CN110025664B - Pharmaceutical composition for preventing and treating cerebral infarction and/or vascular dementia and application thereof - Google Patents
Pharmaceutical composition for preventing and treating cerebral infarction and/or vascular dementia and application thereof Download PDFInfo
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- CN110025664B CN110025664B CN201910459138.0A CN201910459138A CN110025664B CN 110025664 B CN110025664 B CN 110025664B CN 201910459138 A CN201910459138 A CN 201910459138A CN 110025664 B CN110025664 B CN 110025664B
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- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
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Abstract
The invention discloses a pharmaceutical composition for preventing and treating cerebral infarction and/or vascular dementia and application thereof, wherein the pharmaceutical composition is composed of pueraria flavonid extract, salvia miltiorrhiza total phenolic acid extract and total tanshinone extract, and the proportion of active ingredients in the pharmaceutical composition is as follows: the weight ratio of the pueraria flavonid extract calculated by puerarin to the salvia miltiorrhiza total phenolic acid extract calculated by salvianolic acid B to the total tanshinone extract calculated by tanshinone is 10 (2-50) to (0.2-5), and the pharmaceutical composition can be applied to the drugs for preventing and treating cerebral infarction and/or vascular dementia and can obtain remarkable curative effect.
Description
Technical Field
The invention relates to a pharmaceutical composition with the function of preventing and treating cerebral infarction and/or vascular dementia and the application of corresponding drugs, in particular to the new application of the corresponding composition which takes plant extract components as active ingredients.
Background
Cerebral Infarction (CI) is a generic term for ischemic stroke (ischemic stroke), including cerebral thrombosis, lacunar infarction, cerebral embolism and the like, accounting for about 70% of all cerebral strokes, and is a cerebral lesion caused by cerebral blood supply disorder. Cerebral infarction is caused by sudden reduction or stop of blood flow of local blood supply artery of brain tissue, so that the brain tissue in the blood supply area of the blood vessel is ischemic, and hypoxia causes necrosis and softening of the brain tissue, and is accompanied with clinical symptoms and signs of corresponding parts, such as symptoms of nerve function loss of hemiplegia, aphasia and the like. The disease belongs to the category of the Chinese medicine 'apoplexy', the principal is the principal deficiency and the secondary excess, the obstruction of collaterals by blood stasis is the basic pathogenesis of cerebral infarction, and the basic therapeutic principle of activating blood and dissolving stasis is the basic therapeutic principle. The traditional Chinese medicine has a history of thousands of years for treating cerebral infarction, and gradually deepens from the pure pursuit of clinical curative effect to the mechanism research, so that the traditional Chinese medicine has the action characteristics and advantages of multiple targets and multiple ways and conforms to the development process of pathophysiology and complexity of cerebral infarction.
Cerebral infarction is one of the main diseases causing disability and even death of middle-aged and elderly people, can cause symptoms such as limb hemiplegia, numbness, difficulty in speaking and the like, can also cause cognitive dysfunction with different degrees such as memory loss, aphasia, agnosia and the like, and even causes dementia. Post-infarction cognitive dysfunction is the most common complication of cerebral infarction and may be caused by vascular causes, neurodegeneration or other confounding factors, and 25-83% of cerebral infarction patients will immediately or later develop cognitive dysfunction, affecting recovery of neurological function, daily living ability and social adaptation ability. There are reports in the literature that even mild cognitive dysfunction can increase mortality in patients with cerebral infarction. Vascular Dementia (VD) is a common complication in patients with cerebral infarction, and has serious effects on the quality of life and health of life of patients. The clinical medicine considers that the vascular dementia is a cognitive function and memory dysfunction disease caused by cerebral infarction, is a type of cerebral infarction multi-complication, and the incidence of the vascular dementia after cerebral infarction is continuously increased along with the increasing of cerebral infarction patients, and the incidence of the vascular dementia is 2 nd in the total incidence of senile dementia. According to the assessment of the 2012 world health organization, about 3560 million people suffer from dementia in the world, the world global dementia patient reaches 1.15 million people and becomes a world important public health problem in 2050, the modern medicine has no exact effective medicine or specific method for treating VD, the traditional Chinese medicine takes the overall view and syndrome differentiation treatment as the guiding idea, and the traditional Chinese medicine has the characteristics and advantages in treating VD. Traditional chinese physicians have recognized that dementia is closely related to stagnant blood. Modern researches also confirm that the syndrome of brain collateral obstruction by blood stasis is a common syndrome of VD, one research reports that about 50% of VD patients dialectically have the syndrome of brain collateral obstruction by blood stasis (Tianjin Zhou, the research thought of traditional Chinese medicine for senile dementia, the Chinese medical science, 2000, 15 (5): 52-54), and the other research reports that the syndrome of brain collateral obstruction by blood stasis is the most common traditional Chinese medicine syndrome of vascular dementia (Shijing, the traditional Chinese medicine syndrome characteristic of vascular cognitive impairment, the traditional Chinese medicine J.2012, 53 (5): 503 + 506). However, the traditional Chinese medicine treatment research of VD focuses on kidney tonifying methods mostly, the clinical research on the method for treating VD by the blood circulation promoting and blood stasis removing method is relatively few, and the traditional Chinese medicine theory considers that pathogenic factors are key factors for the development of VD, so that the blood circulation promoting and blood stasis removing method has great potential in treating VD.
Kudzu root and red sage root are commonly used Chinese medicines for promoting blood circulation and removing blood stasis. The literature reports that puerarin injection, salvia miltiorrhiza injection and tanshinone IIA sodium sulfonate injection have certain curative effect on treating cerebral infarction. Because tanshinone is difficult to dissolve in water, the main effective component in the salvia miltiorrhiza water decoction (clinical decoction) and the salvia miltiorrhiza injection is water-soluble salvianolic acid, and no or only a small amount of tanshinone component is contained. The applicant's chinese patent CN101953887B discloses a composition for preventing and treating diabetic complications, which takes total salvianolic acids, total tanshinone and total flavonoids of pueraria root as effective components.
Disclosure of Invention
The invention provides a new application of a pharmaceutical composition prepared by taking total salvianolic acid, total tanshinone and total flavonoids of kudzuvine root as effective components, and the pharmaceutical composition can be applied to preventing and treating cerebral infarction and/or vascular dementia.
The pharmaceutical composition consists of pueraria flavonid extract, salvia miltiorrhiza total phenolic acid extract and total tanshinone extract, and when the pharmaceutical composition is applied to the drugs for preventing and treating cerebral infarction and/or vascular dementia, the proportion of the effective components in the pharmaceutical composition is as follows: the weight ratio of the pueraria flavonid extract calculated by puerarin, the salvia miltiorrhiza total phenolic acid extract calculated by salvianolic acid B and the total tanshinone extract calculated by tanshinone is 10 (2-50) to (0.2-5).
A specific application scheme is that the pharmaceutical composition for preventing and treating cerebral infarction and/or vascular dementia consists of a pueraria flavonid extract, a salvia miltiorrhiza total phenolic acid extract and a total tanshinone extract, wherein the weight ratio of the pueraria flavonid extract calculated by puerarin to the salvia miltiorrhiza total phenolic acid extract calculated by salvianolic acid B to the total tanshinone extract calculated by tanshinone is 10 (5-20) to (0.5-2).
Another specific application scheme is that the pharmaceutical composition for preventing and treating cerebral infarction and/or vascular dementia consists of a pueraria flavonid extract, a salvia miltiorrhiza total phenolic acid extract and a total tanshinone extract, wherein the weight ratio of the pueraria flavonid extract calculated by puerarin to the salvia miltiorrhiza total phenolic acid extract calculated by salvianolic acid B to the total tanshinone extract calculated by tanshinone is 10 (2-20) to (0.2-2).
Another specific application scheme is that the pharmaceutical composition for preventing and treating cerebral infarction and/or vascular dementia consists of a pueraria flavonid extract, a salvia miltiorrhiza total phenolic acid extract and a total tanshinone extract, wherein the weight ratio of the pueraria flavonid extract calculated by puerarin to the salvia miltiorrhiza total phenolic acid extract calculated by salvianolic acid B to the total tanshinone extract calculated by tanshinone is 10 (21-50) to (2.1-5).
Within the proportion range of the pharmaceutical composition in the scheme, at least when the weight ratio of the pueraria flavonid extract calculated by puerarin, the salvia miltiorrhiza total phenolic acid extract calculated by salvianolic acid B and the total tanshinone extract calculated by tanshinone is 10:10:1, the remarkable effect of preventing and treating cerebral infarction and/or vascular dementia can be achieved.
In order to minimize and avoid possible adverse effects caused by or due to the existence of excessive kinds and/or proportional amounts of other components in the extracts, the corresponding extract in the composition in each scheme is preferably in a form that the puerarin weight content in the pueraria flavonid extract is more than or equal to 20%, and/or the salvianolic acid B weight content in the salvia miltiorrhiza total phenolic acid extract is more than or equal to 50%, and/or the tanshinone weight content in the total tanshinone extract is more than or equal to 20%. It can be understood that, when the technical scheme of the invention is implemented, the pharmaceutical composition at least meets any one of three conditions that the weight content of puerarin in the pueraria flavonid extract is more than or equal to 20%, the weight content of salvianolic acid B in the salvia miltiorrhiza total phenolic acid extract is more than or equal to 50%, and the weight content of tanshinone in the total tanshinone extract is more than or equal to 20%, and better, the pharmaceutical composition meets the three conditions simultaneously, so that the quality and the effect of the composition can be ensured and improved more reliably.
CN104189073A discloses a method for preparing total salvianolic acid extract, which can also obtain total tanshinone extract at the same time. In the composition in the above form, in addition to being obtained by various methods reported and/or used at present, the total salvianolic acid extract and/or total tanshinone extract is preferably obtained by the method reported in chinese patent CN104189073A by the applicant. Namely, percolating and extracting the crushed salvia miltiorrhiza with ethanol with the volume content of 80 +/-5% at the temperature of more than or equal to 20 ℃, removing the ethanol from the collected percolate, adjusting the pH value to be less than or equal to 4, precipitating, and carrying out solid-liquid separation to obtain a total tanshinone extract (precipitate); adsorbing the water solution after solid-liquid separation with macroporous resin, eluting with water with pH value less than or equal to 7 to remove impurities, eluting with 40-80% ethanol, collecting ethanol eluate, and removing solvent to obtain total salvianolic acid extract.
The pueraria flavonid extract in the composition in the form can be prepared by adopting the conventional macroporous adsorption resin separation and purification method at present, namely, pueraria lobata is extracted by water or ethanol water solution with the volume content of ethanol being less than or equal to 80 percent, the water extract or the water solution obtained by removing the ethanol from the ethanol water solution extract is adsorbed by macroporous resin and then washed by water to remove impurities, then the pueraria flavonid extract is eluted by 50 to 80 percent ethanol (v/v), and the eluent is concentrated and dried to obtain the pueraria flavonid extract; wherein the macroporous resin is HPD-100, HPD-300 or D101.
The water or water-alcohol solution extraction of the kudzuvine root in the method comprises the conventional methods such as a percolation method, a reflux method, an ultrasonic method, stirring and warm immersion and the like which are reported and/or used at present.
On the basis of the composition, the composition is taken as an effective component, and the composition and acceptable auxiliary and/or additive components in the medicine can be prepared into the medicine for preventing and treating cerebral infarction and/or vascular dementia according to the conventional process and method. For example, in a preferred form, the above-mentioned composition is used as an active ingredient, and mixed with usual auxiliary/additive ingredients such as a disintegrant, an excipient, a lubricant, a binder, and a filler, which are acceptable in oral preparations, and then processed by a corresponding conventional process and method to prepare a corresponding pharmaceutical preparation in oral form such as a tablet, a pill, and a capsule, or a sustained-release agent, a controlled-release agent, and the like in an appropriate form.
As is well known, the exertion of the drug effect of the traditional Chinese medicine has the synergistic integration effect of multiple components, multiple targets and multiple ways. The existing research shows that the pueraria flavonid extract contains 3' -hydroxy puerarin, 3-methoxy puerarin, daidzin, daidzein and other flavonids besides puerarin, and the ingredients can generate the similar action with puerarin and also have the unique characteristics of the puerarin; the total tanshinone extract contains cryptotanshinone, tanshinone I and other similar components besides tanshinone IIA, and has some characteristics of tanshinone IIA; similarly, the total salvianolic acid extract contains salvianolic acid A, salvianolic acid C, rosmarinic acid, lithospermic acid and the like besides salvianolic acid B, and has the similar action to that of salvianolic acid B and unique characteristics.
The further research on the effective components of the radix puerariae and the radix salviae miltiorrhizae shows that the radix puerariae total flavonoids can obviously enhance the effect of the radix puerariae total flavonoids on resisting cerebral infarction and vascular dementia, and the addition of the total tanshinone is further beneficial to not only improving the drug effect of resisting cerebral infarction and vascular dementia, but also comprehensively utilizing the effective components of the traditional Chinese medicinal materials.
The results of intensive research and experiments show that the combination of the components can respectively strengthen the effects of the puerarin, the salvianolic acid B and the tanshinone IIA which are known at present, can play a significant role in mutual synergy and complementation in the comprehensive use of the respective components for preventing and treating cerebral infarction and/or vascular dementia, particularly in the comprehensive effect aspect after the combination of the extracts, can ensure that the drug effect after the combination is obviously superior to that of a drug composition consisting of single puerarin, the salvianolic acid B and/or the tanshinone IIA with corresponding proportion, and simultaneously avoids the preparation of the puerarin, the salvianolic acid B and/or the tanshinone IIA with single component, so that the drug composition comprises 3' -hydroxypuerarin, 3-methoxy puerarin, daidzin, daidzein, salvianolic acid A, salvianolic acid C, rosmarinic acid, The loss and waste of other more beneficial effective components such as alkannic acid, cryptotanshinone, tanshinone I and the like enable traditional Chinese medicine resources to be more fully and better utilized, obviously reduce production cost and price and benefit the livelihood. Therefore, the compound has remarkable advantages in the aspects of medicinal economy and pharmacodynamic action.
The invention discovers that the pueraria flavonid extract, the salvia miltiorrhiza total phenolic acid extract and the total tanshinone extract are used as effective components in the medicine for preventing and treating cerebral infarction and/or vascular dementia, have obvious prevention and treatment effects, improve the medicinal value of the pueraria and the salvia miltiorrhiza, and comprehensively utilize the effective components of the traditional Chinese medicinal materials.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Pulverizing Saviae Miltiorrhizae radix powder (sieving with 10 mesh sieve), percolating with 80% (v/v) ethanol water solution at about 3mL/min kg at about 30 deg.C, collecting 8 times of percolate, recovering ethanol under reduced pressure, diluting with water to about 0.5g/mL (calculated as crude drug, the same below), adjusting pH to 3 (preferably hydrochloric acid), standing for precipitation, filtering or centrifuging to obtain total tanshinone extract; passing the filtered or centrifuged water solution through HPD-100 macroporous adsorbent resin column, washing with 2 times of column bed volume of water to remove impurities, eluting with 50% ethanol, collecting 3 times of column bed volume of ethanol eluate, recovering solvent, and removing to obtain total salvianolic acid extract.
Pulverizing radix Puerariae, extracting with water under reflux for 2 times, adding water 13 times for the first time, adding water 10 times for the second time, each for 1 hr, filtering, mixing filtrates, passing through HPD-100 macroporous adsorbent resin column, washing with 2 times of column bed volume of water, discarding water solution, eluting with 50% ethanol, collecting 2.5 times of column bed volume of ethanol eluate, recovering and removing solvent to obtain radix Puerariae total flavone extract.
The contents of the corresponding effective components in the above extracts are shown in tables 1-3 (the same applies below).
Respectively taking 100g of the pueraria flavonid extract (calculated by puerarin), 100g of the salvia miltiorrhiza total phenolic acid extract (calculated by salvianolic acid B) and 10g of the total tanshinone extract (calculated by tanshinone), adding 1000g of starch serving as an auxiliary material, uniformly mixing, granulating and pressing into 5000 tablets to obtain the tablets.
Example 2
Pulverizing Saviae Miltiorrhizae radix powder (20 mesh), percolating with 75% (v/v) ethanol at 20-25 deg.C, percolating at 2-3 mL/min/kg, collecting percolate 8-10 times, recovering ethanol under reduced pressure, diluting with water to about 0.2g/mL (based on crude drug), adjusting pH to 4 with hydrochloric acid, standing for precipitation, filtering or centrifuging to obtain total tanshinone extract; passing the filtered or centrifuged water solution through a D101 macroporous adsorption resin column, washing with acid water with the volume 3 times of the column bed and the pH value of 4, eluting with 40% ethanol with the volume 4 times of the column bed, collecting ethanol eluate, and recovering and removing the solvent to obtain the total salvianolic acid extract.
Pulverizing radix Puerariae, extracting with water under reflux for 3 times, adding 10 times of water for the first time, adding 8 times of water for the second time and the third time, each for 1 hr, filtering, mixing filtrates, passing through D101 macroporous adsorbent resin column, washing with 3 times of column bed volume of water, discarding water solution, eluting with 70% ethanol, collecting 2 times of column bed volume of ethanol eluate, recovering and removing solvent to obtain radix Puerariae total flavone extract.
Respectively taking 100g of the pueraria flavonid extract (calculated by puerarin), 500g of the salvia miltiorrhiza total phenolic acid extract (calculated by salvianolic acid B) and 50g of the total tanshinone extract (calculated by tanshinone), adding the mixture into the PEG-6000 molten liquid, fully and uniformly stirring, and preparing 10000 pills in a pill dropping machine to obtain the dripping pill dosage form medicament.
Example 3
Pulverizing Saviae Miltiorrhizae radix powder (sieving with 40 mesh sieve), percolating with 85% ethanol at 25-30 deg.C, collecting 10-12 times of percolate, recovering ethanol under reduced pressure, diluting with water to about 1g/mL crude drug, adjusting pH to 2 with hydrochloric acid, standing for precipitation, and filtering or centrifuging to obtain total tanshinone extract; passing the filtered or centrifuged water solution through HPD-300 macroporous adsorbent resin column, washing with 3 times of column bed volume of water, eluting with 3 times of column bed volume of 80% ethanol, collecting ethanol eluate, recovering solvent, and removing solvent to obtain total salvianolic acid extract.
Pulverizing radix Puerariae, extracting with water under reflux for 3 times, adding 12 times of water for the first time, adding 10 times of water for the second time and the third time, each for 0.5 hr, filtering, mixing filtrates, passing through HPD-300 macroporous adsorbent resin column, washing with 2.5 times of column bed volume of water, discarding water solution, eluting with 60% ethanol, collecting 2.5 times of column bed volume of ethanol eluate, recovering and removing solvent to obtain radix Puerariae total flavone extract.
Respectively taking 100g of the pueraria flavonid extract (calculated by puerarin), 20g of the salvia miltiorrhiza total phenolic acid extract (calculated by salvianolic acid B) and 2g of the total tanshinone extract (calculated by tanshinone), adding a proper amount of auxiliary materials, carrying out dry pressing granulation, and packaging into 5000 capsules to obtain the capsules.
Example 4
Pulverizing radix Puerariae, reflux-extracting with 50% ethanol water solution for 2 times, adding 12 times of the ethanol water solution for the first time, adding 10 times of the ethanol water solution for the second time, each time for 2 hr, filtering, mixing filtrates, recovering ethanol, purifying the water solution with HPD-100 macroporous resin column, washing with 2.5 times of column bed volume of water, removing impurities, eluting with 3 times of 50% ethanol, removing impurities from ethanol eluate or the water solution after recovering ethanol completely, separating with polyethersulfone ultrafiltration membrane, recovering solvent, and removing solvent to obtain radix Puerariae total flavone extract.
Taking 100g of the pueraria flavonid extract (calculated by puerarin) and 50g of the total salvianolic acid extract (calculated by salvianolic acid B) and 5g of the total tanshinone extract (calculated by tanshinone) in the embodiment 1, adding 1000g of starch serving as an auxiliary material, uniformly mixing, granulating, and pressing into 5000 tablets to obtain the tablets.
Example 5
Taking 100g of the pueraria flavonid extract (calculated by puerarin), 200g of the salvia miltiorrhiza total phenolic acid extract (calculated by salvianolic acid B) and 2g of the total tanshinone extract (calculated by tanshinone) in example 1 respectively, adding a proper amount of auxiliary materials, carrying out dry pressing granulation, and packaging into 5000 capsules to obtain the capsules.
Example 6
Taking 100g of the pueraria flavonid extract (calculated by puerarin), 20g of the salvia miltiorrhiza total phenolic acid extract (calculated by salvianolic acid B) and 50g of the total tanshinone extract (calculated by tanshinone) in example 3 respectively, adding a proper amount of auxiliary materials, carrying out dry pressing granulation, and packaging into 5000 capsules to obtain the capsules.
The beneficial effects of the invention are demonstrated by the following specific pharmaceutical research and pharmacodynamic experimental results.
First, study of pharmaceutical experiment
Experiment 1 influence of different extraction methods on extract yield and content
The salvia miltiorrhiza and the kudzuvine root are respectively crushed, 200g of the powder is weighed, and the preparation method is as follows.
1. Extracting Saviae Miltiorrhizae radix with water under reflux for 2 times, the first time adding 13 times of water, the second time adding 10 times of water, each for 1 hr, filtering, mixing filtrates, recovering under reduced pressure, concentrating, and drying to obtain Saviae Miltiorrhizae radix extract (A).
2. Extracting radix Puerariae with water under reflux for 2 times, the first time with 13 times of water, the second time with 10 times of water, each for 1 hr, filtering, mixing filtrates, recovering under reduced pressure, concentrating, and drying to obtain radix Puerariae extract (B).
3. Extracting Saviae Miltiorrhizae radix and radix Puerariae (1: 1) with water under reflux for 2 times, the first time with 13 times of water, the second time with 10 times of water, each for 1 hr, filtering, mixing filtrates, recovering under reduced pressure, concentrating, and drying to obtain Saviae Miltiorrhizae radix and radix Puerariae extract (C).
The content of each extract (A, B, C) and the pueraria flavonid extract, the salvia miltiorrhiza total phenolic acid extract and the total tanshinone extract in the embodiments are measured according to the following method.
Puerarin: measured according to the method under the item of kudzu root in the 2015 version of Chinese pharmacopoeia (page P.333).
Salvianolic acid B, tanshinone IIA, tanshinone: the assay is carried out according to the method (page P.76) under the item of Salvia miltiorrhiza in the 2015 version of Chinese pharmacopoeia, wherein the tanshinone content comprises tanshinone IIA, cryptotanshinone and tanshinone I.
TABLE 1 Total Salvianolic acid extract yield and content
| Total salvianolic acid extract | Example 1 | Example 2 | Example 3 | Salvia miltiorrhiza extract A | Radix Salviae Miltiorrhizae and radix Puerariae extract C |
| Yield (%) | 6.7 | 6.3 | 6.4 | 33.1 | 29.8 |
| Salvianolic acid B content (%) | 53.7 | 56.8 | 54.9 | 7.2 | 4.1 |
TABLE 2 Total tanshinone extract yield and content
| Total tanshinone extract | Example 1 | Example 2 | Example 3 | Salvia miltiorrhiza extract A | Radix Salviae Miltiorrhizae and radix Puerariae extract C |
| Yield (%) | 1.4 | 1.5 | 1.3 | 33.1 | 29.8 |
| Tanshinone content (%) | 22.3 | 21.8 | 23.6 | — | — |
| Tanshinone IIA content (%) | 12.2 | 11.5 | 13.0 | — | — |
Note: "-" means no detection (lower than detection limit)
TABLE 3 Pueraria flavone extract yield and content
As can be seen from tables 1-3, in examples 1 to 4, the content of puerarin in the total flavonoids of pueraria lobata was more than 20%, the content of salvianolic acid B in the total salvianolic acid extract was more than 50%, and the content of tanshinone in the total tanshinone extract was more than 20%. The Saviae Miltiorrhizae radix water decoction extract (A) and the Saviae Miltiorrhizae radix and radix Puerariae water decoction extract (C) do not contain tanshinone, and the content of salvianolic acid B or puerarin in the water decoction extracts is low.
Second, pharmacodynamic experimental study
The following pharmacodynamic experiments performed on the pharmaceutical composition of the present invention prepared with the pueraria flavonid extract, the salvia miltiorrhiza total phenolic acid extract and the total tanshinone extract described in example 1 as active ingredients as a test drug show the beneficial effects of the pharmaceutical composition of the present invention.
Experiment 2 protective action against endothelial cell and neuronal hypoxia re-oxygenation
1. The experimental method comprises the following steps: see "tissue culture and molecular biology cytology techniques" by hui province, beijing: beijing Press, 12 months 1994, page 438.
(1) Determination of endothelial cell survival rate by MTT method
After the dense monolayer cells are acted by the drug, the cells are washed for 2 times by using ice-cold PBS solution, 100 mu l of 0.5mg/ml MTT solution is added, the solution is doped for 4 hours at 37 ℃, residual liquid is absorbed, 100 mu l of acidified isopropanol color developing solution is added, and the absorbance A value is measured by using an enzyme-labeling instrument at the position of 595nm within 30 minutes. The effect of the test drug on the survival of the cultured cells was observed.
(2) Determination of neuron survival rate by MTT method
After 10 days of cell culture, 10 mul of 0.5 percent MTT is added into each hole for further culture for 4 hours, the culture solution is removed by suction, 200 mul of dimethyl sulfoxide (DMSO) is added into each hole, the particles are placed on an enzyme-labeling instrument after being dissolved, and the absorbance A value of each hole is detected at the position of 570nm of wavelength. Observing the influence of the test medicine on the survival of the cultured neurons.
(3) Model for culturing cells to lack oxygen/supply fine oxygen
Normal medium used 95% N2And 5% CO2After the mixed gas is balanced for 30 minutes, an anoxic culture medium is obtained. Suspending the cells in an anoxic culture medium, placing the post-culture plate into an anoxic chamber (continuously introducing 95% N)2And 5% CO2The mixed gas is an anoxic environment), after 2 hours of incubation at 37 ℃ (anoxic time), the normal culture medium is immediately replaced, and the incubation is carried out for 4 hours (oxygen is supplied). Untreated cells were used as controls.
(4) Method of drug administration
The test drug was formulated in a medium to a concentration of 6 ug/ml. Wherein, the groups I to VII are respectively the compositions/medicines of the pueraria flavonid extract, the salvia miltiorrhiza total phenolic acid extract and the total tanshinone extract (respectively calculated by puerarin, salvianolic acid B and tanshinone) prepared by the method of the embodiment 1 in different proportions; group VIII is a mixture of puerarin A: salvianolic acid B: a composition of tanshinone IIA (in a mass ratio of 10:10: 1); the IX-XI groups are respectively the single component pueraria flavonid extract (calculated by puerarin), total savianolic acid extract (calculated by salvianolic acid B) and total tanshinone extract (calculated by tanshinone) corresponding to the embodiment 1; XII is salvianolic acid B in patent document CN 201110009037.7: tanshinone IIA: ferulic acid: ligustilide: a puerarin (mass ratio is 6: 0.4: 0.2: 1: 5). The medicine is prepared by using an anoxic culture medium during the anoxic period, and then the medicine is prepared by using a common culture medium during the oxygen supply period.
2. Results of the experiment
(1) Protective effect on injury of endothelial cells after being anoxic for 2 hours and then oxygenated for 4 hours
After the newborn bovine brain microvascular endothelial cells are subjected to hypoxia for 2 hours and then to oxygen supply for 4 hours, an obvious death phenomenon is generated, MTT (methyl thiazolyl tetrazolium) detection shows that the absorbance of the cells in an anoxic and oxygen supply (H/R) group is obviously reduced, the cells protected by the test drug of the invention all show very obvious protection effects (I-V), and P is less than 0.01 compared with a control group, as shown in Table 4. Furthermore, it is clear from table 4 that:
1) the medicinal composition of the invention comprises the following general pueraria flavone extracts: total salvianolic acid extract: the total tanshinone extract is combined according to the weight ratio of 10:10:1 (calculated by puerarin, salvianolic acid B and tanshinone respectively), and the protective effect on endothelial cell hypoxia and oxygen (H/R) supply is optimal (I);
2) the composition lacking the total salvianolic acid extract is 10:0:1 (VI), the composition lacking the total tanshinone extract is 10:10:0 (VII), or the ratio of puerarin in the group I is only the ratio of the corresponding amount: salvianolic acid B: a single component composition (viii) of tanshinone IIA (10:10:1), and salvianolic acid B in patent document CN 201110009037.7: tanshinone IIA: ferulic acid: ligustilide: composition (XII) of puerarin (6: 0.4: 0.2: 1: 5), P <0.05 compared to group I.
(2) Protective effect on injury of cultured neurons after being anoxic for 2 hours and then oxygenated for 4 hours
After cerebral neurons of newborn rats are subjected to hypoxia for 2 hours and then to oxygen supply for 4 hours, an obvious death phenomenon is generated, MTT detection shows that the absorbance of cells in a hypoxia oxygen supply (H/R) group is obviously reduced, cells protected by the test drug of the invention all show very obvious protection effects (I-V), and P is less than 0.01 compared with a control group, as shown in Table 5. Furthermore, it is clear from table 5 that:
1) the medicinal composition of the invention comprises the following general pueraria flavone extracts: total salvianolic acid extract: the total tanshinone extract is combined according to the weight ratio of 10:10:1 (calculated by puerarin, salvianolic acid B and tanshinone respectively), and the protective effect on the oxygen (H/R) re-supply of the oxygen due to the oxygen deficiency of the neurons is optimal (I);
2) the composition lacking the total salvianolic acid extract is 10:0:1 (VI), the composition lacking the total tanshinone extract is 10:10:0 (VII), or the ratio of puerarin in the group I is only the ratio of the corresponding amount: salvianolic acid B: a single component composition (viii) of tanshinone IIA (10:10:1), and salvianolic acid B in patent document CN 201110009037.7: tanshinone IIA: ferulic acid: ligustilide: composition (XII) of puerarin (6: 0.4: 0.2: 1: 5) had no significant protection (P > 0.05).
TABLE 4 protective effects of the pharmaceutical compositions of the present invention on endothelial cell hypoxia re-oxygenation (H/R)
Note: x ± s, n ═ 6, compared to the control group:**P<0.01，*P<0.05; comparison with group i:#P<0.05。
TABLE 5 protective effects of the pharmaceutical compositions of the present invention on neuronal hypoxia re-oxygenation (H/R)
Note: x ± s, n ═ 6, compared to the control group:**P<0.01，*P<0.05。
experiment 3 therapeutic action on thrombosis rat focal cerebral ischemia reperfusion injury model
1. Test animals: SD rats 150 were randomly divided into 10 groups.
2. The test method comprises the following steps: see xu jiang Ping et al, journal of first aid combined with traditional Chinese and western medicine, 2003; 10(1): 31.
the test drugs or solvent control were administered by intragastric administration for 7 days, respectively, and the following procedure was performed 2 hours after the last administration.
Rats were anesthetized with 3ml/kg of 10% chloral hydrate by intraperitoneal injection, a median cervical incision was made, and the proximal common carotid artery, the external carotid artery and the branch arteries were isolated and ligated. The right internal carotid artery was isolated, the palatine artery was isolated down the internal carotid artery, and the branch was ligated at the root. An artery clamp is placed at the proximal end and the distal end of an internal carotid artery, a notch is formed at the bifurcation of a common carotid artery, a 4-0 nylon wire is inserted, the depth of the nylon wire is 17-20 mm, a plug wire enters the internal carotid artery and enters the skull to reach the anterior cerebral artery, and all blood flow sources of the middle cerebral artery are blocked. Removing the artery clamp, tightening the prepared thread, leaving a 1cm long thread end outside, and suturing the skin. Reperfusion was carried out after 2 hours of ischemia without re-anaesthetizing and cutting the skin, and the end of the nylon thread was gently pulled until resistance was present, indicating that the end of the nylon thread had reached the incision of the common carotid artery, and the blood flow was then resumed. The procedure was as above except that the sham group was not cannulated.
After 24h of reperfusion of the surviving rats, behavior changes of the rats are observed and behavior scoring is carried out. Reference Zea Longa five-score scoring criteria: score 0, normal, no symptoms of nerve damage; 1 minute, the contralateral forepaw can not be fully extended; 2 min, turning the ring to the outside; 3 min, pouring towards the opposite side; 4 points, spontaneous walking and loss of consciousness. Then, the brains of the experimental mice are taken after the head is quickly cut off, wet weights of a left hemisphere and a right hemisphere are respectively weighed by one part of the brains, the wet weights are weighed after the parts are placed in an oven at 160 ℃ for 24 hours, the dry weights are weighed, and the water content of the brain tissues is calculated according to the following formula: brain tissue water content (%) ═ wet-dry weight/wet weight × 100%; another part was cut out of the coronal brain slice approximately 2mm thick at the anterior commissure plane and immediately placed in 2% TTC solution and incubated at 37 ℃ for 30 minutes. Infarcted areas appeared white and non-infarcted areas appeared red. Taking a record by a digital camera, measuring the total volume of the brain slice and the volume of the infarct area by using Medbrain 2.0 software, and calculating the percentage (%) of the infarct area in the whole brain tissue; the other part is used for observing the tissue morphology: after the brain tissue is fixed, the brain is cut from the coronal section, dehydrated by the conventional method, embedded in paraffin for flaking, stained by HE, and examined by light microscope.
3. Test drugs and dose settings:
test drug i: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10:10:1) is administered to rat at a dosage of 70mg/kg (calculated as puerarin, salvianolic acid B, tanshinone).
Test drug ii: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10: 50: 5) is administered to rat at a dosage of 70mg/kg (calculated as puerarin, salvianolic acid B, tanshinone).
Test drug iii: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10: 2: 0.2) is administered at a dosage of 70mg/kg (calculated as puerarin, salvianolic acid B, tanshinone) in rat.
Test drug IV: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10:10: 0) is administered to rat at a dosage of 70mg/kg (calculated as puerarin and salvianolic acid B).
Test drug V: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10: 0:1) is administered to rat at a dosage of 70mg/kg (calculated as puerarin and tanshinone).
Test drug vi: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (0: 10:1) is administered to rat at a dosage of 70mg/kg (calculated as salvianolic acid B and tanshinone).
Test drug vii: puerarin: salvianolic acid B: tanshinone IIA (10:10:1), the administration dose of rat is 70mg/kg (corresponding to the single-component pure composition of puerarin, salvianolic acid B and tanshinone IIA with corresponding amount in the test medicament I).
4. Preparing the medicine: mixing with 4% Tween-80, preparing with purified water to desired concentration, and performing intragastric administration at a dose of 1ml/100g (such as 70mg/kg for administration at a dose of 1ml/100g for intragastric administration, mixing with 4% Tween-80, preparing with purified water to a concentration of 7mg/ml, and performing intragastric administration for 200g rat at a dose of 2 ml).
5. Solvent comparison: 4% Tween 80 in purified water at 1ml/100 g.
6. The administration route is as follows: and (5) performing intragastric administration.
7. The administration times are as follows: the administration is continued for 7 days, 1 time daily.
8. Observation indexes and observation time: the behavior, cerebral infarction volume and histomorphometry of the rats were observed. The observation time was 24 hours for reperfusion.
9. And (3) test results: see table 6.
(1) Impact on behavior: the rats in the sham operation group have no abnormal behaviors, and the neurobehavioral score is 0; the rats in the solvent control group have the symptoms of nerve injury that the rats can not be fully stretched, and the contralateral forepaws turn outwards or fall towards the contralateral side, and the behavior score is 1.70 +/-0.76; the test drugs I-III can obviously reduce the neurobehavioral scores of rats, and have very obvious difference (P <0.05, P <0.01) compared with a solvent control group; the tested medicines IV, V, VI and VII have no obvious difference (P is more than 0.05).
TABLE 6 Effect on neurological scores, cerebral hemisphere Water content and cerebral infarct volume in rats ischemic for 2 hours reperfusion for 24 hours
Note: compared with the group of the pseudo-operation,##P<0.01; compared with the solvent control group, the preparation method has the advantages that,*P<0.05,**P<0.01. comparison with group i:#P<0.05。
(2) effect on brain tissue water content: the water content of the brain tissue on the ischemia-reperfusion side (right hemisphere) of the brain in the solvent control group was significantly higher than that in the sham group. The water content of the brain tissues of the test medicaments I-III is obviously lower than that of a solvent control group (P is less than 0.05, and P is less than 0.01); the tested medicines IV, V, VI and VII have no obvious difference (P is more than 0.05).
(3) Effect on cerebral infarct volume: the brain tissue of the sham operation group has no infarction, the cerebral tissue of the ischemia side of the solvent control group has infarction, and the percentage of infarction area in the whole brain tissue is 28.7 +/-7.1%. The experimental medicaments I to VII can remarkably reduce the infarct volume of ischemic lateral brain tissues and have very remarkable difference (P is less than 0.05, and P is less than 0.01) compared with a solvent control group; meanwhile, the experimental medicines IV, V, VI and VII have obvious difference (P <0.05) compared with the I group.
(4) Effect on tissue morphology: the brain tissues on both sides of the sham-operated group were normal, and the non-ischemic brain tissues of the solvent control group and the test drug groups I to VII were normal. For ischemic lateral hemispheres: the solvent control group has cerebral tissue hemorrhage necrosis, severe edema of cerebral tissue, and focal necrosis, and the experimental drug groups I-VII can reduce the hemorrhage necrosis focus; and the hemorrhagic necrosis range of the tested drugs I-III is obviously smaller than that of the tested drugs IV, V, VI and VII.
The results of the above comparative experiments fully show that the composition of the invention, which is taken as a corresponding medicine of the effective medicinal components, can obviously reduce the cerebral tissue hemorrhage necrotic focus caused by cerebral ischemia reperfusion injury and alleviate the injuries of nerve cells and nerve fibers.
Experiment 4 improving effect on cognitive dysfunction of mouse with vascular dementia
1. Test drugs and dose settings
Test drug i: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10:10:1) is administered at a dosage of 90mg/kg (calculated by puerarin, salvianolic acid B and tanshinone) in mice.
Test drug ii: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10: 50: 5) is administered at a dosage of 90mg/kg (calculated as puerarin, salvianolic acid B, tanshinone) in mice.
Test drug iii: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10: 2: 0.2) is administered at a dosage of 90mg/kg (calculated as puerarin, salvianolic acid B and tanshinone) in mice.
Test drug IV: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10:10: 0) is administered at a dosage of 90mg/kg (calculated as puerarin and salvianolic acid B) in mice.
Test drug V: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (10: 0:1) is administered at a dosage of 90mg/kg (calculated as puerarin and tanshinone) in mice.
Test drug vi: kudzu root total flavone extract: total salvianolic acid extract: the total tanshinone extract (0: 10:1) is administered at a dosage of 90mg/kg (calculated as salvianolic acid B and tanshinone) in mice.
Test drug vii: puerarin: salvianolic acid B: tanshinone IIA (10:10:1), the administration dosage of the mouse is 90mg/kg (equivalent to the single-component pure composition of puerarin, salvianolic acid B and tanshinone IIA with corresponding amount in the test medicament I).
Preparing the medicine: mixing with 4% Tween-80, adding purified water to desired concentration, and performing intragastric administration at a concentration of 1ml/100 g.
Solvent comparison: 4% Tween 80 in purified water at 1ml/100 g.
2. Test animals: healthy male C57BL6/G mice, weighing at (25. + -. 2) G, were randomly assigned to Sham (Sham) group, VD model group, drug treatment group, 12 per group.
3. The test method comprises the following steps: see zun medical college bulletin, 2012, of keen fang et al; 35(5): 371.
3.1 vascular dementia mouse model establishment
Mice were fasted for 8h before surgery and water was prohibited for 4 h. 10% chloral hydrate (0.35mL/100g) is injected into abdominal cavity to anaesthetize the mouse, a median incision is made on the neck of the mouse, the left and right Common Carotid Arteries (CCAs) are separated obtusely along the intramuscular side edges of the sternocleidomastoid on two sides, the No. 0 line is hung, the common carotid arteries on two sides are clamped by artery clamps to cause cerebral tissue ischemia, the clamping is carried out for 10min, then the perfusion is carried out for 20min, the operation is repeated for 3 times, then iodophor disinfection is carried out, the incision is sewed layer by layer, and 80 mu penicillin is used for anti-infection treatment for 3d after the operation. sham groups only underwent bilateral common carotid artery isolation and did not undergo occlusion by ischemia reperfusion. Test drugs were administered to the drug group mice 1 time a day, 3 days before surgery and 28 days after surgery, respectively. The treatment course is 28 days, and the mice in the Sham group and VD model group are given solvent control according to the same volume, and the times and the treatment course are the same as those in the drug group.
3.2 measurement of spatial learning and memory Capacity of mice
The Morris water maze is a circular water pool with the diameter of about 100cm, the water depth is about 33cm, the water temperature is kept at (23 +/-1) DEG C, the platform height is about 30cm, the plane at the top end of the platform is 6cm multiplied by 6cm, the platform is submerged under water by 3-4 cm, in the experimental process, reference objects around the water pool are kept unchanged, the water pool is divided into 4 quadrants I, II, III and IV, 4 starting points for placing mice into water are respectively arranged, the Morris water maze experiment is carried out on each group of mice before and after operation by 28d, and the experiment is divided into a positioning navigation experiment of the first 5d and a space exploration experiment of the 6 d.
3.2.1 the navigation experiment is positioned for 5 days, each mouse is put into water for adaptive training 1d before the experiment, then the mouse is put on the platform and stays for 20s, so that the mouse can memorize the platform, the total time of the experiment is 120s, an automatic image monitoring system tracks the swimming track of the mouse in the experiment process, and the time for the mouse to jump to the platform is recorded. Each mouse was placed into water from 4 different quadrants, one time per quadrant, and the average was taken as the escape latency per day. In the experiment, the mice jump on the platform within 120s and stay for 3s, the record is taken as one time, if the mice which do not jump on the platform within 120s are placed on the platform in an artificial guiding mode and stay for 3s, the record time is 120s, each group of mice has a rest for 20min after undergoing the experiment in one quadrant, and then enter the experiment in the next quadrant.
3.2.2 space exploration experiment in experiment 6d, remove the platform in the pond, put the mouse into water towards the pool wall at same water inlet point, Morris water maze system automatic record it crosses the number of times of former platform relevant position in 120 s.
4. Results (improving learning and memory ability of VD mouse)
4.1 the positioning navigation experiment lasts for 5d, the escape latency of each group of mice is shortened to different degrees along with the increase of training times, and the escape latency of the mice in the VD model group is obviously longer than that of the mice in the Sham group (P is less than 0.01) at 28d after the operation; the escape latency of the mice of the test drugs I to VII is obviously shorter than that of the mice of the VD model group (P <0.05 and P <0.01), and the test drugs IV to VII are obviously different from the mice of the I group (P <0.05) (see table 7).
Table 7 each group of mice was compared for evasion latency in localized voyage experiments (n-6,
)
note: in comparison with the Sham group,##P<0.01; compared with the VD group, the method has the advantages that,*P<0.05，**P<0.01. comparison with group i:
P<0.05。
4.2 the difference of the times of the Sham group, the VD model group and the drug group passing through the platform before the space exploration experiment has no statistical significance (P is more than 0.05); at 28d after surgery, the number of platform crossings by the VD model group was significantly less than that of the Sham group (P < 0.01). The frequency of the test drugs I to VII passing through the platform is obviously more than that of the VD model group (P <0.05, P <0.01), and the test drugs IV to VII have obvious difference (P <0.05) compared with the test drug I (see Table 8).
Table 8 comparison of the number of platen crossings for each group of mice (n 6,
)
| group of | Before operation | 28 days after operation |
| Blank control (Sham group) | 8.92±3.38 | 9.15±2.83 |
| Model contrast (VD group) | 9.25±3.41 | 2.79±0.61## |
| Test drug I | 9.07±3.15 | 5.46±1.35** |
| Test drug II | 8.94±3.02 | 4.97±1.02** |
| Test drug III | 9.36±3.84 | 5.13±1.26** |
| Test drug IV | 9.11±2.97 | 4.23±1.07*▽ |
| Test drug V | 9.30±3.16 | 4.08±1.02*▽ |
| Test drug VI | 9.25±3.23 | 4.12±0.96*▽ |
| Test drug VII | 8.96±3.08 | 4.36±1.13*▽ |
Note: in comparison with the Sham group,##P<0.01; compared with the VD group, the method has the advantages that,*P<0.05，**P<0.01. comparison with group i:▽P<0.05。
experiment 5 influence on spatial learning and memory ability of experimental vascular dementia rats
170 rats with the weight of 220-240g are subjected to qualified animal screening after 3 days of Morris water maze training, so that the platform can be found to be qualified within 60s after 4 times of training. 100 qualified animals are taken and divided into 10 groups randomly according to weight layering, wherein the 10 groups are respectively a blank control group, a model control group, test drug I-VII groups and a positive control (DH) group. The test drug I is a pueraria flavonid extract: total salvianolic acid extract: the total tanshinone extract (10:10:1) is administered to rat at a dosage of 70mg/kg (calculated by puerarin, salvianolic acid B and tanshinone); the test medicine II is a pueraria flavonid extract: total salvianolic acid extract: the total tanshinone extract (10: 20: 2) is administered to rat at a dosage of 70mg/kg (calculated by puerarin, salvianolic acid B and tanshinone); the test medicine III is a pueraria flavonid extract: total salvianolic acid extract: the total tanshinone extract (10: 5: 0.5) is administered at a dosage of 70mg/kg (calculated by puerarin, salvianolic acid B and tanshinone) in rats; the test drug IV is a pueraria flavonid extract: total salvianolic acid extract: the total tanshinone extract (10:10: 0) is administered to rat at a dosage of 70mg/kg (calculated as puerarin and salvianolic acid B). The test drug V is a pueraria flavonid extract: total salvianolic acid extract: the total tanshinone extract (10: 0:1) is administered to rats at a dosage of 70mg/kg (calculated as puerarin and tanshinone); the test medicament VI is a pueraria flavonid extract: total salvianolic acid extract: the total tanshinone extract (0: 10:1) is administered to rats at a dosage of 70mg/kg (calculated as salvianolic acid B and tanshinone); the test medicament VII is puerarin: salvianolic acid B: tanshinone IIA (10:10:1), the administration dose of rat is 70mg/kg (corresponding to the single-component pure composition of puerarin, salvianolic acid B and tanshinone IIA with corresponding amount in the test medicament I). Preparing the medicine: mixing with 4% Tween-80, preparing with purified water to desired concentration, and performing intragastric administration at a concentration of 1ml/100 g; solvent comparison: 4% Tween 80 in purified water at 1ml/100 g.
Performing intragastric administration on the corresponding test substance according to the test medicament and the dosage, 1 time per day for 60 consecutive days; injecting sodium nitroprusside 2mg/kg into abdominal cavity on day 50, separating bilateral common carotid artery, clamping for 10min, releasing for 10min, clamping for 10min, then releasing, and suturing. Training is carried out after administration for 45min on the 57 th day, continuously for 3 days, 4 times a day, each time does not exceed 60s, and the escape latency each day is used as an index; space exploration tests were performed 45min after the 60 th day of dosing, with the number of platform crossings within 60s as an indicator. The results are shown in Table 9.
TABLE 9 Effect on spatial learning and memory ability of rats with experimental vascular dementia
| Group of | Escape latency(s) | Number of passes through the platform |
| Blank control | 21.7±9.8 | 3.2±1.5 |
| Model comparison | 42.5±14.9## | 1.2±0.6## |
| Test drug I | 27.3±10.1* | 2.2±0.9** |
| Test drug II | 28.8±9.3* | 2.0±0.7* |
| Test drug III | 29.6±11.5* | 1.9±0.8* |
| Test drug IV | 32.4±11.9 | 1.7±0.7 |
| Test drug V | 31.3±10.6 | 1.5±0.6 |
| Test drug VI | 33.2±11.7 | 1.6±0.7 |
| Test drug VII | 32.1±10.4 | 1.8±0.9 |
| Positive control (Anrishen) | 34.7±12.2 | 1.9±0.7* |
Note: compared with the control group, the compound of the formula,##P<0.01; in comparison with the set of models,*P<0.05，**P<0.01。
the results show that rats with experimental vascular dementia can develop spatial learning memory impairment with prolonged escape latency in the water maze and reduced number of platform crossings (P < 0.01). The test drugs I-III are continuously administered for 60 days, the spatial learning and memory ability of the rat with vascular dementia can be improved to different degrees, the escape latency is shortened compared with that of a model group, and the frequency of passing through a platform is increased (P is less than 0.05 and P is less than 0.01); the tested medicines IV to VII have no obvious difference (P is more than 0.05).
While the invention has been described with reference to illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the spirit and scope of the principles of this disclosure. More specifically, various variations and modifications may be made to the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure herein. In addition to variations and modifications in the component parts and/or arrangements, other uses will also be apparent to those skilled in the art.
Claims (4)
1. An application of a pharmaceutical composition in preparing a medicament for preventing and treating cerebral infarction and/or vascular dementia, the pharmaceutical composition is composed of a pueraria flavonid extract, a salvia miltiorrhiza total phenolic acid extract and a total tanshinone extract, and is characterized in that the weight ratio of the pueraria flavonid extract calculated by puerarin, the salvia miltiorrhiza total phenolic acid extract calculated by salvianolic acid B and the total tanshinone extract calculated by tanshinone is 10 (2-50) to (0.2-5);
the total salvianolic acid extract and/or total tanshinone extract is prepared by the following method: percolating pulverized Saviae Miltiorrhizae radix with 80 + -5 vol% ethanol at a temperature of 20 deg.C or higher, collecting percolate, removing ethanol, and adjusting pH to 4 or below to obtain total tanshinone extract precipitate; adsorbing the water solution after solid-liquid separation with macroporous resin, eluting with water with pH value less than or equal to 7 to remove impurities, eluting with 40-80% ethanol, collecting ethanol eluate, recovering solvent to obtain total salvianolic acid extract;
the preparation method of the pueraria flavonid extract comprises the following steps: extracting radix Puerariae with water or ethanol water solution with volume content of ethanol not more than 80%, removing ethanol from water extractive solution or ethanol water solution, adsorbing with macroporous resin, washing with water, removing impurities, eluting with 50-80% ethanol, collecting ethanol eluate, recovering solvent to obtain radix Puerariae total flavone extract; wherein the macroporous resin is HPD-100, HPD-300 or D101.
2. The use of the pharmaceutical composition as claimed in claim 1 in the preparation of a medicament for the prevention and treatment of cerebral infarction and/or vascular dementia, wherein the weight ratio of the total flavonoids of pueraria lobata calculated as puerarin, the total phenolic acids of salvia miltiorrhiza calculated as salvianolic acid B and the total tanshinone extracts calculated as tanshinone is 10 (5-20) to (0.5-2).
3. The use of the pharmaceutical composition as claimed in claim 1, in the preparation of a medicament for the prevention and treatment of cerebral infarction and/or vascular dementia, wherein the weight ratio of the pueraria flavonid extract calculated as puerarin, the salviae miltiorrhizae total phenolic acid extract calculated as salvianoic acid B and the total tanshinone extract calculated as tanshinone is 10:10: 1.
4. The use of the pharmaceutical composition as claimed in any one of claims 1 to 3, in the preparation of a medicament for preventing and treating cerebral infarction and/or vascular dementia, wherein the content by weight of puerarin in the pueraria flavonid extract is not less than 20%, and/or the content by weight of salvianolic acid B in the salvia miltiorrhiza total phenolic acid extract is not less than 50%, and/or the content by weight of tanshinone in the total tanshinone extract is not less than 20%.
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