CN102048818A - Total salvianolic acid, panax notoginseng saponins, and compatibility thereof in prevention and treatment of diseases caused by microcirculatory disturbance - Google Patents
Total salvianolic acid, panax notoginseng saponins, and compatibility thereof in prevention and treatment of diseases caused by microcirculatory disturbance Download PDFInfo
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- CN102048818A CN102048818A CN2009100711642A CN200910071164A CN102048818A CN 102048818 A CN102048818 A CN 102048818A CN 2009100711642 A CN2009100711642 A CN 2009100711642A CN 200910071164 A CN200910071164 A CN 200910071164A CN 102048818 A CN102048818 A CN 102048818A
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- ZAVXXBAIPSQJGS-UHFFFAOYSA-B tetracalcium;tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ZAVXXBAIPSQJGS-UHFFFAOYSA-B 0.000 description 1
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Abstract
The invention relates to total salvianolic acid and panax notoginseng saponins serving as Chinese medicinal products and new application of compatibility thereof, in particular to total salvianolic acid, panax notoginseng saponins, and compatibility thereof in prevention and treatment of diseases caused by microcirculatory disturbance.
Description
Technical field:
The present invention relates to tcm product Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and the new purposes of compatibility, particularly Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and compatibility prevention and treatment of diseases effect that microcirculation disturbance is caused.
Background technology:
Ischemical reperfusion injury is the main pathological basis that occurs damage behind interventional therapy, surgical operation, the thrombolytic.The main pathology link that leukocyte and vascular endothelial cell stick behind the ischemia-reperfusion, mast cell degranulation is blood vessel injury.
Microcirculation is the vascular bed that comprises arteriole, blood capillary, thin vein, accounts for 90% of the interior blood vessel of body, is to keep metabolic pith.Hyperlipemia, hypertension, infection, direct stimulation, traumatic injury, operation, interventional therapy etc. can cause microcirculation disturbance.Microcirculation disturbance comprises that blood vessel directly changes, peroxide generation, blood vessel endothelium adhesion factor ICAM-1, leukocyte adhesion factor CD11b/CD18 expression, leukocyte and vaso-active substance such as vascular endothelial cell adheres to, plasma albumin leaks outside, the outer mast cell degranulation of blood vessel discharges TNF-α, histamine, five hydroxytryptamine, inflammatory factor and form the complex process that blood is fastened, too many levels such as hemorrhage changes.
Mast cell degranulation is the main pathology link of an allergic reaction type, is pollinosis, dermatosis, asthma, diarrheal main pathological basis.
Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins are the key components of Radix Salviae Miltiorrhizae and Radix Notoginseng among the CP.We had proved FUFANG DANSHEN DIWAN (Cardiotonic at research in the past
CP) (ischemia and reperfusion I/R) causes that rat heart, liver, mesentery microcirculation disturbance have the improvement effect to ischemia-reperfusion.But, it be unclear that the key component Radix Salviae Miltiorrhizae total phenolic acids (TSA) as Radix Salviae Miltiorrhizae in the FUFANG DANSHEN DIWAN and Radix Notoginseng, which link that Radix Notoginseng total arasaponins (PNS) has improved microcirculation disturbance, whether both different proportion compatibilities have synergism etc.For this reason, this research with dynamically, method for visualizing resolves TSA, PNS, and the improvement effect link of compatibility rat microcirculation mesentery microcirculation disturbance that I/R is caused.
The present invention finds Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins through experiment, and compatibility can improve the mesentery microcirculation disturbance that ischemia-reperfusion causes, thereby reach the effect of the disease that treats and/or prevents the microcirculation disturbance initiation, and a kind of Chinese medicine pharmaceutical preparation is provided.
Summary of the invention:
The present invention finds tcm product Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and the new purposes of compatibility, particularly Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and the prevention and the treatment improvement effect of compatibility mesentery microcirculation disturbance that ischemia-reperfusion is caused.Thereby be applied to treat and/or prevent the disease that microcirculation disturbance causes, as:, hyperlipemia, hypertension, infection, direct stimulation, traumatic injury, pollinosis, dermatosis, asthma, the microcirculation disturbance that diarrhoea, operation or interventional therapy etc. cause.
The present invention's discovery, Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and the pre-administration of compatibility can suppress to pour into leukocytic rolling and adhesion in the mesentery thin vein of back with the back administration, the inhibition mast cell degranulation again.
Radix Salviae Miltiorrhizae total phenolic acids of the present invention is a kind of composition in the salviamiltiorrhizabung, can buy from the market, also can be according to prior art for preparing, Radix Notoginseng total arasaponins is a kind of composition in the Chinese medicine Radix Notoginseng, can buy from the market, also can all belong to prior art according to prior art for preparing.Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins that the present invention uses are the products that meets medicinal standard, preferred purity＞50%, more preferably purity＞90%, most preferably purity＞98%.
Medicine of the present invention is with above-mentioned Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and the pharmaceutical composition that is prepared into as active constituents of medicine of compatibility.
Pharmaceutical composition of the present invention, can contain the medicine acceptable carrier as required, wherein Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and compatibility is as active constituents of medicine, its shared percentage by weight in preparation can be 0.1-99.9%, and all the other are the medicine acceptable carrier.Pharmaceutical composition of the present invention exists with unit dosage form, and described unit dosage form is meant the unit of preparation, as every of tablet, and capsular every capsules, every bottle of oral liquid, every bag of granule, every of injection etc.
The above compatibility is the combination of Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, and its part by weight is 1-4: 4-1, preferred 1-2: 2-1, most preferably 1: 1.
Pharmaceutical composition of the present invention can be any pharmaceutically useful dosage form, and these dosage forms comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch.
Pharmaceutical composition of the present invention, the preparation of its oral administration can contain excipient commonly used, such as binding agent, filler, diluent, tablet agent, lubricant, disintegrating agent, coloring agent, flavoring agent and wetting agent, can carry out coating to tablet in case of necessity.
The filler that is suitable for comprises cellulose, mannitol, lactose and other similar filler.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivatives, for example sodium starch glycollate.Suitable lubricant comprises, for example magnesium stearate.The acceptable wetting agent of appropriate drug comprises sodium lauryl sulphate.Can fill by mixing, the method that tabletting etc. are commonly used prepares solid oral composition.Mix repeatedly active substance is distributed in those compositionss of a large amount of filleies of whole use.
The form of oral liquid for example can be aqueous or oily suspensions, solution, Emulsion, syrup or elixir, perhaps can be a kind of available water before use or other suitable composite dry products of carrier.This liquid preparation can contain conventional additive, such as suspending agent, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat, emulsifying agent, for example lecithin, anhydro sorbitol-oleate or arabic gum; Non-aqueous carrier (they can comprise edible oil), for example almond oil, fractionated coconut oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerol; Antiseptic, for example para hydroxybenzene methyl ester or propyl p-hydroxybenzoate or sorbic acid, and if desired, can contain conventional flavouring agent or coloring agent.
For injection, the liquid unit dosage forms of preparation contains active substance of the present invention and sterile carrier.According to carrier and concentration, this chemical compound can be suspended or dissolving.The preparation of solution is normally by being dissolved in active substance in a kind of carrier filter-sterilized before it is packed into a kind of suitable bottle or ampoule, sealing then.For example a kind of local anesthetic of adjuvant, antiseptic and buffer agent also can be dissolved in this carrier.In order to improve its stability, can be after the bottle of packing into that this compositions is freezing, and under vacuum, water is removed.
Pharmaceutical composition of the present invention, when being prepared into medicament, optionally add suitable medicine acceptable carrier, described medicine acceptable carrier is selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, soil temperature 80, agar, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Pharmaceutical preparations composition of the present invention is determined usage and dosage according to patient's situation in use.
Therapeutic use of the present invention experimental results show that by following:
Material and method
1 reagent
TSA (Radix Salviae Miltiorrhizae total phenolic acids), PNS (Radix Notoginseng total arasaponins) are provided by Kunming Fengshanjian Medicine Research Co., Ltd..The albumin of toluidine blue, dihydro Luo Daming and FITC labelling is all purchased the company in Sigma.
2 laboratory animals
The male wistar rat of 200～250g is provided by the outstanding beautiful Experimental Animal Center of Japan.Animal is placed in conventional feeding environment (24 ± 1 ℃ of temperature, humidity 50 ± 5% were alternately thrown light on 12 hours).The processing of animal answers the animal of university of private school charging no tuition medical board regulation to handle according to celebrating and the ethics policy is carried out.The fasting feedwater is 12 hours before the experiment.
3.I/R the foundation of model and administration
I/R group: press the consumption of 30mg/kg body weight, execute lumbar injection with sodium pentobarbital and anaesthetize.Right external jugular vein rat is inserted No. 3 polyethylene intravenous tube, and keeps somewhere.Cut 20-30mm along the abdomen median line, gently nearly the ileum of ileocecus takes out outside the abdomen, is expanded on the observation platform of microscope slide.Krebs-Ringer buffer with 37 ℃ drips on unfolded mesentery continuously.The mesentery microcirculation dynamically with the handstand biological microscope (Diaphot TMD-2S, Nikon, Tokyo) that places 37 ℃ of calorstats, at 12V, is observed under the white light conditions of 100W.Under 20 times of composition lens, select look-out station,, observed content is preserved with the record of S-VHS video-tape with the free video recording system that shows.The look-out station of selecting is the microcirculatory vascular bed of diameter at non-branch of the thin vein between the 25-35um (length is more than 200 μ m).Finished to observing by the quiet continuously normal saline that splashes into of the dosage of 5mg/kg/h through jugular vein before 20 minutes at ischemia.With the preceding mesentery arteriovenous of polyethylene tube ligation observation portion circulation 10 minutes, remove ligation again, will transfer to 0 place the time, observe dynamic 60 minutes of the microcirculation of the same visual field continuously.
Sham-operation (Sham) group: open abdomen with I/R group rat anesthesia, get mesentery and observe, do not make I/R and handle, finish to observing by the quiet continuously normal saline that splashes into of the dosage of 5mg/kg/h through jugular vein.
The pre-administration of TSA (TSA+I/R) group: finished to observing by the quiet continuously TSA that splashes into of the dosage of 5mg/kg/h through jugular vein before 20 minutes at ischemia.
The pre-administration of PNS (PNS+I/R) group: finished to observing by the quiet continuously PNS that splashes into of the dosage of 5mg/kg/h through jugular vein before 20 minutes at ischemia.
The pre-administration of TP (4: 1) (TP (4: 1)+I/R) group: the dosage of press 5mg/kg/h before 20 minutes through jugular vein at ischemia, with TSA and PNS ratio compatibility, quiet continuously splashing into to the observation end by 4: 1.
The pre-administration of TP (1: 1) (TP (1: 1)+I/R) group: the dosage of press 5mg/kg/h before 20 minutes through jugular vein at ischemia, with TSA and PNS ratio compatibility, quiet continuously splashing into to the observation end by 1: 1.
The pre-administration of TP (1: 4) (TP (1: 4)+I/R) group: the dosage of press 5mg/kg/h before 20 minutes through jugular vein at ischemia, with TSA and PNS ratio compatibility, quiet continuously splashing into to the observation end by 1: 4.
Administration behind the TSA (I/R+TSA) group: at I/R10 minute after jugular vein finish to observing by the quiet continuously TSA that splashes into of the dosage of 5mg/kg/h.
Administration behind the PNS (I/R+PNS) group: finished to observing by the quiet continuously PNS that splashes into of the dosage of 5mg/kg/h through jugular vein before 20 minutes at ischemia.
TP (4: 1) back administration (I/R+TP (4: 1)) group: the dosage of press 5mg/kg/h before 20 minutes through jugular vein at ischemia, with TSA and PNS ratio compatibility, quiet continuously splashing into to the observation end by 4: 1.
TP (1: 1) back administration (I/R+TP (1: 1)) group: the dosage of press 5mg/kg/h before 20 minutes through jugular vein at ischemia, with TSA and PNS ratio compatibility, quiet continuously splashing into to the observation end by 1: 1.
TP (1: 4) back administration (I/R+TP (1: 4)) group: the dosage of press 5mg/kg/h before 20 minutes through jugular vein at ischemia, with TSA and PNS ratio compatibility, quiet continuously splashing into to the observation end by 1: 4.
Wherein, get 6 rats for every group, be used to observe that roll, stick, swim out of in thin vein blood vessel footpath, leukocyte, thin vein blood vessel wall DHR fluorescence intensity.Other gets 6 rats observation plasma albumins and spills and mast cell degranulation.
3. microcirculation is observed dynamically
Microcirculation is dynamically with CCD camera system (CC-090, Flovel, Tokyo) that is connected in the handstand biological microscope and SIT fluorescent camera (C-2400-08, shore pine Off オ ト ニ Network ス, shore pine) record continuously.
The mensuration of blood vessel warp: in the CD of playback video recording, with Image-Pro Plus 5.0 softwares before ischemia, during 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes when beginning perfusion, get 3 positions, rat mesentery thin vein blood vessel footpath and measure again, get its meansigma methods.
Along the thin vein leukocytic counting that rolls: on the image of playback, before ischemia, again during 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes when beginning perfusion, count in 10 seconds kinds the leukocyte number of in 200 microns thin veins, rolling.
Adhere to the leukocyte count counting of thin vein tube wall: on the image of playback, before ischemia, again during 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes when beginning perfusion, counting stops the leukocyte (adhesion leukocyte) more than 30 seconds at the same position of thin vein tube wall, calculate adherent leukocyte count on the long thin vein of 100 μ m.
Thin vein tube wall DHR fluorescent strength determining: drip the fluorescent probe DHR (10uM) that experiences hydrogen peroxide continuously on observed rat mesentery surface.With inverted fluorescence microscope observe (DM-IRB, Leica, Germany), the 455nm exciting light, mercury lamp is as transmitting illuminant (100W).Before respectively organizing ischemia with CD videocorder record, the image 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes time during perfusion beginning is again measured the fluorescence intensity of thin vein tube wall and blood vessel outer room matter with Image-Pro Plus 5.0 softwares.Difference with thin vein tube wall before the ischemia and blood vessel outer room matter is a basic value, calculates the ratio of each time point numerical value and basic value, in order to the rate of change of expression rat mesentery thin vein tube wall DHR fluorescence intensity.
The mensuration that the thin vein albumin oozes out: get 6 rats in addition for every group, slowly inject the bovine serum albumin (50mg/kg) of FITC-labelling along jugular vein, the basis was observed after 10 minutes, observe (DM-IRB with inverted fluorescence microscope, Leica, Germany), the 455nm exciting light, mercury lamp is as transmitting illuminant (100W).With each group of CD videocorder continuous record before ischemia, again during 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes when beginning perfusion in the thin vein blood vessel and the FITC fluoroscopic image of adjacent blood vessel outer room matter.Measuring in the thin vein blood vessel and the FITC fluorescence intensity of adjacent blood vessel outer room matter with Image-Pro Plus 5.0 softwares, is basic value with the ratio of the preceding thin vein tube wall of ischemia and the FITC fluorescence of blood vessel outer room matter.Calculate the ratio of each time point numerical value and basic value, in order to the rate of change of representing that rat mesentery thin vein albumin oozes out.Can be formulated: Rt=Pt/Po wherein, Rt is illustrated in the FITC fluorescence intensity ratio of certain time point; Pt is illustrated in this time point blood vessel wall and the outer fluorescence intensity ratio of blood vessel; The outer fluorescence intensity ratio of blood vessel wall and blood vessel when Po represents 0 minute.
Mast cell degranulation rate: after pouring into 60 fens again, 0.1%toluidine blue is dripped at look-out station, note down with ccd video camera.With 20 times to 5 visuals field of object lens countings take off granule and not degranulated mastocyte number, calculate the percentage ratio that degranulated mastocyte accounts for the whole mastocyte number of counting, be the mast cell degranulation rate.
4. statistical disposition
Each measured value is handled with one-way analysis of variance (ANOVA), each group through the time change check with T, relatively check between each group with F.Each measured value represents that with the mean value standard error P＜0.05 is a significance.
Description of drawings:
Fig. 1 was illustrated in this observing time, and I/R group rat thin vein blood vessel does not directly take place by significant the variation.
Figure 1A represents TSA, PNS and the pre-influence that drops into I/R rat mesentery thin vein caliber of the two compatibility.Sham: sham operated rats; I/R: I/R group; Administration group before TSA+I/R: the TSA; Administration group before PNS+I/R: the PNS; TP (4: 1)+I/R: TSA and PNS4: administration group before 1 compatibility; TP (1: 1)+I/R: TSA and PNS1: administration group before 1 compatibility; TP (1: 4)+I/R: TSA and PNS1: administration group before 4 compatibilities.The result represents with meansigma methods ± standard error.Figure 1B represents to drop into behind TSA, PNS and the two compatibility influence to I/R rat mesentery thin vein caliber.Sham: sham operated rats; I/R: I/R group; I/R+TSA: administration group behind the TSA; I/R+PNS: administration group behind the PNS; I/R+TP (4: 1): TSA and PNS4: administration group behind 1 compatibility; I/R+TP (1: 1): TSA and PNS1: administration group behind 1 compatibility; I/R+TP (1: 4): TSA and PNS1: administration group behind 4 compatibilities.The result represents with meansigma methods ± standard error.
Fig. 2 represents the influence that rat mesentery thin vein leukocyte that TSA, PNS and the two compatibility cause I/R rolls.The leukocyte that the rat mesentery thin vein rolls behind the I/R significantly increases, and the leukocytic increase of rolling does not all have significant inhibitory effect to rat mesentery thin vein behind the I/R for pre-input of TSA, PNS and the two compatibility (Fig. 2 A) and back input (Fig. 2 B).
Fig. 2 A represents TSA, PNS and the pre-influence that drops into the rat mesentery thin vein leukocyte rolling that I/R is caused of the two compatibility.Sham: sham operated rats; I/R: I/R group; Administration group before TSA+I/R: the TSA; Administration group before PNS+I/R: the PNS; TP (4: 1)+I/R: TSA and PNS4: administration group before 1 compatibility; TP (1: 1)+I/R: TSA and PNS1: administration group before 1 compatibility; TP (1: 4)+I/R: TSA and PNS1: administration group before 4 compatibilities.Fig. 2 B represents to drop into behind TSA, PNS and the two compatibility influence that rat mesentery thin vein leukocyte that I/R is caused rolls.Sham: sham operated rats; I/R: I/R group; I/R+TSA: administration group behind the TSA; I/R+PNS: administration group behind the PNS; I/R+TP (4: 1): TSA and PNS4: administration group behind 1 compatibility; I/R+TP (1: 1): TSA and PNS1: administration group behind 1 compatibility; I/R+TP (1: 4): TSA and PNS1: administration group behind 4 compatibilities.The result represents with meansigma methods ± standard error.* represent to compare p＜0.05 with sham operated rats.
Fig. 3 represents TSA, PNS and the two compatibility to adhering to leukocytic influence in the rat mesentery thin vein of I/R initiation, and the Sham group only has a spot of leukocyte adhesion in thin vein when this observation finishes.I/R group rat just has leukocyte adhesion in the thin vein tube wall in early days in perfusion again, along with dabbling carrying out again, sticks leukocyte and increases gradually.The compatibility that TSA, PNS and three kinds of ratios are given in pre-throwing has all suppressed leukocytic adhesion significantly after pouring into 40 fens again.Pouring into again 10 fens, leukocyte has been arranged when the thin vein wall, back throwing TSA, PNS, TP (4: 1), TP (1: 1), TP (1: 4) can suppress to adhere in the thin vein leukocyte later in 20 minutes significantly in input, and wherein, the inhibitory action of TP (4: 1) is the strongest.
Fig. 3 A represents TSA, PNS and the pre-influence that drops into the rat mesentery thin vein leukocyte adhesion that I/R is caused of the two compatibility.Sham: sham operated rats; I/R: I/R group; Administration group before TSA+I/R: the TSA; Administration group before PNS+I/R: the PNS; TP (4: 1)+I/R: TSA and PNS4: administration group before 1 compatibility; TP (1: 1)+I/R: TSA and PNS1: administration group before 1 compatibility; TP (1: 4)+I/R: TSA and PNS1: administration group before 4 compatibilities.Fig. 3 B represents to drop into behind TSA, PNS and the two compatibility influence of the rat mesentery thin vein leukocyte adhesion that I/R is caused.Sham: sham operated rats; I/R: I/R group; I/R+TSA: administration group behind the TSA; I/R+PNS: administration group behind the PNS; I/R+TP (4: 1): TSA and PNS4: administration group behind 1 compatibility; I/R+TP (1: 1): TSA and PNS1: administration group behind 1 compatibility; I/R+TP (1: 4): TSA and PNS1: administration group behind 4 compatibilities.The result represents with meansigma methods ± standard error.* represent to compare p＜0.05 with sham operated rats; # represents to compare p＜0.05 with the I/R group.
Fig. 4 represents the influence that TSA, PNS and the two compatibility are swum out of the rat mesentery thin vein leukocyte of I/R initiation.The Sham group is not observed via the leukocyte of thin vein when this observation finishes and is swum out of.Significantly increase pouring into the leukocyte of swimming out of via thin vein again at 30 o'clock, and continue to increase when this observation finishes.The preceding administration of TSA, PNS and three kinds of compatibilities thereof and back administration have all suppressed I/R significantly after swum out of by the leukocyte of mesentery thin vein.
Fig. 4 A represents the influence that TSA, PNS and the pre-input of the two compatibility are swum out of the rat mesentery thin vein leukocyte of I/R initiation.Sham: sham operated rats; I/R: I/R group; Administration group before TSA+I/R: the TSA; Administration group before PNS+I/R: the PNS; TP (4: 1)+I/R: TSA and PNS4: administration group before 1 compatibility; TP (1: 1)+I/R: TSA and PNS1: administration group before 1 compatibility; TP (1: 4)+I/R: TSA and PNS1: administration group before 4 compatibilities.Fig. 4 B represents to drop into the influence that the rat mesentery thin vein leukocyte of I/R initiation is swum out of behind TSA, PNS and the two compatibility.Sham: sham operated rats; I/R: I/R group; I/R+TSA: administration group behind the TSA; I/R+PNS: administration group behind the PNS; I/R+TP (4: 1): TSA and PNS4: administration group behind 1 compatibility; I/R+TP (1: 1): TSA and PNS1: administration group behind 1 compatibility; I/R+TP (1: 4): TSA and PNS1: administration group behind 4 compatibilities.The result represents with meansigma methods ± standard error.* represent to compare p＜0.05 with sham operated rats; # represents to compare p＜0.05 with the I/R group.
Fig. 5 A represents that TSA, PNS and pre-input of compatibility thereof produce dynamic influence to rat mesentery thin vein tube wall peroxide behind the I/R.The Sham group is in this viewing duration, and the fluorescence intensity of thin vein tube wall DHR is not significant to be changed.I/R group thin vein tube wall DHR fluorescence intensity after perfusion begins again begins to increase, and continues to increase.The pre-input of each compatibility group of TSA, TSA and PNS has suppressed the generation of rat mesentery thin vein tube wall peroxide behind the I/R significantly, and the pre-input of PNS does not show significant inhibitory effect.
Fig. 5 B represents to drop into the dynamic influence of rat mesentery thin vein tube wall peroxide generation behind the I/R behind TSA, PNS and the compatibility thereof.TSA and TP (4: 1) have suppressed the generation of rat mesentery thin vein tube wall peroxide behind the I/R respectively significantly after dropping into 40 and 50 fens, do not show significant inhibitory effect and drop into behind the compatibility of other ratios of PNS, TSA and PNS.
Fig. 5 A represents TSA, PNS and the pre-influence that drops into the rat mesentery thin vein blood vessel wall peroxide that I/R is caused of the two compatibility.Sham: sham operated rats; I/R: I/R group; Administration group before TSA+I/R: the TSA; Administration group before PNS+I/R: the PNS; TP (4: 1)+I/R: TSA and PNS4: administration group before 1 compatibility; TP (1: 1)+I/R: TSA and PNS1: administration group before 1 compatibility; TP (1: 4)+I/R: TSA and PNS1: administration group before 4 compatibilities.Fig. 5 B represents to drop into behind TSA, PNS and the two compatibility influence of the rat mesentery thin vein blood vessel wall peroxide that I/R is caused.Sham: sham operated rats; I/R: I/R group; I/R+TSA: administration group behind the TSA; I/R+PNS: administration group behind the PNS; I/R+TP (4: 1): TSA and PNS4: administration group behind 1 compatibility; I/R+TP (1: 1): TSA and PNS1: administration group behind 1 compatibility; I/R+TP (1: 4): TSA and PNS1: administration group behind 4 compatibilities.The result represents with meansigma methods ± standard error.* represent to compare p＜0.05 with sham operated rats; # represents to compare p＜0.05 with the I/R group.
Fig. 6 represents the influence that rat mesentery intravenous plasma albumin leaks outside after TSA, PNS and compatibility thereof are to I/R.The Sham group is when the observation process finished in 60 minutes, only there is a spot of plasma albumin to spill via the rat mesentery thin vein, and I/R organizes rat after perfusion begins again, and the plasma albumin that spills via the rat mesentery thin vein just increases significantly, and along with dabbling lasting further enhancing again.TSA, TP (4: 1), TP (1: 1) compatibility all can suppress spilling of rat mesentery thin vein plasma albumin that I/R causes significantly with dropping into.When pouring into the back administration again, TSA, TP (1: 1) compatibility still has significant inhibitory effect to the spilling of rat mesentery thin vein plasma albumin that I/R causes, still, the compatibility of PNS and other ratios can not suppress spilling of plasma albumin.
Fig. 6 A represents to drop in advance the influence that albumin in the rat mesentery thin vein blood vessel that TSA, PNS and the two compatibility cause I/R oozes out variation.Sham operated rats; I/R: I/R group; Administration group before TSA+I/R: the TSA; Administration group before PNS+I/R: the PNS; 4: 1 preceding administration groups of compatibility of TP (4: 1)+I/R: TSA and PNS; TP (1: 1)+I/R: TSA and PNS1: administration group before 1 compatibility; TP (1: 4)+I/R: TSA and PNS1: administration group before 4 compatibilities.Fig. 6 B represents that back input TSA, PNS and the two compatibility ooze out the influence of variation to albumin in the rat mesentery thin vein blood vessel of I/R initiation.Sham: sham operated rats; I/R: I/R group; I/R+TSA: administration group behind the TSA; I/R+PNS: administration group behind the PNS; I/R+TP (4: 1): TSA and PNS4: administration group behind 1 compatibility; I/R+TP (1: 1): TSA and PNS1: administration group behind 1 compatibility; I/R+TP (1: 4): TSA and PNS1: administration group behind 4 compatibilities.The result represents with meansigma methods ± standard error.* represent to compare p＜0.05 with sham operated rats; # represents to compare p＜0.05 with the I/R group.
Fig. 7 represents that TSA, PNS and compatibility thereof are to the influence of matter mast cell degranulation between the rat mesentery rat mesentery behind the I/R.When pouring into 60 minutes again, compare with Sham group, I/R group mast cell degranulation rate significantly increases, TSA, PNS and compatibility thereof and drop into and all can suppress the increase of mast cell degranulation rate in the matter between rat mesentery that I/R causes significantly.In perfusion again the back taking place throws and gives TSA and then can not suppress mast cell degranulation, the back input of PNS can partly suppress mast cell degranulation, and the back input of each compatibility of TSA and PNS all can suppress between rat mesentery that I/R causes mast cell degranulation rate in the matter significantly.
Fig. 7 A represents TSA, PNS and the pre-influence that drops into mast cell degranulation around the rat mesentery thin vein blood vessel of I/R initiation of the two compatibility.Sham: sham operated rats; I/R: I/R group; Administration group before TSA+I/R: the TSA; Administration group before PNS+I/R: the PNS; TP (4: 1)+I/R: TSA and PNS4: administration group before 1 compatibility; TP (1: 1)+I/R: TSA and PNS1: administration group before 1 compatibility; TP (1: 4)+I/R: TSA and PNS1: administration group before 4 compatibilities.Fig. 7 B represents to drop into the rat mesentery thin vein blood vessel influence of mast cell degranulation on every side that I/R is caused behind TSA, PNS and the two compatibility.Sham: sham operated rats; I/R: I/R group; I/R+TSA: administration group behind the TSA; I/R+PNS: administration group behind the PNS; I/R+TP (4: 1): TSA and PNS4: administration group behind 1 compatibility; I/R+TP (1: 1): TSA and PNS1: administration group behind 1 compatibility; I/R+TP (1: 4): TSA and PNS1: administration group behind 4 compatibilities.The result represents with meansigma methods ± standard error.* represent to compare p＜0.05 with sham operated rats; # represents to compare p＜0.05 with the I/R group.
Conclusion:
1.I/R rear rat mesentery blood vessel does not directly have marked change, and the mast cell degranulation rate that the plasma albumin of the leukocyte count that rolls, adheres to and swim out of, thin vein vascular wall DHR fluorescence intensity, FITC mark spills in rate, the blood vessel outer room matter tissue significantly increases.
2.TSA front administration to I/R after the rat mesentery blood vessel directly have no significant effect, the leucocyte that rolls along thin vein there is not significant inhibitory action, but, anti-adhesion and swim out of the increase of leukocyte count significantly, suppress the increase of thin vein tube wall DHR fluorescence intensity, the blood vessel that suppresses plasma albumin spills outward, suppresses mast cell degranulation. And administration behind the TSA, except can not suppressing significantly the mast cell degranulation, other effects are identical with front administration.
3.PNS front administration and rear administration to I/R after the rat mesentery blood vessel directly have no significant effect, the leucocyte that rolls along thin vein there is not significant inhibitory action, but anti-adhesion and the increase of swimming out of leukocyte count suppress mast cell degranulation significantly. The front administration of PNS and rear administration all do not suppress the increase of the rat mesentery thin vein tube wall DHR fluorescence intensity that I/R causes.
(4.TP 4: 1), TP (1: 1), TP (1: 4)) front administration to I/R after the improvement effect of Rat Mesenteric Microcirculation obstacle identical with the effect of TSA, PNS, but, when TP (4: 1), TP (1: 1), the rear administration of TP (1: 4), it suppresses mast cell degranulation and significantly strengthens, during the rear administration of TP (4: 1), its effect that suppresses leukocyte adhesion significantly strengthens, and behind the TP (1: 4) during administration, it suppresses a little less than the effect of leukocyte adhesion. Conclusion: TSA, PNS, and the improvement effect of the rat microcirculation Mesentery microcirculation obstacle that all can ischemia-reperfusion causes of compatibility. Wherein, TSA improves effect and the leukocytic adhesion of its inhibition of microcirculation disorder and swims out of, and the generation that suppresses thin vein tube wall peroxide is relevant; Wherein, PNS improves effect and the leukocytic adhesion of its inhibition of microcirculation disorder and swims out of, and suppresses mast cell degranulation and is correlated with. The compatibility of TSA and PNS has increased the effect of its mast cell degranulation, and the compatibility of TP (4: 1) has also increased it and suppressed the effect of leukocyte adhesion.
In a word, the present invention proves, salvianolic acid, arasaponin, and compatibility can prevent and treat the microcirculation disorder that ischemia-reperfusion causes. Thereby be applied to treat and/or prevent the disease that microcirculation disorder causes, as: anaphylactia, hyperlipidemia, hypertension, infection etc. and because of direct stimulation, traumatic injury, pollinosis, skin disease, asthma, the microcirculation disorder that diarrhoea, operation or PCI etc. cause.
The specific embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Tablet
[prescription] Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins 1: 1,105g microcrystalline Cellulose 55g micropowder silica gel 3g magnesium stearate 1.5g
[method for making] got former, adjuvant and crossed 100 mesh sieves respectively; Get Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins 1: 1, microcrystalline Cellulose, mixing in right amount as binding agent system soft material, is crossed 20 mesh sieve system granules with 60% ethanol, 60 ℃ of dryings are taken out, and cross 30 mesh sieve granulate, add micropowder silica gel and magnesium stearate, mixing, tabletting is made 1000, promptly.
[prescription] Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins 1: 485g calcium sulfate 118g microcrystalline Cellulose 37g micropowder silica gel 2.4g magnesium stearate 1.2g
[method for making] got former, adjuvant and crossed 100 mesh sieves respectively; Get Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins 1: 4, microcrystalline Cellulose, mixing in right amount as binding agent system soft material, is crossed 20 mesh sieve system granules with 60% ethanol, 60 ℃ of dryings are taken out, and cross 30 mesh sieve granulate, add an amount of micropowder silica gel and magnesium stearate, mixing, tabletting is made 1000, promptly.
[prescription] Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins 4: 1133g calcium sulfate 208g microcrystalline Cellulose 68g micropowder silica gel 5g magnesium stearate 2.5g
[method for making] got former, adjuvant and crossed 100 mesh sieves respectively; Get Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins 4: 1, microcrystalline Cellulose, mixing in right amount as binding agent system soft material, is crossed 20 mesh sieve system granules with 60% alcohol, 60 ℃ of dryings are taken out, and cross 30 mesh sieve granulate, add an amount of micropowder silica gel and magnesium stearate, mixing, tabletting is made 1000, promptly.
Capsule
Get Radix Salviae Miltiorrhizae total phenolic acids 60g, add appropriate amount of starch, adjuvants such as magnesium stearate are granulated, granulate, and the capsule of packing into No. 1, promptly.
Oral liquid
Get Radix Salviae Miltiorrhizae total phenolic acids 8g, add an amount of sucrose, antiseptic adds water to 1000ml, is distributed into one of 10ml, promptly gets oral liquid.
Granule
Get Radix Notoginseng total arasaponins 80g, add an amount of dextrin, steviosin, dry granulation, granulate, packing, promptly.
Injection
Radix Notoginseng total arasaponins 7g is dissolved in water, and sodium chloride, ethylparaben add the hot water dissolving, mixing, adjust pH in addition.Water for injection is diluted to 1000ml, filters with hollow-fibre membrane, and fill, sterilization, promptly.
Injection
Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins 4: 12g is dissolved in water, and sodium chloride, ethylparaben add the hot water dissolving, mixing, adjust pH in addition.Water for injection is diluted to 1000ml, filters with hollow-fibre membrane, and fill, sterilization, promptly.
Claims (10)
1. Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and the application of compatibility in the medicine of the disease that preparation prevention and treatment microcirculation disturbance cause.
2. the application of claim 1, it is characterized in that wherein the now preceding administration of the application table of Radix Salviae Miltiorrhizae total phenolic acids can suppress to adhere to and swim out of the increase of leukocyte count significantly, suppresses the increase of thin vein tube wall DHR fluorescence intensity, the blood vessel that suppresses plasma albumin spills outward, suppresses mast cell degranulation.
3. the application of claim 1, it is characterized in that the wherein application table of Radix Salviae Miltiorrhizae total phenolic acids back administration now can suppress to adhere to and swim out of the increase of leukocyte count significantly, suppress the increase of thin vein tube wall DHR fluorescence intensity, the blood vessel that suppresses plasma albumin spills outward.
4. the application of claim 1 is characterized in that, wherein now preceding administration of the application table of Radix Notoginseng total arasaponins and back administration can suppress to adhere to and swim out of the increase of leukocyte count significantly, suppress mast cell degranulation.
5. the application of claim 1 is characterized in that, wherein said compatibility is the combination of Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins, and its part by weight is 1-4: 4-1, preferred 1-2: 2-1, most preferably 1: 1.
6. the application of claim 1, it is characterized in that, the present TP of the application table of wherein said Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins compatibility (4: 1), TP (1: 1), TP (1: 4)) preceding administration can suppress to adhere to and swim out of the increase of leukocyte count significantly, suppress the increase of thin vein tube wall DHR fluorescence intensity, the blood vessel that suppresses plasma albumin spills outward, suppresses mast cell degranulation.
7. the application of claim 1, it is characterized in that, when the present TP of the application table of wherein said Radix Salviae Miltiorrhizae total phenolic acids and Radix Notoginseng total arasaponins compatibility (4: 1), TP (1: 1), the administration of TP (1: 4) back, it suppresses mast cell degranulation and significantly strengthens, during TP (4: 1) administration afterwards, its effect that suppresses leukocyte adhesion significantly strengthens.
8. the application of claim 1 is characterized in that, wherein said application comprises following disease, as: anaphylactic disease, hyperlipemia, hypertension, infection etc. and because of direct stimulation, traumatic injury, pollinosis, dermatosis, asthma, the microcirculation disturbance that diarrhoea, operation or interventional therapy etc. cause.
9. the application of claim 1 is characterized in that, wherein said medicine is with above-mentioned Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, and the pharmaceutical composition that is prepared into as active constituents of medicine of compatibility.
10. the application of claim 1, it is characterized in that, wherein said Radix Salviae Miltiorrhizae total phenolic acids is a kind of composition in the salviamiltiorrhizabung, can buy from the market, also can be according to prior art for preparing, Radix Notoginseng total arasaponins is a kind of composition in the Chinese medicine Radix Notoginseng, can buy from the market, also can be according to prior art for preparing, all belong to prior art, Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins that the present invention uses are the products that meets medicinal standard, preferred purity＞50%, more preferably purity＞90%, most preferably purity＞98%.
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| CN103520509A (en) * | 2013-10-25 | 2014-01-22 | 刘晓伟 | Traditional Chinese medicine for treating mesenteric panni culitis |
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| 韩晶岩等: "复方丹参滴丸及其主要有效成分对缺血再灌注引起的大鼠肠系膜微循环障碍的改善作用及其原理", 《中国微循环学会第五届中国微循环学术大会论文摘要汇编》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103520509A (en) * | 2013-10-25 | 2014-01-22 | 刘晓伟 | Traditional Chinese medicine for treating mesenteric panni culitis |
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