, measure the blood vessel warp with blood vessel footpath analyzer (IV-560, ホ ウ エ イ, Tokyo).Counting stops leukocyte more than 30 seconds on the position for adhering to leukocyte at thin vein, adheres to leukocytic numerical table with the long thin vein of every 100um and shows.
Behind the ischemia-reperfusion 30 minutes, in field of view, the toluidine blue with 0.1% dyes mastocyte.Observe with ccd video camera.Count the number that takes off granule and do not take off the granule mastocyte with 20 object lens of taking advantage of.The mastocyte numerical table that removes counting with degranulated mastocyte number shows mast cell degranulation rate (%).
Dynamic for generation position and the generation of observing peroxide, other gets animal and repeats above-mentioned moulding.Drip peroxide dependency luminescent substance dihydrorhodamine 123 (DHR) (Molecular Probes, Eugene, OR, USA) of 10 μ M concentration on the mesentery surface of observing continuously, use luminescence microscope, the video camera photography.Observe on monitor screen by aforesaid condition.With digital image processor (NIH Image 1.60) software, measure the fluorescence intensity of tube wall and the fluorescence intensity of blood vessel outer room matter along the thin vein tube wall.With the fluorescence intensity of blood vessel wall before the ischemia-reperfusion and the difference of a matter fluorescence intensity is basic value, and after pouring into, 10 minutes, 20 minutes, the difference of the blood vessel wall fluorescence intensity of 30 timesharing and a matter fluorescence intensity was represented DHR fluorescence intensity ratio divided by basic value again.DHR is by in the cell and the H of extracellular
2O
2Oxidation, become rhodamine 123, and luminous.
4. administration
Before the ischemia 60 minutes, with Radix Notoginseng extract (containing Radix Notoginseng total arasaponins 30%), Folium Ginkgo extract (the apricot yellow ketone 24% of argentiferous, bilobalide 6%, ginkgoic acid 5ppm is following), the extract of Fructus Crataegi extract (containing Fructus Crataegi flavone 3-5%) and above-mentioned standard, by Radix Notoginseng extract 10%, Folium Ginkgo extract 5%, (above water solubility extract extracts with well-known method Fructus Crataegi extract 85% blended extract mixture mixture (to call intermixture in the following text), Shi Li group provides by the sky, Tianjin), press the dosage of 0.4/kg and irritate stomach with the normal saline dilution.Before ischemia 30 minutes, the dosage of quiet jugular vein 12000units/kg body weight/h, vein drips and stays the superoxide dismutase SOD that removes negative oxygen anion continuously.Or the dosage of pressing 20mg/kg body weight/h through jugular vein, continuous intravenous infusion is removed H
2O
2Catalase (CAT).
More than the proportioning of the effective component content of Ti Shi three kinds of Chinese medicine extract and each extract is best proportioning.But, can guarantee that also it plays a role when the proportioning of its active ingredient and each extract is adjusted by following scope.In this adjusting range, can obtain the effect of the present invention's expectation, to each treatment of diseases effect, guarantee drug effect and the interaction separately of each medicine.
(1) content of each effective components of Chinese medicinal in this intermixture
A. Radix Notoginseng total arasaponins: the 10-50% that accounts for Radix Notoginseng extract
B. the composition of Folium Ginkgo extract: the used Folium Ginkgo extract of this intermixture is international habitual composition, its ginkgetin, and bilobalide, the content of ginkgoic acid are difficult for change by above proportioning.
C. Fructus Crataegi flavone: the 3-10% that accounts for Fructus Crataegi extract
(2) proportioning of each Chinese medicine extract of this intermixture
A. Radix Notoginseng extract: 3-30%
B. Semen Ginkgo extrac: 3-30%
C. Fructus Crataegi extract: 50-90%
5. add up and experimental group
Each measured value is handled with one-way analysis of variance (ANOVA), makes Fisher ' s post hoc test and detects.Each measured value is represented with mean ± standard deviation.Set the following difference significance in p＜0.05.
Each only organizes rat 6-10.Both blood vessel directly, the leukocyte of adhesion and thin vein, the mensuration of mast cell degranulation: matched group (non-processed group, n=6), ischemia-reperfusion group (I/R group, n=10), SOD+ ischemia-reperfusion group (SOD+I/R group, n=6), CAT+ ischemia-reperfusion group (CAT+I/R group, n=8), Radix Notoginseng extract+ischemia-reperfusion group (Radix Notoginseng+I/R group, n=8), Folium Ginkgo extract+ischemia-reperfusion group (Semen Ginkgo+I/R group, n=8), Fructus Crataegi extract+ischemia-reperfusion group (Fructus Crataegi+I/R group, n=8), intermixture extract+ischemia-reperfusion group (intermixture+I/R group, n=6).The DHR fluorescent is measured: non-processed group (n=8), I/R group (n=6), SOD+I/R group (n=8), CAT+I/R group (n=7), Radix Notoginseng+I/R group (n=8), Semen Ginkgo+I/R group (n=6), Fructus Crataegi+I/R group (n=6), intermixture+I/R organize (n=7).
II. result
1. the variation in blood vessel footpath
Before the ischemia-reperfusion, the blood vessel of mesentery arteriole and thin vein is through being 20.4 ± 1.5,35.4 ± 1.5 μ m respectively.After the ischemia-reperfusion, the significant variation directly do not take place in blood vessel.The administration of intermixture and other drug does not cause the change (seeing Fig. 2 (A), (B)) of the thin arteriovenous caliber of mesentery in this viewing duration.
2. adhere to the variation of the leukocyte count of thin vein endothelium
Shown in Fig. 3 (A), before the ischemia, each is organized rat and is not almost observed and the adherent leukocyte of mesentery thin vein endothelium.Non-processed group was observed when finishing at 30 minutes, and a spot of leukocyte adhesion (1.8 ± 0.6/100 μ m) is only arranged.I/R group just has leukocyte adhesion (10.1 ± 1.1/100 μ m), afterwards after perfusion beginning again, adhere to leukocyte count and continue to increase, and is pouring into 30 timesharing again, and the leukocyte count that adheres to the thin vein endothelium is increased to 18.3 ± 1.36/100 μ m.SOD has suppressed leukocytic adhesion significantly after pouring into 10 minutes again.CAT has suppressed leukocytic adhesion significantly after pouring into 20 minutes again.Intermixture has suppressed leukocytic adhesion significantly after pouring into 20 minutes again, pouring into 30 timesharing again, and is almost identical with non-processed group.
When pouring into 30 minutes again, each administration group suppresses the comparative result of effect shown in Fig. 3 (B).SOD, CAT, Radix Notoginseng extract, Semen Ginkgo extrac, Fructus Crataegi extract administration group, the leukocyte count that adheres to the thin vein endothelium reduces significantly, still, still is higher than non-processed group.The intermixture group is not only near non-processed group, and than Semen Ginkgo extrac, Fructus Crataegi extract is compared for individually dosed group, reduces significantly.
3. the variation of thin vein wall DHR fluorescence intensity
Fig. 4 (A) (B) is respectively before the ischemia and pours into H after 30 minutes again
2O
2Reactive DHR fluorescent image.30 timesharing are organized in filling again, and can observe the thin vein wall has DHR fluorescent luminous (Fig. 4 (B)) significantly.
Fig. 4 (C) is (D) respectively the time before the intermixture administration rat ischemia and pour into 30 back H again
2O
2Reactive DHR fluorescent image.Pour into 30 timesharing again, the DHR fluorescence intensity reduces (Fig. 4 (D)) significantly.
Before and after Fig. 5 (A) expression ischemia-reperfusion, the variation of each administration group thin vein wall DHR fluorescence intensity.Non-processed group does not almost change in this viewing duration.I/R group DHR fluorescence intensity after pouring into 10 fens more increases, after, continue to increase.SOD had suppressed the increase of thin vein wall DHR fluorescence intensity significantly before pouring into again 10 fens.After pouring into 10 fens again, its inhibitory action weakens.The administration of CAT and intermixture has suppressed the increase of perfusion back thin vein wall DHR fluorescence intensity more significantly.
After pouring into 30 fens again, SOD, the Radix Notoginseng extract group suppresses that the effect of thin vein wall DHR fluorescence intensity is weak, CAT, Folium Ginkgo extract group, and the effect that the Fructus Crataegi extract group suppresses perfusion back thin vein wall DHR fluorescence intensity again is strong (Fig. 5 (B)).
5. take off the counting of granule mastocyte rate
After pouring into 30 fens again, with 30 fens Hous of perfusion again, the toluidine blue with 0.1% dyes mastocyte, can observe between mesentery thin vein side in the matter by the painted mastocyte of toluidine blue with the microscopical CCD camera of the thing of delivering a child.
Fig. 6 (A) is the image that pours into again after 30 minutes, can observe many degranulated mastocytes.Fig. 8 (B) is that intermixture administration rat is poured into the image of 30 timesharing again, and the granule that takes off of matter mastocyte is suppressed between mesentery.
Fig. 7 shows the comparison of loud, high-pitched sound perfusion each administration group intestinal cell membrane mast cell degranulation rate after 30 minutes again.Compare with non-processed group, the granule rate of taking off of I/R group significantly increases.CAT and Folium Ginkgo extract do not suppress the granule rate of taking off of mastocyte.Radix Notoginseng extract, Fructus Crataegi extract have suppressed the mast cell degranulation rate, still, do not reach the level of non-processed group.SOD, intermixture have stronger inhibitory action to mast cell degranulation, and almost the granule rate of taking off with non-processed group is consistent.Particularly intermixture is better than Radix Notoginseng extract and Fructus Crataegi extract to the inhibitory action of mast cell degranulation.
III. sum up
1. use the rat mesentery model of microcirculation obstacle, compared intermixture, the improvement effect of the microcirculation disturbance that Radix Notoginseng extract, Folium Ginkgo extract, Fructus Crataegi extract, SOD, CAT cause ischemia-reperfusion.
2.SOD can suppress the generation of thin vein wall peroxide behind the ischemia-reperfusion, suppress leukocyte and adhere to, the inhibition mast cell degranulation with the thin vein blood vessel endothelium.But after pouring into 20 fens again, its effect that suppresses peroxide weakens.
3.CAT can suppress to pour into again the generation of back thin vein wall peroxide, suppress the adhesion of leukocyte and thin vein endothelium, still, mast cell degranulation there is not inhibitory action.
4. Radix Notoginseng extract can pour into the adhesion that the back suppresses leukocyte and thin vein endothelium again, suppresses mast cell degranulation, and still, it suppresses a little less than the effect of thin vein wall peroxide.
5. after Folium Ginkgo extract can suppress to pour into again, the generation of thin vein wall peroxide suppressed the adhesion of leukocyte and thin vein endothelium, and still, Folium Ginkgo extract does not have inhibitory action to mast cell degranulation.This research has confirmed in vivo that first Folium Ginkgo extract has the effect of removing peroxide, does not have inhibitory action to mast cell degranulation.
6. this research has confirmed in vivo that first Fructus Crataegi extract can suppress to pour into the adhesion of back leukocyte and thin vein endothelium again, suppresses the generation of thin vein wall peroxide, and mast cell degranulation is had more weak inhibitory action.
7. by Fructus Crataegi extract, Radix Notoginseng extract, Folium Ginkgo extract are by the intermixture of the proportioning formation of this research, and to pouring into the stronger inhibitory action that is stained with of back leukocyte and thin vein endothelium again, its effect is better than Folium Ginkgo extract, and Fructus Crataegi extract is individually dosed.Intermixture can suppress to pour into the generation of back thin vein wall peroxide again, and it is individually dosed that its effect is better than Radix Notoginseng extract.Intermixture can suppress to pour into the back mast cell degranulation again, and its effect is better than Radix Notoginseng extract, Folium Ginkgo extract, Fructus Crataegi extract individually dosed.
Above result of study has confirmed that by a spot of Radix Notoginseng extract Folium Ginkgo extract cooperates the intermixture that constitutes can improve the microcirculation disturbance that ischemia-reperfusion causes with Fructus Crataegi extract.The effect that has confirmed intermixture microcirculation improvement obstacle is by suppressing the generation of peroxide, the adhesion of inhibition leukocyte and vascular endothelial cell, the realization of inhibition mast cell degranulation.Confirmed that intermixture improves little effect that follows obstacle and is better than Radix Notoginseng extract, Folium Ginkgo extract, individually dosed (Fig. 8) of Fructus Crataegi extract.
＜the high triglyceride that long term alcohol picked-up is caused and the improvement effect of fatty liver 〉
I. experimental technique
Answer university of private school charging no tuition Experimental Animal Center regulation by celebrating, get the rat that body weight is 100-150g (Charles River laboratory animal, Tokyo), the pairing grouping is raised, and makes the ethanol picked-up model of going slowly by the method for having reported.Both used protein 18%, lipid 36%, the comprehensive nutrient liquid feed that carbohydrate 47% is made (Liqud rat diet, Bio-Serv=annotate and survey trade mark, Frenchtown, and NJ USA) raised for 8 weeks continuously, was non-ethanol picked-up matched group.In above-mentioned comprehensive nutrient liquid feed, 36% of carbohydrate energy is replaced as ethanol, make the alcohol liquid feedstuff (1kcal/ml) of homenergic, raised for 8 weeks continuously, be ethanol picked-up group.
In the 6th week of raising, press the dosage of 0.4g/kg/ day, in non-ethanol picked-up matched group+intermixture group, add intermixture in the liquid feed of ethanol picked-up group+intermixture group, continue to raise for 2 weeks.Before raising, 8 weeks raised when finishing, and measured body weight.With phenobarbital (35mg/kg) intraperitoneal injection of anesthesia, abdomen venous blood collection, survey triglyceride, T-CHOL, total protein, albumin, AST, ALT with conventional UV method method.Get liver, fixing, execute HE dyeing (Fig. 9).
Each measured value is handled with one-way analysis of variance (ANOVA), makes Fisher ' s post hoc test and detects.Each measured value is represented with mean ± standard deviation.Set the following difference significance in p＜0.05.
II. result
1. body weight
Raised for 8 weeks, the non-administration group of ethanol picked-up group+intermixture, ethanol picked-up group+intermixture administration group, the non-administration group of non-ethanol picked-up group+intermixture, body weight does not have significant difference (data omission) between each group of ethanol picked-up group+intermixture administration group.Both the long term alcohol picked-up was to not influence of rat body weight, and the administration of intermixture does not influence the growth of rat.
2. end blood triglyceride and T-CHOL slightly
Raising for 8 weeks, ethanol picked-up group rat significantly raises than the tip blood triglyceride of non-ethanol picked-up group rat.The intermixture administration can suppress the rising (Figure 10 A) of ethanol picked-up group rat tip blood triglyceride significantly.
The tip blood T-CHOL of ethanol picked-up group is compared with non-ethanol picked-up group rat, does not significantly raise.The intermixture administration does not have remarkable influence (Figure 10 B) to the tip blood triglyceride.
3. tip blood total protein and albumin
Raising for 8 weeks, the tip blood total protein of ethanol picked-up group rat is compared with non-ethanol picked-up group rat with albumin, does not have significant difference.The intermixture administration does not have remarkable influence (data omission) to tip blood total protein and albumin.Both both mixed not influence of nutritional status to rat.
4. liver function
Raising for 8 weeks, the AST of ethanol picked-up group rat compares with non-ethanol picked-up group rat with ALT, does not have significant difference.The intermixture administration does not have remarkable influence (data omission) to AST and ALT.
5. liver organization
The rat liver of raising for 8 weeks is fixed, done HE dyeing, (Figure 11, A) hepatocyte of ethanol picked-up group rat is interior by a large amount of fat drops (fatty liver).(Figure 11, B) fat drop in the ethanol picked-up+intermixture administration group rat liver significantly reduces.Both the rat fat liver that causes drinking for a long time of the administration of intermixture had the improvement effect.
III. conclusion
Originally studies confirm that intermixture can be at the blood plasma total protein that does not influence long term alcohol picked-up rat, albumin, liver function, on the basis of body weight, triglyceride reducing improves fatty liver.
＜to the effect of hypertension and apoplexy 〉
I. material and method
1. animal, medication
Buy the SHR-SP/Izm rat in 4 ages in week from disease model animal use research associations (capital of a country) such as SHR.At 22 ± 1C
0Room temperature, 60 ± 10% humidity, 12 hours 1 weeks of raising indoor feeding of illumination (6:00-12:00) by turns.Give SP feedstuff and tap water ad lib drinking-water during this period.Confirm that weight increase is normal, the thing abnormal response.
Get 26 of above-mentioned SFR-SP rats, be divided into the non-administration group of intermixture (to call SHR group in the following text, N=13) and intermixture administration group (to call the intermixture group in the following text, N=13).Feed the basic feedstuff of SP of bridge farm (strain) preparation to SHR group rat.Feed the feedstuff that in the basic feedstuff of SP of bridge farm (strain) preparation, adds 3.3% intermixture to the intermixture group.
On the same day of grouping, measure the blood pressure of rat, body weight, the pairing grouping guarantees that two groups are not having difference aspect blood pressure and the body weight.
The raising of laboratory animal and processing are handled by " zooperal regulation in the physiology field " that Japanese physiological society formulates.
2. the mensuration of body weight and blood pressure
Before administration, each 1 week is measured body weight and blood pressure respectively after the administration.Rat is placed 38 degree warmers 10 minutes, treat that it complies with after, under the state of thing anesthesia, with the tail-cuff method with automatic blood pressure determinator (UR-1000, last field makes institute) survey systolic pressure and diastolic pressure.Every rat is surveyed 3 times, averages.Note down heart rate simultaneously.Blood pressure determination is constant indoor in temperature and humidity, carries out between the 2-5 point in the afternoon.
3. cerebral hematoncometry
At the 28th day that feeds to culturing feed, get 5 rats, use the laser Doppler measuring cerebral blood flow for every group.Both,, cut scalp, exposed skull, with laser-Doppler blood-stream image device PIMII (lisuka, Sweden) sweep measuring cerebral blood flow rat anesthesia.
4. stroke onset rate and survival rate
Raising the beginning back the 120th, calculate sickness rate and the survival rate of respectively organizing apoplexy.
5. statistical procedures
Each measured value is handled with one-way analysis of variance (ANOVA), makes Fisher ' s post hoc test and detects.Each measured value is represented with mean ± standard deviation.Set the following difference significance in p＜0.05.
II. result
1. body weight
In this viewing duration, the body weight of SHR-SP rat and SHR-SP+ intermixture group rat does not have significant difference.Both intermixture was to the not influence (measured value omission) of growth of SHR-SP rat.
2. blood pressure
As Figure 12 (A), (B) shown in, the SHR-SP rat is being raised beginning the 2nd week of back, systolic pressure and diastolic pressure begin intentionally that the free burial ground for the destitute raises, and continue later on to rise.The intermixture administration after raised for the 3rd week, the systolic pressure of the SHR-SP rat that has suppressed and the rising of diastolic pressure.
3. the measurement result of cerebral blood flow
Measure the rat brain blood flow with laser-Doppler continuous sweep, its result as shown in figure 15, the cerebral blood flow 13 (B) of intermixture administration group SHR-SP raises significantly than SHR-SP (A).
4. the sickness rate of apoplexy and survival rate
As shown in figure 14, raised the 120th, apoplexy all takes place in SHR-SP group rat, and dead.Intermixture administration group has 2 SHR-SP rats that apoplexy takes place, and dead.Raising 120, is 0 to compare with SHR-SP group survival rate, and the SHR-SP rat survival rate of intermixture administration group reaches 75%.
III. conclusion
The long term administration of intermixture can suppress the sickness rate and the raising survival rate of the apoplexy of apoplexy liability hypertension liability rat (SHR-SP).This effect is relevant with the effect that intermixture could bring high blood pressure down and improve cerebral blood flow.
[possibility that industry is utilized]
The present invention both can be used as prevention and had treated microcirculation disorder, hypertension, cerebral apoplexy, fat The habits and customs such as fat liver medicine also can be used as again the food with said function. As daily The healthy food of taking not only can be produced but also can market.
Claims (6)
1. be used to prevent and treat the medicine or the food of microcirculation disturbance and hyperlipidemia, fatty liver, hypertension, apoplexy disease, it contains the intermixture that Fructus Crataegi extract, Radix Notoginseng extract and Folium Ginkgo extract constitute,
Wherein, the content of the total saponins in radix notoginseng of Radix Notoginseng extract is 10-50%,
Fructus Crataegi flavone content in the Fructus Crataegi extract is 3-10%,
The flavonoid of ginkgo biloba of Semen Ginkgo extrac is 24%, bilobalide content is 6%, ginkgoic acid content is below the 5ppm.
2. the medicine or the food of the prevention of claim 1 and treatment microcirculation disturbance and hyperlipidemia, fatty liver, hypertension, apoplexy disease, wherein Radix Notoginseng extract and Folium Ginkgo extract respectively account for 3-30%, and Fructus Crataegi extract accounts for more than 30%.
3. the medicine or the food that are used to prevent and treat microcirculation disturbance and hyperlipidemia, fatty liver, hypertension, apoplexy disease of claim 1, wherein intermixture is 50-90% with the Fructus Crataegi extract.
4. the medicine or the food that are used to prevent and treat microcirculation disturbance and hyperlipidemia, fatty liver, hypertension, apoplexy disease of claim 1, wherein Radix Notoginseng extract and Folium Ginkgo extract respectively account for 3-10%, and Fructus Crataegi extract accounts for 80-90%.
5. the medicine or the food that are used to prevent and treat microcirculation disturbance and hyperlipidemia, fatty liver, hypertension, apoplexy disease of claim 3, wherein Radix Notoginseng extract and Folium Ginkgo extract respectively account for 3-10%, and Fructus Crataegi extract accounts for 80-90%.
6. each the medicine or the food that are used to prevent and treat microcirculation disturbance and hyperlipidemia, fatty liver, hypertension, apoplexy disease in the claim 1,2,3,4,5, wherein the state of extract comprises Powdered, graininess, flexible glue cryptomere, ebonite cryptomere, tablet, paste, liquid any.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1308955A (en) * | 2000-12-20 | 2001-08-22 | 郭兴华 | Natural composition for preventing and treating cardiovascular and cerebrovascular diseases and its application |
| CN1491658A (en) * | 2003-09-05 | 2004-04-28 | 云南植物药业有限公司 | Notiginseng total saponin liposome and its preparation |
| CN1166397C (en) * | 2002-11-13 | 2004-09-15 | 贵州百灵制药有限公司 | Medicine for treating cardiovascular and cerebrovascular system disease, apoplectic sequel |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1308955A (en) * | 2000-12-20 | 2001-08-22 | 郭兴华 | Natural composition for preventing and treating cardiovascular and cerebrovascular diseases and its application |
| CN1166397C (en) * | 2002-11-13 | 2004-09-15 | 贵州百灵制药有限公司 | Medicine for treating cardiovascular and cerebrovascular system disease, apoplectic sequel |
| CN1491658A (en) * | 2003-09-05 | 2004-04-28 | 云南植物药业有限公司 | Notiginseng total saponin liposome and its preparation |
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