CN101244127B - Medicament for treating vascular dementia - Google Patents

Medicament for treating vascular dementia Download PDF

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CN101244127B
CN101244127B CN2007101115676A CN200710111567A CN101244127B CN 101244127 B CN101244127 B CN 101244127B CN 2007101115676 A CN2007101115676 A CN 2007101115676A CN 200710111567 A CN200710111567 A CN 200710111567A CN 101244127 B CN101244127 B CN 101244127B
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hippocampus
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CN101244127A (en
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张庆华
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Boji Pharmaceutical Technology Co ltd
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HUNAN FANGSHENG PHARMACEUTICAL CO Ltd
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Abstract

The invention provides a medicine used to treat the vascular dementia with main symptoms of sputum blockage, blood stasis and deficiency of kidney and spermatozoa, as well as a method to prepare the medicine. The medicine in the invention is made of the following materials in weight proportions: 0.1-10 portions of ginkgo leaf extract, 22-37 portions of earthworm, 22-37 portions of epimedium, 11-25 portions of rhizoma ligustici wallichii, and 11-25 portionspolygala root.

Description

The medicine that is used for the treatment of vascular dementia
Technical field
The present invention relates to a kind ofly contain the medicine that Folium Ginkgo extract is used for the treatment of vascular dementia, the pharmaceutical composition that contains it, and the method for preparing it.
Background technology
Along with the aging of world population, the sickness rate of senile dementia also increases greatly, has become one of four big diseases of serious threat senior health and fitness.According to investigations, straight line rises the sickness rate of vascular dementia with the age, and old people's annual morbidity of over-65s estimates that 1.2%～4.2% the annual number of patients of old people is 6～12 examples/1000 people more than 70 years old.Average course of disease 5 years, mortality rate are 25.7%.China is the maximum country of aging population in the world, belong to one of developing country again, therefore research and develop the medicine that is used for the treatment of vascular dementia safe, effective, quality controllable, cheap, long-term taking convenience, has obvious social, can reduce simultaneously the control cost of this disease again, for society brings remarkable economic efficiency.
Disease categories such as vascular dementia belongs to that the traditional Chinese medical science is forgetful, dizzy, dementia, demented, apoplexy.The traditional Chinese medical science thinks that its morbidity is by wind, fire, expectorant, stasis of blood retardance brain network, on disturb brain god, or liver, kidney, the heart, spleen lose empty, brains lose fill due to.Its sick position influences brains, brain key at the brain network, and is relevant with liver, kidney, the heart, spleen; Its characteristic of disease is a deficiency in origin and excess in superficiality, and is empty at yang blood and qi, and how tangible wind, fire, expectorant, the stasis of blood are based on the double folder of deficiency and excess.Its treatment should be mingled with mutually according to deficiency and excess what, or, take into account in fact, or, hold concurrently and mend its void based on eliminating evil based on tonify deficiency.
Tang Qisheng thinks that suffering from a deficiency of the kidney is that the basic reason with development takes place vascular dementia, and expectorant is turbid stop poly-and venation block after removing toxic substances cause harm, the poison of the interior life of generation then is the basic pathology link (Chinese Medicine journal, 1996,5) in the vascular dementia pathogenic process.
The palace turbulent waves has been discussed the relation of kidney essense and vascular dementia from physiology, pathology two aspects, think that kidney essense is the basis of human body normal psyche conscious activity, also is that the vital organs of the human body are rely and moistened foster source.Deficiency of kidney-essence not only can cause the abnormal emotion of visceral controllings, and is the key that the dull-witted pathological factor expectorant stasis of blood produces, and is therefore determining dull-witted generation (Zhejiang Journal of Traditional Chinese Medicine, 2005,11).
Wei Zhenhua has looked back the understanding of ancient Chinese medicine doctor to dementia, comprehensive modern medical theory, thinking mostly vascular dementia is to replace in platform, fluctuation, three phases of downslide is ladder progress in the change process, three phase syndromes have nothing in common with each other, deficiency of kidney-essence, phlegm and blood stasis, obstruction of collateral are the generation bases of vascular dementia, the expectorant stasis of blood is pented up, made and gives birth to turbid poison, ruins brain network brains is the key (the Shanxi traditional Chinese medical science, 2005,6) that vascular dementia develops.
Miao Guifen etc. think that according to clinical observation old vascular dementia belongs to the clear key of traditional Chinese medical science stagnation of phlegm blood stasis brain more, and first god is for it due to the mist.Think that waking up the patient from unconsciousness by clearing away phlegm, disperse blood stasis and dredge collateral are the important method of treatment (Jilin Chinese medicine, 2005,12) of old vascular dementia treatment.
In summary, vascular dementia key character is phlegm stagnation in collateral, deficiency of kidney essence.
Treat Western medicine targetedly for vascular dementia, all do not have the successful report of research both at home and abroad.
With the vascular dementia is the Chinese patent medicine of main disease to be treated, XIAOSHUAN TONGLUO PIAN (Pharmacopoeia of the People's Republic of China, version was first one in 2005) is only arranged: Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, the Radix Astragali, Rhizoma Alismatis, Radix Notoginseng, Flos Sophorae, Ramulus Cinnamomi, Radix Curcumae, the Radix Aucklandiae, Borneolum Syntheticum Fructus Crataegi.This medicine is used for blood circulation promoting and blood stasis dispelling, and promoting the flow of QI in the collateral by warming the meridian cures mainly the dementia that cerebral thrombosis causes, has listed national essential drug catalogue and basic medical insurance medication catalogue in.
Main disease to be treated is not a vascular dementia, but the Chinese patent medicine that the clinical practice report is arranged, HUATUO ZAIZAO WAN (Chinese medicine information is arranged, 1997,6), Radix Salviae Miltiorrhizae Injection (Chinese combination of Chinese and Western medicine magazine, 1992,7), QINKAILING ZHUSHEYE (Beijing College of Traditional Chinese Medicine's journal, 1992,3), MAILUONING ZHUSHEYE (Zhejiang College Of Traditional Chinese Medicine journal, 1994,6), the white ball of Gallus Domesticus (Beijing Journal of Traditional Chinese Medicine, 1993,6), Folium Ginkgo (practical tcm internal medicine magazine, 2003,4), 25-component pearl ball (Chinese Chinese medicine information magazine, 2003,10) etc.
The vascular dementia medicine of studying at present has FUFANG DANSHEN PIAN, the safe capsule of brain arteries and veins etc.
More than the Chinese patent medicine of treatment vascular dementia is most based on activating blood and removing stasis drug, and small part is not the medicine of vascular dementia phlegm stagnation in collateral, deficiency of kidney essence card based on heat and toxic materials clearing away medicine.
Therefore, market is that the medicine of the vascular dementia of main symptom exists demand to treatment with phlegm stagnation in collateral, deficiency of kidney essence.
Summary of the invention
The purpose of this invention is to provide a kind of medicine, being used for the treatment of with phlegm stagnation in collateral, deficiency of kidney essence is the vascular dementia of main symptom.
Another object of the present invention provides a kind of method for preparing said medicine.
Medicine provided by the invention is made by following materials of weight proportions:
0.1～10 part of Folium Ginkgo extract
22～37 parts of Pheretimas
22～37 parts of Herba Epimedii
11～25 parts of Rhizoma Chuanxiongs
11～25 parts of Radix Polygalaes (system).
Preferably, medicine provided by the invention is made by following materials of weight proportions:
1～5 part of Folium Ginkgo extract
27～33 parts of Pheretimas
27～33 parts of Herba Epimedii
14～23 parts of Rhizoma Chuanxiongs
14～23 parts of Radix Polygalaes (system).
Medicine provided by the invention can be made several formulations: comprise in tablet, pill, capsule, capsule tablet, powder, granule, suspending agent, gel, the paste any one.
The preparation manufacturing method for above mentioned medicine may further comprise the steps: comprising:
(a) get Pheretima, Herba Epimedii, Rhizoma Chuanxiong, Radix Polygalae four Chinese medicine material in proportion, extracting preferred 70% ethanol with the ethanol water immersion of %60～95% is that solvent refluxing extracted 1～10 hour, and number of times is 1～3 time;
(b) reclaim ethanol, concentrated, dry, be ground into fine powder;
(c) get Folium Ginkgo extract in proportion, with described fine powder mix homogeneously;
(d) add an amount of excipient and/or other additives, make suitable dosage forms.
Medicine provided by the invention can obviously improve mice learning and memory ability, improves every index of correlation: can significantly improve the unusual of stasis syndrome rat whole blood viscosity, plasma viscosity and packed cell volume; Can obviously improve the auricular microcirculation of mice; Plasma cyclic nucleotide to cortisone yang deficiency rat and hypothyroidism mice has good regulating action, can obviously improve the plasma cAMP level, reduces the cGMP level, rising cAMP/cGMP ratio.
Description of drawings
Fig. 1 is mice sham operated rats Hippocampus CA1 district pathological section (HE * 400 times).
Fig. 2 is mouse model group Hippocampus CA1 district pathological section (HE * 400 times).
Fig. 3 is mice duxil group Hippocampus CA1 district pathological section (HE * 400 times).
Fig. 4 is mice compound gingkgo blade high dose group Hippocampus CA1 district pathological section (HE * 400 times).
Fig. 5 is dosage group Hippocampus CA1 district pathological section in the mice compound gingkgo blade (HE * 400 times).
Fig. 6 is mice compound gingkgo blade low dose group Hippocampus CA1 district pathological section (HE * 400 times).
Fig. 7 is rat sham operated rats Hippocampus CA1 district pathological section (HE * 400 times).
Fig. 8 is rat model group Hippocampus CA1 district pathological section (HE * 400 times).
Fig. 9 is rat duxil group Hippocampus CA1 district pathological section (HE * 400 times).
Figure 10 is rat compound gingkgo blade high dose group Hippocampus CA1 district pathological section (HE * 400 times).
Figure 11 is dosage group Hippocampus CA1 district pathological section in the rat compound gingkgo blade (HE * 400 times).
Figure 12 is rat compound gingkgo blade low dose group Hippocampus CA1 district pathological section (HE * 400 times).
Figure 13 is rat sham operated rats Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times).
Figure 14 is rat model group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times).
Figure 15 is rat duxil group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times).
Figure 16 is rat compound gingkgo blade high dose group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times).
Figure 17 is dosage group CA1 district Hippocampus SS dyeing in the rat hippocampus (SABC * 400 times).
Figure 18 is rat low dose group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times).
Figure 19 is rat sham operated rats Hippocampus CA1 district BAX dyeing (SABC * 400).
Figure 20 is rat model group Hippocampus CA1 district BAX dyeing (SABC * 400).
Figure 21 is rat duxil group Hippocampus CA1 district BAX dyeing (SABC * 400).
Figure 22 is rat compound gingkgo blade high dose group Hippocampus CA1 district BAX dyeing (SABC * 400).
Figure 23 is dosage group Hippocampus CA1 district BAX dyeing (SABC * 400) in the rat compound gingkgo blade.
Figure 24 is rat compound gingkgo blade low dose group Hippocampus CA1 district BAX dyeing (SABC * 400).
The specific embodiment
The traditional Chinese medical science prescription that is used for the treatment of vascular dementia provided by the invention is made by Folium Ginkgo extract, Pheretima, Herba Epimedii, Rhizoma Chuanxiong, Radix Polygalae Chinese medicine of the five flavours.To be the inventor propose according to for many years traditional Chinese medical science working experience with to the deep understanding of theory of Chinese medical science this prescription.The function of each composition is as follows in the prescription:
(1) Folium Ginkgo extract, sweet, bitter, puckery, flat, GUIXIN, lung meridian, blood circulation promoting and blood stasis dispelling impels the brain arteries and veins to recover unobstructed, thereby increases the keeping of brain internal organs QI and blood, makes the multiple spirit of brain key, and it hinders this initial cause of disease at the brain arteries and veins stasis of blood and works the monarch drug in the side of being.
(2) Pheretima, salty, cold, return liver, spleen, urinary bladder channel, clearing heat for calming endogenous wind, collateral dredging, wherein the auxiliary monarch drug Folium Ginkgo extract of the collateral dredging interaction energy of Pheretima strengthens its effect of invigorating blood circulation; Excessive sheep, the leaves of pulse plants, hot, sweet, warm, return liver, kidney channel, kidney-replenishing, bone and muscle strengthening, wind-damp dispelling.The warming the kidney to invigorate YANG of Herba Epimedii, replenishing essence supplementing the brain work to this main pathogenesis of suffering from a deficiency of the kidney.The cold temperature with Herba Epimedii of Pheretima matches, and works in coordination, and complements each other the ministerial drug in the common conduct side.
(3) Rhizoma Chuanxiong, hot, warm, return liver, gallbladder, pericardium channel, blood-activating and qi-promoting, wind-expelling pain-stopping.Its blood-activating and qi-promoting can be helped principal drug assistance Folium Ginkgo extract, ministerial drug Pheretima strengthening its function of promoting blood circulation to disperse blood clots, and Rhizoma Chuanxiong is double goes into edema caused by disorder of QI, cooperates Folium Ginkgo extract specially to go into blood system, and QI and blood is also controlled, the adjuvant drug in the side of being.
(4) Radix Polygalae, bitter, hot, warm, GUIXIN, kidney, lung meridian eliminate the phlegm and have one's ideas straightened out, mind tranquilizing and the heart calming, Fructus Alpiniae Oxyphyllae can be eliminated the phlegm, and works at this Secondary cases cause of disease of expectorant; Can have one's ideas straightened out again mind calming, the Fructus Alpiniae Oxyphyllae of calming the nerves, assistant helps the ministerial drug Herba Epimedii to strengthen its brain healthy effect; Can also " lead to regulation of mental activities gas " (" book on Chinese herbal medicine justice "), can be used as the tying-in of above-mentioned each medicine, so the adjuvant in the side of can be.
More than all medicines cooperate, reach blood circulation promoting and blood stasis dispelling jointly, the effect of the collateral dredging that eliminates the phlegm, nourishing the brain and improving intelligence, have treating both the principal and the secondary aspects of a disease at the same time based on take stopgap measures, using medicines of both cold and hot natures simultaneously based on Heibei provincial opera, the QI and blood people having the same aspiration and interest to control the characteristics of blood, what suit vascular dementia is basis to suffer from a deficiency of the kidney, be the anxious pathogenesis of mark but standard card with stasis of blood expectorant, so be suitable for genus phlegm stagnation in collateral, the syndrome of deficiency of kidney essence person of vascular dementia.Its legislation, select medicine, prescription, meet Chinese medical theory and adapt to the etiology and pathogenesis of disease.
The medicine that is used for the treatment of vascular dementia according to the present invention is to be made by the following weight proportion raw material:
0.1～10 part of Folium Ginkgo extract
22～37 parts of Pheretimas
22～37 parts of Herba Epimedii
11～25 parts of Rhizoma Chuanxiongs
11～25 parts of Radix Polygalaes.
In a typical embodiment of the present invention, this medicine that is used for the treatment of vascular dementia is to be made by the following weight proportion raw material:
1～5 part of Folium Ginkgo extract
27～33 parts of Pheretimas
27～33 parts of Herba Epimedii
14～23 parts of Rhizoma Chuanxiongs
14～23 parts of Radix Polygalaes.
In a specific embodiment of the present invention, this medicine that is used for the treatment of vascular dementia is to be made by the following weight proportion raw material:
1.5 parts of Folium Ginkgo extract
30 parts of Pheretimas
30 parts of Herba Epimedii
18 parts of Rhizoma Chuanxiongs
18 parts of Radix Polygalaes.
The Folium Ginkgo extract that uses among the present invention market is at home buied easily, and general the employing meets 2005 editions " commercially available prod of Chinese pharmacopoeia Folium Ginkgo extract quality standard is the raw material Folium Ginkgo extract of the refreshing horse in Changzhou pharmaceutcal corporation, Ltd (for example from).It is usually by alcohol reflux, and macroporous resin adsorption is sprayed then and done, pulverizes and make.It typically is sundown to chocolate brown powder; Mildly bitter flavor.
Other raw materials that the present invention uses are all medical herbs, and it can be the medical herbs finished product of selling in pharmacy, also can be the medical herbs of new results, for the latter's situation, generally new medical herbs will be dried or are dried, to remove moisture content substantially.As preferably, Radix Polygalae wherein is through concocting.
The method for preparing medicine of the present invention is a conventional method, usually, take by weighing Pheretima, Herba Epimedii, Rhizoma Chuanxiong, Radix Polygalae (system) by weight, add 60%～95% ethanol water and soak extraction appropriate time and suitable number of times, time, between 1～10 hour, number of times was 1～3 time usually.Reclaim ethanol then, concentrated, dry, be ground into fine powder.Conventional equipment is all used in these operations.With the Folium Ginkgo extract fine powder mixing of above-mentioned fine powder and appropriate components, add suitable excipient.
Can make tablet according to medicine of the present invention.On the basis of determining dosage form, pharmacological action according to prescription drug character and effective ingredient, in conjunction with experimentation (comprising the investigation of extracting solvent, extraction time, reaching aqueous extraction-alcohol precipitation technology), determined the extraction process route of this preparation, that is: Pheretima, Herba Epimedii, Rhizoma Chuanxiong, Radix Polygalae (system) four Chinese medicine material, the ethanol with 60%～95%, preferred 65%～80% are that solvent refluxing extracts secondary; Folium Ginkgo extract directly is used as medicine when preparations shaping.In the research of alcohol extraction process condition, with icariin leaching amount and yield of extract is evaluation index, adopt orthogonal experiment that soak time, alcohol adding amount, extraction time have been carried out preferably, determine that alcohol extraction optimum process condition is: added the 65-75% soak with ethanol 1.5 hours, extract 2 times, alcohol adding amount is respectively 10 times, 8 times of medical material, and extraction time was respectively 2.0 hours, 1.5 hours.
In the concentrate drying technical study,, show that it is that 1.30 (60 ℃ of heat are surveyed) back (is good 0.08MPa) in 60 ℃ of vacuum dryings that extracting solution is concentrated into relative density through contrast test.
Pharmaceutical excipient is meant that for the useful excipient of pharmaceutical compositions, it is safe, nontoxic and desirable usually, and comprises the excipient that can be applicable to veterinary and human medicine.This class excipient can be solid, liquid, semisolid, or is gas under the situation that aerosol is formed.
Medicine of the present invention can give with the oral formulations form per os of doing.Medicine of the present invention can give with per os such as tablet, pill, capsule, capsule tablet, powder, granule, suspending agent, gel, pastes.Orally administered composition can comprise common carrier, excipient and diluent.The peroral dosage form of pharmaceutical composition of the present invention can prepare with technology known in the art, and contains the ingredient that effective dose is gone up in treatment.Determine by standard clinical techniques according to working doctor's judgement for the effective oral dose of the treatment of preparation of the present invention.For example, except that the information that medical science handbook and materia medica document provide, can help determine optimal dose with chemical examination in the external or body of knowing.
Medicine of the present invention can use separately, perhaps under suitable situation, is used in combination with other drug.
Medicine of the present invention can contain one or more pharmaceutical excipients.Excipient is added in the ingredient for multiple purpose.This ingredient can provide with unit dosage form easily, and is prepared by methods known in the art.Such method comprises that wherein carrier itself can comprise one or more auxiliary elements with extract component and the combined step of carrier.Usually, the preparation of this dosage form is by extract component and liquid-carrier or powder solid carrier or the combination of the two are mixed mutually, and this product then in case of necessity is shaped.
Preferably, this pharmaceutical preparation is the peroral dosage form of doing.Preferably, this pharmaceutical preparation is solid dosage forms.Preferably, this pharmaceutical composition is the peroral dosage form that is selected from the group that is made of tablet, pill, capsule, capsule tablet, powder and granule.The dosage form of doing can comprise the pharmacy acceptable additive, as excipient, carrier, diluent, stabilizing agent, plasticizer, binding agent, fluidizer, disintegrating agent, filler, lubricant, plasticiser, coloring agent, film former, flavour enhancer, antiseptic, drug administration carrier (dosing vehicle) and aforementioned in any combination.These all are well-known to those skilled in the art, do not repeat them here.
The selection of excipient and consumption by the preparation designer rule of thumb and consider that standard procedure and this area reference material are easy to determine.Solid drugs of the present invention comprises powder, granule, aggregation and compacting component.Preferred route of administering of the present invention is oral.This dosage can provide easily with unit dosage forms, and prepares with any well-known process of pharmaceutical field.Dosage form comprises solid dosage forms, as tablet, pill, powder, capsule, granule, capsule tablet, pouch agent, tablet and lozenge.The particularly preferred dosage form of the present invention is a tablet.
The form of paste solution or freeze-dried powder is used for the gastrointestinal tract external administration.Can in powder, add suitable diluent or other pharmaceutical carrier before using and carry out reprovision.Liquid formulations normally cushions, etc. ooze, aqueous solution.The example of suitable diluent has standard normal isotonic saline solution, 5% D/W.This class prescription especially is fit to the gastrointestinal tract external administration, but also can be oral.Preferably add excipient, as polyvinylpyrrolidone, gelatin, oxidized cellulose, arabic gum, Polyethylene Glycol, mannitol, sodium chloride or sodium citrate.
Replacedly, these chemical compounds can be encapsulated, tablet or prepare in Emulsion or syrup, be used for oral.In order to strengthen or stable composition or help preparation of compositions, can add medicinal solid or liquid-carrier.Liquid-carrier comprises syrup, Oleum Arachidis hypogaeae semen, olive oil, glycerol, saline, alcohols or water.Solid carrier comprises starch, lactose, calcium sulfate, dihydrate, Gypsum Fibrosum powder, magnesium stearate or stearic acid, Pulvis Talci, pectin, arabic gum, agar or gelatin.Carrier also can comprise sustained-release materials, such as glycerol monostearate or the acid of glycerol distearyl, separately or with wax.The amount of solid carrier has nothing in common with each other, and still, preferably, each dosage unit is between about 1g at about 20mg.
Traditional process for preparing medicine is followed in the medicine preparation, with regard to the preparation tablet, relates to grinding, mixing, granulating and compression (when in case of necessity); Or with regard to the preparation hard capsule, relate to grinding, mix and fill.When using liquid-carrier, pharmaceutical preparation is syrup, elixir, Emulsion or aqueous or non-aqueous suspension form.Can directly oral (p.o.) administration or be packed in the soft capsule for this liquid dosage form.
In a specific embodiment of the present invention, described medicine is made into tablet.When this dosage form of preparation, can be with medicated powder and microcrystalline Cellulose (3: 2) mixing in proportion, add an amount of 95% alcoholic solution that contains 2% polyvidone (PVP) as the wet grain of binding agent system, 40～50 ℃ of dryings, cross 20 mesh sieve granulate, add 1% magnesium stearate mixing then, tabletting, and bag film-coat.
In addition, investigated the hygroscopicity of drug particles, in conjunction with knowhow, think this product molding process control relative humidity carry out below 50% comparatively suitable.
Preparation embodiment
Embodiment 1
Get 27 parts of Pheretimas, 27 parts of Herba Epimedii, 15 parts of Rhizoma Chuanxiongs, Radix Polygalae (system) and (be weight portion for 15 parts, down together), add 65% ethanol water and soaked 1.5 hours, extract 2 times, add for the first time 10 times of amount ethanol extractions 2 hours, add for the second time 8 times of amount ethanol extractions 1.5 hours, merge extractive liquid, reclaims ethanol, being concentrated into relative density is 1.30～1.35 (60 ℃), at 0.08MPa and 60 ℃ of following vacuum dryings, be ground into fine powder, standby.Get Folium Ginkgo extract fine powder 1.5 weight portions and above-mentioned fine powder mixing, add the polyvinylpolypyrrolidone (PVPP) of an amount of microcrystalline Cellulose and 3%, mixing is used 2% 30 POVIDONE K 30 BP/USP 30(PVP) 95% alcoholic solution system soft material pushed 16 eye mesh screens, 40～50 ℃ of dryings, and granulate, the carboxymethyl starch sodium (CMS-Na) of adding 3% and 0.3% magnesium stearate mixing, compacting is (0.40g/ sheet) in flakes, the bag film-coat, promptly.
Embodiment 2
Get 33 parts of Pheretimas, 33 parts of Herba Epimedii, 22 parts of Rhizoma Chuanxiongs, 22 parts of Radix Polygalaes (system), adding 85% ethanol water soaked 1.5 hours, extract 2 times, add 5 times of amount ethanol 2 hours for the first time, add 3 times of amount ethanol 1.5 hours for the second time, merge extractive liquid,, reclaim ethanol, being concentrated into relative density is 1.30～1.35 (60 ℃), at 0.08MPa and 60 ℃ of following vacuum dryings, be ground into fine powder, standby.Get Folium Ginkgo extract fine powder 5 weight portions and above-mentioned fine powder mixing, add the polyvinylpolypyrrolidone (PVPP) of an amount of microcrystalline Cellulose and 3%, mixing is used 2% 30 POVIDONE K 30 BP/USP 30(PVP) 95% alcoholic solution system soft material pushed 16 eye mesh screens, 40～50 ℃ of dryings, and granulate, the carboxymethyl starch sodium (CMS-Na) of adding 3% and 0.3% magnesium stearate mixing, compacting is (0.40g/ sheet) in flakes, the bag film-coat, promptly.
Embodiment 3
Get 22 parts of Pheretimas, 22 parts of Herba Epimedii, 11 parts of Rhizoma Chuanxiongs, 11 parts of Radix Polygalaes (system), add 5 times of amount 90% ethanol waters and soaked 3 hours, extract 1 time, reclaim ethanol, being concentrated into relative density is 1.30～1.35 (60 ℃), at 0.08MPa and 60 ℃ of following vacuum dryings, be ground into fine powder, standby.Get Folium Ginkgo extract fine powder 10 weight portions and above-mentioned fine powder mixing, add the polyvinylpolypyrrolidone (PVPP) of an amount of microcrystalline Cellulose and 3%, mixing is used 2% 30 POVIDONE K 30 BP/USP 30(PVP) 95% alcoholic solution system soft material pushed 16 eye mesh screens, 40～50 ℃ of dryings, and granulate, the carboxymethyl starch sodium (CMS-Na) of adding 3% and 0.3% magnesium stearate mixing, compacting is (0.40g/ sheet) in flakes, the bag film-coat, promptly.
Embodiment 4
Get 37 parts of Pheretimas, 37 parts of Herba Epimedii, 24 parts of Rhizoma Chuanxiongs, 24 parts of Radix Polygalaes (system), adding 70% ethanol water soaked 1.5 hours, extracted 10 hours, merge extractive liquid,, reclaim ethanol, being concentrated into relative density is 1.30～1.35 (60 ℃), at 0.08MPa and 60 ℃ of following vacuum dryings, be ground into fine powder, standby.Get Folium Ginkgo extract fine powder 0.5 weight portion and above-mentioned fine powder mixing, add the polyvinylpolypyrrolidone (PVPP) of an amount of microcrystalline Cellulose and 3%, mixing is used 2% 30 POVIDONE K 30 BP/USP 30(PVP) 95% alcoholic solution system soft material pushed 16 eye mesh screens, 40～50 ℃ of dryings, and granulate, the carboxymethyl starch sodium (CMS-Na) of adding 3% and 0.3% magnesium stearate mixing, compacting is (0.40g/ sheet) in flakes, the bag film-coat, promptly.
Embodiment 5
Get 30 parts of Pheretimas, 30 parts of Herba Epimedii, 18 parts of Rhizoma Chuanxiongs, 18 parts of Radix Polygalaes (system), adding 70% ethanol water soaked 1.5 hours, extract 2 times, add 5 times of amount ethanol 2 hours for the first time, add 3 times of amount ethanol 1.5 hours for the second time, merge extractive liquid,, reclaim ethanol, being concentrated into relative density is 1.30～1.35 (60 ℃), at 0.08MPa and 60 ℃ of following vacuum dryings, be ground into fine powder, standby.Get Folium Ginkgo extract fine powder 1.5 weight portions and above-mentioned fine powder mixing, add the polyvinylpolypyrrolidone (PVPP) of an amount of microcrystalline Cellulose and 3%, mixing is used 2% 30 POVIDONE K 30 BP/USP 30(PVP) 95% alcoholic solution system soft material pushed 16 eye mesh screens, 40～50 ℃ of dryings, and granulate, the carboxymethyl starch sodium (CMS-Na) of adding 3% and 0.3% magnesium stearate mixing, compacting is (0.40g/ sheet) in flakes, the bag film-coat, promptly.
This drug prescription derives from a clinical distinguished veteran doctors of TCM through proved recipe, and is used for hypophrenia due to phlegm stagnation in collateral, the deficiency of kidney-essence, and is refreshing slow-witted forgetful, dizziness and headache, soreness of the waist and knees, the dark moist and slippery fur of tongue etc.Vascular dementia has above-mentioned proposita.Usage and dosage: the preparation that makes with embodiment 5 is example, and is oral, 1 time 3,3 times on the 1st, 3 months is a course of treatment.
Pharmacodynamics test
1. experiment material and result
1.1 medicine and reagent
(1) compound gingkgo blade: it is a kind of product of the present invention, and its preparation method such as embodiment 5 are disclosed.The clinical daily crude drug amount 16.24g that is grown up, experiment is 9.31g (crude drug)/g with dry extract concentration.Be made into the suspension of variable concentrations during experiment with distilled water.
(2) duxil (vascular dementia model test positive control drug): be the compound preparation of almitrine and raubasine composition.Be used for subacute or chronic cerebrovascular insufficiency disfunction, cerebral ischemia sequela.Vascular retinal function obstacle and the imbalance of ischemic cochlea vestibular function etc.40mg (effective ingredient)/sheet, clinical consumption are 1 slice/time, 2 times/day.The accurate word J20030019 of traditional Chinese medicines, French Les Laboratoires servier production, lot number: 5A0153.Be made into suspension with distilled water during experiment.
(3) FUFANG DANSHEN PIAN (blood circulation promoting and blood stasis dispelling test positive control drug): composition is Radix Salviae Miltiorrhizae, Radix Notoginseng, Borneolum Syntheticum, has blood circulation promoting and blood stasis dispelling, the effect of regulating QI to relieve pain.Uncomfortable in chest, pareordia twinge that the thoracic obstruction that is used for caused by energy stagnation and blood stasis, disease are seen; Angina pectoris.0.3g (patent medicine)/sheet, clinical consumption are 3 slices/time, 3 times/day.The accurate word Z44023372 of traditional Chinese medicines, White Cloud Mountain, Guangzhou and meter Huangpu Chinese medicine company limited are produced lot number: J5A006.Be made into suspension with distilled water during experiment.
(4) GUIFU DIHUANG WAN (yang deficiency test positive control drug): composition is Radix Rehmanniae Preparata, Radix Aconiti Lateralis Preparata (system), Cortex Cinnamomi, Fructus Corni (system), Rhizoma Dioscoreae, Rhizoma Alismatis, Cortex Moutan, Poria.Have the effect of warming and recuperating the kidney-YANG, be used for soreness of the waist and knees, the cold extremities frequent micturition is deficiency syndrome class nonprescription drugs.The accurate word Z43020144 of traditional Chinese medicines, per 8 balls are equivalent to the 3g crude drug.Clinical consumption is one time 8 ball, 3 times on the one.Changsha Jiuzhitang Co., Ltd. produces, lot number: 20060213.Be made into suspension with distilled water during experiment.
(5) adrenalin hydrochloride injection, 1ml/1mg/ props up, lot number: 0510061, Tianjin gold credit aminoacid company limited is produced.
(6) liquid paraffin, lot number: 20041014, Hunan remittance rainbow reagent company limited is produced,
(7) nipride ampoule, lot number: 20051016, Hunan Central South Kelun Medicine Co., Ltd. produces.
(8) gentamicin injection liquid, lot number: 4050302-2, Tianjin Pharmaceutical Jiaozuo Co., Ltd. produces.
(9) 0.9% sodium chloride injections, lot number: D050925, Hunan Cologne Pharmaceutical Co., Ltd produces.
(10) hydrocortisone injection, 2ml/10mg/ props up, lot number: 06010511, Tianjin Pharmaceutical Jiaozuo Co., Ltd. produces.
(11) thiamazole sheet, the 5mg/ sheet, lot number: 050807, Beijing, Beijing pharmaceutical factory produces.Be made into suspension with distilled water during experiment.
(12) Coomassie brilliant blue protein determination kit, lot number: 20060330,
(13) MDA test kit, lot number: 20060324,
(14) SOD test kit, lot number: 20060331,
(15) acetylcholinesterase test kit, lot number: 20060328,
More than (9)-(13) build up bio-engineering research by Nanjing and provide.
(16) rabbit anti--Bax, rabbit be anti--SSTR2 antibody, SABC SABC test kit, DBA colour reagent box, the date of manufacture: in April, 2006, Wuhan doctor's moral bio-engineering corporation provides.
(17) cAMP, cGMP measure test kit, lot number: 20060524, and Shanghai Univ. of Traditional Chinese Medicine's Nuclear Medical Laboratory provides.
1.2 animal
Kunming mice, SD rat, cleaning level, wound laboratory animal science service portion provides by Changsha Kaifu District east, the quality certification number: scxk (Hunan) 2006-0001.
1.3 instrument
(1) FA1004 Shanghai electronic analytical balance: go up Instr Ltd. of Nereid section
(2) ES-C-600 electronic balance: Hunan instrument balance equipment factory
(3) DT-200 mice diving tower instrument: Chengdu TME Technology Co., Ltd.
(4) biological microscope (is with micro-micrometer, 0.01mm): optical instrument factory, the south of the River
(5) HHW-21CU-600 electric heating constant temperature tank: Shanghai Fuma Experiment Equipment Co., Ltd.
(6) the desk-top autobalance centrifuge of TD4-II: the triumphant industry development company limited that reaches in Hunan
(7) UV-1600 type spectrophotometer: Beijing Rayleigh company
(8) the rotary blood viscometer of LBY-N6 type: Beijing Puli gives birth to company
(9) DM LB 2Type binocular microscope: German LEICA company
(10) 325 type paraffin slicing machines: Britain Shandon company
(11) XW-80A vortex mixer: go up Industrial Co., Ltd. of Nereid section
(12) KDC-2046 low temperature high capacity centrifuge: good photoelectric instrument branch company in the University of Science and Technology of China,technology industry Corp
(13) GC-1200 γ radioimmunity enumerator: the good photoelectric instrument branch company in the head office that opens up industries of China Science ﹠ Technology University
1.4 dosage setting (see Table 1 and table 2)
Table 1. mice dosage
Table 2. rat dosage
Figure G071B1567620070629D000181
Annotate: *Drug dose: the compound gingkgo blade is respectively organized, osmanthus attached glutinous rehmannia bolus quantities group is made a living dose, and duxil is an active constituent content, and the FUFANG DANSHEN PIAN group is for becoming dose
2. to the influence of mice vascular dementia model
Get 100 of 25～30g kunming mices, male and female half and half by the layering of sex body weight, are divided into 2 groups at random: 10 of sham operated rats, all the other are 90 of operation groups.List of references [2]Operation group mice is with 1% chloral hydrate 300mg/kg lumbar injection, after the anesthesia, dorsal position is fixed on the operating-table, 75% alcohol disinfecting throat skin, row neck median incision, it is standby to separate the bilateral common carotid arteries threading, close bilateral common carotid arteries 10min with noinvasive bulldog clamp folder, simultaneously at the docking of tail point, blood-letting 0.3ml.Unclamp the logical again 10min of bulldog clamp, folder closes 10min again, removes line, sews up the incision.Lamp is according to insulation in the operation.Sham operated rats is sewed up after only separating common carotid artery 30min, blocking blood flow not, not blood-letting of afterbody.Postoperative intramuscular injection every day gentamycin 5mg/kg, continuous 5 days.The operation group mice that will survive in the 3rd day carries out diving tower to be measured, and selects in the operation group 50 close mices of response time and evenly is divided into 5 groups (the basic, normal, high dosage group of compound gingkgo, duxil group, model group), and each group gavages relative medicine.Model group and sham operated rats such as give at the distilled water of capacity, are administered once every day, and following index is measured in administration after 14 days:
1. the diving tower method is measured ability of learning and memory: test set is the passive avoidance response case, 3min conforms to allow mice (not switch on) on the copper grid in reaction chamber earlier, give the energising of copper grid then, after being shocked by electricity first, the record mice jumps onto safety board required time (response time), jump off round platform number of times (errors number) in the 5min, as school grade.After 24 hours, earlier with the energising of copper grid, then mice is placed in the case on the safety board, the record mice skips to copper grid required time (latent time) from safety board first, jumps off round platform number of times (errors number) in the 5min, as the memory achievement.(rat rests on and surpasses 5min on the platform during test, and its incubation period is in 300s).The results are shown in Table 3, table 4.
Table 3 compound gingkgo blade is to the influence of vascular dementia model learning ability of mice
Figure G071B1567620070629D000191
Figure G071B1567620070629D000192
Annotate: compare * P＞0.05, * * P＜0.05, * * * P＜0.01 with model group.
Table 4 compound gingkgo blade is to the influence of vascular dementia model mouse memory ability
Figure G071B1567620070629D000193
Figure G071B1567620070629D000194
Annotate: compare with model group: * P＞0.05, * * P＜0.05, * * * P＜0.01.
2. serum malonaldehyde (MDA) is measured: the last administration is extractd eyeball and is got blood after 1 hour, and strictness is measured by the test kit explanation.See Table 5.
3. brain tissue homogenate's superoxide dismutase (SOD) vigor, acetylcholinesterase (AchE) are measured.Get left half brain, add 9 times of weight normal saline after weighing and prepare homogenate, strictness is measured by the test kit explanation.See Table 5.
Table 5 compound gingkgo blade is to the influence of vascular dementia model mice biochemical indicator
Figure G071B1567620070629D000201
Figure G071B1567620070629D000202
Annotate: compare with model group: * P＞0.05, * * P＜0.05, * * * P＜0.01.
4. cerebral hippocampus district pathological examination.Get right half brain, place fixedly 24h of 10% formalin, repair and get hippocampal tissue, gradient alcohol dehydration, transparent, waxdip, paraffin embedding, the continuous coronal section, the thick 6 μ m of sheet, haematoxylin-Yihong (HE) dyeing, 400 times of light microscopics are observed down.See accompanying drawing 1-6.Wherein:
Fig. 1 is mice sham operated rats Hippocampus CA1 district pathological section (HE * 400 times), the densification of pyramidal cell marshalling, and endochylema is clear bright and clear, and kernel is obvious, and Cytoplasm is abundant.Do not see karyopycnosis.
Fig. 2 is mouse model group Hippocampus CA1 district pathological section (HE * 400 times), and pyramidal cell reduces and the distortion shrinkage, and not of uniform size, arrangement disorder, nucleus are shaped as triangle or polygon, and structure is unclear, is karyopycnosis, and kytoplasm is dense to be dyed, the broadening of cell peripheral gap.
Fig. 3 is mice duxil group Hippocampus CA1 district pathological section (HE * 400 times), and pyramidal cell is more clear, arranges still neatly, a small amount of karyopycnosis is arranged, the formation fragment that has.
Fig. 4 is mice compound gingkgo blade high dose group Hippocampus CA1 district pathological section (HE * 400 times), the pyramidal cell marshalling, and endochylema is clear, and kernel is obvious, accidental karyopycnosis.
Fig. 5 is dosage group Hippocampus CA1 district pathological section in the mice compound gingkgo blade (HE * 400 times), and pyramidal cell reduces and some shrinkages are arranged, and nuclear structure is unclear, visible part karyopycnosis, dense dying.
Fig. 6 is mice compound gingkgo blade low dose group Hippocampus CA1 district pathological section (HE * 400 times), and pyramidal cell reduces, arrange disorderly, and part shrinkage, dense dying.As seen karyopycnosis.
Close common carotid artery with folder repeatedly as can be known by the statistical result in above-mentioned three tables and merge the blood-letting blood pressure lowering and make vascular dementia model mice modeling success, its model group every surveys index and sham operated rats more all has significant difference (P＜0.01).By table 3, table 4 as seen, each dosage group of compound gingkgo blade all can shorten the response time, prolongs latent time and reduce errors number, with model group significant difference (P＜0.05) is arranged more all, the learning capacity that this explanation compound gingkgo blade can improve fourth ventricle in mice with vascular dementia, strengthen the memory ability of mice, show that the compound gingkgo blade has certain therapeutical effect to the dementia that is caused by cerebrovascular.In the table 5, each dosage group serum MDA of compound gingkgo blade is compared with model group all and is reduced, and brain tissue homogenate's SOD vigor all strengthens, and this reflection compound gingkgo blade has certain antioxidation, can strengthen cerebral tissue SOD vigor and remove too much oxygen-derived free radicals, thereby degree of injury is reduced.But the rising of each dosage group acetylcholine esterase inhibition of compound gingkgo blade simultaneously, relatively there were significant differences (P＜0.01) for wherein middle dosage group and model group, this explanation compound gingkgo blade can improve the choline systemic-function, regulates the physiological metabolism of cerebral tissue acetylcholine, and treatment is dull-witted.By accompanying drawing 1-accompanying drawing 6 as seen, the compound gingkgo blade has to a certain degree repair to the damage of cerebral hippocampal pyramidal cell.
3. to the influence of rat aorta dementia model
Get each 50 of the female sd inbred rats of male and 200～250g of 250～300g, by the layering of sex body weight, be divided into 2 groups at random: 10 of sham operated rats, all the other are 90 of operation groups.List of references Wang Rui, Yang Qinfei, Tang Yipeng waits rat to intend the foundation and the Chinese medicine 9602 preventive and therapeutic effect pre-tests [J] of vascular dementia model. Chinese Journal of Pathophysiology, 2000,16 (10): 914-916, operation group rat is with 10% chloral hydrate 350mg/kg lumbar injection, and after the anesthesia, dorsal position is fixed on the operating-table, 75% alcohol disinfecting throat skin, row neck median incision separates bilateral common carotid arteries and threading, and sodium nitroprusside is pressed the 2.5mg/kg lumbar injection, close bilateral common carotid arteries 10min with noinvasive bulldog clamp folder immediately, unclamp the logical again 10min of bulldog clamp, folder closes 10min again, removes line, sew up the incision, lamp is according to insulation in the art.Sham operated rats is only separated common carotid artery, sews up not ligation behind the 30min.Postoperative intramuscular injection every day gentamycin 5mg/kg, continuous 5 days.The operation group rat that postoperative was observed survival on the 3rd day opens the case experiment.Select the spacious close rat of case score and be divided into 5 groups (the basic, normal, high dosage group of compound gingkgo, duxil group, model group) at random, each group gavages relative medicine.Model group and sham operated rats such as give at the distilled water of capacity, are administered once every day, and following index is measured in administration after 14 days:
1. serum malonaldehyde (MDA) is measured.1 hour posterior orbit vein of last administration is got blood, and strictness is measured by the test kit explanation.See Table 6.
2. brain tissue homogenate's superoxide dismutase (SOD) vigor, acetylcholinesterase (AchE) is measured.Get left half brain, add 9 times of weight normal saline after weighing and prepare homogenate, strictness is measured by the test kit explanation.See Table 6.
Table 6 compound gingkgo blade is to the influence of vascular dementia model rat biochemical indicator
Figure G071B1567620070629D000221
Annotate: compare with model group: *P＞0.05, *P＜0.05, * *P＜0.01.
3. cerebral hippocampus CA1 district pathological examination and Bax and Hippocampus SS positive cell number are measured.Get right half brain, place fixedly 24h of 4% paraformaldehyde solution, repair and get hippocampal tissue, conventional dehydration, waxdip, paraffin embedding, the continuous coronal section, the thick 6 μ m of sheet make haematoxylin-Yihong (HE) dyeing and SABC method immunohistochemical staining respectively.Carry out according to test kit description step, show Bax and Hippocampus SS positive cell, each 5 visual field of section of picked at random under 400 times of light microscopics are with MIAS medical image analysis systematic analysis Hippocampus CA1 district's positive cell number and optical density value.See Table 7 and table 8 and accompanying drawing 7-24.
The influence that table 7 compound gingkgo blade is expressed Hippocampal Neurons in Rat Models SS
Figure G071B1567620070629D000232
Figure G071B1567620070629D000233
Annotate: compare * P＞0.05, * * P＜0.05, * * * P＜0.01 with model group.
The influence that table 8 compound gingkgo blade is expressed vascular dementia model rat Bax
Figure G071B1567620070629D000241
Figure G071B1567620070629D000242
Annotate: compare with model group: * P＞0.05, * * P＜0.05, * * * P＜0.01.
In Fig. 7-24:
Fig. 7 is rat sham operated rats Hippocampus CA1 district pathological section (HE * 400 times), and pyramidal cell is complete clear, the densification of cell marshalling, and endochylema is bright and clear, and kernel is obvious.Do not see karyopycnosis.
Fig. 8 is rat model group Hippocampus CA1 district pathological section (HE * 400 times), and pyramidal cell obviously reduces and be out of shape shrinkage, and size is irregular, arrangement disorder, and nuclear structure disappears, and karyopycnosis is obvious, and kytoplasm is dense to be dyed, the broadening of cell peripheral gap.
Fig. 9 is rat duxil group Hippocampus CA1 district pathological section (HE * 400 times), and pyramidal cell is more clear, and shape is rule not too, marshalling densification, visible a small amount of karyopycnosis.
Figure 10 is rat compound gingkgo blade high dose group Hippocampus CA1 district pathological section (HE * 400 times), and pyramidal cell is clear, the marshalling densification, and kernel is more obvious, and karyopycnosis is few.
Figure 11 is dosage group Hippocampus CA1 district pathological section in the rat compound gingkgo blade (HE * 400 times), and pyramidal cell is arranged more loose, irregular, not of uniform size, and karyopycnosis is few.
Figure 12 is rat compound gingkgo blade low dose group Hippocampus CA 1 district's pathological section (HE * 400 times), and pyramidal cell reduces, and is misaligned, out-of-shape, part karyopyknosis, the formation fragment that has.
Figure 13 is rat sham operated rats Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times), and the pyramidal cell marshalling is tight, and kernel is clear, visible a large amount of cell membrane xanthochromias, and numerous brown yellow granules are intensive, and the positive expression cell is many.
Figure 14 is rat model group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times), and pyramidal cell reduces, and sparse being dispersed in has the part cavity, do not see obvious brown yellow granule, a little less than positive cell is expressed.
Figure 15 is rat duxil group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times), and pyramidal cell is arranged more sparse, part endochylema after birth xanthochromia, and the positive expression cell is on the low side.
Figure 16 is rat compound gingkgo blade high dose group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times), the pyramidal cell marshalling, and endochylema after birth xanthochromia, visible a large amount of intensive brown yellow granules, widely distributed, painted darker, positive expression is stronger.
Figure 17 is dosage group CA1 district Hippocampus SS dyeing in the rat hippocampus (SABC * 400 times), the intensive but out-of-shape of pyramidal cell, and visible a large amount of cell cytosol after birth karyons are yellowish-brown, color depth, and the positive expression cell is more.
Figure 18 is rat low dose group Hippocampus CA1 district Hippocampus SS dyeing (SABC * 400 times), and pyramidal cell is less, arranges looser, visible brown yellow granule on a small quantity, painted more shallow, the positive expression cell is less.
Figure 19 is rat sham operated rats Hippocampus CA1 district BAX dyeing (SABC * 400), and pyramidal cell is complete clear, marshalling, and kernel is obvious, does not see tangible yellowish-brown endochylema, does not see the positive expression cell.
Figure 20 is rat model group Hippocampus CA1 district BAX dyeing (SABC * 400), and the pyramidal cell number is few, and cell space is less, and positive material is intensive in the endochylema, dyes dark brown, and positive expression is strong.
Figure 21 is rat duxil group Hippocampus CA1 district BAX dyeing (SABC * 400), and pyramidal cell is more clear, and kernel is obvious, parts of fine after birth engrain, and the positive expression cell slightly increases.
Figure 22 is rat compound gingkgo blade high dose group Hippocampus CA1 district BAX dyeing (SABC * 400), and pyramidal cell is clear, and kernel is obvious, marshalling, and minority after birth endochylema is light yellowish-brown, and the positive expression cell is less.
Figure 23 is dosage group Hippocampus CA1 district BAX dyeing (SABC * 400) in the rat compound gingkgo blade, and pyramidal cell is clear, visible most yellowish-brown granules, and the dyeing of part after birth endochylema is darker, and positive expression is stronger.
Figure 24 is rat compound gingkgo blade low dose group Hippocampus CA1 district BAX dyeing (SABC * 400), and pyramidal cell is clear, and kernel is obvious, arranges more neat, visible minority brown yellow granule, after birth is painted shallow, the positive expression cell is less.
Close common carotid artery merging blood pressure lowering manufacturing vascular dementia model rat modeling success with pressing from both sides repeatedly as can be known by the statistical result in above-mentioned three tables, its model group every surveys index and sham operated rats more all has significant difference (P＜0.05), the compound gingkgo blade can significantly reduce MDA in the table 2, improve the SOD vigor, but and the rising of acetylcholine esterase inhibition, the prompting Wheat Protein, and can improve the choline systemic-function.Each dosage group of compound gingkgo blade and model group more all have significant difference, and low dose group has the difference (P＜0.01) of highly significant.As shown in Table 3, the Hippocampus SS of model group expresses and is starkly lower than sham operated rats, and positive cell number and optical density value all reduce (P＜0.01), illustrate that cerebral ischemia can suppress the secretion of cerebral tissue SS.Each dosage group of duxil and compound gingkgo blade all can strengthen the expression of Hippocampus SS, increase Hippocampus SS positive cell number and strengthen optical density, with model group significant difference (P＜0.05) is arranged more all, prompting compound gingkgo blade can promote the secretion of Hippocampus SS, effectively regulate the release of interior multiple hormone of brain and neurotransmitter, promote intelligence restoration.As shown in Table 4, model group cerebral tissue Bax expresses apparently higher than sham operated rats (P＜0.01), illustrate that cerebral ischemia can make short apoptogene hyperproteosis express, thereby acceleration apoptosis amount, duxil and compound gingkgo blade are expressed cerebral tissue Bax certain inhibitory action, the positive cell number is reduced, and optical density is weakened, prompting has the effect of antagonism apoptosis amount, but dosage group and model group compare there was no significant difference (referring to accompanying drawing 13-23 in the compound gingkgo blade, positive cell is pale brown color, and as seen the colour developing position has after birth, endochylema, karyon).By in the HE of accompanying drawing 7-accompanying drawing 12 dyeing as seen, the compound gingkgo blade to modeling after the pathological change of cerebral tissue the improvement effect is arranged, can promote the reparation of the brain neuron of ischemic injuries.
4. blood circulation promoting and blood stasis dispelling test is to the influence of blood stasis type hemorheology of rat
Get 180～220g, 60 of SD rats, male and female half and half are divided into 6 groups at random, 10 every group, are respectively blank group, FUFANG DANSHEN PIAN group, the basic, normal, high dosage group of compound gingkgo.Each group gavages relative medicine every day 1 time, blank group is given and is waited the capacity distilled water, continuous 7 days, blank group rat skin lower injection normal saline after the last administration, twice of the equal subcutaneous injection 1mg/ml of all the other each treated animals epinephrine inj (0.08ml/100g body weight), 4 hours at interval, between the double injection epinephrine inj, rat is dipped in 5min in the frozen water, cause blood stasis model [5], stop eating to inferior morning, cut off the carotid artery blood sampling and measure hemorheology index.Each specimen is taken out to detect in back two hours and is finished.Data compare through t inspection statistics in groups, the results are shown in Table 9.
Table 9 compound gingkgo blade is to the influence of blood stasis type hemorheology of rat
Figure G071B1567620070629D000282
Annotate: compare with model group: * P＞0.05, * * P＜0.05, * * * P＜0.01.
By table 9 as seen, compare with the blank group, the whole blood viscosity of model group, plasma viscosity and packed cell volume have significant difference, show blood stasis model modeling success; With model group relatively, each dosage group of compound gingkgo blade all has significant difference, shows that the compound gingkgo blade can improve dense, sticking, the state with fixed attention of stasis syndrome rat model blood, has the effect of certain blood circulation promoting and blood stasis dispelling.The positive control drug FUFANG DANSHEN PIAN also has the effect of blood circulation promoting and blood stasis dispelling preferably.
5. kidney tonifying experiment, the compound gingkgo blade is to the influence of cortisone insufficiency of kidney-YANG rat plasma cyclic nucleotide
Get 200～220g, 60 of SD rats, male and female half and half by the layering of sex body weight, are divided into 6 groups at random, 10 every group, are respectively blank group, model group, GUIFU DIHUANG WAN group, the basic, normal, high dosage group of compound gingkgo blade.Blank group rat intramuscular injection every day normal saline, all the other respectively organize intramuscular injection every day hydrocortisone (2mg/100g body weight), (department grass is good to make it obvious yang deficiency symptom occur, Chen Youxiang, Hou Anji waits influence [J] .2005 of kidney invigorating and YANG supporting side to the strange nephrasthenia syndrome rat of climacteric, 24 (8): 675), stop to inject hydrocortisone after 10 days, each group gavaged corresponding Chinese medicine continuous 14 days.Weigh after the last administration, rat body weight respectively organized in record, broken end blood sampling behind the 30min.Press the explanation of cAMP and cGMP radioimmunological kit and handle, and measure plasma cAMP, cGMP content.Data compare through t inspection statistics in groups, the results are shown in Table 10,11.
Table 10 compound gingkgo blade is to the influence of cortisone insufficiency of kidney-YANG rat plasma cyclic nucleotide
Figure G071B1567620070629D000291
Annotate: compare with model group: * P＞0.05, * * P＜0.05, * * * P＜0.01.
Table 11 compound gingkgo blade is to the influence of cortisone insufficiency of kidney-YANG rat body weight
Figure G071B1567620070629D000293
Figure G071B1567620070629D000294
Annotate: compare with model group: * P＞0.05, * * P＜0.05, * * * P＜0.01.
By table 8 as seen, with the blank group relatively, model group rat plasma cAMP obviously reduces, and cGMP obviously raises, and cAMP/cGMP ratio significantly reduces, the prompting model of yang asthenia duplicates successfully by rat.Three dosage groups of compound gingkgo blade all can well be regulated plasma cAMP and cGMP level, and rising cAMP reduces cGMP.Wherein low dosage and high dose and model group comparing difference significantly (P＜0.05), high dose also has tangible trend, shows that the compound gingkgo blade has the effect of kidney-replenishing.By table 9 as seen, body weight is starkly lower than blank group behind the model group rat experiment, and significant difference (P＜0.01) is arranged, and illustrates that the rat model growth is subjected to severe inhibition, has reflected insufficiency of kidney-YANG model modeling success.Body weight is all than model group height after the experiment of three dosage groups of compound gingkgo blade, and middle and high dosage group can significantly increase rat body weight (P＜0.05), and this prompting compound gingkgo blade can promote rat growthing development, and the effect of certain the kidney invigorating and essence nourishing is arranged.
By to intending the research of tests such as vascular dementia rats and mouse model experiment and blood circulation promoting and blood stasis dispelling, kidney-replenishing, the result shows: the compound gingkgo blade can obviously improve mice learning and memory ability, improves every index of correlation: can significantly improve the unusual of stasis syndrome rat whole blood viscosity, plasma viscosity and packed cell volume; Can obviously improve the auricular microcirculation of mice; Plasma cyclic nucleotide to cortisone yang deficiency rat and hypothyroidism mice has good regulating action, can obviously improve the plasma cAMP level, reduces the cGMP level, rising cAMP/cGMP ratio.
It will be recognized by those skilled in the art, perhaps just can determine the equivalence replacement of a lot of specific embodiment of the invention described herein according to conventional experience.The disclosure content of the publication that the application quotes also all is incorporated herein with reform, with as a reference.Yet should be understood that scope of the present invention is not limited to the above-mentioned specific embodiment.Particularly point out at this, although only listed a kind of preparation (tablet) of medicine of the present invention in specific embodiment, it will be understood by those skilled in the art that the present invention is not limited thereto, other dosage forms of mentioning herein can be implemented fully.Therefore the present invention also can implement not according to these specific descriptions, and still within the scope of appended claim.

Claims (6)

1. medicine that is used for the treatment of vascular dementia, its medicament for making by the following weight proportion raw material:
1～5 part of Folium Ginkgo extract
27～33 parts of Pheretimas
27～33 parts of Herba Epimedii
14～23 parts of Rhizoma Chuanxiongs
14～23 parts of Radix Polygalaes.
2. medicine according to claim 1, its medicament for making by the following weight proportion raw material:
1.5 parts of Folium Ginkgo extract
30 parts of Pheretimas
30 parts of Herba Epimedii
18 parts of Rhizoma Chuanxiongs
18 parts of Radix Polygalaes.
3. medicine according to claim 1 and 2, it is in tablet, pill, capsule, capsule tablet, powder, granule, suspending agent, gel, the paste any one.
4. medicine according to claim 3, it is in tablet, pill, capsule, powder, the granule any one.
5. the preparation method of the described medicine of claim 1 comprises:
(a) get Pheretima, Herba Epimedii, Rhizoma Chuanxiong, Radix Polygalae four Chinese medicine material in proportion, the ethanol water with 60%～95% soaks and extracted 1～10 hour, and number of times is 1～3 time;
(b) reclaim ethanol, concentrated, dry, be ground into fine powder;
(c) get Folium Ginkgo extract in proportion, with described fine powder mix homogeneously;
(d) add an amount of excipient and/or other additives, make suitable dosage form.
6. according to the preparation method of the described medicine of claim 5, wherein:
Extraction time is 1～3 hour, and extraction time is 2 times.
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