CN101632726B - Application of Chinese medicinal composition in preparing medicament for treating blood vessel micro-embolization - Google Patents
Application of Chinese medicinal composition in preparing medicament for treating blood vessel micro-embolization Download PDFInfo
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Abstract
The invention discloses application of a Chinese medicinal composition in preparing a medicament for treating blood vessel micro-embolization. The Chinese medicinal composition comprises ginseng, leech, centipede, scorpion, ground beeltle, cicada slough, red paeony root, borneol and the like, and has the effects of invigorating Qi and activating blood, and dispersing blood stasis and dredging collateral. The Chinese medicinal composition has obvious curative effect of treating the blood vessel micro-embolization; and clinical experiments prove that the Chinese medicinal composition is safe and effective in treating the blood vessel micro-embolization and is free from generating adverse reactions.
Description
Technical field
The present invention relates to a kind of new purposes of Chinese medicine composition, particularly, the present invention relates to the application of a kind of Chinese medicine composition in the medicine of preparation treatment blood vessel micro-embolization, belong to the Chinese medicine application.
Background technology
Blood vessel micro-embolization is meant the blood capillary thromboembolism, and blood capillary is meant the blood vessel of blood vessel diameter less than 200nm, mainly is meant arteries.Little bolt of blood vessel and multiple cardiovascular and cerebrovascular disease have a strong impact on cardiovascular and cerebrovascular vessel patient's prognosis closely to the pass.Common blood vessel micro-embolization mainly occurs in coronary artery and intracranial, occurs in blood vessel micro-embolization coronarius and is called arteria coronaria micro-embolization (CME), and the blood vessel micro-embolization that occurs in intracranial is called intracranial microemboli (CMS).
Pathological data confirms: be not in the mood for disease of ZANG-organs and die from all visible arteria coronaria micro-embolization (CME) in various degree of vehicle accident person, hypertension patient, diabetics and cardiogenic sudden the dead.Clinical data shows: CME or small heart infarction take place in about 15-43% functions in patients with unstable angina.Thromboembolism does not reach the major reason that the bolt environment is CME that causes behind the thrombolytic entirely in the thromboembolism treatment.Various percutaneous coronary interventions (PCI) are in mediation when coronary artery reaches myocardial revascularization, because mechanism makes vascular damaged, nearly all with the formation of plaque rupture and small embolus or microthrombus, and cause CME and the small heart infarction of peri-operation period thus.Clinically; Our frequent discovery is many to have obvious chest pain, ECG or/and treadmill stress testing has the patient of typical myocardial ischemia performance; Significantly do not lead the blood coronary stenosis and only show as the TIMI blood flow and reduce but coronary angiography has or do not have, infer that these patients possibly be myocardium microangiopathies or micro-embolization.
For a long time attention more be heart surface bigger lead blood coronary stenosis or inaccessible influence to heart muscle perfusion.In recent years, through the TIMI blood flow of coronary angiography behind the thrombolytic being observed and do not had discovering of flow phenomenon: CME in case take place again, solution is limited, to the influence of prognosis even surpass and lead blood coronary stenosis or obturation.More deep discovers: after acute myocardial infarction thromboembolism treatment and various PCI comprise the direct PCI of acute myocardial infarction, reduce if the TIMI blood flow takes place, mostly its reason is CME; Then prognosis of patients is relatively poor if CME takes place, and the ischemic cardiomyopathy probability takes place subsequently significantly to be increased, and survival rate obviously reduces.Therefore, CME has a strong impact on patient's prognosis.
Thromboembolism is the one of the main reasons that causes Ischemic Stroke, and finds the microemboli omen of cerebral embolism often in the cerebral arteries.Intracranial vessel is narrow to be the main cause that microemboli produces, and one of source of prompting microemboli is an atheromatous plaque.The microemboli recall rate increased when tremulous pulse was simultaneously with pathological changes outside the intracranial, and this also is the mechanism of apoplexy tremulous pulse-arterial thrombosis.
Clinical treatment for the little bolt of blood vessel does not at present have specific drug, mainly adopts treatments such as aspirin, low molecular sodium heparin, uses these Drug therapys to have serious adverse reactions such as bleeding tendency.
The present invention is the improvement invention of on the basis of No. 01131203.3 and No. 200410048292.2 patent, carrying out, and quotes in full the content of this two patent documents record at this.The application of unexposed this Chinese medicine composition of above-mentioned two patents in the treatment blood vessel micro-embolization.
Summary of the invention
The object of the invention provides the application of a kind of Chinese medicine composition in the medicine of preparation treatment blood vessel micro-embolization, and said Chinese medicine composition is processed by following bulk drugs:
Radix Ginseng 3-10 Hirudo 3-11 Eupolyphaga Seu Steleophaga 5-10 Olibanum (system) 1-5 Radix Paeoniae Rubra 3-9 Lignum Dalbergiae Odoriferae 1-5
Lignum Santali Albi 1-5 Scorpio 3-9 Periostracum Cicadae 3-12 Scolopendra 1-3 Borneolum Syntheticum 1-7 Semen Ziziphi Spinosae (stir-fry) 3-10;
Preferably, this Chinese medicine composition is processed by following bulk drugs:
Radix Ginseng 6 Hirudo 10 Eupolyphaga Seu Steleophagas, 7 Olibanums (system) 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 7 Periostracum Cicadaes 7 Scolopendra 1 Borneolum Syntheticum, 5 Semen Ziziphi Spinosaes (stir-fry) 5;
Or:
Radix Ginseng 10 Hirudo 8 Eupolyphaga Seu Steleophagas, 7 Olibanums (system) 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 9 Periostracum Cicadaes 7 Scolopendra 1 Borneolum Syntheticum, 5 Semen Ziziphi Spinosaes (stir-fry) 5;
Or:
Radix Ginseng 6 Hirudo 11 Eupolyphaga Seu Steleophagas, 7 Olibanums (system) 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 3 Periostracum Cicadaes 7 Scolopendra 1 Borneolum Syntheticum, 5 Semen Ziziphi Spinosaes (stir-fry) 5;
The active component of above-mentioned Chinese medicine composition is made up of following ingredients:
The a mean diameter is less than Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga, Periostracum Cicadae and the Olibanum (processed) medicated powder of 100 μ m;
B Borneolum Syntheticum medicated powder;
The volatile oil that c is extracted by Lignum Dalbergiae Odoriferae and Lignum Santali Albi;
The alcohol-extracted extract of the alcohol extract of d Radix Ginseng after after concentrating with ethanol extraction;
The water extracted immersing paste that is condensed into behind the water extract after the Lignum Dalbergiae Odoriferae behind the e extraction composition c and water extract, Radix Paeoniae Rubra and the Semen Ziziphi Spinosae (parched) decocte with water of Lignum Santali Albi medicinal residues and the water extract filtration of the medicine residues of Radix Ginseng after the extraction ingredient d, the mixing.
The invention also discloses that to contain above-mentioned Chinese medicine composition be capsule, tablet, granule, powder, oral liquid or pill as the pharmaceutical preparation of active component.
The invention provides this Chinese medicine composition preparation and treat the application in blood vessel micro-embolization medicine, the application in intracranial microemboli medicine is treated in the application or the preparation of this Chinese medicine composition that are preferably in this Chinese medicine composition preparation treatment arteria coronaria micro-embolization medicine.
In the Chinese medicine composition of the present invention, as the latin name of the crude drug of active component and processing method thereof from " Chinese medicine voluminous dictionary " (in July, 1977, front page, Shanghai science tech publishing house) and " Chinese pharmacopoeia (version in 2005, Chemical Industry Press).
Chinese medicine composition of the present invention can also be by the extraction and the preparation process of routine; For example; The preparation technology of Fan Biting " pharmacy of Chinese materia medica " (Shanghai Science Press 1997 December the 1st edition) record; Process the acceptable any conventional dosage form of pharmaceutics, for example capsule, tablet, granule, powder, oral liquid or pill etc.
In the application of the present invention; Said Chinese medicine composition is capsule, tablet, granule, powder, oral liquid or pill; For above-mentioned dosage form can be realized; Need when these dosage forms of preparation, to add the pharmacy acceptable auxiliary, for example: filler, disintegrating agent, lubricant, suspending agent, binding agent, sweeting agent, correctives, antiseptic, substrate etc.Filler comprises: starch, pregelatinized Starch, lactose, mannitol, chitin, microcrystalline Cellulose, sucrose etc.; Disintegrating agent comprises: starch, pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose etc.; Lubricant comprises: magnesium stearate, sodium lauryl sulphate, Pulvis Talci, silicon dioxide etc.; Suspending agent comprises: polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, agar, hydroxypropyl emthylcellulose etc.; Binding agent comprises, starch slurry, polyvinylpyrrolidone, hydroxypropyl emthylcellulose etc.; Sweeting agent comprises: saccharin sodium, Aspartane, sucrose, cyclamate, enoxolone etc.; Correctives comprises: sweeting agent and various essence; Antiseptic comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its esters, benzalkonium bromide, fixed, the Folium eucalypti globueli (Eucalyptus globulus Labill.) wet goods of acetic acid chloroethene; Substrate comprises: PEG6000, PEG4000, insect wax etc.
Capsule of the present invention is preferably processed through following method for preparing: five kinds of Chinese medicine such as the Hirudo of said ratio, Scorpio, Periostracum Cicadae, Eupolyphaga Seu Steleophaga, Scolopendra cleaned, and oven drying at low temperature, subsequent use; Lignum Santali Albi, Lignum Dalbergiae Odoriferae extract volatile oil, and medicinal residues and aqueous solution are subsequent use; Radix Ginseng extracts secondary with 70% alcohol heating reflux, and 3 hours for the first time, 2 hours for the second time, merge extractive liquid, reclaimed ethanol to there not being the alcohol flavor; The medicinal residues of medicine residues of Radix Ginseng and Lignum Santali Albi, Lignum Dalbergiae Odoriferae merge with aqueous solution, add Radix Paeoniae Rubra, Semen Ziziphi Spinosae (stir-fry), the decocte with water secondary; 3 hours for the first time, 2 hours for the second time, collecting decoction; Filter, filtrating is concentrated into the clear paste that relative density is 1.20-1.25 (60 ℃), adds above-mentioned panaxynol extract; Mixing, cold drying is ground into fine powder; The five tastes such as Olibanum (system) and Hirudo are ground into fine powder altogether; The Borneolum Syntheticum porphyrize, with above-mentioned fine powder facing-up, mixing sprays into volatile oil respectively, and mixing incapsulates, and promptly gets.
Perhaps, capsule of the present invention is preferably processed through following method for preparing:
A) weight ratio of crude drug is: Radix Ginseng 3-10 part, Hirudo 3-11 part, Eupolyphaga Seu Steleophaga 5-10 part, Olibanum (processed) 1-5 part, Radix Paeoniae Rubra 3-9 part, Lignum Dalbergiae Odoriferae 1-5 part, Lignum Santali Albi 1-5 part, Scorpio 3-9 part, Periostracum Cicadae 3-12 part, Scolopendra 1-3 part, Borneolum Syntheticum 1-7 part, Semen Ziziphi Spinosae (parched) 3-10 part;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 100 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae decocte with water, after the water extract filters, extractum to be condensed into; Radix Ginseng with ethanol extraction after, reuse water extraction, alcohol extract are condensed into alcohol-extracted extract after reclaiming ethanol, the water extract filter with all water extract mixings after be condensed into the water extracted immersing paste;
D) preparation process:
In Fluidbedgranulatingdrier, add the superfine powder flour, again the step c) gained is extracted extractum and spray into granulation; The granule of processing through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, process capsule behind the mixing.
Perhaps, capsule of the present invention is preferably processed through following method for preparing:
A) weight ratio of crude drug is: Radix Ginseng 3-10 part, Hirudo 3-11 part, Eupolyphaga Seu Steleophaga 5-10 part, Olibanum (system) 1-5 part, Radix Paeoniae Rubra 3-9 part, Lignum Dalbergiae Odoriferae 1-5 part, Lignum Santali Albi 1-5 part, Scorpio 3-9 part, Periostracum Cicadae 3-12 part, Scolopendra 1-3 part, Borneolum Syntheticum 1-7 part, Semen Ziziphi Spinosae (parched) 3-10 part;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 100 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae decocte with water, after the water extract filters, extractum to be condensed into; Radix Ginseng with ethanol extraction after, reuse water extraction, alcohol extract are condensed into alcohol-extracted extract after reclaiming ethanol, the water extract filter with all water extract mixings after be condensed into the water extracted immersing paste, extractum directly is spray dried to spray powder;
D) preparation process:
The superfine powder flour is added in the Fluidbedgranulatingdrier with step c) gained spray drying powder, sprays solvent again and process granule; The granule of processing through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, process capsule behind the mixing.
The consumption of pharmaceutical composition of the present invention is converted to the weight of raw medicinal material, is each 0.8-3 gram, and take 2-4 every day, is preferably each 1.11-2.22 and restrains, and takes every day three times.
The specific embodiment
Embodiment 1:
A) the crude drug prescription is:
Radix Ginseng 39.6g Hirudo 72.6g Eupolyphaga Seu Steleophaga 46.2g Olibanum (system) 13.2g
Radix Paeoniae Rubra 33g Lignum Dalbergiae Odoriferae 13.2g Lignum Santali Albi 13.2g Scorpio 19.8g
Periostracum Cicadae 46.2g Scolopendra 6.6g Borneolum Syntheticum 33g Semen Ziziphi Spinosae (stir-fry) 33g;
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 30-40 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae add suitable quantity of water and decoct secondary, and each 3 hours, merge the water extract, after the filtration, be condensed into extractum; Radix Ginseng is with an amount of 70% ethanol extraction secondary; Each 3 hours, merge extractive liquid, reclaimed ethanol to there not being the alcohol flavor; The reuse water extraction; Alcohol extract is condensed into 60 ℃, and to measure relative densities be 0.9～1.1 alcohol-extracted extract, the water extract filter with above-mentioned all water extract mixings after be concentrated into 60 ℃ to measure relative densities be 0.9～1.1 clear paste, subsequent use;
D) preparation process:
In Fluidbedgranulatingdrier, add the superfine powder flour, again the step c) gained is extracted extractum and spray into granulation; The granule of processing through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, by the capsule filler filling, process 1000 capsules behind the mixing.
Amount of drug of the present invention for each 2-4 grain, is taken three times every day.
Embodiment 2
A) the crude drug prescription is:
Radix Ginseng 66g Hirudo 52.8g Eupolyphaga Seu Steleophaga 46.2g Olibanum (system) 13.2g
Radix Paeoniae Rubra 33g Lignum Dalbergiae Odoriferae 13.2g Lignum Santali Albi 13.2g Scorpio 59.4g
Periostracum Cicadae 46.2g Scolopendra 6.6g Borneolum Syntheticum 33g Semen Ziziphi Spinosae (stir-fry) 33g
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes the medicated powder mean diameter less than 70-90 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae add suitable quantity of water and decoct secondary, and each 3 hours, merge the water extract, after the filtration, extractum to be condensed into; Radix Ginseng is with an amount of 70% ethanol extraction secondary; Each 3 hours, merge extractive liquid, reclaimed ethanol to there not being the alcohol flavor; The reuse water extraction; Alcohol extract is condensed into relative density and is determined as 1.0～1.05 alcohol-extracted extracts at 60 ℃, the water extract filter with above-mentioned all water extract mixings after be concentrated into 60 ℃ to measure relative densities be 1.0～1.1 clear paste, subsequent use;
D) preparation process:
In Fluidbedgranulatingdrier, add the superfine powder flour, again the step c) gained is extracted extractum and spray into granulation; The granule of processing through granulate, is added the Borneolum Syntheticum fine powder, spray into the volatile oil that extracts by Lignum Dalbergiae Odoriferae and Lignum Santali Albi, be pressed into 1000 by conventional formulation technology.
Amount of drug of the present invention for each 2-4 sheet, is taken three times every day.
Embodiment 3: the preparation of pill
A) the crude drug prescription is:
Radix Ginseng 39.6g Hirudo 66g Eupolyphaga Seu Steleophaga 46.2g Olibanum (system) 13.2g
Radix Paeoniae Rubra 33g Lignum Dalbergiae Odoriferae 13.2g Lignum Santali Albi 13.2g Scorpio 46.2g
Periostracum Cicadae 46.2g Scolopendra 6.6g Borneolum Syntheticum 33g Semen Ziziphi Spinosae (stir-fry) 33g
B) pulverizing medicinal materials technology:
Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga and five kinds of worm medicines of Periostracum Cicadae are prepared burden by prescription through the Olibanum (processed) that cleans, washes after handling the back and cleaning the process of preparing Chinese medicine, pulverized by pulverizer, the medicated powder fineness reaches more than 80 orders; Medicated powder behind the coarse powder carries out micronizing through various superfine communication techniques, makes medicated powder mean diameter 10-20 μ m; Medical material to be pulverized is prepared burden after the cleaning, drying sterilization;
C) extract concentrated and drying process:
Reuse water extraction behind Lignum Dalbergiae Odoriferae and the Lignum Santali Albi elder generation extracting in water volatile oil, Radix Paeoniae Rubra and Semen Ziziphi Spinosae add suitable quantity of water and decoct secondary, and each 3 hours, merge the water extract, after the filtration, extractum to be condensed into; Radix Ginseng is with an amount of 70% ethanol extraction secondary; Each 3 hours, merge extractive liquid, reclaimed ethanol to there not being the alcohol flavor; The reuse water extraction; Alcohol extract is condensed into 60 ℃, and to measure relative densities be 0.9～1.0 alcohol-extracted extract, the water extract filter with above-mentioned all water extract mixings after be concentrated into 60 ℃ to measure relative densities be 1.0～1.1 clear paste, subsequent use;
D) preparation process:
Press conventional formulation technology, process 1000 pills.
Amount of drug of the present invention for each 2-4 grain, is taken three times every day.
For illustrating the therapeutic activity of Chinese medicine composition of the present invention to blood vessel micro-embolization; Use the capsule (to call medicine of the present invention in the following text) that makes by the foregoing description 1 method to carry out following pharmacology and clinical trial proving its curative effect, but it can not constitute any restriction to scope of the present invention.
Experimental example 1:
1 material
1.1 laboratory animal
64 of SPF level SD male rats, body weight 280～320g.Effluent north medical university Experimental Animal Center provides, and laboratory animal and experimental procedure meet national management of laboratory animal regulations.
1.2 experiment reagent
The Tunel test kit is provided by Roche company; The immunohistochemistry matched reagent relies amino acid etc. to step the neoplasm company limited by Foochow to provide like the fast red liquid, colour developing liquid, PBS buffer, poly redyed of: pepsin, citric acid antigen retrieval buffer, nuclear, and medicine effluent of the present invention north provides with mountain range Medicine Research Academy.
2. experimental technique
2.1 arteria coronaria micro-embolization model preparation
The SPF level rat of about 300 grams of body weight; Get tail vein 1ml for every and add the short thrombosis that is frozen into of epinephrine 2ml; 60 ℃ roasting incubator oven dry, the glass grinding device grinds 5min, and after the drainage screen of 50～100 μ m size filters, making it to become diameter is 10～100 μ m microemboli granules uniformly.After intraperitoneal injection of ketamine (66.7mg/Kg) and stable (6.67mg/Kg) combined anesthesia, get dorsal position, the sterilization of art district preserved skin, tracheal intubation, respirator assisted ventilation (300ml/min).Get the horizontal transverse incision of the 2nd intercostal, cut off breastbone, cut pericardium, expose aortic root, clamp ascending aorta temporary interruption blood flow to apex injection microemboli 1mg, unclamps the ascending aorta of clamp with fine needle behind the 10s, and the breast recovery is closed in the hemostasis of compressing puncture orifice.For preventing postoperative infection, intramuscular injection every day penicillin 400,000 U/ only, for three days on end.
2.2 animal divides into groups and administration
64 rats are divided into 4 groups at random, i.e. matched group (CL group), sham operated rats (SO group), arteria coronaria micro-embolization group (ME group) and medication therapy groups of the present invention (TL group), 16 every group.
(1) after the preparation of TL group arteria coronaria micro-embolization model,, is diluted to 5ml with normal saline and irritates stomach, once a day, raise after 28 days and put to death with drug substance contents of the present invention 450mg every day crude drug/Kg;
(2) after the preparation of ME group arteria coronaria micro-embolization model, give normal saline and irritate stomach, once a day, a 5ml raises after 28 days and puts to death;
(3) SO group operation method is organized with ME, injects normal saline from aortic root portion and substitutes the thrombosis microgranule, and postoperative gives normal saline and irritates stomach, and once a day, a 5ml raises after 28 days and puts to death;
(4) rat that do not undergo surgery of CL group organize as normal CL, and postoperative gives normal saline and irritates stomach, and once a day, a 5ml raises execution after 28 days.
3. observation index and method
3.1HE staining and small myocardial infarction kitchen range counting, shared viewing area percentage test
CL group, SO group, ME group and TL group rat; 28 days ketamines of postoperative and stable intraperitoneal injection of anesthesia; Cut femoral vein, intravenous injection 10%KCl2ml makes asystole diastasis, opens breast rapidly and takes out heart; After the heparin-saline flushing, 10% neutral formalin constant voltage (90mmHg) perfusion arteria coronaria 15min.Remove trunk and atrial tissue, parallel chamber inter-drain direction is the thick piece of tissue of 2mm with the ventricle crosscut, and 10% neutral formalin is 24h fixedly, buries wax, section, HE dyeing.
Index and observational technique are following: little infarction is defined as: microscopically be dispersed in, the dead kitchen range of stigma of focal distribution; Per hundred visuals field small myocardial infarction kitchen range quantity (Nmmi, individual) are calculated in microscopic image microcomputer analysis system (IMAGING PRO 4) random observation 100 * 100 visuals field, the shared percentage ratio of the small myocardial infarction kitchen range in every visual field, get its meansigma methods (Ammi, %).
3.2 cardiac muscular tissue's collagen fiber account for viewing area percentage ratio and measure
CL group, SO group, ME group and TL group, 28 days ventricle tissue paraffin section des of postoperative routine dewaxes to water, and celestine blue liquid dyed nuclear 3 minutes; Distillation washing 3 times; The red saturated bitterness acid solution dyeing of Sirius 15 minutes, dehydrated alcohol differentiation and dehydration, the transparent and neutral gum sealing of xylene.
Index and observational technique: collagen fiber albumen is dyed redness, and myocardial cell is yellow.100 * 100 visuals field are observed by microscopic image microcomputer analysis system (IMAGING PRO 4), calculate the percentage ratio of collagen fiber area occupied under each visual field, get its meansigma methods (Fcf, %).
3.3 ultrasoundcardiogram and parameters of left ventricular function are measured
CL group, SO group, ME group and TL group rat, echocardiogram fan sweeping angle 15 degree, frame frequency＞360/Min.Before the art, respectively observe 1 time in the 1st, 2,4 weeks of postoperative, obtain left chamber minor axis series section image.
Observation index and method: interventricular septum and LVPW systole and relaxing period thickness (IVSS, IVSD, LVPWS, LVPWD), left ventricle systole and Dd (LVEESD, LVEED), left LVSF (LVFS) and left ventricular ejection mark (LVEF).
3.4 apoptosis of cardiac muscle detection method and index
3.4.1 SABC detects
CL group, SO group, ME group and TL group rat, 28 days ventricle tissue paraffin section des of postoperative routine dewaxes to water, microwave antigen retrieval (citrate buffer solution; PH 6.0), the disconnected endogenous peroxidase of 1% peroxidating water resistance 10 minutes, and press SP SABC test kit: add activated form caspase-3 (dilution in 1: 50); 4 ℃ of incubated overnight; Add two anti-, three anti-, the DAB colour developing, haematoxylin is redyed.Do not add an anti-generation with the negative contrast of PBS.
Observation index and method: the normal myocardium cell is dyed light green, and dying palm fibre xanchromatic is the apoptosis myocardial cell.Computer micro-image analytical system random observation 100 * 200 high power field activated form caspase-3 SABC positive cardiomyocytes numbers calculate apoptosis myocardial cell number under each visual field and account for the percentage ratio of total myocardial cell number (Rapo1 %), averages.
3.4.2 original position end labelling (TUNEL) detects
CL group, SO group, ME group and TL group rat, postoperative 1 day and the conventional dewaxing of ventricle tissue paraffin section de in 28 days, aquation, 0.5% pepsin incubated at room 30min permeable membrane; The PBS flushing, the TUNEL reactant liquor was hatched 1 hour for 37 ℃, the PBS flushing; The alkaline phosphatase enzyme antibody is hatched 30min for 37 ℃, PBS flushing, BCIP/NBT colour developing; Fast red the redying of nuclear, the mounting microscopy.Do not add the negative contrast of TdT enzyme person in the step, the normal myocardium tissue produces the DNA chain interruption as positive control through dna polymerase i (1U/ml is hatched 30min for 37 ℃) digestion.
Observation index and method: normal myocardium nuclei dyeing pinken, the cardiac cell nucleus of apoptosis is black-and-blue.Microscope combines computer micro-image analytical system random observation 100 * 400 visual field TUNEL positive cardiomyocytes numbers, calculates apoptosis myocardial cell number under each visual field and accounts for the percentage ratio of total myocardial cell number (Rapo2 %), averages.
3.5VIII coronule arteries and veins density in the myocardial cell is observed in factor dyeing
CL group, SO group, ME group and TL group rat, the postoperative conventional dewaxing of ventricle tissue paraffin section de in 1,28 days, pepsin antigen retrieval (citrate buffer solution; PH 6.0), the disconnected endogenous peroxidase of 1% peroxidating water resistance 10 minutes, and add the anti-Mus VIII of rabbit factor related antigen polyclonal antibody (dilution in 1: 100) successively according to SP SABC test kit description; 4 ℃ of incubated overnight; Add two anti-, three anti-, the DAB colour developing, haematoxylin is redyed.Do not add an anti-generation in the step with the negative contrast of PBS.
Observation index and method: the arteria coronaria vascular endothelial cell is dyed yellowish-brown.100 * 200 times visuals field of microcomputer micro image analysis system random observation, the small coronary artery quantity of unit of account area 10～100 μ m (Nmv, individual/mm2).
3.6 statistical analysis technique
Use the SPSS12.0 software kit and carry out statistical analysis.Measurement data is represented with X ± S, relatively adopts e-Way ANNOVA to analyze between group, and variance neat person check with LSD, and heterogeneity of variance the person check with Game-Howell, relatively adopts t check in groups between the group mean.P＜0.05 difference has significance.
4 experimental results
4.1HE dyeing and the quantitative analysis of small myocardial infarction kitchen range
Postoperative 28 days, it is respectively 0.04 ± 0.01,0.03 ± 0.01,4.76 ± 1.28 and 1.13 ± 0.65 that CL group, SO group, ME group and TL organize per hundred visuals field small myocardial infarction kitchen range quantity Nmmi; Every visual field shared percentage ratio Ammi of small myocardial infarction kitchen range is respectively (1.55 ± 0.09) %, (1.67 ± 0.07) %, (37.02 ± 13.11) % and (6.77 ± 2.49) %.With CL group ratio, ME group Nmmi and Ammi showed increased (P＜0.01); With ME group ratio, TL group Nmmi and Ammi significantly reduce (P＜0.01); CL group and SO group ratio, Nmmi no significant difference (P＞0.05).
The result shows that the rat CME model that this institute is made is successful, has formed small myocardial infarction kitchen range; Drug therapy of the present invention significantly reduces small myocardial infarction result and sees table 1 after 28 days.
The therapeutic effect of Nmmi, Ammi and medicine of the present invention behind the table 1CME (X ± S)
Annotate:
*Compare P＜0.01 with the SO group; # and ME group compare P＜0.01
4.2 myocardium interstitial collagen fiber basis weight analysis result
Postoperative 28 days, CL group, SO group, ME group and TL group Fcf are respectively (0.55 ± 0.43) %, (0.57 ± 0.41) %, (27.99 ± 5.37) % and (2.44 ± 0.77) %.With CL group ratio, ME organizes Fcf showed increased (P＜0.01); Compare with the ME group, TL group Fcf significantly reduces (P＜0.01); CL group and SO group ratio, Fcf no significant difference (P＞0.05).Postoperative 28 days, each organizes epimyocardium district Fcf is respectively (0.27 ± 0.12) %, (0.22 ± 0.10) %, (0.30 ± 0.15) % and (0.28 ± 0.09) %, difference does not have significance (P＞0.05).Inner membrance district Fcf is respectively (0.25 ± 0.11) %, (0.28 ± 0.13) %, (28.06 ± 8.03) % and (10.47 ± 2.01) %; With CL or SO group ratio, ME organizes Fcf showed increased (P＜0.01); Compare with the ME group, TL group Fcf significantly reduces (P＜0.01).
The result shows that myocardial cell dead behind the CME is replaced by collagen fiber, forms the microfibre kitchen range, is distributed in the subendocardial layer cardiac muscle more; Pharmaceutical intervention of the present invention obviously suppressed the collagen fiber hypertrophy in 28 days, and the result sees table 2.
Each group and interior adventitia district Fcf variation thereof and medication effect of the present invention behind the table 2CME (X ± S)
Annotate:
*Compare P＜0.01 with the SO group; # and ME group compare P＜0.01
4.3 ultrasoundcardiogram changes of cardiac function and index measurement
Before the art, the difference of CL group, SO group, ME group and TL group LVEDD, LVESD, IVSS, IVSD, LVPWS, LVPWD, LVFS, each index of LVEF does not have significance (P all＞0.05).
1 week of postoperative, 2 week and 4 weeks, ME group and CL group ratio, LVEDD, LVESD, IVSS, IVSD, LVPWS, LVPWD, LVFS, LVEF significant difference (P＜0.01); TL and ME organize ratio, LVEDD, LVESD, IVSS, IVSD, LVPWS, LVPWD, LVFS, LVEF significant difference (P＜0.01); CL group and SO group no significant difference (P＞0.05); Show that relatively 1 week of postoperative, 2 weeks, 4 all LVEDD, LVESD, IVSS, IVSD, LVPWS, LVPWD, LVFS, LVEF sexually revise (P＜0.01) in the ME group.
The result shows, the progressive reduction of left chamber function behind the CME, and 4 week of Drug therapy of the present invention, the obvious left chamber function deterioration result that reduces in back saw table 3.
Change of ultrasoundcardiogram parameters of left ventricular function and medication effect of the present invention behind the table 3CME (X ± S)
Annotate:
*Compare P＜0.01 with the SO group; # and ME group compare P＜0.01
4.4 apoptosis of cardiac muscle detection method and index
4.4.1 SABC detects
Postoperative 28 days, CL group, SO group, ME group and TL group myocardial cell Rapo1 are respectively (1.33 ± 0.31) %, (1.48 ± 0.41) %, (5.17 ± 0.44) % and (3.02 ± 0.25) %; With CL group ratio, ME group Rapo1 significantly increases (P＜0.01); CL group and SO group ratio, Rapo1 no significant difference (P＞0.05); The TL group significantly reduces (P＜0.01) with ME group ratio, TL group Rapo1.Explain that Drug therapy of the present invention can significantly reduce apoptosis of cardiac muscle in 28 days.
Postoperative 28 days, CL group, SO group, ME group and TL group adventitia district myocardial cell Rapo1 are respectively (1.59 ± 0.42) %, (1.46 ± 0.38) %, (1.61 ± 0.32) % and (1.53 ± 0.09) %; Each organizes adventitia district Rapo1 no significant difference (P＞0.05).CL group, SO group, ME group and TL group endocardial areas Rapo1 are respectively (1.45 ± 0.37) %, (1.57 ± 0.43) %, (6.43 ± 0.31) % and (3.61 ± 0.27) %; With CL group ratio, ME group endocardial areas myocardial cell Rapo1 significantly raise (P＜0.01); With ME group ratio, TL group endocardial areas myocardial cell Rapo1 significantly is lower than ME group (P＜0.01).
Overall result shows that endocardial areas caspase-3 expression and apoptosis of cardiac muscle are apparently higher than the adventitia district behind the CME; Drug therapy of the present invention significantly reduced caspase-3 in 28 days to be expressed and apoptosis of cardiac muscle, and the result sees table 4.
Each group of table 4 and respectively organize adventitia and inner membrance district Rapo1 and medication effect of the present invention (X ± S)
Annotate:
*Compare P＜0.01 with the SO group; # and ME group compare P＜0.01
4.4.2 original position end labelling (TUNEL) testing result
Postoperative 28 days, CL group, SO group, ME group and TL group Rapo2 are respectively (1.51 ± 0.27) %, (1.56 ± 0.37) %, (4.88 ± 0.29) % and (2.15 ± 0.18) %; With CL group ratio, ME group Rapo2 obviously raise (P＜0.01); CL group and SO group ratio, Rapo2 no significant difference (P＞0.05); With ME group ratio, TL group Rapo2 obviously reduces (P＜0.01).Explain that Drug therapy of the present invention significantly reduced apoptosis of cardiac muscle in 28 days.
Postoperative 28 days, CL group, SO group, ME group and TL group adventitia district Rapo2 are respectively (1.58 ± 0.26) %, (1.51 ± 0.24) %, (1.53 ± 0.16) % and (1.47 ± 0.10) %; Each organizes adventitia district Rapo2 no significant difference (P＞0.05).CL group, SO group, ME group and TL group endocardial areas Rapo2 are respectively (1.59 ± 0.22) %, (1.55 ± 0.21) %, (10.21 ± 0.51) % and (3.37 ± 0.15) %; With CL group ratio, ME group endocardial areas Rapo2 obviously raise (P＜0.01); With ME group ratio, TL group endocardial areas Rapo2 significantly reduces (P＜0.01).Overall result shows that the endocardial areas apoptosis of cardiac muscle is apparently higher than the adventitia district behind the CME, and Drug therapy of the present invention significantly reduced apoptosis of cardiac muscle in 28 days, and the result sees table 5.
Each group of table 5 and respectively organize adventitia and inner membrance district Rapo2 and medication effect of the present invention (X ± S)
Annotate:
*Compare P＜0.01 with the SO group; # and ME group compare P＜0.01
4.5VIII coronule arteries and veins density in the myocardial cell is observed in factor dyeing
Postoperative 28 days, CL group, SO group, ME group and TL group Nmv are respectively 4.47 ± 1.37/mm
2, 4.21 ± 1.29 pieces/mm
2, 1.18 ± 0.36 pieces/mm
2, 2.88 ± 0.56 pieces/mm
2With CL group ratio, ME organizes myocardium Nmv and significantly reduces (P＜0.01); With ME group ratio, TL organizes myocardium Nmv and significantly increases (P＜0.01); The CL group is organized than Nmv no significant difference (P＞0.05) with SO.
The result shows, the minimizing of chronic process center intramuscular capillary bed density behind the rat CME; Drug therapy of the present invention can significantly increase small arteria coronaria quantity in the cardiac muscle in 28 days, and the result sees table 6.
Small arteria coronaria variable density and medication effect of the present invention in the cardiac muscle behind the table 6CME (X ± S)
Annotate:
*Compare P＜0.01 with the SO group; # and ME group compare P＜0.01
5 conclusions
Behind the arteria coronaria micro-embolization; Because of the infringement that apoptosis of cardiac muscle, a matter blood capillary are lost and collagen fiber propagation produces cardiac muscle and cardiac function; Medicine of the present invention reduces apoptosis of cardiac muscle, the myocardium tiny blood vessels of minimizing is lost and suppress interstitial collagen fibroplasia; Reduce cardiac damage, and then can improve cardiac function, can effectively treat the little bolt of arteria coronaria.
Experimental example 2:
1 data and method
1.1 physical data
Observe 60 examples altogether, be divided into treatment group and matched group at random.30 examples are organized in treatment, male 18 examples, women 12 examples, age 46-72 year, 59.6 ± 5.3 years old mean age; Matched group 30 examples, male 11 examples, women 19 examples; Age 45-73 year, 58.5 ± 5.1 years old mean age.
1.2 diagnosis and exclusion standard
Detect intracranial microemboli (MES) positive patient through colored multispectral the reining in of cranium (TCD); Cerebral infarction diagnosis meet national cerebrovascular academic conference revision diagnostic criteria [national cerebrovascular academic conference. all kinds of cerebrovascular disease diagnosis will be put China department of neurology magazine; 1996; 29 (6): 379.]; And through head CT (and/or) MRI confirms, gets rid of the cerebral infarction that other reasonses such as heart source property cerebral embolism, cerebral arteritis, disease in the blood system cause.
2 methods
2.1 Therapeutic Method
The matched group acute stage, give low molecular sodium heparin, each 4250-6400IUaXa, subcutaneous administration, twice of every day; Acute stage, give Aspirin Enteric-coated Tablets later, and each 50mg is oral; Once a day, give symptomatic treatment simultaneously, the treatment group adds on the basis of matched group administration uses medicine of the present invention; Each 3, every day 3 times, be for 4 weeks two groups of courses of treatment.
2.2 observation index and method
Carry out equal routine before the 60 routine patient treatments and do the TCD detection.Method is following: guard fixedly both sides temporo window of the headstock, the left and right MCA of synchronizing detection, 4 different depth site frequency spectrums about demonstration with 2MHz probe and spencer; Select frequency spectrum two sites clearly, adjacent two sites distance differs more than the 4mm, opens the VPV curve switch in the automatic record of embolus and 4 sites; Turn off the artefact switch; Embolus record reliability is decided to be 75%, and each patient-monitoring 30～60min is generally 40min.The embolus monitoring system will be noted the reliability, intensity, speed, persistent period, position of embolus sum and each embolus etc. and artificial cognition true and false embolus in addition under off-line state automatically; MES criterion of identification [Consensus Committee of the 9th InternationalCerbral Hemodynamic Symposium.Basic identification criteria of Dopplermicroembolic signals [J] .Stroke that standard adopts the 9th international brain hematodinamics meeting to work out; 1995,26 (6): 923-925.].Do same TCD detection in treatment 2 all backs and 4 Zhou Houzai, observe the variation of MES positive rate.All patients followed up a case by regular visits to 1 year, the relapse rate of record cerebral infarction.
2.3 statistical analysis
Adopt the SPCS10.0 statistical software, enumeration data is used χ
2Check, P＜0.05 difference has significance.
3 therapeutic outcomes
3.1MES the variation of positive rate
The MES positive rate of treatment group and matched group is in 2 week of treatment back obvious difference, and the treatment group significantly is lower than matched group at treatment two all backs MES positive rates, and the result sees table 7
Table 7 liang group treatment back MES number positive is N (%) as a result
| Group | N | 1 all MES are positive | 2 weeks are positive | 4 weeks are positive |
| Matched group | 30 | 25(83.3) | 20(66.7) | 12(40.0) |
| The treatment group | 30 | 24(80.0) | 11(36.7) * | 3(10.0) * |
Annotate:
*Compare P＜0.05 with matched group
3.2 two groups of Follow-up results
It is 6 examples that matched group recurred cerebral infarction in 1 year, and no case was recurrence for the treatment group, and visible medicine of the present invention can effectively be treated the intracranial microemboli.
3.3 untoward reaction detects
The treatment group is found bleeding tendency 3 examples, gastrointestinal reaction 2 examples, and matched group is found bleeding tendency 2 examples, gastrointestinal reaction 2 examples are through two groups of untoward reaction there was no significant differences of statistics.
4. conclusion
Medicine of the present invention can effectively be removed the intracranial microemboli for intracranial microemboli determined curative effect, reduces the relapse rate of cerebral infarction, and can not increase adverse reaction rate such as bleeding tendency.
Claims (8)
1. the application of Chinese medicine composition in the medicine of preparation treatment blood vessel micro-embolization is characterized in that this Chinese medicine composition is processed by following bulk drugs:
Radix Ginseng 3-10 Hirudo 3-11 Eupolyphaga Seu Steleophaga 5-10 Olibanum (processed) 1-5 Radix Paeoniae Rubra 3-9 Lignum Dalbergiae Odoriferae 1-5
Lignum Santali Albi 1-5 Scorpio 3-9 Periostracum Cicadae 3-12 Scolopendra 1-3 Borneolum Syntheticum 1-7 Semen Ziziphi Spinosae (parched) 3-10.
2. application as claimed in claim 1 is characterized in that, this Chinese medicine composition is processed by following bulk drugs:
Radix Ginseng 6 Hirudos 10 Eupolyphaga Seu Steleophagas 7 Olibanum (processed)s 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 7 Periostracum Cicadaes 7 Scolopendras 1 Borneolum Syntheticum 5 Semen Ziziphi Spinosae (parched)s 5.
3. application as claimed in claim 1 is characterized in that, this Chinese medicine composition is processed by following bulk drugs:
Radix Ginseng 10 Hirudos 8 Eupolyphaga Seu Steleophagas 7 Olibanum (processed)s 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 9 Periostracum Cicadaes 7 Scolopendras 1 Borneolum Syntheticum 5 Semen Ziziphi Spinosae (parched)s 5.
4. application as claimed in claim 1 is characterized in that, this Chinese medicine composition is processed by following bulk drugs:
Radix Ginseng 6 Hirudos 11 Eupolyphaga Seu Steleophagas 7 Olibanum (processed)s 2 Radix Paeoniae Rubra 5 Lignum Dalbergiae Odoriferaes 2
Lignum Santali Albi 2 Scorpios 3 Periostracum Cicadaes 7 Scolopendras 1 Borneolum Syntheticum 5 Semen Ziziphi Spinosae (parched)s 5.
5. like each described application among the claim 1-4, it is characterized in that the active component of said Chinese medicine composition is made up of following ingredients:
The a mean diameter is less than Scorpio, Hirudo, Scolopendra, Eupolyphaga Seu Steleophaga, Periostracum Cicadae and the Olibanum (processed) medicated powder of 100 μ m;
B Borneolum Syntheticum medicated powder;
The volatile oil that c is extracted by Lignum Dalbergiae Odoriferae and Lignum Santali Albi;
The alcohol-extracted extract of the alcohol extract of d Radix Ginseng after after concentrating with ethanol extraction;
The water extracted immersing paste that is condensed into behind the water extract after the Lignum Dalbergiae Odoriferae behind the e extraction composition c and water extract, Radix Paeoniae Rubra and the Semen Ziziphi Spinosae (parched) decocte with water of Lignum Santali Albi medicinal residues and the water extract filtration of the medicine residues of Radix Ginseng after the extraction ingredient d, the mixing.
6. like each described application among the claim 1-4, it is characterized in that this Chinese medicine composition is capsule, tablet, granule, powder, oral liquid or pill as the pharmaceutical preparation of active component.
7. like each described application among the claim 1-4, it is characterized in that the application of this Chinese medicine composition in the medicine of preparation treatment arteria coronaria micro-embolization.
8. like each described application among the claim 1-4, it is characterized in that the application of this Chinese medicine composition in the medicine of preparation treatment intracranial microemboli.
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