CN101129430A

CN101129430A - Traditional Chinese medicine composition used for preventing and controlling cardiovascular disease, processes for producing same and application of the same

Info

Publication number: CN101129430A
Application number: CNA2007101454548A
Authority: CN
Inventors: 锁占荣
Original assignee: INNER MONGOLIA HEFU PHARMACEUTICAL CO Ltd
Current assignee: INNER MONGOLIA HEFU PHARMACEUTICAL CO Ltd
Priority date: 2007-09-13
Filing date: 2007-09-13
Publication date: 2008-02-27

Abstract

The invention discloses a Chinese medicinal composition for preventing and treating cardiovascular diseases, wherein the active constituents include the following raw material herbs (by weight portion): ginkgo leaf 3-300 parts, notoginseng 1-100 parts, boxwood 2-200 parts and baras camphor 0. 002-2. 0 parts.

Description

A kind of Chinese medicine composition that is used to prevent and treat cardiovascular and cerebrovascular disease and preparation method thereof and its application

Technical field

The present invention relates to a kind of Chinese medicine composition of preventing and treating cardiovascular and cerebrovascular disease and preparation method thereof and its application.

Background technology

According to " World Health Report in 2002 ", cardiovascular and cerebrovascular disease becomes the major disease of the highest and serious threat people ' s health of case fatality rate, and the whole world is annual because of dead about 1,700 ten thousand people of cardiovascular and cerebrovascular disease.Along with the change of people's dietary habit, dietary structure and life style, and the prolongation of the average life span, as the increase of three high dietetics, and hypokinesia, overweight and ratio obese people significantly increases, and the onset risk of cardiovascular and cerebrovascular disease obviously improves.China annual New Development apoplexy 2,000,000 people, ill 7,000,000 people, and there is serious sequela in the patients with cerebral apoplexy of significant proportion, and therefore forfeiture or lose self-care ability substantially; Annual New Development myocardial infarction 500,000 people, ill 2,000,000 people; Heart failure 4,000,000 people; Pulmonary heart disease 5,000,000 people.Die from the cardiovascular and cerebrovascular vessel patient every year up to 2,500,000, its medical expense reaches 1,100 hundred million yuans.

Therefore, the research of strengthening chd prevention and treatment is to reduce patient's slight illness, reduces the important step of myocardial ischemia, myocardial infarction incidence and mortality, also becomes one of the important topic in world medicine field.And from traditional Chinese medicine, seek a kind of determined curative effect, safe, nontoxic, and the new medicine preparation of taking convenience, enjoy the concern of domestic and international medical circle.

Summary of the invention

The object of the present invention is to provide a kind of pharmaceutical composition that is used to prevent and treat cardiovascular and cerebrovascular disease, preparation compositions raw materials of effective components composition is counted Folium Ginkgo 3-300 part, Radix Notoginseng 1-100 part, Ramulus Buxi Sinicae 2-200 part and Borneolum Syntheticum 0.002-2.0 part by weight.

Further, preparation compositions raw materials of effective components composition is counted Folium Ginkgo 6-150 part, Radix Notoginseng 2-50 part, Ramulus Buxi Sinicae 4-100 part and Borneolum Syntheticum 0.004-1.0 part by weight.

Further, preparation compositions raw materials of effective components composition is counted Folium Ginkgo 12-75 part, Radix Notoginseng 4-25 part, Ramulus Buxi Sinicae 8-50 part and Borneolum Syntheticum 0.008-0.5 part by weight.

Further, preparation compositions raw materials of effective components is formed and is counted by weight, 0.02 part of 3 parts of Folium Ginkgos, 1 part of Radix Notoginseng, 2 parts of Ramulus Buxi Sinicaes and Borneolum Syntheticum.

Folium Ginkgo is the dried leaves of Ginkgoaceae plant Ginkgo biloba [Ginkgo bilola L.], is rich in compositions such as flavone, flavonoid compounds and terpene lactones, and its extract has better curative effect for coronary heart disease, asthma and senile dementia.

Radix Notoginseng is the dry root and rhizome of Araliaceae (Araliaceae) plant Radix Notoginseng [Panax notoginseng (Burk.) F.H.Chen], is China's Chinese medicine, has effects such as styptic powder silt, reducing swelling and alleviating pain.Main effective ingredient is the tetracyclic triterpene saponin, has the effect that increases coronary flow, reduces myocardial oxygen consumption and arteriotony, to preventing and treating coronary heart disease and curative effect to treat angina pectoris is remarkable, also be usually used in treating diseases such as hyperlipidemia, heart failure, pulmonary heart disease, hypertension.

Ramulus Buxi Sinicae is called for short Buxus sinica (Rehd.et Wils.) again, is the stem branch of Buxus sinica (Rehd.et Wils.) Ochnaceae plant [Buxus microphylla Sied.et Zucc.var sinicaRehd.Et Wils.] little leaf boxwood wood and congener thereof.Its effective ingredient is cyclovirobuxinum D and alkaloid, has promoting flow of QI and blood, and the effect of removing obstruction in the collateral to relieve pain can be used for obstruction of qi in the chest and cardialgia, the irregularly intermittent and regularly intermittent pulse of caused by energy stagnation and blood stasis, and coronary heart disease, arrhythmia are seen above-mentioned patient.

Borneolum Syntheticum has another name called Borneolum Syntheticum, borneol, borneol or Borneolum Syntheticum, and the processing crystallization product for Dipterocarpaceae aiphyllium Borneolum Syntheticum resin are one of conventional Chinese medicine.Natural Broneolum Syntheticum has the branch of Borneolum Syntheticum and Chinese mugwort brain, and the latter is the crystallization that feverfew Herba Blumeae Balsamiferae leaf extracts, and Borneolum Syntheticum is the certified products in the Borneolum Syntheticum, and its main component is a Borneolum Syntheticum, also contains the epimer isoborneol of a large amount of Borneolum Syntheticum; Synthetic borneol mainly contains Borneolum Syntheticum and isoborneol, synthesizes through chemical reaction with raw materials such as Oleum Terebinthinae, Camphoras.Borneolum Syntheticum has the function of the refreshment of having one's ideas straightened out, clearing away heat to alleviate pain; Be used for that calentura coma, convulsion are fainted, apoplexy syncope due to accumulation of phlegm, stagnation of QI sudden syncope, attacked by pestiferous factors stupor, aphtha, laryngopharynx swelling and pain, conjunctival congestion, auditory meatus suppurate.At present, Borneolum Syntheticum is used for coronary heart disease, anginal control.

Further, the effective ingredient of Folium Ginkgo is a Folium Ginkgo extract in the compositions, and its preparation method is: 1) Folium Ginkgo or its coarse powder are put in the extractor, add water or 20-95% water-alcohol solution that medical material 2-20 doubly measures, reflux, extract, 1-5 time, each 0.5-5 hour, filter merging filtrate; 2) concentrated filtrate filters to an amount of, gets filtrate; 3) gained filtrate is behind resin absorption, and water and 10-95% ethanol elution are collected ethanol elution successively, concentrate, and drying, promptly.

Wet concentration of the present invention is preferably purified water from any or its combination of purified water, deionized water, distilled water.

Water-alcohol solution of the present invention is that alcoholic solvent well known in the art adds the solution that water makes, described alcoholic solvent is selected from any or its combination of methanol, ethanol, ethylene glycol, propylene glycol, isopropyl alcohol, ethyl acetate, acetone, dimethyl sulfoxide, ether, dimethyl formamide, is preferably ethanol.

Further, the consumption of described water-alcohol solution is 5-15 a times of Folium Ginkgo medical material amount, is preferably 6-10 doubly.

Further, the concentration of described water-alcohol solution is 40-90%, is preferably 50-85%, more preferably 70-80%.

Further, can be 1) charge into protective gas in the step reflux, extract, process, described protective gas is selected from any or its combination of nitrogen, helium, is preferably nitrogen.

Further, 2) but under 20-100 ℃ of condition of step gained filtrate, add flocculant solution, it is complete to make it flocculation sediment, and the temperature conditions that preferably adds flocculating agent is 40-90 ℃, more preferably 60-80 ℃, most preferably is 70 ℃.

Further, described flocculating agent is selected from any or its combination of ZTC1+1 clarifier, chitosan, 101 fruit juice clarifiers, sodium alginate, is preferably chitosan, more preferably 2% chitosan.Described flocculating agent can effectively be removed saccharide in the medicinal liquid, protein, suspended material, tannin etc., improves the purity of product and the efficient of resin treatment, and effectively protects advantage such as resin.

Further, 3) going on foot described adsorbent resin is macroporous resin, the model of described macroporous resin is selected from any or its combination of D101, D201, D315, HD-2, HD-8, AB-8, LSA-5B, LSA-20, AAS, NAK-12, DM130, HPD600 or HPD450, is preferably HPD450.

Further, the water consumption of eluting resin is 5-20 a times of column volume, is preferably 8-15 doubly, and more preferably 10-12 doubly.

Further, the alcoholic solution consumption of eluting resin is 4-20 times of the dress column volume, is preferably 5-15 doubly, and more preferably 7-10 doubly.

The concentrated mode that simmer down to of the present invention this area is commonly used, any or its combination of preferred vacuum concentration, concentrating under reduced pressure or thin film concentration is beneficial to keep the effective ingredient in the extract.

Drying of the present invention is this area drying mode commonly used, and preferred vacuum drying or spray-dired any or its combination are beneficial to keep the effective ingredient in the extract.In case of necessity, extract obtainedly can be crushed to required particle diameter as required.

Further, the effective ingredient of Radix Notoginseng is a Radix Notoginseng extract in the compositions, and the preparation method of described Radix Notoginseng extract is: Radix Notoginseng or its coarse powder are put in the extractor, water or 30-95% water-alcohol solution that adding pseudo-ginseng 5-20 doubly measures extract 1-5 time, and each 0.5-5 hour, merge extractive liquid,, be concentrated into and do not have the alcohol flavor, or thin up is to an amount of, behind resin absorption, and water and 10-95% ethanol elution successively, collect ethanol elution, concentrate, drying, promptly.

Further, the consumption of described water-alcohol solution is 7-15 a times of pseudo-ginseng amount, is preferably 9-10 doubly.

Further, the concentration of described water-alcohol solution is 60-90%, is preferably 70-90%, more preferably 80-90%.

Further, described adsorbent resin is a macroporous resin, and the model of described macroporous resin is selected from any or its combination of XAD-2, HP-20, AB-8, HPD-600, ADS-2, S-038, D101 or HPD100, is preferably HPD100.

Further, the water consumption of eluting resin is for taking off liquid molish reaction negative to stream.

Further, the alcoholic solution consumption of eluting resin is 4-8 times of the dress column volume, is preferably 5-7 doubly.

Further, the effective ingredient of Buxus sinica (Rehd.et Wils.) is the Buxus sinica (Rehd.et Wils.) extract in the compositions, described Buxus sinica (Rehd.et Wils.) preparation method of extract is: 1) Ramulus Buxi Sinicae or its coarse powder are put in the extractor, aqueous acid or 30-95% water-alcohol solution that adding Buxus sinica (Rehd.et Wils.) medical material 4-20 doubly measures extract 1-5 time, each 0.5-5 hour, merge extractive liquid; 2) be concentrated into nothing alcohol flavor, add aqueous acid precipitation concentrated solution, filtration; 3) gained filtrate, after the absorption of kayexalate resin column, after washing was clean, taking-up was dried; 4) add the ammonia wet resin, extract, filter, get filtrate with the 50-95% water-alcohol solution; 5) filtrate is concentrated into does not have the alcohol flavor, places and separates out precipitation, filters; 6) precipitation through alcohol wash, drying, promptly.

The acid of forming aqueous acid of the present invention is selected from any or its combination of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, is preferably any or its combination, the more preferably hydrochloric acid of hydrochloric acid or acetic acid.

Further, the acid content of described aqueous acid is 0.1-10%, is preferably 0.5-5%.

Further, the consumption of described water-alcohol solution is 6-9 a times of Buxus sinica (Rehd.et Wils.) medical material amount, is preferably 7-8 doubly.

Further, 2) addition of described aqueous acid of step is to make the acid content in the concentrated solution reach 0.5-5%, is preferably 1-3%, more preferably 1-2%.

Further, 4) concentration of described ammonia spirit of step is 5-20%, is preferably 8-16%, more preferably 10-14%.

Further, contained Radix Notoginseng total arasaponins must not be lower than 30.0mg in the ginsenoside Rb1 in the units dosage composition.

Further, contained box total alkaloid must not be lower than 700 μ g in cyclovirobuxinum D in the units dosage composition.

Further, contained total flavonoids must not be less than 20.0mg in the units dosage composition, and described total flavonoids comprises any or its combination of Quercetin, kaempferol, isorhamnetin.

Further, contained Borneolum Syntheticum must not be less than 15.0mg in the total amount of Borneolum Syntheticum and isoborneol in the units dosage composition.

The unit dose of the present invention minimum dose unit that to be pharmaceutical composition use for the patient, its unit comprises grain, sheet, ball, prop up etc.

Folium Ginkgo extract of the present invention, Radix Notoginseng extract or Buxus sinica (Rehd.et Wils.) extract are selected from its extractum or extract powder of extracting concentrated solution, extracting the dry gained of concentrated solution.

Compositions of the present invention can be various dosage form well known in the art, and can adopt the preparation technique of this area routine to prepare.Be suitable for preparation of the present invention and be selected from oral formulations, injection or external preparation, be preferably oral formulations or injection.

Further, described oral formulations is selected from pill, powder, granule, tablet, soft extract, capsule, drop pill, oral cavity disintegration tablet, effervescent, paste, medicinal tea, suspension, syrup, mixture or Emulsion; Be preferably drop pill, oral cavity disintegration tablet, powder, suspension, granule, tablet, capsule or effervescent.In case of necessity, but coating preferably wraps film-coat.

Described pharmaceutically acceptable carrier is well known usual excipients or the adjuvant that is used to prepare above-mentioned preparation, and excipient that oral formulations or external preparation are commonly used or adjuvant include but are not limited to filler (claim not only diluent), lubricant (but also claiming fluidizer or antitack agent), dispersant, wetting agent, binding agent, regulator, solubilizing agent, antioxidant, antibacterial, emulsifying agent, correctives, odorant etc.Binding agent, for example syrup, arabic gum, gelatin, xanthan gum, cellulose and derivant thereof, starch slurry or polyvinylpyrrolidone, preferably syrup, arabic gum, gelatin, starch slurry; Filler, for example lactose, Icing Sugar, dextrin, starch and derivant thereof, cellulose and derivant thereof, inorganic calcium salt, sorbitol or glycine are preferably lactose, Icing Sugar, dextrin, starch and derivant thereof, cellulose and derivant thereof; Lubricant, for example micropowder silica gel, magnesium stearate, Pulvis Talci, aluminium hydroxide, boric acid, hydrogenated vegetable oil or PEG are preferably micropowder silica gel, magnesium stearate; Disintegrating agent, for example starch and derivant thereof, polyvinylpyrrolidone or microcrystalline Cellulose, the preferred starch derivant is carboxymethyl starch sodium, hydroxypropyl starch or corn starch; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.

Further, the substrate of described drop pill is selected from any or its combination of Polyethylene Glycol (PEG) 4000, PEG6000, PEG8000, is preferably PEG6000.

In addition, also active component can be mixed by its preparation requirement with pharmaceutically acceptable slow-released carrier or controlled release carrier, again according to the preparation method of slow releasing preparation well known in the art or controlled release preparation, prepare slow releasing preparation or its controlled release preparation, as add the blocker coating or with making micropill after the active principle microcapsulesization again, as slow-release micro-pill or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the coating blocker etc. of mixing, and described oil to mix agent be glyceryl monostearate, castor oil hydrogenated, Dormant oils, polysiloxanes, dimethyl siloxane; Described hydrophilic colloid is cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, or PVP, arabic gum, tragcanth or carbopol etc.; Described coating blocker is ethyl cellulose (EC), hydroxypropyl methylcellulose (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic acid resinoid etc.

Another object of the present invention is to provide a kind of preparation to be used to prevent and treat the method for the pharmaceutical composition of cardiovascular and cerebrovascular disease, comprise Folium Ginkgo extract, Radix Notoginseng extract, Buxus sinica (Rehd.et Wils.) extract, Borneolum Syntheticum and pharmaceutically acceptable carrier uniform mixing, it is characterized in that Folium Ginkgo 3-300 part, Radix Notoginseng 1-100 part, Ramulus Buxi Sinicae 2-200 part and Borneolum Syntheticum 0.002-0.2 part.

Further, preparation compositions raw materials of effective components composition is counted Folium Ginkgo 6-150 part, Radix Notoginseng 2-50 part, Ramulus Buxi Sinicae 4-100 part and Borneolum Syntheticum 0.004-0.1 part by weight.

Further, preparation compositions raw materials of effective components composition is counted Folium Ginkgo 12-75 part, Radix Notoginseng 4-25 part, Ramulus Buxi Sinicae 8-50 part and Borneolum Syntheticum 0.008-0.05 part by weight.

Further, the water consumption of eluting resin is 5-20 times of the dress column volume, is preferably 8-15 doubly, and more preferably 10-12 doubly.

Further, the acid content of described aqueous acid is 0.1-10%, is preferably 1-5%.

Further, contained Radix Notoginseng total arasaponins must not be lower than 3.00mg in the ginsenoside Rb1 in the units dosage composition.

Further, contained box total alkaloid must not be lower than 70 μ g in cyclovirobuxinum D in the units dosage composition.

Further, contained total flavonoids must not be less than 2.0mg in the units dosage composition, and described total flavonoids comprises any or its combination of Quercetin, kaempferol, isorhamnetin.

Further, contained Borneolum Syntheticum must not be less than 1.5mg in the total amount of Borneolum Syntheticum and isoborneol in the units dosage composition.

Except as otherwise noted, percentage composition of the present invention is weight percentage, and described umber is parts by weight.

Another object of the present invention is to provide the application of pharmaceutical composition of the present invention in the medicine of preparation control cardiovascular and cerebrovascular disease or its relevant disease.

Modern scientific research shows: mainly contain terpene lactone, flavones ingredient in Folium Ginkgo or its extract, have effects such as clear and definite anti-oxidation stress, anxiety, calmness; Have blood lipid regulation, suppress hematoblastic function, prevent functions such as thrombosis; Expansible cardiovascular and cerebrovascular vessel, the reperfusion injury of protection cardiac-cerebral ischemia is dwindled focal cerebral infarction scope and suppresses ischemic tissue of brain producing Endothelin effects such as (ET).Mainly contain Radix Notoginseng total arasaponins in Radix Notoginseng or its extract, have cAMP content in the platelet increasing, reduce the generation of thromboxane A2 (TXA2), obviously reduce effects such as experimental thrombosis formation, experimental arrhythmia model is all had obvious antagonism; And have obvious blood vessel dilating, and increase the effect of blood flow volume, and can reduce heart oxygen consumption, strengthen the hypoxia-bearing capability of tissue, anticoagulant reduces blood viscosity, improves the blood supply of ischemic region, helps promoting the neuronic recovery of reversibility.Cyclobuxine D contained in Ramulus Buxi Sinicae or its extract has arrhythmia, and has tangible dose-dependent inhibition effect; Suppress lipid peroxidation, remove free radical, increase coronary flow, improve myocardial oxygen delivery, hemodynamics and hemorheology be to resisting myocardial ischemia.Borneolum Syntheticum (Borneolum Syntheticum, isoborneol) has the promotion drug absorption, has the medicine of promotion and sees through blood brain barrier, improves bioavailability and blood drug level in the medicine body; CBSF is gone up, and decreased heart rate reduces myocardial oxygen consumption, helps the control of coronary spasm, and can alleviate the myocardial damage that ischemia causes; Prolong the time of mice anoxia enduring, the mouse sleep time that the significant prolongation pentobarbital causes, and produce synergism with pentobarbital.Therefore, pharmaceutical composition of the present invention has effects such as blood circulation promoting and blood stasis dispelling, regulating QI to relieve pain, collateral dredging, and has synergistic function between each component, can be used for preventing and treating coronary heart disease, angina pectoris, cerebral ischemia diseases or its complication, and be used for that obstruction of qi in the chest and cardialgia, the heart that obstruction of collaterals by blood stasis causes are vexed, apoplexy, hemiplegia, stiff tongue language be stuttering, coronary heart disease, angina pectoris, cerebral infarction are seen above-mentioned disease person.

The daily dosage of pharmaceutical composition of the present invention, day is taken number of times and the cycle of taking can decide according to patient's composite factors such as the state of an illness, age, sex, body constitution and other medicining conditions.Common daily dosage is 55mg-1000mg/ day, is preferably 110mg-800mg/ day, more preferably 220mg-600mg/ day, most preferably is 275mg-550mg/ day.Take number of times and be 1-4 time/day or 2-3 time/day or 1 time/day or 1 time/next day.

The specific embodiment

Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.

Embodiment 1The preparation of drop pill

1, the preparation of extract

The preparation of Folium Ginkgo extract: get Folium Ginkgo 30.0g, be ground into coarse powder, put in the extractor, add 80% ethanol of 5 times of amounts of medical material, charge into nitrogen then, reflux, extract, 3 times each 1 hour, filters, merging filtrate, decompression recycling ethanol to liquor capacity is 1/2 of a medical material weight, keeps temperature to 7 ℃, under stirring, 2% chitosan solution that adds total concentrated solution 1/5 volume, mix, make it flocculation fully, the solution clarification, filter, after filtrate added the purified water dilution, last HPD450 macroporous adsorbent resin was with 10 times of amount purified water eluting, then with 5 times of amount 75% ethanol elutions, merge 75% ethanol elution, decompression recycling ethanol becomes extractum shape, vacuum drying; Or the concentrated solution spray drying, promptly.

The preparation of Radix Notoginseng extract: get pseudo-ginseng 10.0g, be ground into coarse powder, add 10 times of amount 90% alcohol reflux 1h, filter, residue adds 10 times of amount 90% ethanol, repeats to extract 3 times by the said extracted method, filter, merging filtrate, decompression recycling ethanol be not to there being the alcohol flavor, adds purified water and be diluted to every 1ml and contain the 0.5g crude drug, last HPD100 type macroporous adsorptive resins, be eluted to effluent molish reaction negative with purified water, discard, add 70% ethanol elution then, collect the effluent of 5 times of column volumes, decompression recycling ethanol, vacuum drying or spray drying, promptly.

The preparation of boxwood extract: get Ramulus Buxi Sinicae medical material 15.0g, be ground into coarse powder, add 8 times of amount 90% alcohol reflux 2 times, each 1h, filter, merging filtrate, decompression recycling ethanol extremely every 1ml contain 2g crude drug amount, add hydrochloric acid to solution and contain 1% hydrochloric acid, stir, standing over night filters; Get filtrate, last kayexalate resin column does not have the chloride ion reaction with the purified water eluting; Take out resin, dry, it is moistening to add 14% ammonia, adds 95% ethanol extraction to the inanimate object alkali reaction, filtration, and filtrate recycling ethanol is to a small amount of, and placement is spent the night, and filters, and precipitation is washed with small amount of ethanol, promptly.

2, the preparation of drop pill

With Folium Ginkgo extract, Radix Notoginseng extract, the Buxus sinica (Rehd.et Wils.) extract uniform mixing of recipe quantity, add the 2.0g Borneolum Syntheticum, PEG6000 or PEG6000 fine powder are an amount of, and mix homogeneously under agitation heats melting, drips the piller of making 55mg, makes 1000 balls altogether.

In case of necessity, can be to gained drop pill bag film-coat, and actual according to producing, adjust the ratio of medicated powder and drop pill substrate, viscosity and stability to improve drop pill improve its yield rate.

Embodiment 2The preparation of drop pill

Precision takes by weighing Folium Ginkgo extract 400g, Radix Notoginseng extract 200g, boxwood extract 5g, Borneolum Syntheticum 100g pulverized 100 mesh sieves, in proportion the incremental method mix homogeneously, sieve, add PEG6000 fine powder 2045g then, heavy altogether 2750g, mix homogeneously is put extremely all fusions of heated and stirred on the water-bath, puts in the drop pill machine, adjust 8 ℃ of drop pill machine parameter fluid temperature, 10-12 ℃ of silicone oil temperature, dripping speed is 50 of per minutes, the system of dripping, every 55mg.

Dropping pill formulation of the present invention increases the characteristics such as dispersion, dissolution and dissolubility of medicine, have characteristics such as quick-acting, efficient, bioavailability height, be suitable for preventing and treating cardiovascular and cerebrovascular disease, have simultaneously that volume is little, dose is little and advantage such as easy to carry, better stability of preparation.

Illustrate: Folium Ginkgo extract 40g is equivalent to Folium Ginkgo medical material 15Kg, and Radix Notoginseng total arasaponins 200g is equivalent to pseudo-ginseng 5Kg, and boxwood extract 5g is equivalent to Ramulus Buxi Sinicae medical material 10Kg.

Embodiment 3-8The preparation of drop pill and study on the stability thereof

Folium Ginkgo 15Kg among the embodiment 3-8, Radix Notoginseng 10Kg, Buxus sinica (Rehd.et Wils.) 20Kg, Borneolum Syntheticum 100g prepares its extract and drop pill according to the preparation method of embodiment 1 and embodiment 2, and investigates its yield rate, the results are shown in Table 1.

The composition of table 1 embodiment 3-8 drop pill and yield rate are investigated

Embodiment	3	4	5	6	7	8
Embodiment	3	4	5	6	7	8	Folium Ginkgo extract weight	389g	399g	401g	402g	399g	401g
Radix Notoginseng extract weight	203g	196g	197g	197g	196g	199g	Folium Ginkgo extract weight	389g	399g	401g	402g	399g	401g
Radix Notoginseng extract weight	203g	196g	197g	197g	196g	199g	Boxwood extract weight	5.47g	5.23g	5.25g	5.05g	5.12g	5.07g
Borneolum Syntheticum	100g	100g	100g	100g	100g	100g	Boxwood extract weight	5.47g	5.23g	5.25g	5.05g	5.12g	5.07g

PEG6000	2052.53g	2049.77g	2046.75g	2045.95g	2049.88g	2044.93g
PEG6000	2052.53g	2049.77g	2046.75g	2045.95g	2049.88g	2044.93g	Gross weight	2750g	2750g	2750g	2750g	2750g	2750g
Theoretical grain number	50000	50000	50000	50000	50000	50000	Gross weight	2750g	2750g	2750g	2750g	2750g	2750g
Theoretical grain number	50000	50000	50000	50000	50000	50000	Actual grain number	45500	46200	46900	46300	47600	48400
Yield rate	91.0％	92.4％	93.8％	92.6％	95.2％	96.8％	Actual grain number	45500	46200	46900	46300	47600	48400

The result shows: drop pill of the present invention has stable processing technique, product percent of pass height, advantages such as steady quality.

Embodiment 9The preparation of oral cavity disintegration tablet

According to embodiment 1 preparation Folium Ginkgo extract, Radix Notoginseng extract, Buxus sinica (Rehd.et Wils.) extract.

1) precision takes by weighing Folium Ginkgo extract 40g, Radix Notoginseng extract 20g, and boxwood extract 0.5g, Borneolum Syntheticum 10g pulverized 100 mesh sieves; 2) the sieve powder behind the incremental method mix homogeneously, sieves in proportion; 3) 2) add polyvinylpolypyrrolidone 5.5g, microcrystalline Cellulose 34g, lactose 4.2g, citric acid 2.8g, sodium bicarbonate 2.0g, aspartame 0.07g and magnesium stearate 0.93g in the step gained sieve powder, behind the mix homogeneously, tabletting, that is, control strip heavily is about the 600mg/ sheet.

Below verify the pharmacological action of pharmaceutical composition of the present invention by the test example.

Test example 1Pharmaceutical composition and component thereof to myocardial damage due to the isoproterenol after the protective effect of free radical

1, the composition of test sample, reference substance and configuration

Test sample 1: preparation 50mg compositions raw materials of effective components composition is counted by weight, 30 parts of Folium Ginkgos, and 10 parts of Radix Notoginseng, 20 parts in Buxus sinica (Rehd.et Wils.), 0.2 part of Borneolum Syntheticum, wherein Folium Ginkgo, Radix Notoginseng and Buxus sinica (Rehd.et Wils.) all prepare test sample 1 with its extract.

Test sample 2: preparation 550mg compositions raw materials of effective components composition is counted by weight, 30 parts of Folium Ginkgos, and 10 parts of Radix Notoginseng, 20 parts in Buxus sinica (Rehd.et Wils.), wherein Folium Ginkgo, Radix Notoginseng and Buxus sinica (Rehd.et Wils.) all prepare test sample 2 with its extract.

Test sample 3: preparation 550mg compositions raw materials of effective components composition is counted by weight, 30 parts of Folium Ginkgos, and 0.2 part of Borneolum Syntheticum, wherein Folium Ginkgo prepares test sample 3 with its extract.

Test sample 4: preparation 550mg compositions raw materials of effective components composition is counted by weight, and 30 parts of Folium Ginkgos prepare test sample 3 with its extract.

Test sample 5: preparation 550mg compositions raw materials of effective components composition is counted by weight, 10 parts of Radix Notoginseng, and 0.2 part of Borneolum Syntheticum, wherein Radix Notoginseng prepares test sample 5 with its extract.

Test sample 6: preparation compositions raw materials of effective components composition is counted by weight, and 10 parts of Radix Notoginseng prepare test sample 6 with its extract.

Test sample 7: preparation 550mg compositions raw materials of effective components composition is counted by weight, 20 parts in Buxus sinica (Rehd.et Wils.), and 0.2 part of Borneolum Syntheticum, wherein Buxus sinica (Rehd.et Wils.) prepares test sample 7 with its extract.

Test sample 8: preparation 550mg compositions raw materials of effective components composition is counted by weight, and 20 parts in Buxus sinica (Rehd.et Wils.) prepares test sample 8 with its extract.

Positive control drug: FUFANG DANSHEN DIWAN, sky, Tianjin Shi Li pharmaceutical Co. Ltd.

Illustrate: test sample and positive control drug are facing the time spent, all are mixed with solution with PEG400.

2, experimental technique

100 of Westers rats, body weight 200-250g, male and female half and half are divided into 10 groups at random: 8 groups of model group, positive controls, 1 group of test sample, 2 groups of test samples, 3 groups of test samples, 4 groups of test samples, 5 groups of test samples, 6 groups of test samples, 7 groups of test samples and test samples, 10 every group.Tested preceding 3 days, each experimental group is irritated stomach respectively and is given test sample 1-8 and positive control drug, model group and solvent control group give the PEG400 of equivalent, every day 1 time, 30min after the 3rd day and the administration in the 4th day, subcutaneous injection isoproterenol 30mg/kg, the solvent control group gives isometric(al) physiologic saline for substitute isoproterenol.2h behind the 4th day subcutaneous injection isoproterenol, sacrificed by decapitation is cored dirty.

3, biochemical indicator

Heart is portion's clip 0.3g deep down, adds the 3ml normal saline, and cardiac muscular tissue's homogenate of 10% is made in homogenate, and the centrifugal 20min of 4000r/min gets supernatant, measures the vigor of SOD in cardiac muscular tissue's homogenate supernatant and the content of MDA.The result is referring to table 2:

Table 2 pharmaceutical composition of the present invention and component thereof are to the influence of rats with myocardial ischemia SOD of heart tissue due to the isoproterenol and MDA

Group	Number of animals (only)	Dosage (mg/kg)	SOD(nU/ml)	MDA(μmol/L)
Group	Number of animals (only)	Dosage (mg/kg)	SOD(nU/ml)	MDA(μmol/L)	Model group matched group test sample 1	10 10 10	250 220	238.22±62.55 397.68±72.38 ^ 365.56±51.15 ^	67.73±16.73 40.92±11.23 ^ 43.60±10.30 ^

Test sample 2 test samples 3 test samples 4 test samples 5 test samples 6 test samples 7 test samples 8

10 10 10 10 10 10 10

220 220 220 220 220 220 220

371.66±52.18 ^** 313.21±47.23 ^** 307.90±53.53 ^** 290.28±53.25 ^* 284.91±45.22 ^* 314.13±39.93 ^** 323.02±26.96 ^**

46.57±11.39 ^** 48.45±12.63 ^** 47.51±14.0 ^** 50.58±14.99 ^** 50.63±13.92 ^* 50.78±13.89 ^* 49.87±12.53 ^**

Draw thus, 1) after isoproterenol causes the rat heart muscle ischemia, SOD in cardiac muscle cells content obviously reduces, pharmaceutical composition and component thereof can improve the content of SOD in the anoxia myocardial cell to some extent, through variance analysis and intuitive analysis, three kinds of components (Semen Ginkgo extrac, Radix Notoginseng extract and boxwood extract) of forming pharmaceutical composition of the present invention all can effectively improve the content of SOD in the ischemic myocardial cells, and have synergistic function.

2) behind the myocardial ischemia, MDA content obviously raises in the myocardial cell, pharmaceutical composition of the present invention and component thereof all can reduction myocardial cell in various degree in the content of MDA, and Semen Ginkgo extrac is remarkable to the content effect that reduces MDA in the myocardial cell.

Test example 2Pharmaceutical composition of the present invention and component thereof are to the influence of electricity irritation rat carotid artery thrombus formation time

1, the composition of test sample, reference substance and configuration

The composition of test sample 1-8 faces the time spent to be mixed with solution with PEG400 with test example 1.

Positive control drug: aspirin, the Beijing Double-Crane Pharmaceutical Co., Ltd, every contains 300mg, faces with preceding with PEG400: water (1: 1) dissolving preparation.

2, experimental technique

100 of SD male rats, body weight 300 ± 20g, be divided into 10 groups at random, i.e. 1 group of test sample, 2 groups of test samples, 3 groups of test samples, 4 groups of test samples, 5 groups of test samples, 6 groups of test samples, 7 groups of test samples, 8 groups of test samples, positive drug control group and blank group (claiming the solvent control group again).15% urethane anesthetized rat.It is fixing that rat is lain on the back, and the capable 3cm otch of cervical region separates right carotid, and it is standby to wear plastic strip.Gastric infusion, administration every day 1 time is clocked, and the right carotid of standby separator well is connected with the thrombosis analyzer.10min gives 2mA galvanism blood vessel 3min after the administration, the record thrombus formation time.The blank group gives 0.9% normal saline of equal volume.Experimental result sees Table 3:

Table 3 pharmaceutical composition of the present invention and component are to the influence of electricity irritation rat artery thrombus formation time

Group	Number of animals (only)	Dosage (mg/kg)	Thrombus formation time (min)
Group	Number of animals (only)	Dosage (mg/kg)	Thrombus formation time (min)	Blank positive drug control group test sample 1 test sample 2 test samples 3 test samples 4 test samples 5 test samples 6 test samples 7 test samples 8	10 10 10 10 10 10 10 10 10 10	/ 10 220 220 220 220 220 220 220 220	8.91±1.21 13.56±4.33 15.78±4.24 ^ 15.48±5.18 ^ 14.04±5.42 ^ 14.47±5.02 ^ 11.58±3.75 ^* 12.09±4.11 ^* 10.30±3.14 10.60±3.46

Illustrate: ^*Represent P＜0.05, ^*Represent P＜0.01.

The result shows: except that test sample 7 and 8, all can effectively prolong thrombus formation time in pharmaceutical composition of the present invention and the component thereof.Through variance analysis and intuitive analysis, Semen Ginkgo extrac, Radix Notoginseng extract have significant difference for prolonging thrombus formation time, and have synergistic function.

Test example 3Pharmaceutical composition and component thereof are blocked the influence of (MCAO) cerebral ischemic model to intraluminal middle cerebral artery occlusion in rats

1, the composition of test sample, reference substance and configuration

Positive control drug:, face the time spent with PEG400: water (1: 1) dissolving preparation with test example 1.

2, experimental technique

100 of male SD rats, body weight 300-320g, be divided into 10 groups at random, 10 every group, i.e. model group, matched group, 1 group of test sample, 2 groups of test samples, 3 groups of test samples, 4 groups of test samples, 5 groups of test samples, 6 groups of test samples, 7 groups of test samples, 8 groups of test samples and normal saline group.Gastric infusion, before ischemia behind 30min, the ischemia behind 3h and the ischemia 24h divide three administrations.Concrete operations are as follows:

Operation group rat is weighed, 7% chloral hydrate (350mg/kg, ip) anesthesia, oral administration.Cervical region center row 2cm operative incision, isolate common carotid artery, external carotid artery and internal carotid artery, threading and ligation common carotid artery proximal part and external carotid artery insert the about 22mm of internal carotid artery place with the nylon wire of the good length of labelling, and with surgical thread ligation, fixing, layer-by-layer suture skin.Postoperative 3h is gastric infusion once more, and stomach administration is for the third time irritated in postoperative 24h anesthesia back, and the 15min sacrificed by decapitation is got brain after the administration, reject rhinencephalon, low brain stem and cerebellum, on ice with brain along parallel essentially identical 5 sections of the thickness that is cut into of coronalplane, 3 ℃ of red tetrazolium (TTC) temperature is bathed 30min dyeing.It is rose-colored that normal cerebral tissue is, and infarcted region is a white.The formalin of the brain sheet being put 40g/L after the dyeing is fixed, and takes by weighing the gross weight of each cerebral tissue, and the infarcted region that cleans with a pointed instrument under reuse pocket knife and the operating microscope is weighed.The infarcted region brain heavily accounts for the heavy percentage ratio of full brain and is the percentage ratio that the cerebral infarction dead band accounts for full brain volume.Sham operated rats is only gone otch, separates carotid artery, plug wire not, and not administration is sewed up back 24h and is got brain.The normal saline group is consistent with the operation of operation group, gives the normal saline of equal volume when being administration.Experimental result sees Table 4:

Table 4 pharmaceutical composition of the present invention and component are blocked the influence of (MCAO) damage to intraluminal middle cerebral artery occlusion in rats

Group	Number of animals (only)	Dosage (mg/kg)	Cerebral infarction percentage ratio (%)
Group	Number of animals (only)	Dosage (mg/kg)	Cerebral infarction percentage ratio (%)	Model group positive drug control group test sample 1 test sample 2 test samples 3 test samples 4 test samples 5 test samples 6 test samples 7 test samples 8	10 10 10 10 10 10 10 10 10 10	/ 250 220 220 220 220 220 220 220 220	42.87±17.64 12.69±6.38 ^ 15.69±12.31 ^ 18.98±13.25 ^ 16.02±12.67 ^ 21.13±11.67 ^** 27.63±13.35 ^* 35.77±16.91 30.51±14.20 36.27±17.66

Illustrate: ^*Represent P＜0.05, ^*Represent P＜0.01

The result shows: except that test sample 6-8, pharmaceutical composition of the present invention and component thereof all can obviously reduce the area that intraluminal middle cerebral artery occlusion in rats is blocked the cerebral infarction that (MCAO) cause.Through variance analysis and intuitive analysis, Semen Ginkgo extrac, Radix Notoginseng extract and Borneolum Syntheticum have significant difference for reducing cerebral infarct size, and have synergistic function.

Test example 4Pharmaceutical composition of the present invention is to the influence of anesthesia dirty hemodynamics of Cor Canitis and myocardial oxygen consumption

1, experimental technique

30 of healthy mongrels, body weight 12-15kg, male and female are regardless of, and male is main, female not conceived.Experimental animal is with pentobarbital sodium 30mg/kg intravenous injection anesthesia, and tracheal intubation connects the phrenoton.Left side fourth, fifth intercostal is opened breast, struts rib with machine for chest-opening, exposes heart, cuts off pericardium, makees the pericardium bed.Separate LCA and aortic root, place electromagnetic flowmeter (MFV-1200 type, the Japanese photoelectricity company produces) probe of suitable diameter respectively, measure coronary flow and cardiac output.To coronary sinus vein, a side femoral artery branch intubate is taken a blood sample respectively and is measured coronary sinus vein and arterial oxygen content respectively with AVL990 type blood gas analyzer, the calculating myocardium oxygen consumption through right external jugular vein intubate.The opposite side femoral arteriography is measured arteriotony.Observe standard I I lead electrocardiogram and count heart rate with limb lead.By formula calculate cardiac output, SI, cardiac index, cardiac muscular tension time index ((blood pressure * heart rate) ^-2), coronary artery and hemodynamic indexs such as systemic vascular resistance, the work done of left chamber.One lateral vein drop normal saline.Inject heparin sodium 500 units/kg anticoagulant by femoral vein.

Operation finishes, treat that observed index is stable after, value before the record administration.5.0ml/kg duodenal administration or solvent, 6 every group: (1) solvent control group: PEG200; (2) medicine low dose group (7.05mg/kg); (3) dosage group (14.1mg/kg) in; (4) high dose group (28.2mg/kg); (5) positive controls (81mg/kg FUFANG DANSHEN DIWAN).After the administration 5,10,15,20,25,30,45,60,70,80,90,100,110,120,150,180min writes down relevant index.Before the administration, after the administration 30,60,120,180min, extract coronary sinus vein respectively and femoral artery blood carries out blood gas analysis, survey oxygen consumption.Each phase observation index and parameter are carried out statistical procedures, with the numerical value of different observing times, carry out before and after the administration, between the group of self comparison and rate of change (before the administration in 100%) relatively, judge its significance with the t check.

2. experimental result

2.1 influence to Canis familiaris L. arteriotony and heart rate

The high, medium and low dosage group of pharmaceutical composition has no significant change to systolic pressure, diastolic pressure, the mean pressure of Canis familiaris L..

After giving the pharmaceutical composition of height, middle dosage, Canis familiaris L. performance decreased heart rate.Middle dosage group 30min heart rate after administration begins to reduce.Compare with the solvent control group, high dose group is 25min, 75-150min after administration, and significant difference p＜0.05 is arranged; Middle dosage group 75min, 105min, 150min, 180min after administration have significant difference (p＜0.05=; FUFANG DANSHEN DIWAN and blank group be no significant difference relatively.The results are shown in Table 5-8.

2.2 influence to Canis familiaris L. coronary flow and arteria coronaria resistance

With the solvent control group relatively, give the pharmaceutical composition of height, middle dosage after, the coronary flow of Canis familiaris L. increases, behind the administration 45min, coronary flow significantly increases, and continues 180min; After giving FUFANG DANSHEN DIWAN, coronary flow increases, and 30min-180min after the administration all has significant difference p＜0.05.

After the administration, coronary resistance decreases.Compare with the solvent control group, 75-165min after the high dose group administration has significant difference p＜0.05; After the FUFANG DANSHEN DIWAN administration, coronary resistance decreases, but there was no significant difference.The results are shown in Table 11, table 13.

2.3 influence to Cor Canitis output and total peripheral resistance

The high, medium and low dosage group of pharmaceutical composition all makes anesthesia Cor Canitis output increase to some extent.Compare with the solvent control group, 60-135min, 180min after the high dose group administration, 20-45min, 90-105min after the administration of middle dosage group, 30-60min after the low dose group administration has significant difference p＜0.05; FUFANG DANSHEN DIWAN also increases anesthesia Cor Canitis output, and 60-135min, 180min after the administration have significant difference p＜0.05.

High, medium and low dosage group all has certain reduction effect to systemic vascular resistance.But compare with the solvent control group, only high dose group has significant difference; Composite Salvia Dropping Pill group is not obvious to the influence of peripheral vascular resistance.The results are shown in Table 10, table 12.

2.4 influence to anesthesia Cor Canitis stroke volume and cardiac muscular tension time index

The high, medium and low dosage group of pharmaceutical composition all makes anesthesia Cor Canitis stroke volume all increase.Compare with the solvent control group, high dose group is 25min, 60-165min after administration, and 75-180min after the administration of middle dosage group has significant difference; FUFANG DANSHEN DIWAN can increase the cardiac output of anesthesia Canis familiaris L., and 25-30min after the administration has significant difference.

Pharmaceutical composition can reduce the cardiac muscular tension time index.With comparison before the administration, 60-180min after the high dose group administration has significant difference.Compare with the solvent control group, after the high dose group administration 105,135,150min, significant difference is arranged; 60-90min after the FUFANG DANSHEN DIWAN administration has significant difference.The results are shown in Table 9-10.

2.5 influence to anesthesia dirty index of Cor Canitis and SI

The high, medium and low dosage group of pharmaceutical composition all can raise and anaesthetize the dirty index of Cor Canitis.Compare with the solvent control group, high dose group is 25min, 60-165min after administration, 75-180min after the administration of middle dosage group, and 30-90min, 135min have significant difference after the low dose group administration; The FUFANG DANSHEN DIWAN cardiac index that can obviously raise, 75-135min after the administration, 180min has significant difference.

The high, medium and low dosage group of pharmaceutical composition all can increase SI.Compare with the solvent control group, 75-165min after the administration of high dose group group, 75-180min after the administration of middle dosage group has significant difference; Composite Salvia Dropping Pill group significantly increases SI, no significant difference.The results are shown in Table 16-17.

2.6 influence to anesthesia Cor Canitis flesh oxygen consumption and myocardium coefficient of oxygen utilization

Along with the carrying out of experiment, solvent control treated animal myocardial oxygen consumption constantly increases.After the administration, the oxygen consumption of the high, medium and low dosage group of pharmaceutical composition is suppressed.With the solvent control group relatively, after the high dose group administration 60,180min, there is significant difference in 180min after the administration of middle dosage group to the inhibition of oxygen consumption; FUFANG DANSHEN DIWAN decreases to the increase of oxygen consumption, but no difference of science of statistics.The results are shown in Table 19-20.

2.7 influence to anesthesia Canis familiaris L. left indoor pressure and the work done of left chamber

After the administration, the pharmaceutical composition anesthetized dog left indoor pressure that raises to some extent.Compare with the solvent control group, 60-105min after the only middle dosage group administration has significant difference.

Pharmaceutical composition high, medium and low dosage group anesthesia Canis familiaris L. left side chamber work done is increased to some extent.Compare with the solvent control group, only 75min after the low dose group administration has significant difference; 60-105min after the FUFANG DANSHEN DIWAN administration, the left side chamber work done of anesthesia Canis familiaris L. significantly increases.The results are shown in Table 15, table 18.

Table 5 pharmaceutical composition to anesthetized dog systolic pressure influence (mmHg, )

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min 25min 30min 45min 60min before the administration	146.97±40.32 140.15±42.25 94.88±5.405 137.71±43.32 92.91±7.43 130.78±34.12 89.66±9.29 138.18±44.20 93.23±8.81 137.08±39.62 93.22±8.81 132.68±35.74 90.55±6.78 128.99±33.98 88.53±10.82 126.56±32.75	146.01±21.56 144.43±23.35 98.77±2.29 145.88±31.55 99.20±7.348 147.53±28.636 100.56±7.239 145.23±24.625 99.24±4.71 143.90±23.81 98.40±5.31 139.15±22.448 95.24±5.950 138.37±21.40 94.75±5.35 140.89±18.59	28.2mg/kg	14.1mg/kg	7.05mg/kg	116.09±24.55 116.55±23.62 100.67±5.44 117.48±23.51 101.54±6.03 116.15±24.51 100.45±9.88 118.61±24.31 102.60±8.94 113.71±27.73 98.23±14.47 108.52±14.71 94.88±10.00 111.08±20.15 96.29±6.21 105.06±15.55	114.55±22.54 111.70±21.80 98.30±2.41 112.54±21.245 99.59±4.60# 112.30±19.655 100.85±3.86# 115.85±19.680 103.57±3.57# 113.24±24.211 101.08±9.87 113.93±24.409 100.94±9.73# 117.16±21.003 107.02±9.21## 119.59±23.797	132.87±27.148 127.05±24.870 96.04±5.423 124.64±26.14 94.07±6.79 124.13±24.80 94.21±10.78 122.43±23.212 93.13±10.99 122.10±23.62 92.94±11.77 119.81±23.52 91.60±14.21 119.65±24.6 91.68±15.97 120.55±23.98

75min 90min 105min 120min 135min 150min 165min 180min

87.07±11.94 120.67±31.45 82.93±10.79 125.12±28.58 86.93±13.18 124.36±33.228 85.33±11.53 126.41±33.92 86.66±10.28 125.92±33.50 86.31±9.63 125.28±37.22 85.23±11.31 120.90±35.12 82.57±11.28 123.72±36.75 84.29±12.84

96.72±5.51 145.56±19.53 99.90±5.55## 139.98±17.50 96.20±5.64 140.59±17.00 96.70±7.06 145.88±28.40 99.52±8.92# 143.69±21.56 98.59±8.52# 138.41±19.27 95.36±11.63 134.31±19.11 92.54±11.37 129.50±26.00 89.28±17.29

91.66±9.32 96.43±22.19 83.57±11.67 102.72±23.67 88.81±10.57 100.99±22.60 87.94±16.40 101.30±24.44 88.00±16.99 111.15±28.50 96.19±19.53 103.07±22.51 89.98±19.16 95.75±23.03 84.51±22.78 95.91±22.11 86.94±16.43

108.57±10.35## 118.71±25.831 105.66±12.30# 119.08±23.921 104.99±12.73# 116.88±24.709 105.84±14.83# 114.31±23.872 105.70±16.39# 113.33±24.616 106.12±16.92# 111.57±23.844 101.32±14.91# 109.92±24.556 97.09±12.37# 108.11±25.213 94.53±11.13

92.92±18.12 124.56±24.082 95.77±17.31 109.26±49.31 82.50±36.72 123.82±23.53 95.30±16.67 117.73±23.92 91.05±19.59 123.78±20.23 95.93±19.62 124.51±20.14 96.83±22.32 124.38±21.13 96.79±24.32 116.60±19.20 82.39±9.60

Annotate: first row: original value, each does not compare after organizing administration simultaneously with before the administration, ^*P＜0.05, ^*P＜0.01, ^{* *}P＜0.001

Second row: data are the percent of comparison before phase measured value and the administration simultaneously not after the administration in the table.

Each administration group not simultaneously with contrast group simultaneously relatively, #p＜0.05 ##p＜0.01, ###P＜0.001

Table 6 pharmaceutical composition to anesthetized dog diastolic pressure influence (mmHg,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min before the administration	100.16±39.08 94.31±38.38 93.62±5.92 95.92±39.95 94.60±11.19 100.19±36.20 101.22±11.14 100.06±37.98 100.57±12.15	104.58±15.684 125.77±35.092 123.73±48.229 104.43±20.826 99.39±7.927 109.55±17.210 104.89±9.728 116.16±17.064 111.69±12.331	28.2mg/kg	14.1mg/kg	7.05mg/kg	74.05±15.40 80.91±22.94 108.16±10.58# 75.66±25.60 100.41±14.46 73.56±16.01 99.27±4.68 77.27±23.23 103.28±13.95	76.36±18.46 74.32±20.38 99.27±11.32 70.69±19.43 97.43±13.39 73.46±19.78 99.14±9.78 81.54±15.76 117.55±13.01	95.34±31.23 86.27±21.21 92.52±10.24 85.73±22.17 91.50±7.53 88.30±20.95 95.00±12.25 80.97±25.42 85.56±12.82 ^*

25min 30min 45min 60min 75min 90min 105min 120min 135min 150min 165min 180min

99.15±34.74 100.57±11.68 95.81±31.29 97.99±11.63 101.97±42.27 101.73±12.68 85.96±40.46 83.14±27.40 86.45±29.09 88.88±14.83 91.10±29.24 93.69±13.78 93.83±29.42 96.94±15.27 91.60±22.35 96.67±17.84 94.64±23.08 99.81±17.88 100.63±26.30 105.71±18.41 96.15±27.69 100.15±15.54 96.17±29.6 99.37±12.95

116.18±15.587 111.79±11.556 113.18±14.637 109.33±14.553 111.54±15.355 107.43±12.923 112.23±12.272 108.14±10.270 111.25±16.135 107.03±12.215# 108.24±15.553 104.05±10.928 109.92±15.082 105.68±11.430 112.08±38.352 106.32±29.999 109.94±19.877 105.50±14.887 107.58±17.645 103.20±13.424 100.05±16.062 96.36±14.834 92.25±21.916 90.47±26.523

79.34±19.44 107.85±18.30 74.86±15.63 101.53±10.74 78.46±20.40 105.51±11.69 69.58±21.78 92.57±12.86 71.29±18.69 96.19±12.82 69.71±19.81 93.56±13.95 67.55±16.89 91.09±12.19 66.88±18.26 89.95±14.67 64.93±16.12 87.83±14.19 62.57±17.42 85.36±20.87 66.17±22.13 90.50±29.58 68.54±25.06 96.04±31.16

81.96±15.26 117.66±10.95 79.12±13.68 113.89±12.08 80.37±15.79 117.69±13.02 86.55±18.71 122.79±13.36## 86.01±20.13 120.92±13.014## 85.92±19.75 119.79±13.782## 86.40±19.41 120.02±15.6# 80.56±16.65 116.74±16.92 65.94±32.04 99.57±47.92 76.27±16.16 109.38±20.70 81.12±23.44 106.72±16.53 77.90±16.529 106.95±19.21

85.58±18.54 92.87±15.07 85.77±18.96 93.15±16.20 86.21±20.48 94.07±20.15 81.66±14.33 90.28±20.58 88.61±16.97 97.49±20.92 91.57±20.11 99.94±18.41 92.52±22.12 97.77±20.88 89.62±24.13 95.02±23.90 99.08±30.14 103.07±20.86 91.82±22.02 96.11±15.54 91.77±21.88 97.04±23.53 85.50±18.86 87.03±15.11

Annotate: first row: original value, each does not compare after organizing administration simultaneously with before the administration, ^*P＜0.05, ^*P＜0.01, ^{* *}P＜0.001.

Each administration group not simultaneously with contrast group simultaneously relatively, #p＜0.05##p＜0.01, ###P＜0.001.

Table 7 pharmaceutical composition to anesthetized dog mean pressure influence (mmHg,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min before the administration	115.76±39.34 109.59±39.63	118.39±15.06 131.99±22.22	28.2mg/kg	14.1mg/kg	7.05mg/kg	88.06±18.31 95.01±22.81	89.09±19.63 86.78±20.28	107.85±28.11 99.86±21.82

10min 15min 20min 25min 30min 45min 60min 75min 90min 105min 120min 135min 150min 165min 180min

94.09±5.30 109.85±40.87 93.85±8.75 110.39±35.21 96.02±8.06 112.77±39.94 97.08±8.30 111.79±36.27 97.11±8.54 108.10±32.68 94.48±7.48 110.98±38.39 95.92±8.78 99.49±37.22 85.37±17.80 97.86±29.61 86.00±11.10 102.44±28.38 90.54±11.098 104.00±30.34 91.66±12.35 103.21±25.77 91.86±11.59 105.07±26.07 93.45±10.658 108.85±29.55 96.40±11.761 104.40±29.84 92.07±10.10 105.36±31.59 92.39±9.20

113.27±27.23 118.24±22.93 99.27±7.44 122.21±19.00 103.04±7.76 125.85±18.65 106.31±7.78 125.42±17.42 106.06±7.87 121.84±15.96 103.29±9.74 120.49±15.05 102.05±7.75 121.78±11.67 103.29±5.74 122.69±16.879 103.80±8.31 118.82±16.18 100.42±5.97 120.14±15.20 101.73±8.55 123.35±34.86 103.09±20.24 ^* 121.19±19.94 102.39±11.25 117.86±16.97 99.80±11.68 111.47±16.46 94.49±12.13 104.67±23.02 89.65±22.69

107.52±9.45## 89.60±24.40 100.77±6.97 87.76±18.75 99.70±5.99 91.05±23.29 102.88±9.30 90.80±21.29 103.43±13.96 86.08±15.13 98.44±7.34 89.34±20.16 101.30±6.12 81.41±19.06 92.11±5.18 79.67±19.60 90.59±11.57 80.71±20.56 91.31±9.76 78.70±17.81 89.49±10.31 78.36±19.37 88.88±12.55 80.34±19.04 91.30±13.10 76.07±17.90 87.20±17.33 76.03±21.47 87.66±24.02 77.66±22.49 91.81±20.83

98.99±6.35 84.64±19.82 98.33±8.90 86.41±19.58 99.90±6.79 92.98±16.65 111.30±7.57# 92.39±17.49 110.26±7.52# 90.72±16.39 108.07±7.18# 92.63±17.09 112.90±10.28# 97.56±19.95 116.44±10.92## 96.91±21.69 114.14±11.90### 96.97±20.73 113.22±12.27## 96.56±20.52 113.70±14.68# 91.81±18.80 111.79±16.20 81.74±25.73 102.19±32.08 88.04±18.42 105.70±17.49 90.72±23.72 102.40±14.19 87.97±19.04 101.38±14.87

93.66±7.60 98.70±23.23 92.07±3.91 100.24±21.79 94.15±9.45 94.79±23.37 88.53±8.30 97.75±19.73 92.38±11.76 97.12±19.99 91.97±13.42 97.36±21.56 92.52±16.85 94.62±16.63 90.81±17.69 100.59±18.31 96.27±17.97 97.47±26.49 91.73±18.61 102.95±22.34 96.28±18.03 98.99±23.82 92.96±21.22 107.31±26.14 99.91±19.46 102.71±21.25 95.91±17.21 102.64±21.40 96.52±23.29 95.87±17.98 84.71±12.34

Table 8 pharmaceutical composition to the influence of anesthetized dog heart rate (beats/min,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/g
			5min 10min 15min 20min 25min 30min 45min 60min 75min 90min 105min 120min 135min 150min 165min before the administration	137.47±45.53 138.45±46.56 100.54±8.94 140.82±48.06 102.00±10.52 140.10±50.41 101.20±15.34 137.87±49.44 99.54±12.25 139.60±49.41 101.07±12.56 133.98±45.16 97.55±12.82 131.20±46.66 94.96±12.12 122.05±46.65 87.05±10.86 126.44±42.91 91.71±6.05 122.02±38.55 89.30±3.18 125.21±34.46 92.59±8.06 121.19±28.36 91.14±11.93 117.80±30.94 87.75±7.97 119.47±28.64 89.73±11.84 114.60±31.39	131.80±8.58 131.40±8.36 99.71±1.11 128.80±9.63 97.71±3.18 128.20±13.22 97.22±6.76 124.00±7.45 94.17±3.97 120.40±11.17 91.52±8.34 120.00±15.78 90.77±7.47 126.60±14.78 95.92±7.29 130.20±19.32 98.99±14.76 124.40±19.99 94.45±13.96 124.80±17.46 94.57±10.17 130.00±27.13 98.40±17.32 119.80±19.49 91.23±16.40 121.00±20.16 91.50±11.21 112.40±24.33 85.25±16.76 111.40±30.42	28.2mg/kg	14.1mg/kg	7.05mg/g	118.10±21.66 120.57±23.95 102.22±12.32 118.34±25.15 99.86±7.83 116.57±22.01 98.86±8.97 107.17±24.20 90.80±14.55 105.91±25.01 89.06±4.79 106.76±27.20 91.36±22.52 105.36±17.84 90.14±13.56 94.68±17.17 80.39±6.87 87.69±11.50 ^* 75.46±12.22## 86.79±7.69 ^ 75.25±13.52# 83.98±9.49 ^ 72.24±10.17## 91.64±16.91 ^* 78.21±11.00 80.56±12.54 69.94±16.10# 80.79±10.37 ^ 70.28±15.93# 81.06±15.72 ^	128.64±30.99 123.93±31.22 100.76±9.142 125.64±37.07 101.15±13.57 124.00±36.57 101.23±16.677 116.86±34.56 88.27±11.99 120.07±34.47 89.78±14.55 127.93±26.85 97.70±10.40 121.07±33.39 88.82±12.23 108.07±37.14 83.90±13.84 101.00±30.39 ^* 74.37±10.10# 105.50±36.93 81.55±11.96 102.36±34.02# 76.16±10.76 ^* 98.64±32.05# 76.29±13.61 ^* 98.57±38.38 75.56±16.34 95.71±30.97 ^* 75.27±11.63# 94.71±20.13 ^*	134.14±23.31 138.86±27.19 103.52±11.10 131.86±25.77 98.02±4.16 138.86±30.09 103.27±13.22 133.57±30.29 99.26±13.34 136.29±32.49 101.32±16.22 133.86±27.76 100.46±18.22 132.57±26.34 98.80±11.09 126.00±26.39 93.74±9.95 128.29±25.51 95.53±9.21 123.86±17.96 93.24±12.63 121.83±21.264 88.60±9.449 116.83±29.199 84.75±18.948 130.17±34.620 94.81±24.284 124.83±30.063 90.31±16.827 121.83±36.859

180min

85.05±7.92 112.22±32.09 83.09±9.49

83.85±18.79 105.60±30.86 79.57±20.05

70.67±19.93 84.83±11.17 73.19±19.98

75.65±9.34 90.57±22.05 ^** 71.92±9.60#

88.28±25.048 110.50±44.814 81.31±34.301

Table 9 pharmaceutical composition is to the influence of anesthetized dog cardiac muscular tension time index ((mmHg * beats/min) ^1/2,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20mm 25min 30min 45min 60min 75min 90min 105min 120min before the administration	124.91±36.28 122.01±37.77 97.10±3.77 123.25±39.72 97.60±5.94 123.60±39.07 98.08±5.73 123.60±39.35 97.97±5.56 123.88±37.48 98.72±5.16 119.71±35.55 95.65±5.20 119.94±38.81 95.02±4.91 109.62±40.18 85.77±11.67 110.87±33.96 88.51±4.84 111.45±31.52 89.73±5.53 113.90±31.34 91.65±3.42 111.71±26.42	124.64±8.823 131.39±13.334 105.63±11.332 122.80±11.817 98.39±2.583 124.46±8.133 99.91±2.50 124.69±11.32 99.95±2.72 122.82±13.78 98.40±6.40 120.65±13.40 96.82±8.40 123.28±12.38 98.83±5.50 125.76±14.12 100.70±5.372# 123.45±17.74 98.70±8.18# 121.61±15.49 97.27±5.46# 124.73±19.71 99.64±9.34 120.83±23.64	28.2mg/kg	14.1mg/kg	7.05mg/kg	100.70±7.40 104.97±6.11 104.64±8.95 100.70±6.20 100.13±3.74 100.16±12.50 99.23±6.68 96.69±7.78 96.24±7.71 96.58±11.47 95.79±7.48 94.53±9.51 94.33±12.48 95.69±6.52 95.25±6.76 86.40±5.12 ^* 85.94±3.77 82.77±8.95 ^ 82.41±9.25 83.13±10.94 ^ 82.56±9.02 80.69±9.01 ^ 80.14±7.20## 83.56±9.83 ^**	100.60±12.22 97.51±15.58 99.67±5.99 95.00±17.06 97.40±11.17 95.13±17.80 97.44±12.23 95.83±16.02 97.84±9.89 96.97±18.19 96.93±9.06 101.85±14.16 103.41±6.39# 97.97±20.30 98.22±11.62 93.01±20.54 95.12±13.56 91.38±16.30 90.61±9.18 92.60±18.71 94.22±11.67 91.89±18.19 92.56±11.26 88.36±14.01	119.53±22.949 116.91±19.158 101.41±3.183 113.20±19.851 103.22±6.305 117.21±21.687 103.97±7.80 111.87±23.81 106.77±11.35 114.79±22.41 106.73±10.30 113.29±18.88 105.09±6.12 113.14±21.34 107.35±8.83 108.81±18.86 109.05±11.65 113.33±20.34 109.53±15.78 109.43±21.08 109.26±11.22 111.48±18.89 101.87±7.80 106.82±23.67

135min 150min 165min 180min

91.02±7.00 110.95±26.66 90.37±7.04 113.65±27.08 92.68±8.73 109.05±28.72 88.21±5.37 108.43±30.23 87.34±6.06

96.37±13.26 120.70±17.39 96.52±8.00 114.92±19.77 91.91±12.39 111.00±22.00 88.71±13.83 104.62±24.41 83.78±17.87

83.10±9.43 79.41±8.76 ^** 79.20±10.73 77.75±10.63 ^** 77.62±12.96# 77.87±16.00 ^** 77.92±18.90# 80.55±15.12 ^* 81.26±17.58

92.67±12.55 81.54±22.30 86.48±21.49 84.09±15.58 87.73±13.88 87.82±11.22 88.43±9.49 84.25±10.33 ^* 85.65±9.91

102.39±9.30 117.65±27.62 101.99±7.54 112.77±23.23 99.89±8.48 111.37±27.46 100.23±9.69 102.07±30.79 101.04±11.41

Each administration group not simultaneously with contrast group simultaneously relatively, #p＜0.05##p＜0.01, ###P＜0.001

Table 10 pharmaceutical composition to the kinemic influence of anesthetized dog (1/min,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min 25min 30min 45min before the administration	2.10±0.52 2.07±0.54 98.01±4.681 2.09±0.45 99.48±2.89 2.09±0.45 99.58±3.02 2.07±0.42 98.97±3.98 2.03±0.34 97.72±6.26 2.00±0.34 96.03±6.64 2.00±0.31 96.50±6.82	1.98±0.12 1.98±0.12 100.36±0.66 1.99±0.12 100.47±0.83 1.99±0.13 100.48±1.295 2.00±0.13 101.12±1.00 2.01±0.13 101.59±1.22 2.01±0.12 101.68±0.79 2.02±0.12 102.17±1.42	28.2mg/kg	14.1mg/kg	7.05mg/kg	1.99±0.22 2.02±0.24 101.06±1.43 1.98±0.21 99.28±1.40 1.96±0.20 98.32±2.32 2.05±0.30 102.38±6.63 2.04±0.30 101.89±7.40 1.96±0.24 98.33±8.07 2.09±0.28 104.86±8.42	2.17±0.65 2.20±0.50 98.69±12.343 2.22±0.60 101.75±8.12 2.24±0.62 102.76±7.402 2.28±0.66 103.79±6.62# 2.29±0.66 105.62±7.30## 2.33±0.70 106.62±7.81## 2.38±0.74 110.73±11.55##	1.86±0.46 1.88±0.50 101.41±3.18 1.91±0.48 103.22±6.31 1.92±0.47 103.97±7.80 1.97±0.48 106.77±11.35 1.97±0.48 106.73±10.30 1.95±0.49 105.09±6.12# 1.99±0.51 107.35±8.83#

60min 75min 90min 105min 120min 135min 150min 165min 180min

1.99±0.31 95.76±6.65 1.99±0.34 95.48±5.92 1.98±0.36 95.09±5.30 1.96±0.35 94.06±5.83 1.93±0.29 93.29±8.20 1.92±0.30 92.53±7.47 1.90±0.25 91.77±9.26 1.91±0.27 92.16±8.83 1.89±0.28 91.10±8.09

2.02±0.13 102.28±1.20 2.03±0.12 102.61±0.71# 2.02±0.12 102.46±0.71# 2.03±0.11 ^* 102.55±1.61# 2.01±0.12 101.92±1.99# 2.01±0.12 101.67±1.06# 1.99±0.13 100.87±0.85 1.98±0.13 100.18±1.03 1.98±0.11 99.91±1.69#

2.08±0.26 104.27±5.23# 2.06±0.20 103.21±2.07# 2.07±0.24 103.97±4.34## 2.09±0.23 105.13±4.94## 2.15±0.35 107.81±12.80# 2.17±0.39 108.89±14.51# 2.24±0.57 112.18±24.78 2.28±0.57 113.97±24.78 2.26±0.59 116.10±27.01#

2.34±0.68 116.86±26.76 2.37±0.67 119.20±31.06 2.35±0.57 112.29±18.42# 2.35±0.67 111.62±18.11# 2.23±0.51 112.81±18.99 2.13±0.51 110.49±22.79 2.11±0.47 110.90±24.29 2.09±0.47 106.47±15.77 2.10±0.49 107.43±19.34

2.01±0.47 109.05±11.65# 2.04±0.59 109.53±15.78 2.03±0.53 109.26±11.22 1.94±0.54 101.87±7.80# 1.95±0.53 102.39±9.30 1.93±0.49 101.99±7.54# 1.90±0.55 99.89±8.48 1.91±0.54 100.23±9.69 1.58±0.94 101.04±11.41

Table 11 pharmaceutical composition to the influence of anesthetized dog coronary flow (ml/min,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min before the administration	95.36±35.72 96.29±35.48 101.12±1.130 97.21±34.56 102.32±4.89 96.71±33.73 101.90±3.60 94.86±29.76 100.76±4.40	72.10±9.17 74.20±9.10 102.99±2.12 75.00±8.90 104.12±2.69 74.60±8.86 103.64±4.46 76.20±8.65 105.81±1.68#	28.2mg/kg	14.1mg/kg	7.05mg/kg	92.58±26.93 94.83±27.37 102.47±2.82 94.33±28.97 101.55±6.29 92.92±25.93 100.81±5.21 93.25±20.85 102.18±7.67	95.29±44.06 93.71±37.58 102.45±8.53 95.64±37.12 102.77±6.12 94.93±35.55 100.92±9.25 99.43±39.10 104.93±11.06	110.64±25.42 108.21±24.77 98.24±8.14 106.79±24.78 97.32±11.47 105.14±25.43 95.93±13.16 104.43±25.80 95.41±14.84

25min 30min 45min 60min 75min 90min 105min 120min 135min 150min 165min 180min

95.36±31.32 101.01±4.69 93.86±29.67 99.70±5.09 92.79±31.77 98.11±5.30 90.21±25.92 96.43±6.72 88.64±24.69 94.89±6.73 87.79±23.941 94.09±7.607 88.00±29.29 93.16±4.03 87.79±27.38 93.29±5.68 87.36±29.61 92.40±6.67 85.50±29.30 90.41±7.09 84.36±27.27 89.51±7.58 83.64±28.31 88.44±7.23

76.34±9.44 105.91±2.32 79.39±9.22 110.24±3.26## 80.59±10.70 111.70±2.92### 83.79±9.78 116.32±1.47### 82.39±10.93 114.28±3.59### 87.60±8.21 ^* 121.91±5.62### 86.10±6.22 ^* 120.08±6.88### 85.56±7.88 ^* 119.21±7.79### 81.50±6.44 113.95±12.27## 78.25±6.63 109.18±8.95## 76.31±5.73 106.40±6.19## 74.96±5.10 104.70±8.72##

93.42±23.01 102.39±12.37 98.67±28.60 107.20±9.84 101.25±31.80 109.57±10.67# 103.50±34.57 111.72±12.34# 107.50±38.70 115.48±12.73## 105.67±34.61 114.45±14.86## 106.00±39.43 113.98±16.96## 108.83±40.02 116.89±14.68## 110.75±40.52 118.77±12.38### 103.67±37.25 111.33±11.98## 97.67±31.58 105.56±10.41## 99.60±30.33 106.78±8.50##

97.79±36.92 102.54±8.40 101.64±38.04 105.56±9.53 106.36±39.19 111.54±9.94## 110.07±49.37 112.72±7.28### 113.79±58.63 115.27±9.38### 115.57±54.00 118.49±7.93### 115.57±59.04 118.53±11.95### 114.50±58.89 116.93±8.36### 113.43±59.94 113.74±8.13### 113.93±61.40 112.68±11.65### 113.57±64.72 111.65±13.242### 107.21±62.808 109.11±10.13###

105.86±23.70 97.16±15.32 106.79±25.04 97.95±15.80 104.79±26.19 95.69±14.47 105.21±27.99 95.19±11.24 102.43±26.84 93.31±14.16 102.64±29.16 93.15±14.65 101.00±21.66 92.09±12.55 104.50±28.62 94.41±13.52 102.58±29.64 93.30±18.12 105.17±30.81 94.87±16.08 101.33±28.19 91.69±15.44 87.60±12.42 84.81±12.41

Table 12 pharmaceutical composition to the influence of anesthetized dog total peripheral resistance (KPa * min/L,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min before the administration	57.62±21.08 55.60±21.00 96.09±5.376	60.16±9.11 66.62±11.02 112.84±27.694	28.2mg/kg	14.1mg/kg	7.05mg/kg	44.54±9.69 48.02±14.06 106.51±10.80#	42.65±8.11 39.81±5.20 101.60±13.75	61.86±25.22 56.39±19.64 92.50±8.850

54.58±20.94 94.26±7.137 54.57±18.32 96.51±8.794 55.79±20.24 98.23±9.466 55.92±18.27 99.88±12.538 55.33±17.78 98.85±11.643 56.13±19.13 100.02±13.646 51.43±19.46 88.64±14.816 50.22±15.81 90.61±14.841 53.01±15.72 95.66±14.293 54.32±16.57 97.94±15.377 54.12±13.76 99.81±20.023 55.60±13.91 102.16±18.800 58.01±15.01 106.39±19.400 55.30±15.47 101.26±18.644 56.47±16.34 102.32±15.026

59.78±12.31 98.77±6.738 61.85±11.02 102.56±7.691 63.13±9.92 105.11±7.260 62.57±9.06 104.37±7.235 60.78±8.45 101.59±9.779 59.85±8.33 99.92±8.117 60.53±7.24 101.01±6.001 60.64±8.64 101.18±8.447 58.87±8.68 98.03±6.098 59.38±7.55 99.21±8.261 61.32±17.25 101.14±19.830 60.43±10.26 100.73±11.278 59.28±9.14 98.96±11.780 56.39±7.61 94.30±11.861 52.89±11.05 90.00±23.865

45.57±12.21 101.48±6.46 44.92±8.68 101.52±7.87 45.17±12.11 100.89±12.27 45.21±11.18 101.95±16.28 44.37±8.20 100.38±7.31 43.55±11.88 97.03±8.85 39.84±10.91 88.63±8.30 39.19±10.70 87.68±10.19 39.27±10.68 87.82±8.67 37.82±8.97 85.10±8.65 37.23±11.12 82.70±10.27 37.67±10.01 84.40±12.69 34.88±8.51 79.17±15.54# 34.62±12.19 78.27±22.38 35.65±13.37 81.13±21.45

39.08±7.23 97.20±11.95 39.83±8.10 97.69±10.63 42.46±7.81 107.71±11.24 41.82±8.03 104.95±11.74 40.56±8.27 101.81±10.55 40.67±8.56 103.19±15.87 43.46±10.71 103.85±24.32 42.13±8.89 101.05±26.01 42.46±10.75 103.86±22.17 42.45±10.09 104.74±24.15 41.70±6.58 102.14±25.02 39.17±11.94 95.50±34.85 42.33±8.25 99.44±27.01 44.49±12.82 98.44±21.31 42.83±9.06 97.77±25.01

54.53±18.78 89.61±8.143 54.60±17.09 91.08±11.981 49.85±15.03 83.51±10.036# 51.85±15.11 87.35±14.843 52.80±17.90 87.80±14.466 51.36±16.53 86.77±18.281 49.28±14.09 84.16±19.423 53.30±19.19 90.45±23.472 51.05±22.18 85.14±20.648 56.73±21.37 94.98±19.508 54.15±21.57 91.96±24.435 58.62±21.32 98.58±20.866 57.38±19.27 96.43±18.151 56.49±17.42 96.82±24.269 52.88±14.18 85.40±15.952

Table 13 pharmaceutical composition to the influence of anesthetized dog coronary resistance (mmHg * min/ml,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min 25min 30min 45min 60min 75min 90min 105min 120min 135min 150min 165min 180min before the administration	1.35±0.57 1.26±0.55 93.03±4.74 1.24±0.54 91.85±9.08 1.26±0.530 94.40±9.54 1.29±0.56 96.59±10.16 1.27±0.52 96.19±7.80 1.25±0.50 95.02±9.69 1.30±0.55 98.19±12.29 1.21±0.541 88.16±15.97 1.18±0.48 91.26±15.50 1.26±0.49 96.80±14.93 1.30±0.52 98.51±13.93 1.28±0.467 98.78±14.178 1.32±0.49 101.34±11.83 1.41±0.56 106.60±9.93 1.36±0.56 103.29±12.86 1.40±0.59 104.75±10.48	1.67±0.337 1.80±0.365 109.96±26.738 1.59±0.349 95.34±6.63 1.65±0.30 99.59±8.80 1.66±0.28 100.55±8.40 1.66±0.27 100.16±7.55 1.54±0.20 93.76±9.48 1.51±0.23 91.34±6.28 1.47±0.21 88.84±5.660 1.50±0.25 90.98±8.68 1.36±0.21 82.61±7.78 1.40±0.12 85.19±11.19 1.45±0.42 87.11±19.89 1.49±0.26 91.20±17.11 1.51±0.24 92.25±15.73 1.47±0.25 89.35±14.84 1.40±0.33 87.22±26.74	28.2mg/kg	14.1mg/kg	7.05mg/kg	1.01±0.29 1.06±0.32 104.83±7.02## 1.01±0.33 99.52±8.87 1.00±0.31 99.19±8.67 1.02±0.34 101.39±14.13 1.03±0.39 103.19±24.31 0.92±0.25 92.48±10.94 0.94±0.30 93.34±12.06 0.85±0.30 83.39±11.33 0.79±0.25 79.01±11.27 0.81±0.26 80.57±10.68# 0.80±0.24 79.05±7.36# 0.77±0.25 76.39±10.15## 0.79±0.27 77.03±9.99## 0.79±0.28 78.42±14.15## 0.83±0.30 82.68±20.11# 0.83±0.31 86.12±19.32	1.04±0.38 1.00±0.34 97.03±8.50 0.96±0.33 95.91±9.47 0.99±0.33 99.79±12.22 1.02±0.32 106.69±9.10 1.03±0.36 108.10±10.72 0.96±0.29 103.25±12.74 0.94±0.30 102.22±15.61 1.00±0.39 103.98±14.80 0.98±0.40 99.90±15.64 0.96±0.39 96.13±13.83 0.98±0.42 97.04±17.91 0.92±0.35 96.36±17.81 0.82±0.35 90.95±31.45 0.91±0.38 95.61±23.96 0.95±0.40 93.15±19.00 0.97±0.39 93.71±16.91	1.03±0.387 0.96±0.272 96.28±14.593 0.97±0.318 95.71±11.596 1.00±0.325 98.85±8.924 0.96±0.350 94.05±11.422 0.96±0.249 96.17±11.853 0.95±0.270 94.69±10.925 0.98±0.331 96.44±8.021 0.98±0.393 95.25±13.968 1.05±0.347 103.67±16.176 1.04±0.456 99.26±18.064 1.08±0.381 104.21±11.007 1.03±0.457 97.44±9.304 1.13±0.432 109.81±29.146 1.06±0.414 101.80±13.766 1.09±0.414 105.70±18.434 1.16±0.348 95.80±11.377

Table 14 pharmaceutical composition to the influence of anesthetized dog heart stroke volume (ml/beats,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min 25min 30min 45min 60min 75min 90min 105min 120min 135min before the administration	17.34±8.64 17.11±9.04 98.52±11.72 16.86±7.84 98.61±11.09 17.92±11.39 100.22±13.47 17.73±10.08 100.69±9.12 16.94±8.74 97.65±8.52 17.22±9.06 99.46±9.85 17.88±9.62 102.60±9.01 19.51±10.50 111.28±12.81 17.88±8.27 104.57±7.63 17.98±7.42 106.72±7.64 17.02±6.59 102.52±12.15 16.82±4.98 104.60±20.18 17.47±6.08 106.35±13.61	15.01±0.65 15.11±0.52 100.71±1.18 15.44±0.37 102.95±3.99 15.58±1.34 103.72±6.82 16.14±0.63 107.63±5.11 16.78±1.65 112.01±12.30# 16.94±1.93 112.74±10.42# 16.05±1.18 107.08±8.47 15.77±2.38 105.30±17.45 16.60±2.56 110.77±18.09 16.40±1.81 109.30±11.49 16.03±2.74 106.76±18.11 17.13±2.60 114.45±19.08 16.88±2.07 112.48±13.44	28.2mg/kg	14.1mg/kg	7.05mg/kg	17.16±2.49 17.27±4.08 100.23±13.67 17.27±3.77 99.99±8.97 17.09±2.26 100.14±9.23 19.82±4.88 115.16±19.43 19.63±2.96 114.50±7.71## 19.17±4.57 111.95±23.42 20.12±3.12 118.24±18.77 22.36±3.72 ^* 130.35±10.93# 23.77±3.75 ^ 139.46±20.48## 23.94±2.55 ^* 141.95±26.15## 25.09±2.95 ^*** 147.65±19.36### 24.07±5.76 ^* 140.71±30.92# 27.58±6.45 ^** 161.89±37.67##	17.33±5.76 18.29±4.82 98.92±17.63 18.38±5.12 103.38±24.80 18.81±5.42 105.44±28.22 20.41±6.21 120.27±24.43 20.22±7.18 121.48±29.55 18.66±6.15 110.23±13.99 20.77±7.48 127.92±31.18 23.69±9.42 145.26±51.40 24.90±8.65 ^* 162.23±42.68## 24.83±10.59 141.70±41.22# 25.45±11.48 ^* 148.84±28.99## 24.23±8.41 ^* 150.74±28.92# 23.95±8.82 ^* 152.09±42.57#	14.17±3.89 13.74±2.79 98.70±9.20 14.82±3.78 105.42±5.66 14.12±2.99 102.03±14.77 15.08±3.34 109.05±16.87 14.83±3.27 107.44±18.20 14.72±2.88 107.65±21.69 15.14±2.81 109.83±15.04 16.13±2.75 117.27±16.09 16.32±5.12 115.65±20.78 16.57±4.34 118.18±12.62 16.08±4.08 115.73±13.70 17.24±4.33 125.31±24.69 15.34±3.44 112.81±24.98

150min 165min 180min

16.87±5.50 104.03±18.18 18.03±6.55 109.27±13.35 18.49±7.70 110.73±12.98

18.36±3.94 122.68±28.01 18.60±3.91 123.84±25.14 19.73±4.41 131.70±29.72

28.45±8.88 ^* 166.42±51.31# 29.73±11.95 ^* 174.14±72.93# 27.97±11.67 170.96±74.34

23.53±6.62 ^* 150.53±41.43# 22.66±5.60 ^* 141.27±21.11# 24.34±8.46 ^* 150.03±23.32##

15.69±4.30 113.36±19.88 16.66±5.25 121.35±34.19 19.36±8.02 143.81±64.51

The influence intrinsic pressure to the anesthetized dog heart left chamber of table 15 pharmaceutical composition (mmHg,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min 25min 30min 45min 60min 75min 90min before the administration	126.53±28.85 122.39±32.49 96.17±6.27 123.23±31.75 97.07±6.31 124.50±26.88 99.30±10.85 127.19±28.32 101.06±7.95 127.34±28.10 101.22±8.39 124.47±27.66 98.94±8.92 121.69±25.65 97.05±9.54 117.16±23.91 93.67±10.30 113.42±24.78 90.28±7.80 117.72±24.54 93.91±9.34	130.54±16.36 126.40±16.90 96.85±4.22 128.04±22.12 97.87±7.93 129.27±18.72 99.06±7.87 135.48±19.10 104.05±9.74 135.41±19.48 103.89±8.89 130.90±18.16 100.71±11.15 130.32±17.06 100.24±10.08 129.53±16.90 99.58±9.65 131.80±16.64 101.27±8.52# 128.78±14.97 99.05±8.39	28.2mg/kg	14.1mg/kg	7.05mg/kg	133.16±20.79 132.87±21.04 99.82±3.42 130.15±22.27 97.85±7.75 129.99±20.80 97.72±5.48 130.20±24.08 97.62±6.58 129.31±21.42 97.10±4.91 121.95±19.67 91.78±6.64 124.18±23.34 92.95±4.77 120.50±23.84 90.16±6.65 114.33±23.61 85.81±10.04 116.51±24.54 87.17±9.12	128.07±24.90 128.77±25.12 99.32±2.61 127.91±23.24 100.27±2.52 127.71±22.02 101.01±3.68 117.69±40.73 103.54±4.16 131.14±21.87 104.09±3.71 130.53±21.90 102.91±4.85# 132.67±23.76 106.05±6.22# 134.98±25.77 107.79±9.04## 133.98±26.04 105.46±8.10## 133.25±25.31 105.07±9.69#	123.76±25.69 116.51±23.28 94.43±7.63 116.41±22.32 94.60±8.71 111.40±22.19 116.41±22.32 112.52±20.96 111.40±22.19 112.46±17.95 112.52±20.96 115.37±21.18 112.46±17.95 116.09±18.84 115.37±21.18 121.74±27.97 116.09±18.84 115.96±15.09 121.74±27.97 120.83±17.99 115.96±15.09

105min 120min 135min 150min 165min 180min

118.82±25.59 94.56±7.82 115.88±22.58 92.64±9.29 120.89±22.49 96.73±9.36 122.94±24.91 98.25±10.60 119.65±24.74 95.53±9.26 117.20±28.27 92.99±9.49

131.54±14.97 101.19±9.12 129.82±20.12 99.67±12.10 128.85±22.67 99.01±15.00 126.77±17.02 97.48±11.51 121.72±20.28 93.55±14.13 117.21±22.55 90.37±17.88

113.31±22.24 85.06±10.84 116.77±27.35 87.60±16.10 123.09±31.40 91.87±16.60 116.44±25.37 87.31±13.98 110.43±21.37 83.33±13.79 108.26±24.28 83.34±12.97

131.05±24.30 105.63±10.34# 125.19±22.11 102.68±12.61# 128.55±25.26 103.61±13.04# 127.72±25.79 98.62±14.62 129.17±26.88 100.05±9.83 126.54±26.96 97.59±8.74

119.28±21.95 120.83±17.98 113.91±14.78 119.28±21.95# 117.92±20.34 113.91±14.78 118.50±19.03 117.92±20.34 118.32±20.28 118.50±19.03 107.19±16.07 118.32±20.28

Table 16 pharmaceutical composition is to the influence (L/min/m of anesthetized dog cardiac index (CI) ²,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min 25min 30min 45min before the administration	3.50±0.89 3.45±0.92 98.01±4.68 3.47±0.77 99.48±2.90 3.47±0.78 99.58±3.02 3.45±0.72 98.97±3.98 3.39±0.606 97.72±6.26 3.32±0.57 96.03±6.64 3.34±0.57 96.50±6.82	3.19±0.20 3.20±0.19 100.36±0.66 3.20±0.20 100.47±0.83 3.20±0.20 100.48±1.30 3.22±0.20 101.12±1.00 3.24±0.21 101.59±1.22 3.24±0.20 101.68±0.787 3.26±0.186 102.17±1.419	28.2mg/kg	14.1mg/kg	7.05mg/kg	3.17±0.35 3.21±0.39 101.06±1.43 3.15±0.34 99.28±1.40 3.12±0.32 98.32±2.32 3.25±0.45 102.38±6.63 3.23±0.44 101.89±7.40 3.11±0.38 98.33±8.07 3.32±0.42 ^* 104.86±8.42	3.45±1.02 3.50±0.81 98.69±12.34 3.53±0.95 101.75±8.12 3.56±0.97 102.76±7.40 3.63±1.03 103.79±6.62 3.65±1.03 105.62±7.31# 3.71±1.078 106.62±7.81## 3.79±1.14 110.73±11.55##	2.89±0.65 2.93±0.71 101.41±3.18 2.98±0.69 103.22±6.31 2.99±0.67 103.97±7.80 3.07±0.67 106.77±11.35 3.07±0.67 106.73±10.30 3.03±0.69 105.09±6.12# 3.10±0.72 107.35±8.83#

60min 75min 90min 105min 120min 135min 150min 165min 180min

3.32±0.576 95.76±6.65 3.31±0.608 95.48±5.92 3.30±0.64 95.09±5.30 3.27±0.64 94.06±5.83 3.22±0.54 93.29±8.20 3.20±0.57 92.53±7.47 3.16±0.50 91.77±9.26 3.18±0.52 92.16±8.83 3.15±0.54 91.10±8.09

3.26±0.204 102.28±1.20 3.27±0.20 102.61±0.71# 3.26±0.21 102.46±0.71# 3.27±0.22 102.55±1.61# 3.25±0.23 101.92±1.99# 3.24±0.21 101.67±1.06# 3.22±0.21 100.87±0.85 3.19±0.21 100.18±1.03 3.19±0.17 99.91±1.69#

3.31±0.40 ^** 104.27±5.23# 3.27±0.33 ^** 103.21±2.07# 3.30±0.38 ^** 103.97±4.34## 3.33±0.37 ^* 105.13±4.94## 3.42±0.55 ^* 107.81±12.80# 3.45±0.61 ^** 108.89±14.51# 3.56±0.89 ^* 112.18±24.78 3.61±0.87 ^* 113.97±24.78 3.59±0.91 116.10±27.01#

3.72±1.047 116.86±26.76 3.76±1.02 ^* 119.20±31.05 3.73±0.86 112.29±18.42# 3.74±1.02 ^* 111.62±18.11# 3.54±0.78 112.81±18.99 3.38±0.76 ^* 110.49±22.79 3.35±0.70 ^* 110.90±24.29 3.33±0.73 ^* 106.47±15.77 3.34±0.75 ^* 107.43±19.34

3.13±0.66 109.05±11.65# 3.17±0.83 109.53±15.78# 3.15±0.73 109.26±11.22# 2.56±1.33 101.87±7.80 2.57±1.33 102.39±9.30 2.55±1.29 101.99±7.54# 2.51±1.32 99.89±8.48 2.52±1.32 100.23±9.69 2.58±1.59 101.04±11.41

Table 17 pharmaceutical composition is to the influence (mL/beats * m of anesthetized dog SI ²,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min 10min 15min 20min before the administration	28.99±14.56 28.70±15.35 98.52±11.72 28.30±13.60 98.61±11.09 29.97±18.98 100.22±13.47 29.70±16.95	24.24±1.80 24.40±1.59 100.71±1.18 24.91±1.34 102.95±3.99 25.16±2.74 103.72±6.82 26.05±1.63	28.2mg/kg	14.1mg/kg	7.05mg/kg	27.36±4.39 27.48±6.31 100.23±13.67 27.50±6.04 99.99±8.97 27.20±3.59 100.14±9.23 31.51±7.55	27.57±8.97 29.17±7.72 98.92±17.63 29.24±7.97 103.38±24.80 29.89±8.34 105.44±28.22 32.44±9.53	22.07±5.69 21.46±4.32 98.70±9.20 23.10±5.48 105.42±5.66 22.03±4.42 102.03±14.77 23.51±4.75

25min 30min 45min 60min 75min 90min 105min 120min 135min 150min 165min 180min

100.69±9.12 28.40±14.83 97.65±8.52 28.81±15.25 99.46±9.85 29.90±16.15 102.60±9.01 32.72±17.97 111.28±12.81 29.93±14.08 104.57±7.63 30.07±12.64 106.72±7.64 28.44±11.28 102.52±12.15 28.07±8.65 104.60±20.18 29.19±10.41 106.35±13.61 28.19±9.52 104.03±18.18 30.11±11.12 109.27±13.35 30.86±12.98 110.73±12.98

107.63±5.11 27.07±2.63 112.01±12.30 27.37±3.67 112.74±10.42 25.91±2.24 107.08±8.47 25.44±3.85 105.30±17.45 26.80±4.26 110.77±18.09 26.53±3.56 109.30±11.49 25.93±4.87 106.76±18.11 27.65±4.37 114.45±19.08 27.30±4.04 112.48±13.44 29.62±6.25 122.68±28.01 30.09±6.76 123.84±25.14 31.90±7.48 131.70±29.72

115.16±19.43 31.27±4.92 114.50±7.71## 30.48±7.19 111.95±23.42 32.01±4.96 118.24±18.77 35.64±6.40 ^* 130.35±10.93# 37.90±6.58 ^** 139.46±20.48## 38.11±4.17 ^** 141.95±26.15## 39.97±5.21 ^** 147.65±19.36### 38.44±9.82 ^* 140.71±30.92# 43.92±10.65 ^** 161.89±37.67## 45.24±14.17 ^* 166.42±51.31# 47.34±19.15 ^* 174.14±72.93# 44.07±18.39 170.96±74.34

120.27±24.43 32.05±10.78 121.48±29.55 29.60±9.31 110.23±14.00 32.91±11.31 127.92±31.18 37.56±14.43 145.26±51.40 39.57±13.77 ^* 162.23±42.68## 39.40±16.53 141.70±41.22# 40.43±18.08 ^* 148.84±28.99## 38.61±13.84 ^* 150.74±28.92# 38.10±14.37 152.09±42.57# 37.35±10.30 150.53±41.43# 35.99±8.66 ^* 141.27±21.11# 38.58±12.87 ^* 150.03±23.32##

109.05±16.87 23.12±4.72 107.44±18.20 22.97±4.16 107.65±21.69 23.64±4.12 109.83±15.04 25.15±3.84 117.27±16.09 25.40±7.38 115.65±20.78 25.80±6.21 118.18±12.62 24.85±5.90 115.73±13.70 26.75±7.02 125.31±24.69 23.81±5.63 112.81±24.98 24.32±6.69 113.36±19.88 25.92±8.67 121.35±34.19 30.32±13.59 143.81±64.51

Table 18 pharmaceutical composition is to chamber, an anesthetized dog heart left side exponential influence (Kg * m/min/m that does work ²,

)

Time	PEG	Radix Salviae Miltiorrhizae drop pill	Pharmaceutical composition
			Pharmaceutical composition			28.2mg/kg	14.1mg/kg	7.05mg/kg
			5min before the administration	0.569±0.216 0.531±0.221	0.535±0.0610 0.599±0.0938	28.2mg/kg	14.1mg/kg	7.05mg/kg	0.376±0.1409 0.393±0.1430	0.469±0.2021 0.448±0.1913	0.434±0.1097 0.408±0.0911

92.27±8.137 0.537±0.221 93.46±10.80 0.543±0.197 95.59±8.59 0.554±0.2244 96.06±9.247 0.540±0.204 94.79±9.784 0.508±0.167 90.69±9.408 0.530±0.2168 92.44±10.048 0.461±0.182 82.41±20.717 0.458±0.153 81.87±10.681 0.477±0.145 85.92±10.745 0.480±0.155 86.05±12.23 0.473±0.1429 85.20±9.701 0.479±0.1523 86.03±8.449 0.492±0.1690 88.24±12.590 0.473±0.1602 84.47±9.800 0.473±0.1706 84.04±10.793

113.58±26.954 0.537±0.0953 99.77±8.246 0.556±0.0832 103.56±8.085 0.576±0.0817 107.58±8.471 0.578±0.0827 107.82±8.715# 0.561±0.0715 105.04±9.817# 0.557±0.0642 104.26±7.682 0.563±0.0490 105.66±5.760# 0.570±0.0808 106.50±8.270## 0.551±0.0720 102.88±5.932## 0.559±0.0835 104.35±9.142 ^* 0.569±0.1576 105.13±20.905 ^* 0.559±0.0945 104.10±11.358## 0.540±0.0898 100.65±11.728 0.507±0.0962 94.65±12.531 0.477±0.1218 89.26±21.655

104.81±9.879## 0.368±0.1471 97.84±9.058 0.360±0.1277 96.78±6.258 0.383±0.1451 102.91±11.748 0.376±0.1391 101.73±16.181 0.353±0.1078 97.00±16.218 0.381±0.1269 103.69±15.389 0.348±0.1177 94.27±8.309 0.341±0.1092 94.03±16.455 0.352±0.1202 95.95±16.145 0.344±0.114 94.90±20.142 0.350±0.1220 96.74±25.832 0.363±0.1341 99.24±25.115 0.360±0.1603 97.13±31.236 0.337±0.2053 99.33±40.225 0.286±0.238 106.40±38.075

96.81±14.545 0.442±0.1945 99.00±12.353 0.452±0.1900 101.48±9.390 0.493±0.1907 114.29±9.675## 0.494±0.1963 115.12±9.171## 0.494±0.2033 113.97±10.418### 0.515±0.2151 123.52±14.582### 0.531±0.2087 134.11±30.055## 0.536±0.2170 133.34±30.577### 0.525±0.189 124.67±15.193### 0.528±0.202 124.71±19.818### 0.474±0.1651 123.88±21.969# 0.399±0.1730 112.09±41.812 0.428±0.1447 115.40±26.751 0.433±0.1385 107.70±20.467 0.424±0.139 106.76±18.792

94.87±7.308 0.410±0.0973 94.82±3.779 0.423±0.1151 97.70±10.426 0.413±0.1291 94.53±13.71 0.423±0.109 98.31±13.051 0.412±0.0971 96.56±14.362 0.427±0.1346 99.13±18.402 0.419±0.1047 98.80±20.504 0.448±0.1357 103.58±13.062## 0.435±0.145 99.39±17.799 0.436±0.1424 98.14±20.274 0.423±0.1511 94.65±21.543 0.452±0.1325 101.76±20.813 0.427±0.1311 95.98±19.823 0.431±0.1427 96.91±25.147 0.411±0.174 84.94±16.020

Table 19 pharmaceutical composition is to the influence of anesthetized dog myocardial oxygen consumption

Group		Before the administration	30 minutes	60 minutes	120 minutes	180 minutes
Group		Before the administration	30 minutes	60 minutes	120 minutes	180 minutes	The matched group Radix Salviae Miltiorrhizae drop pill	4.45±2.469 5.39±1.187	4.91±2.42 147.98±110.54 6.18±0.87 115.87±8.83	5.02±2.60 131.22±54.77 6.89±0.75 130.16±18.32	5.21±2.96 129.73±66.17 7.96±1.09 149.58±17.77	6.40±3.11 162.21±51.81 5.25±1.98 97.43±35.37
Pharmaceutical composition	28.2mg/kg 14.1mg/kg 7.05mg/kg	7.55±3.495 8.43±2.811 6.42±0.887	7.30±3.64 95.297.02 8.92±2.70 107.06±8.85 7.08±0.42 111.26±9.40	5.26±2.97 65.69±20.28# 8.77±2.34 106.40±11.36 6.34±0.55 100.53±17.82	5.51±2.76 75.49±22.18 9.25±2.57 112.20±13.20 6.75±1.59 104.75±16.50	6.84±3.45 94.81±31.67# 7.97±2.06 98.85±23.26# 7.63±2.79 119.22±44.29	The matched group Radix Salviae Miltiorrhizae drop pill	4.45±2.469 5.39±1.187	4.91±2.42 147.98±110.54 6.18±0.87 115.87±8.83	5.02±2.60 131.22±54.77 6.89±0.75 130.16±18.32	5.21±2.96 129.73±66.17 7.96±1.09 149.58±17.77	6.40±3.11 162.21±51.81 5.25±1.98 97.43±35.37

Each administration group not simultaneously with contrast group simultaneously relatively, #p＜0.05, ##p＜0.01, ###P＜0.001

Table 20 pharmaceutical composition to the influence of anesthetized dog cardiac muscle coefficient of oxygen utilization (%,

)

Group		Before the administration	30 minutes	60 minutes	120 minutes	180 minutes
Group		Before the administration	30 minutes	60 minutes	120 minutes	180 minutes	The matched group Radix Salviae Miltiorrhizae drop pill	27.72±0.503 40.24±1.534	32.66±15.51 42.25±113.32 43.41±1.79 8.01±6.94	33.05±13.16 34.84±58.51 44.14±3.28 9.9912.22	34.69±16.69 41.91±79.31 51.41±3.49 27.85±9.09	44.52±17.11 77.26±63.58 38.91±12.37 -3.85±28.50 ^*
Pharmaceutical composition	28.2mg/kg 14.1mg/kg 7.05mg/kg	43.40±17.790 56.65±12.207 34.80±11.278	39.81±18.65 -8.89±18.53 55.21±11.48 -2.06±7.14 39.09±8.17 16.17±21.25	32.74±22.82 -30.73±26.29 ^* 52.66±8.46 -5.61±10.24 ^* 39.24±11.49 14.30±19.81	31.92±21.49 -28.77±24.04 56.45±6.00 2.62±18.40 42.60±7.66 27.23±22.02	41.15±20.54 -5.55±20.62 ^* 55.68±9.88 2.94±30.79 ^* 47.04±10.59 45.94±55.85	The matched group Radix Salviae Miltiorrhizae drop pill	27.72±0.503 40.24±1.534	32.66±15.51 42.25±113.32 43.41±1.79 8.01±6.94	33.05±13.16 34.84±58.51 44.14±3.28 9.9912.22	34.69±16.69 41.91±79.31 51.41±3.49 27.85±9.09	44.52±17.11 77.26±63.58 38.91±12.37 -3.85±28.50 ^*

Each administration group not simultaneously with contrast group simultaneously relatively, ^*P＜0.05, ^*P＜0.01, ^{* *}P＜0.001

Draw thus, after the administration, each dosage group of pharmaceutical composition of the present invention is all significantly improved the parameter of the cardiac hemodynamic of anesthesia Canis familiaris L., significantly reduces heart rate, and coronary blood flow increasing reduces coronary resistance; Increase cardiac output, obviously increase heart stroke volume, reduce total peripheral resistance; Obviously increase SI, cardiac index and the work done of left chamber.

Test example 5 pharmaceutical compositions of the present invention are to the influence of anesthesia Canis familiaris L. acute myocardial ischemia

1, experimental technique

35 of healthy hybrid dogs, body weight 12-15kg, male and female have concurrently, and male is main, female not conceived, 7 every group.Be divided into 5 groups at random, 1) the solvent control group, PEG200; 2) low dose group of medicine (7.05mg/kg), middle dosage group (14.1mg/kg), high dose group (28.2mg/kg); 3) positive controls (FUFANG DANSHEN DIWAN 81mg/kg).

Laboratory animal is through pentobarbital sodium (30mg/kg) intravenous anesthesia, and tracheal intubation connects SC-3 type electric pulmotor; The the 4th, the 5th intercostal is opened breast in the left side, exposes heart, cuts off pericardium, makees the pericardium bed; Separate the anterior descending coronary stage casing, threading causes the acute experiment myocardial infarction and ischemia model in order to ligation; Seam is put the fixed epicardial lead of multiple spot, connects the many four road physiology monitors of RM-6240 type, traces epicardial electrogram.Behind the ligation branch of coronary artery 30min, carry out record, as control value before the administration, test medicine or PEG200 through duodenum, after the administration 15,30,45,60,90,120,150, the epicardial electrogram of 30 mapping points of 180min record, raising greater than 2mv with the ST section is criterion, and (ST section total mv that raises counts ∑-ST) and myocardial ischemia scope (raise total points N-ST) of ST section with this calculating myocardium degree of ischemia.30min before the ligation coronary artery and behind the ligation coronary artery, 1,2,3 hour extraction arterial blood after the administration, measure lactic acid dehydrogenase (LDH), creatine phosphokinase (CPK), glutamic oxaloacetic transaminase, GOT (AST), α-hydroxybutyric acid decarboxylase (HBDH) with automatic clinical chemistry analyzer.The 180min record finishes behind the medicine, downcuts heart immediately, normal saline flushing, and weighing is heavy whole-heartedly.Below the heart ligature, be parallel to coronary sulcus and be cut into 5 with the ventricle part is cross-section equably, place nitro blue tetrazolium (N-BT) dye liquor then, room temperature dyeing 15min.The infarct (the non-dyeing of N-BT district) of tracing every myocardium bilateral with transparent sulfuric ester paper and non-infarct (N-BT dye district), infarct and non-infarct are weighed respectively, every cardiac muscle is weighed, calculate the area of every cardiac muscle, the ventricle gross area, the infarct gross area and infarct account for ventricle and account for the percentage ratio of dirty weight whole-heartedly.Test data carries out statistical procedures with SPSS 11.0 statistical softwares, judges its significance with the t check.

2, experimental result

2.1 influence to dog myocardial ischemia (epicardial electrogram mapping)

2.1.1 to (the influence of ∑-ST) of dog myocardial ischemia

With solvent control relatively, the high, medium and low dosage group of medicine and FUFANG DANSHEN DIWAN 15min after administration, dog myocardial ischemia begin to reduce gradually that (∑-ST), continue 180min, relatively reaching before and after the self administration all has remarkable or utmost point significant difference.The results are shown in Table 17.

2.1.2 influence to myocardial ischemia scope (N-ST)

PEG200 does not have obvious change to the myocardial ischemia scope; All can reduce the myocardial ischemia scope after each dosage group administration of medicine, high dose group has significant difference (P＜0.05) with model control group behind administration 90min, 150min; After the FUFANG DANSHEN DIWAN administration, can reduce the effect of myocardial ischemia scope.The results are shown in Table 24.

2.2 influence to myocardium zymetology after the dog ligation anterior descending coronary

Matched group is 30min after the anterior descending coronary ligation, and myocardium creatine phosphokinase (CPK), glutamic oxaloacetic transaminase, GOT (AST), lactic acid dehydrogenase (LDH), hydroxybutyric acid decarboxylase (HBDH) all significantly raise, and continues 3 hours; After the ligation modeling, CPKAST, LDH and the HBDH of each group all raise, and compare with the solvent control group, and each dosage of pharmaceutical composition and FUFANG DANSHEN DIWAN all can significantly reduce each index of myocardial enzymes after administration.The results are shown in Table 25.

2.3 influence to dog acute myocardial infarction scope (N-BT staining mensuration)

Learn the N-BT staining with quantitative tissue and show myocardial infarct size.With model group relatively, middle dosage group can significantly be improved the ischemic necrosis situation that causes after the ligation, and ligation district, ventricle, heart infarction percent, all significantly reduces (P＜0.01); FUFANG DANSHEN DIWAN can significantly reduce the ischemic necrosis effect.The results are shown in Table 21-24:

Table 21 pair dog myocardial ischemia (influence of ∑-ST) (mv/30dots, )

Time	Solvent control	Pharmaceutical composition			Positive control
		Pharmaceutical composition				7.05mg/kg	14.1mg/kg	28.2mg/kg
		15min 30min 45min 60min after the modeling	259.24±69.32 276.88±78.26 107.09±15.11 284.19±82.71 108.98±7.30 294.53±65.66 106.41±6.80 267.11±75.98	312.57±13.36 222.77±47.77 ^ 74.55±7.46 ^### 207.34±70.79 ^ 72.20±16.95 ^### 213.86±64.33 ^* 73.60±9.01 ^### 207.70±60.88 ^		7.05mg/kg	14.1mg/kg	28.2mg/kg	252.50±31.86 223.21±34.67 ^* 88.18±4.43 ^### 191.66±23.45 ^* 76.19±5.82 ^### 184.76±34.59 ^ 73.74±13.23 ^### 171.70±38.29 ^*	324.28±104.04 263.47±92.65 ^* 82.05±16.05 ^# 244.96±98.75 ^ 75.18±13.16 ^### 233.91±100.88 ^ 71.42±13.58 ^### 231.07±86.31 ^**	281.21±50.00 195.21±74.94 ^ 67.96±18.06 ^### 165.49±57.17 ^* 57.90±14.04 ^### 152.60±58.94 ^* 53.65±17.86 ^### 156.34±54.75 ^*

90min 120min 150min 180min

102.94±7.97 266.26±78.47 104.14±13.69 266.44±88.07 101.50±12.77 254.07±74.57 97.51±9.11 247.18±72.48 94.97±8.39

75.23±13.74 ^### 203.07±5.13 ^** 73.95±13.41 ^## 205.73±70.02 ^*** 70.77±10.17 197.34±73.55 ^*** 67.37±10.79 ^### 177.19±59.49 ^*** 61.19±8.51 ^###

68.29±13.72 ^### 171.49±32.45 ^*** 68.22±10.93 ^### 172.51±28.22 ^*** 68.33±7.93 ^### 162.60±41.64 ^*** 64.02±11.83 ^### 157.66±37.45 ^** 61.80±8.96 ^###

71.44±10.89 ^### 232.07±94.22 ^* 71.76±14.57 ^## 214.44±82.48 ^** 66.14±12.63 ^### 186.36±101.65 ^** 63.11±12.92 ^### 199.91±71.60 ^** 63.11±13.95 ^###

54.42±13.83 ^### 151.14±54.72 ^*** 52.48±13.52 ^### 148.87±56.82 ^*** 52.03±15.87 ^### 149.99±74.34 ^*** 51.40±18.51 ^### 150.07±66.88 ^*** 51.53±17.33 ^###

Second row: data are hundred min numbers of comparison before phase measured value and the administration simultaneously not after the administration in the table.

Each administration group not simultaneously with contrast group simultaneously relatively, #p＜0.05, ##p＜0.01, ###P＜0.001.

The influence of table 22 pair myocardial ischemia scope (N-ST) (n,

)

Group	Solvent control	Pharmaceutical composition			Positive control
		Pharmaceutical composition				7.05mg/kg	14.1mg/kg	28.2mg/kg
		Normal ligation 15min ligation 30min administration 30min administration 60min administration 90min administration 120min administration 150min administration 180min	28.00±2.83 26.75±1.26 28.00±2.16 27.00±2.16 25.75±3.30 25.50±3.42 25.25±3.59 25.75±2.87 25.25±3.30	2825±2.06 19.75±7.97 26.25±3.30 23.00±5.60 23.75±4.35 24.00±4.08 21.25±3.77 20.50±4.65 21.00±4.69		7.05mg/kg	14.1mg/kg	28.2mg/kg	28.50±2.08 22.25±5.85 28.25±1.26 25.75±3.30 24.75±2.50 22.75±1.89 22.50±3.00 23.75±2.63 23.00±2.94	28.75±2.22 23.00±5.83 29.25±0.96 25.50±1.73 23.50±1.00 20.75±1.26 ^* 22.00±2.00 21.50±1.73 ^* 21.00±2.16	28.00±2.16 22.25±5.50 26.75±3.20 24.00±4.24 21.50±3.70 21.50±2.38 20.75±3.78 19.25±3.30 ^* 15.75±2.50 ^**

Annotate: with contrast group simultaneously relatively ^*P＜0.05 ^*P＜0.01

The influence of myocardium zymetology after the table 23 pair dog ligation anterior descending coronary (U/L, )

Group	Time	AST	LDH	HBDH	CK
Group	Time	AST	LDH	HBDH	CK	Solvent control	Ligation 30min administration 30min administration 60min administration 120min before the ligation	73.88±33.95 77.46±32.37 84.34±35.61 89.68±41.42 110.80±37.11	63.72±7.20 78.14±12.19 72.82±5.13 85.54±15.36 94.86±4.76	36.78±6.11 42.88±14.89 43.64±11.06 47.60±11.25 56.14±11.21	767.16±207.05 945.98±261.21 1154.26±237.88 1391.82±262.76 1764.00±229.74

	Administration 180min	99.82±54.58	112.92±32.34	64.30±9.77	2141.76±191.05
	Administration 180min	99.82±54.58	112.92±32.34	64.30±9.77	2141.76±191.05	Positive control	Ligation 30min administration 30min administration 60min administration 120min administration 180min before the ligation	109.15±133.51 230.97±289.98 198.58±325.98 207.90±316.61 247.88±325.39 154.33±233.80	77.90±52.59 139.63±72.51 112.20±72.70 104.27±65.39 107.45±64.13 87.62±71.92	43.05±19.28 88.80±50.13 64.32±31.51 59.73±28.61 61.93±32.95 46.45±27.30	883.43±444.90 2712.50±1268.00 ^* 1408.60±707.75 1824.95±1016.50 1926.52±1141.16 1135.40±556.42 ^**
High dose group	Ligation 30min administration 30min administration 60min administration 120min administration 180min before the ligation	47.06±11.76 91.50±21.49 59.90±16.96 65.12±15.50 69.74±21.08 54.88±15.26	50.86±25.27 103.76±37.82 58.44±21.40 54.80±17.18 ^* 61.64±18.55 ^ 49.38±22.70 ^	26.86±12.05 58.40±16.85 37.18±17.73 33.80±11.51 37.54±11.74 ^* 28.78±14.66 ^**	536.52±119.50 1589.08±469.38 ^* 892.80±259.53 1027.02±292.01 1166.08±509.78 ^* 687.96±167.10 ^***	Positive control
High dose group						Middle dosage group	Ligation 30min administration 30min administration 60min administration 120min administration 180min before the ligation	50.25±13.54 83.175±10.53 57.925±8.46 60.875±7.22 66.85±8.09 48.05±8.54	40.125±8.20 ^ 110.05±47.89 69.725±31.28 70.075±26.33 64.4±13.84 ^ 43.875±4.76 ^**	26.137.50 60.425±23.47 39.7±10.71 39.5±10.28 28.75±20.19 ^* 25±5.52 ^***	742.43160.00 1685.33532.70 ^* 1028.2±259.27 1148.85±273.70 1279.38422.91 793.78168.26 ^***
Low dose group	Ligation 30min administration 30min administration 60min administration 120min administration 180min before the ligation	50.2827.56 87.9345.05 58.3±24.62 74.025±45.23 61.25±19.59 ^* 51.25±32.34	48.45±20.00 100.0852.67 50.425±17.88 ^* 112.2±69.96 53.95±16.03 ^*** 57±29.23 ^*	24.2811.90 ^* 60.05±31.51 29.1±10.34 ^* 68.4±49.25 29.25±9.08 ^ 22.675±18.53 ^	539.575±285.84 1948.325±888.21 ^* 952.4±338.52 1383.975±833.98 1084.725±304.34 ^ 938±535.05 ^	Middle dosage group

Annotate: with contrast group simultaneously relatively, ^*P＜0.05 ^*P＜0.01

Table 24 dog acute myocardial infarction scope (N-BT staining mensuration) (%, )

Group	Dosage (mg/kg)	Number of animals	Ischemia % under the ligation	Ventricular ischemia %	Global ischemia %
Group	Dosage (mg/kg)	Number of animals	Ischemia % under the ligation	Ventricular ischemia %	Global ischemia %	Solvent control positive control pharmaceutical composition	- 81 7.05 14.1 48	10 10 10 10 10	65.30±3.98 33.00±10.25 ^ 48.67±7.38 41.57±2.91 ^ 23.96±19.5 ^4**	26.86±.29 14.04±5.52 ^* 21.82±4.74 17.84±1.82 ^ 10.96±8.08 ^	22.62±2.91 11.53±4.47 ^ 17.64±4.00 14.66±1.31 ^ 8.94±6.60 ^**

Annotate: compare with model group ^*P＜0.05 ^*P＜0.01

Draw thus, pharmaceutical composition of the present invention can alleviate by the degree of myocardial ischemia of epicardial electrogram mapping (∑-ST), obviously reduce through the shown infarct of N-BT dyeing, obviously alleviate degree, have significant function of resisting myocardial ischemia by myocardial ischemia due to the ligation dog coronary artery and myocardial infarction.

Test example 6The influence of the hyperlipidemia that pharmaceutical composition of the present invention causes the rat high lipid food

1, experimental technique

60 of SD rats, rat male and female half and half, body weight 350 ± 25g is behind sex and weight classification, be divided into 6 groups at random, solvent control group, zhibituo group, medicine low dose group (14.1mg/kg), middle dosage group (28.2mg/kg) and high dose group (56.4mg/kg), model group, 10 every group.

Solvent control group experiment whole process is all raised with normal feedstuff.Other 5 groups of whole process are all raised with high lipid food (the high lipid food composition is: Adeps Sus domestica 10%, ripe egg yolk 5%, cholesterol 2%, methylthiouracil 0.2%, normal feedstuff add to 100% to be made).The basic, normal, high dosage group of medicine and zhibituo group (with clinical 10 times of amounts) be from administration in the 8th day, and irritate stomach with high fat liquor (20% propylene glycol adds water to 100% mixing for 30% Adeps Sus domestica, 20% Tween 80) 1ml/100g; Model group is irritated stomach with the high fat of 1ml/100g, feeds to whole process and finishes.

Empty stomach 12h after 28 days is carried out in experiment, and eye socket is got the about 5ml of blood, and 3000 commentaries on classics/min centrifugalize top serum carry out lipid determination.Result data is represented with means standard deviation, carries out the t check between group.

2, experimental result

Model control group and matched group compare, and Chol and LDL-C significantly increase, and show the modeling success.

After the administration 12 days, the basic, normal, high dosage group of pharmaceutical composition all has remarkable reduction effect for each index, and the high blood lipid model rat fat that pharmaceutical composition promptly of the present invention causes for high lipid food raises significantly reduction effect.The results are shown in Table 25:

The influence of the hyperlipidemia that table 25 pharmaceutical composition causes the rat high lipid food (mmol/L,

)

	TG	CHOL	HDL-C	LDL-C
	TG	CHOL	HDL-C	LDL-C	Dosage low dosage in the negative control positive control model group high dose	0.91±0.492 1.56±0.598 1.69±1.19 0.48±0.192 ^* 0.36±0.123 1.17±0.651	2.47±0.495 ^* 0.70±0.257 ^* 3.29±0.79 2.13±0.398 ^ 2.40±0.501 1.47±0.410 ^***	1.06±0.174 ^ 1.48±0.094 ^ 1.56±0.34 1.26±0.182 1.48±0.269 0.87±0.262 ^***	0.99±0.256 0.62±0.065 ^ 1.40±0.54 0.65±0.312 ^ 0.76±0.220 ^* 0.41±0.227 ^***

Annotate: compare with model group ^*P＜0.05 ^*P＜0.01

Test example 7The general pharmacology development test research of pharmaceutical composition of the present invention

General pharmacological action shows: 1) dosage is that the pharmaceutical composition of the present invention of 35.25mg/kg, 70.5g/kg, 141mg/kg is that the general behavior and the coordination exercise of 20-22g Kunming mouse (male and female half and half) do not have obvious influence to body weight, and no significant prolongation pentobarbital sodium sleep is held time; 2) dosage is 28.2mg/kg, and the pharmaceutical composition of the present invention of 56.4mg/kg, 112.8mg/kg does not all have obvious influence to systolic pressure, diastolic pressure, mean pressure, heart rate, cardiac muscular tension time index, respiratory frequency and the amplitude of respiration of hybrid dog.The results are shown in Table 26:

The general pharmacology of table 26 pharmaceutical composition of the present invention is learned research summary

Experimental project	Animal is selected	Administration situation dosage/concentration approach time	With the clinical plan of people magnitude relation (doubly)	Main result of study
Experimental project	Animal is selected	Administration situation dosage/concentration approach time		Main result of study	The collaborative sleep of autonomic activities coordination of function	Kunming mouse Kunming mouse Kunming mouse	Spirit nervous system 35.25mg/kg, 70.5g/kg, 141mg/kg, the PEG200 configuration, gastric infusion 1 35.25mg/kg, 70.5g/kg, 141mg/kg, the PEG200 configuration, gastric infusion 1 35.25mg/kg, 70.5g/kg, 141mg/kg, the PEG200 configuration	15 times, 30 times and 60 times 15 times, 30 times and 60 times 15 times, 30 times and 60 times	Only 141mg/kg perforation significance increase spontaneous activity does not have obvious influence is not had obvious influence

		Gastric infusion 1 time
		Gastric infusion 1 time			The cardiovascular system respiratory system	Hybrid dog hybrid dog	The 28.2mg/kg of cardiovascular-respiratory system, 56.4g/kg, 112.8mg/kg, the PEG200 configuration, duodenal administration 1 28.2mg/kg, 56.4g/kg, 112.8mg/kg, PEG200 configuration, duodenal administration 1 time	12 times, 24 times and 48 times 12 times, 24 times and 48 times	Nothings such as systolic pressure, diastolic pressure, mean pressure, heart rate obviously influence respiratory frequency and amplitude of respiration does not have obvious influence

Test example 8Pharmaceutical composition of the present invention to mice acute toxicity effect research

50 of healthy Kunming mouses, male and female half and half, body weight 18-22g, fasting be can't help water after 16 hours, irritated stomach 30ml/kg, and administration is 1 time in 1 day.Preliminary experiment has been investigated the acute toxicity of solvent (PEG200) to mice, proves that toxicity does not appear in solvent mice under the dosage of 40ml/kg.Under medicine preliminary experiment result's guidance, adopt 5 dosage gastric infusions, observe the acute toxic reaction and the death condition that produce behind the pharmaceutical composition filling stomach of the present invention in 1 day, and use Bliss ' s method to add up its toxicity situation.

The result shows: the toxicity of drug composition oral administration of the present invention is less, the median lethal dose(LD 50) of mouse stomach administration (LD50) is 4814.399 ± 563.3079mg/kg, for clinical consumption 2048 times in safety range, can not cause acute toxicity at clinical plan consumption.

Test example 9Pharmaceutical composition of the present invention is to the acute toxicity effect research of rat

The SD rat, 160-180g irritates stomach with Cmax (original solution 282mg/m1) at every turn and gives pharmaceutical composition heap(ed) capacity (2.5ml/100g), is total to administration 2 times in 24 hours.Observe seven days results, the result shows: the administration activities in rats freely, do not have cry unusual, tremble, convulsions, movement disorder, sialorrhea, shed tears, phenomenons such as rhinorrhea, dyspnea, diarrhoea, constipation, intestinal tympanites take place.Animal skin gloss, none death of rat in one week of administration, administration the 4th, 8 natural gift another name is heavy, and the weight of animals does not have significant change, does not have other abnormal phenomenas.Put to death animal, organs and tissues position no abnormality seens such as perusal rat internal organs, the heart, liver spleen, lung, kidney, stomach, intestinal, testis, prostate, uterus, ovary, thoracic cavity, abdominal cavity on the 8th.

Draw thus, the maximum dosage of pharmaceutical composition of the present invention is 14.1g/kg, is equivalent to 6000 times of people's taking dose, at clinical plan consumption in safety range.

Test example 10Pharmaceutical composition of the present invention is to the long term toxicity effect research of rat

According to intending clinical taking the cycle, investigated 3 months rat long term toxicity test.80 of SD rats, body weight 70-100g, male and female half and half are divided four groups, and 20 every group, i.e. (1) matched group; (2) pharmaceutical composition small dose group (70.5mg/kg, behave clinical plan consumption 30 times); (3) dosage group in the pharmaceutical composition (141mg/kg, behave clinical plan consumption 60 times); (4) the heavy dose of group of pharmaceutical composition (282mg/kg, behave clinical plan consumption 120 times).Every day gastric infusion once, continuous 3 months, during death condition, behavioral activity, outward appearance sign, feces character and the food ration etc. of observed and recorded laboratory animal.

Put to death 10 for every group after 3 months, get hematometry: 1) erythrocyte (RBC), hemoglobin (Hgb), packed cell volume (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) (MCHC), Erythrocyte hemoglobin distribution width (RDW), platelet (PLT), thrombocytocrit (PCT), mean platelet volume (MPV), MPW (PDW), leukocyte (WBC), leukocyte differential count hematological indices such as (W-LY, W-MOR, W-GR); 2) ALT (ALT), aspartic acid aminotransferase (AST), alkali phosphatase (ALP), carbamide (Urea), creatinine (CRE), blood glucose (GLU), T-CHOL (T-CHO), total bilirubin (TBiL), albumin (ALB) and total protein (TP).Serum biochemistry indexs such as the sodium ion of serum, potassium ion, chloride ion, triglyceride.

Rat carries out system to be dissected, record perusal result.Core, liver, spleen, lung, kidney, thymus, adrenal gland, brain, testis (uterus) and prostate (ovary) and weigh, calculate organ coefficient (organ weights * 100/ body weight).Core, internal organs such as liver, spleen, lung, kidney, brain, spinal cord, hypophysis cerebri, optic nerve, trachea, aorta, esophagus, stomach, duodenum, ileum, colon, pancreas, mesenteric lymph node, breastbone, adrenal gland, thymus, thyroid, salivary gland, bladder, testis, epididymis, prostate, ovary, uterus, sciatic nerve, fix with 10% formalin solution, the waxdip embedding, after the section, histopathologic examination is done in HE dyeing.

The result shows: 1) the weight of animals increases gradually, and the weight of animals of each drug dose group, food ration and matched group do not have notable difference, does not have tangible Deviant Behavior activity; 2) respectively organize rat and do not seeing animal dead during the whole administration and between convalescent period; 3) the every index of administration group hematology changes not obvious before and after administration, and the serum biochemistry index all in normal range, compares with matched group, all no difference of science of statistics; 4) each dosage group of medicine does not influence diet, drinking-water and the growth promoter of rat, and organ index, hematological indices, biochemical indicator are not all had obvious influence, and each important organ pathological section is all normal, does not see slow toxicity; 5) the no abnormal variation of each treated animal internal organs of perusal, each treated animal internal organs of microscopy do not have obvious pathological change.Compare with matched group, difference that there are no significant is not seen the overt toxicity reaction, does not find the poisoning target organ.

Draw thus, the pharmacological action of pharmaceutical composition of the present invention is: 1, coronary artery dilator increases myocardial nutrition cardiac flow and the damage of resisting myocardial ischemia property; 2, reduce myocardial oxygen consumption and improve myocardial metabolism; 3, influence hemodynamics, reduce the heart burden.And by many-sided pharmacology comprehensive function, be used to prevent and treat cardiovascular and cerebrovascular disease, and evident in efficacy, drug effect is clear and definite.And system's acute toxicity test of having carried out, chronic toxicity test and general pharmacology are learned result of the test and shown: pharmaceutical composition of the present invention is not seen obvious toxic and side effects, and toxicity is little, and safety range is bigger.

Claims

1. a pharmaceutical composition that is used to prevent and treat cardiovascular and cerebrovascular disease prepares compositions raw materials of effective components composition and counts Folium Ginkgo 3-300 part, Radix Notoginseng 1-100 part, Ramulus Buxi Sinicae 2-200 part and Borneolum Syntheticum 0.002-0.2 part by weight.

2. pharmaceutical composition according to claim 1, preparation compositions raw materials of effective components composition is counted Folium Ginkgo 6-150 part, Radix Notoginseng 2-50 part, Ramulus Buxi Sinicae 4-100 part and Borneolum Syntheticum 0.004-0.1 part by weight.

3. pharmaceutical composition according to claim 2, preparation compositions raw materials of effective components composition is counted Folium Ginkgo 12-75 part, Radix Notoginseng 4-25 part, Ramulus Buxi Sinicae 8-50 part and Borneolum Syntheticum 0.008-0.05 part by weight.

4. pharmaceutical composition according to claim 3, preparation compositions raw materials of effective components are formed and are counted by weight, 0.02 part of 3 parts of Folium Ginkgos, 1 part of Radix Notoginseng, 2 parts of Ramulus Buxi Sinicaes and Borneolum Syntheticum.

5. according to each described pharmaceutical composition of claim 1-4, the effective ingredient of Folium Ginkgo is a Folium Ginkgo extract in the compositions, its preparation method is: 1) Folium Ginkgo or its coarse powder are put in the extractor, add water or 20-95% water-alcohol solution that medical material 2-20 doubly measures, reflux, extract, 1-5 time, each 0.5-5 hour, filter merging filtrate; 2) concentrated filtrate filters to an amount of, gets filtrate; 3) gained filtrate is behind resin absorption, and water and 10-95% ethanol elution are collected ethanol elution successively, concentrate, and drying, promptly.

6. according to each described pharmaceutical composition of claim 1-4, the effective ingredient of Radix Notoginseng is a Radix Notoginseng extract in the compositions, the preparation method of described Radix Notoginseng extract is: Radix Notoginseng or its coarse powder are put in the extractor, water or 30-95% water-alcohol solution that adding pseudo-ginseng 5-20 doubly measures extract 1-5 time, each 0.5-5 hour, merge extractive liquid,, be concentrated into and do not have the alcohol flavor, or thin up is to an amount of, behind resin absorption, and water and 10-95% ethanol elution successively, collect ethanol elution, concentrate, drying, promptly.

7. according to each described pharmaceutical composition of claim 1-4, the effective ingredient of Buxus sinica (Rehd.et Wils.) is the Buxus sinica (Rehd.et Wils.) extract in the compositions, described Buxus sinica (Rehd.et Wils.) preparation method of extract is: 1) Ramulus Buxi Sinicae or its coarse powder are put in the extractor, aqueous acid or 30-95% water-alcohol solution that adding Buxus sinica (Rehd.et Wils.) medical material 4-20 doubly measures extract 1-5 time, each 0.5-5 hour, merge extractive liquid; 2) be concentrated into nothing alcohol flavor, add aqueous acid precipitation concentrated solution, filtration; 3) gained filtrate, after the absorption of kayexalate resin column, after washing was clean, taking-up was dried; 4) add the ammonia wet resin, extract, filter, get filtrate with the 50-95% water-alcohol solution; 5) filtrate is concentrated into does not have the alcohol flavor, places and separates out precipitation, filters; 6) precipitation through alcohol wash, drying, promptly.

8. according to each described pharmaceutical composition of claim 1-4, the preparation type of described pharmaceutical composition is selected from oral formulations, injection or external preparation; Described oral formulations is selected from pill, powder, granule, tablet, soft extract, capsule, drop pill, oral cavity disintegration tablet, effervescent, paste, medicinal tea, suspension, syrup, mixture or Emulsion.

9. a method for preparing each described pharmaceutical composition of claim 1-8 is characterized in that, with Folium Ginkgo extract, Radix Notoginseng extract, Buxus sinica (Rehd.et Wils.) extract, Borneolum Syntheticum and pharmaceutically acceptable carrier uniform mixing.

10. the application of each described pharmaceutical composition of claim 1-8 in the medicine of preparation control cardiovascular and cerebrovascular disease or its relevant disease; Described cardiovascular and cerebrovascular disease or its relevant disease are selected from coronary heart disease, angina pectoris, cerebral ischemia diseases or its complication, and be used for that obstruction of qi in the chest and cardialgia, the heart that obstruction of collaterals by blood stasis causes are vexed, apoplexy, hemiplegia, stiff tongue language be stuttering, coronary heart disease, angina pectoris, cerebral infarction are seen above-mentioned disease person.