CN116870063A - Traditional Chinese medicine composition with blood circulation activating and nerve soothing functions and preparation method thereof - Google Patents
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Abstract
The invention provides a traditional Chinese medicine composition with the functions of activating blood and soothing nerves and a preparation method thereof, wherein the traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 10-50 parts of astragalus membranaceus, 3-20 parts of angelica sinensis, 3-20 parts of ligusticum wallichii, 3-20 parts of peach kernel, 3-20 parts of safflower, 10-30 parts of spina date seed, 3-20 parts of earthworm and 5-25 parts of poria cocos. The invention has the functions of promoting blood circulation to remove meridian obstruction, nourishing blood and tranquillizing, and is used for qi deficiency and blood stasis type ischemic stroke. The invention has the advantages of good clinical curative effect, safety, reliability, convenient administration and the like. Animal experiment research shows that the invention also has the functions of neuroprotection, anti-inflammation, antioxidation and anti-apoptosis.
Description
Technical Field
The invention relates to the technical field of traditional Chinese medicines, in particular to a traditional Chinese medicine composition with the functions of activating blood and soothing nerves and a preparation method thereof.
Background
Ischemic stroke refers to the occurrence of dysfunction of brain blood circulation caused by various reasons, and the occurrence of dysfunction in terms of movement, sensation, language and the like due to neurological impairment caused by necrosis of brain tissue caused by ischemia and hypoxia. Ischemic cerebral apoplexy is a major chronic non-infectious disease seriously harming the health of national people in China, is an important cause of death and disability of adults in China, and has five characteristics of high morbidity, high disability rate, high mortality rate, high recurrence rate and high economic burden. The incidence rate of ischemic cerebral apoplexy in China is in an increasing trend year by year, and the incidence rate is increased from 117/10 ten thousand of 2005 to 145/10 ten thousand of 2019, and accounts for 60% -80% of the total cerebral apoplexy. With the rapid development of medical technology, the death rate caused by ischemic cerebral apoplexy is greatly reduced, but the disability rate is not obviously improved, and about 75% of ischemic cerebral apoplexy patients have disabilities with different degrees according to related statistics, so that the life of the patients is greatly influenced. How to reduce the dysfunction caused by cerebral arterial thrombosis and improve the activity of the daily life of patients is a urgent need to solve the problem.
Stroke, which is the traditional Chinese medicine, is one of the common symptoms of ischemic stroke, and is characterized by hemiplegia, weakness or stiffness of the limbs, contracture and deformation, sallow complexion, less qi and no speaking, and facial distortion. The pathogenesis is qi deficiency and blood stagnation, and the venation stasis is mainly treated by tonifying qi and nourishing blood, removing blood stasis and dredging collaterals. At present, the rehabilitation of ischemic stroke is lack of specific medicines, mainly depends on rehabilitation exercise and physiotherapy, has long treatment period and high cost, and requires high coordination of patients. Stroke is classified into an acute phase, a convalescent phase and a sequelae phase according to the course of the disease. The recovery period is 2 weeks to 6 months from the onset, is a key period of brain tissue repair and functional reconstruction, and has a significant effect on functional recovery of patients. Western medicines have an uncertain curative effect on the recovery period of apoplexy, and traditional Chinese medicines have the advantages of overall appearance and diagnosis and treatment, and have the potential of shortening the recovery process, improving the treatment effect and relieving the economic and social burden of patients. The clinical and pharmacodynamic research results are fully utilized, and the novel traditional Chinese medicine has good prospect for treating ischemic stroke by means of modern preparation technology.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a traditional Chinese medicine composition with the functions of activating blood and soothing nerves and a preparation method thereof, and the traditional Chinese medicine composition can effectively treat ischemic stroke.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides a traditional Chinese medicine composition with the functions of activating blood and soothing nerves, which comprises the following raw materials in parts by weight: 10-50 parts of astragalus membranaceus, 3-20 parts of angelica sinensis, 3-20 parts of ligusticum wallichii, 3-20 parts of peach kernel, 3-20 parts of safflower, 10-30 parts of spina date seed, 3-20 parts of earthworm and 5-25 parts of poria cocos.
Further, the material comprises the following raw materials in parts by weight: 4-8 parts of astragalus membranaceus, 1-3 parts of angelica sinensis, 1-3 parts of ligusticum wallichii, 1-3 parts of peach kernel, 1-3 parts of safflower, 3-5 parts of spina date seed, 1-3 parts of earthworm and 2-4 parts of poria cocos.
Further, the material comprises the following raw materials in parts by weight: 6 parts of astragalus membranaceus, 2 parts of angelica sinensis, 2 parts of ligusticum wallichii, 2 parts of peach kernel, 2 parts of safflower, 4 parts of spina date seed, 2 parts of earthworm and 3 parts of poria cocos.
Further, the preparation method of the traditional Chinese medicine composition with the functions of activating blood and soothing nerves comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding water for decocting twice, adding 8 times of water for soaking for 30 minutes for 60 minutes for the first time, adding 6 times of water for decocting for 30 minutes for the second time, filtering, and combining the filtrates;
(2) Concentrating the filtrate under reduced pressure to obtain extract with relative density of about 1.10-1.15 (65-75 ℃);
(3) Spray drying the extract to obtain dry extract powder;
(4) Taking dry paste powder, adding a proper amount of maltodextrin, and uniformly mixing;
(5) Granulating with granulating device, packaging and sealing to obtain the final product.
The beneficial effects of the invention are as follows: the efficacy of each raw material is as follows:
radix astragali: sweet in flavor and slightly warm in nature, enter lung and spleen meridians. Has effects in invigorating qi, invigorating yang, consolidating superficial resistance, relieving sweating, inducing diuresis, relieving edema, promoting salivation, nourishing blood, removing stagnation, relieving arthralgia, removing toxic substances, promoting pus discharge, healing sore, and promoting granulation, and can be used for treating qi deficiency, debilitation, loose stool, sinking of middle-jiao, chronic diarrhea, rectocele, metrorrhagia, spontaneous perspiration, qi deficiency edema, internal heat diabetes, blood deficiency, sallow complexion, hemiplegia, arthralgia, numbness, carbuncle, ulcer, and chronic ulcer.
Chinese angelica root: sweet in flavor and warm in nature. It enters liver, heart and spleen meridians. Has effects of replenishing blood, promoting blood circulation, regulating menstruation, relieving pain, and loosening bowel to relieve constipation. Can be used for treating sallow complexion due to blood deficiency, dizziness, palpitation, menoxenia, amenorrhea, dysmenorrhea, abdominal pain due to deficiency-cold, rheumatalgia, traumatic injury, carbuncle, skin ulcer, and constipation due to intestinal dryness.
Ligusticum wallichii: pungent and warm in nature. Enter liver, gallbladder and pericardium meridians. Has effects of promoting blood circulation, activating qi-flowing, dispelling pathogenic wind, and relieving pain. Can be used for treating chest pain, hypochondrium pain, traumatic injury, menoxenia, amenorrhea, dysmenorrhea, abdominal pain, headache, and rheumatalgia.
Peach kernel: bitter taste and neutral nature. It enters heart, liver and large intestine meridians. Has effects of promoting blood circulation, removing blood stasis, loosening bowel to relieve constipation, relieving cough and asthma. Can be used for treating amenorrhea dysmenorrhea, abdominal mass, pulmonary abscess, intestinal abscess, traumatic injury, constipation due to intestinal dryness, cough and asthma.
Safflower: pungent and warm in nature. It enters heart and liver meridians. Has effects of promoting blood circulation, dredging channels, removing blood stasis, and relieving pain. Can be used for treating amenorrhea, dysmenorrhea, lochia, abdominal mass, chest pain, abdominal pain due to blood stasis, thorny chest and hypochondrium, traumatic injury, and swelling and pain.
Semen Ziziphi Spinosae: sweet and sour in flavor and neutral in nature. It enters liver, gallbladder and heart meridians. Has effects of nourishing heart, nourishing liver, tranquilizing mind, arresting sweating, and promoting salivation. Can be used for treating dysphoria, insomnia, palpitation, dreaminess, asthenia, excessive sweat, body fluid deficiency, and thirst.
Earthworm: salty taste and cold nature. Enter liver, spleen and bladder meridians. Has effects of clearing heat, arresting convulsion, dredging collaterals, relieving asthma and promoting urination. Can be used for treating hyperpyrexia, unconsciousness, convulsion, arthralgia, numbness of limbs, hemiplegia, lung heat, asthma, cough, edema, and oliguria.
Poria cocos: sweet and light in taste and neutral in nature. It enters heart, lung, spleen and kidney meridians. Has effects of promoting diuresis, removing dampness, invigorating spleen, and calming heart. Can be used for treating edema, oliguria, phlegm retention, palpitation, spleen deficiency, anorexia, loose stool, diarrhea, uneasiness, palpitation, and insomnia.
The symptoms and signs of qi deficiency and blood stasis in the recovery period of ischemic stroke are summarized as qi deficiency and blood stasis and meridian stasis. The qi belongs to yang and is active; blood pertains to yin and is the main static part. Qi and blood complement each other, depend on each other, generate each other, and coordinate and promote vital activities of the human body. "book of changes" cloud: the qi and blood are mutually root and natural theory. The relationship between qi and blood can be summarized by "qi is the general meaning of blood and blood is the mother of qi", that is, qi can produce blood, promote blood circulation, take blood control, blood can transform qi into carrier gas. The body has qi deficiency and blood deficiency, and weak blood circulation, and causes internal stagnation of blood stasis, blood stasis blocking the venation of brain, qi deficiency, qi and blood stagnation of brain, and malnutrition of brain marrow. Therefore, the therapeutic principle of invigorating qi, dredging collaterals, promoting blood circulation and removing blood stasis is adopted in treatment.
The prescription of the invention is derived from the classic formula Buyang Huanwu decoction carried by medical science correction, and the prescription of the Buyang Huanwu decoction comprises the following components: astragalus root, chinese angelica, red paeony root, earthworm, szechuan lovage rhizome, safflower and peach seed. The pathogenesis is deficiency of healthy qi, qi deficiency, blood stagnation, and stagnation of venation. In the recipe, four astragalus root are used as main medicine to replenish the atmosphere in chest, promote blood circulation, chinese angelica root, chuanxiong rhizome, red peony root, peach kernel and safflower, and small amount of blood activating medicine to promote blood circulation and earthworm to dredge meridian. In modern society, pathogenesis becomes more complex, and is comprehensively influenced by various factors including social factors, psychological factors, geographical climate environment, various drug treatments and the like. The modern society has fast life rhythm, and people have great mental pressure, and stroke patients are hit by the disease, so that the heart spirit is easy to be restless, the dysphoria and insomnia are easy to occur, the palpitation and insomnia are caused by the heart spirit malnutrition. Clinically, a large number of patients with ischemic stroke qi deficiency and blood stasis symptoms have sleep disorder, anxiety, depression and other mood disorders, and the conditions lead to poor physical strength and mental state of the patients, and have low coordination degree of rehabilitation treatment, thus seriously affecting the rehabilitation process of diseases. The invention removes red paeony root and adds spine date seed and tuckahoe on the basis of the yang-tonifying five-returning decoction. Adding and subtracting the cutting idea: qi is yang, blood is yin, and modern bad life habits are easy to cause qi deficiency to develop into yang deficiency, so that red paeony root with bitter and slightly cold property is removed, and spine date seed with functions of nourishing blood and tranquillizing mind and poria cocos with functions of calming heart and tranquillizing mind are added to assist heart spirit to nourish, so that people feel sleep and calm.
And (3) square solution: the invention is composed of eight traditional Chinese medicines of astragalus, angelica, szechuan lovage rhizome, peach kernel, safflower, wild jujube seed, earthworm and poria cocos, wherein astragalus is used in the prescription to greatly supplement primordial qi of spleen and stomach, so that qi is enhanced, blood is moved, blood stasis is removed, collaterals are dredged without hurting the vital energy, and the traditional Chinese medicine is a monarch drug; is matched with poria cocos, has the effects of strengthening spleen and promoting diuresis, calming heart and tranquilizing mind, and assists the principal drug to strengthen spleen, and is used as ministerial drug; qi deficiency causes blood stasis to stop internally, and Chinese angelica, peach kernel and safflower are added as blood-activating and stasis-removing medicines, so that the flavor of peach kernel is bitter and reduced, and bitter and blood stasis is relieved, and all symptoms of blood stasis can be treated; safflower, flos Carthami, with the pungent and warm nature, is effective in promoting blood circulation and removing blood stasis, and has the combined actions of both herbs, i.e. dispelling and receiving, and increasing and decreasing, and has the effect of promoting blood circulation and removing blood stasis, has the functions of removing blood stasis, promoting tissue regeneration, relieving swelling and pain, expanding the action range, inducing the stagnation in heart and blood, inducing the stagnation in liver and regulating blood; dang Gui is sweet and heavy in flavor, so it can enrich blood, its qi is light and pungent, so it can promote blood circulation, tonify middle energizer, nourish qi in blood, and also sang Yao in blood; deficiency of healthy qi and unsmooth blood vessels cause malnutrition of heart spirit, so the semen zizyphi spinosae is used for nourishing blood and tranquillizing; lumbricus has effects of dredging meridian passage, guiding medicine into collaterals, and making the medicine be tonic without stagnation, and the medicine be tonic without obstruction; chuan Xiong has the actions of promoting qi and blood circulation, guiding the drugs into the brain, and both are combined as guiding drugs. The medicines are combined to ensure that qi is sufficient to promote blood circulation, remove blood stasis and dredge collaterals, so that the tendons and the meat can be nourished, the flaccidity waste can be healed, and the effects of promoting blood circulation to remove meridian obstruction, nourishing blood and tranquillizing are achieved.
Compared with the traditional Chinese patent medicines which are currently marketed and used for treating qi deficiency and blood stasis in the recovery period of ischemic stroke, such as Naoxintong capsules (16 flavors), longshengzhi capsules (12 flavors), xiaoshentong particles (14 flavors) and the like, the prescription of the invention is relatively simple, only eight flavors exist, and toxic decoction pieces and rare decoction pieces are not contained; meanwhile, the invention has definite safety and curative effect; proved recipe combines modern preparation technology, converts traditional decoction into modern granule, and is convenient for administration and easy for storage. The invention has the functions of promoting blood circulation to remove meridian obstruction, nourishing blood and tranquillizing, and is used for qi deficiency and blood stasis type ischemic stroke. The invention adopts the modern advanced technology of spray drying and dry granulation to prepare the granules, and has the advantages of definite curative effect, safety, reliability, small dosage and the like. Animal experiment research shows that the invention also has the functions of neuroprotection, anti-inflammation, antioxidation and anti-apoptosis.
Drawings
FIG. 1 is a graph of experimental trajectories of spatial exploration of groups of rats;
FIG. 2 shows the results of staining of the CA3 region of Nib in the hippocampus of rats in each group;
FIG. 3 shows Caspase-3 protein expression levels in brain tissue of each group of rats;
FIG. 4 shows the relative expression levels of Caspase-3 protein in brain tissue of each group;
FIG. 5 shows ICAM1, IL-6, TNF- α protein expression levels in brain tissue of each group of rats;
FIG. 6 shows relative expression levels of ICAM1, IL-6, TNF- α proteins in brain tissue of each group of rats.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The present invention will be described in detail with reference to the following examples.
Example 1
The raw materials are prepared from the following raw materials in parts by weight: 10 parts of astragalus, 4 parts of angelica, 4 parts of ligusticum wallichii, 4 parts of peach seed, 4 parts of safflower, 6 parts of wild jujube seed, 4 parts of earthworm and 5 parts of poria cocos.
The preparation method comprises the following steps:
(1) Weighing the raw materials according to the proportion, adding water for decocting twice, adding 8 times of water for soaking for 30 minutes for 60 minutes for the first time, adding 6 times of water for decocting for 30 minutes for the second time, filtering, and combining the filtrates;
(2) Concentrating the filtrate under reduced pressure to obtain extract with relative density of about 1.10-1.15 (65-75 ℃);
(3) Spray drying the extract to obtain dry extract powder;
(4) Taking dry paste powder, adding a proper amount of maltodextrin, and uniformly mixing;
(5) Granulating with granulating device, packaging and sealing to obtain the final product.
Example 2
The traditional Chinese medicine composition for treating ischemic stroke is characterized by being prepared from the following raw materials in parts by weight: 4 parts of astragalus membranaceus, 1 part of angelica sinensis, 1 part of ligusticum wallichii, 1 part of peach seed, 1 part of safflower, 3 parts of spina date seed, 1 part of earthworm and 2 parts of poria cocos. The preparation method is the same as in example 1.
Example 3
The traditional Chinese medicine composition for treating ischemic stroke is characterized by being prepared from the following raw materials in parts by weight: 6 parts of astragalus membranaceus, 2 parts of angelica sinensis, 2 parts of ligusticum wallichii, 2 parts of peach kernel, 2 parts of safflower, 4 parts of spina date seed, 2 parts of earthworm and 3 parts of poria cocos. The preparation method is the same as in example 1.
Example 4
A Chinese medicinal composition for treating ischemic stroke is characterized in that the composition of the medicament is the same as that of the embodiment 3, except that the preparation is a water decoction, and 200ml of water is decocted.
Comparative example
The prescription of the yang-tonifying five-returning decoction comprises the following components: 30g of astragalus, 6g of angelica, 5g of red paeony root, 3g of earthworm, szechuan lovage rhizome, safflower and peach seed respectively, and 200ml of decoction are decocted with water and taken twice a day in the morning and evening.
The invention has the advantages of advanced process, controllable quality, stable preparation, small dosage, safety, reliability, definite curative effect and the like through the inspection of process, quality, stability, toxicity, clinical and pharmacodynamics researches. In addition, pharmacodynamic researches show that the invention also has the effects of neuroprotection, anti-inflammation, antioxidation and anti-apoptosis. The following are the results of the studies related to the present invention:
(one) early random control clinical study
The embodiment 4 of the invention is a decoction prepared according to proved formulas applied clinically for years, has better curative effect on patients with qi deficiency and blood stasis in the recovery period of ischemic stroke, and further confirms whether the invention has superiority compared with comparative examples, so that a random control clinical study in the early stage is developed.
Study object: patients with ischemic stroke in convalescence.
Inclusion criteria: meets the Western diagnosis standard of apoplexy and the differentiation standard of Chinese medicine, and the syndrome refers to the condition of qi deficiency and blood stasis; in the recovery period, namely 2 weeks to 6 months after the onset of the disease; sleep disorders; first onset.
Exclusion criteria: disabled people exist before the disease occurs; combining other nervous system diseases.
The research method comprises the following steps: the test group took the medicine of example 4 of the present invention on the basis of the conventional rehabilitation therapy, the control group took the medicine of comparative example on the basis of the conventional rehabilitation therapy, each group took for 8 weeks, and the two groups were taken according to 1:1, 32 cases of each group, and 64 persons are included.
And (3) observing the indexes: (1) Insomnia Severity Index (ISI): higher scores indicate a heavier sleep disorder; (2) National institutes of health stroke scale score (NIHSS): higher scores indicate a greater impairment of neurological function; (3) Simplifying the Fugl-Meyer athletic function score (FMA), the higher the score, the better the athletic function; (4) improved barchel index (MBI): the higher the score, the better the activity of daily life.
Results: 64 patients with qi deficiency and blood stasis in the recovery period of ischemic stroke are taken together. The ISI score was significantly improved in the experimental group compared to the pre-treatment, while the ISI score was not significantly changed in the control group. The NIHSS, FMA, MBI scores of both groups of patients were significantly improved, and the improvement was greater in the test group than in the control group, with the differences being statistically significant (P < 0.05). See table 1. The occurrence rate of the two groups of adverse events is low, which indicates that the invention is safe and reliable and has small side effect. See table 2.
Conclusion: the invention and the yang-tonifying five-component decoction can improve the neurological deficit, exercise capacity and daily living activity of patients with qi deficiency and blood stasis symptoms in the recovery period of ischemic stroke, and the curative effect of the invention is better. In addition, compared with the yang-tonifying five-returning decoction, the invention has obvious superiority in improving sleep disorder.
Table 1 comparison of ISI, NIHSS, FMA, MBI scores before and after treatment of two groups
a: p < 0.05 compared to prior to treatment in this group; b: p < 0.05 compared to the contemporaneous control group.
Table 2 comparison of the occurrence of two groups of adverse events
The effectiveness and superiority of the formulation of the present invention (example 4) was confirmed by a prior randomized controlled clinical study, followed by the formulation being formulated as granules (example 3), and further process, quality, stability, toxicity, clinical and pharmacodynamic studies were performed on example 3.
(II) Process study
The preparation process of the invention has the technical innovation that: the traditional decoction is developed into a modern traditional Chinese medicine granule, the clinical curative effect is good, the drug loading is large, and the method of spray drying combined with dry granulation and the like is adopted, so that the daily dosage of a prescription is greatly reduced, and in addition, the traditional Chinese medicine granule has the advantages of quick absorption, quick response, convenience in carrying and taking and the like.
Based on clinical application experience, the extraction process selects a water decoction extraction mode, adopts a single factor test and an orthogonal test to examine the influence of key parameters such as water addition quantity, decoction times, decoction time, soaking time and the like on an extraction result, selects astragaloside IV in the monarch drug astragalus membranaceus as an index component, respectively endows weight coefficients to the astragaloside IV transfer rate and the whole ointment yield according to the curative effect correlation, and calculates a comprehensive score as an evaluation index of the extraction process. The final optimized water extraction process comprises the following steps: decocting twice, the first time adding 8 times of water, soaking for 30 minutes, decocting for 60 minutes, and the second time adding 6 times of water, and decocting for 30 minutes. The refining, concentrating and selecting filtering method and reduced pressure concentrating method of the water extract, and inspecting the sieving mesh number and concentrating temperature, and the result shows that the sieving mesh number and concentrating temperature have no obvious influence on the ointment yield and astragaloside IV content in the inspected parameter range. In the drying process study, 3 different drying modes, namely spray drying, belt vacuum drying and vacuum box drying, were all studied. According to the properties, moisture, powder yield, astragaloside IV content, industrial production feasibility and the like of the dry paste powder, the main factors influencing spray drying in different drying modes are examined, and finally, the spray drying mode is determined and selected, and the density of the concentrated solution is adjusted to be 1.10-1.15 (65 ℃ -75 ℃). In the forming process, dry granulation is preferably used as a granulating method, the process parameters of a dry granulator used for fixing an orthogonal test are designed, the pre-prescription research and the prescription screening research of the preparation are fully carried out, and a proper amount of maltodextrin is selected to prepare and form. Finally, three batches of verification are carried out in a laboratory according to the optimized process parameters, and the results show that the optimized process parameters are stable and feasible, have better repeatability and have certain guiding significance for production.
Pilot-test three batches and production process verification three batches of production are carried out according to the determined process conditions and parameters, and important links in the production process are monitored and inspected, wherein the concentration unit is used for: the relative density of the concentrated solution is controlled to be 1.10-1.15 (65-75 ℃), and the paste yield is in the range of 20-31 percent; spray drying unit: the product yield is 21% -25%, and the water content is less than 7%; granulating unit: the addition amount of maltodextrin is in the range of 0-11%, and the total granulating and mixing yield is more than 95%; packaging unit: the granule packaging yield is more than 95%, and the result shows that the whole process is stable and controllable. The test of the pilot-scale three batches and the verification of the production process prove that the products produced by the three batches meet the requirements, and the process is suitable for large-scale industrial production, scientific and reasonable, controllable in production process, stable and reliable in process and qualified and uniform in product quality.
(III) quality study
The quality research of medicinal materials and the quality research of preparations are respectively carried out, and in the quality research of medicinal materials, the identification of all Chinese medicinal material primordia is reliable. In the preparation quality research, according to the functional main treatment, the preparation process, the chemical composition and content of prescription medicine taste and the modern pharmacological research, the content of the index component astragaloside IV of the monarch medicine astragalus in the prescription is measured by adopting a high performance liquid chromatography, and the astragaloside IV is used as a process evaluation and preparation content measurement index. The process parameters are determined by single factor and orthogonal tests to ensure the effectiveness and controllability of the preparation. The preparation is checked in terms of granularity, moisture, dissolubility, loading difference, microorganism limit, heavy metal, harmful elements, aflatoxin, pesticide residue and the like, so that the safety is ensured. Establishes the determination method and limit of astragaloside IV content, defines the thin-layer chromatography identification method of five medicinal materials, and lays a material foundation for ensuring the effectiveness of clinical medication. In conclusion, the invention has controllable quality.
(IV) study of stability of formulations
According to the guidelines of the four 9001 raw material medicaments and preparation stability test of the Chinese pharmacopoeia 2020 edition, the laws of the change of the physical characteristics and chemical characteristics of the granule sample along with time under the influence of environmental factors such as temperature, humidity, light and the like are examined so as to determine the stability of the medicament.
The accelerated test storage condition is that the temperature is 40+/-2 ℃ and the humidity is 75+/-5%, the investigation indexes are properties, granularity, moisture, astragaloside IV content, thin-layer identification and microorganism investigation, and the investigation period is 6 months. The experiment shows that each detection index of the 6 month acceleration test has no obvious change compared with the 0 month. See table 3.
The results show that the product has good stability and stable content of index components.
TABLE 3 results of 6 month accelerated test investigation of the inventive granule stability study
(V) acute toxicity test
The medical dry paste powder of the invention is subjected to an acute toxicity test according to the national non-clinical research quality management Specification (2017 edition) by the national academy of preventive medicine (food and drug safety evaluation center).
The purpose is as follows: in this experiment, the dry extract powder of the present invention was administered to rats in a single oral administration to observe the acute toxic reaction of animals.
The method comprises the following steps: the maximum dose method is adopted. The number of rats is 40, and the rats are randomly divided into 2 groups, namely a test object group and a negative control group, and 20 rats in each group are respectively half male and female. The test group was dosed with 36.0g/kg BW of the dry paste powder suspension of the invention, and the negative control group was dosed with distilled water. Following dosing, observations were continued for 14 days, at the end of the observation period, all animals were anesthetized and exsanguinated and then examined by dissection. The observation indexes include dying/mortality, clinical symptoms, weight, food intake, general section examination, etc.
Results: no unexpected death or dying of animals or obvious toxic symptoms occur in the experimental process. Compared with the corresponding control group: the body weights of the male and female rats in the test subject group are not significantly different: the daily feed intake of the male and female rats of the subject group was increased on days 2 and 3, and the difference was statistically significant (P < 0.05), and the difference was considered clinically insignificant because the increase was small (< 20%). No abnormalities were seen in the gross section of the animals in both the test and negative control groups.
Conclusion: the maximum tolerance of the dry paste powder of the invention to single oral administration of rats is 36.0g/kg BW/day (which is equivalent to 27.9 times of the equivalent dose of rats and 156.5 times of the clinical dose).
Random control clinical study
1. Data and method
Patients with qi deficiency and blood stasis symptoms in the recovery period of ischemic stroke are taken as subjects, and random, double-blind and placebo controlled clinical trial design is adopted. The subjects were randomized to a 2:1 ratio into a test group receiving conventional rehabilitation therapy and the granules of the invention and a control group receiving conventional rehabilitation therapy and placebo. The medicine taking method comprises the following steps: the medicine is taken orally 1 time and 1 bag, 7.5g of the medicine is taken in each bag, 2 times a day, and the administration period is 8 weeks. The influence of the invention on nerve function, sleep quality, motor function, activity capacity of daily life and the like after ischemic stroke is evaluated by analyzing the change conditions of total effective rate, ISI score, NIHSS score, FMA score, improved Barthel index and Chinese medicine symptom scale score of patients before and after treatment.
Western diagnostic criteria: meets the diagnosis standard of cerebral infarction in the revised diagnosis gist of various cerebrovascular diseases of the fourth national cerebrovascular diseases academic conference of China medical society.
Diagnostic criteria for traditional Chinese medicine: according to the prescription composition and the functional indications of the invention, qi deficiency and blood stasis are selected as observation syndromes according to the guidelines of clinical research on treating apoplexy by using new traditional Chinese medicines. Main symptoms are as follows: hemiplegia, facial distortion, slurred speech, or aphasia, hypoesthesia, or disappearance of sensation. Secondary symptoms: pale complexion, shortness of breath, debilitation, spontaneous sweating, pale tongue with white and greasy coating or with teeth marks, deep and thready pulse.
Disease staging criteria: reference is made to the guidelines for prevention and treatment of cerebrovascular diseases (trial edition) of China, the guidelines for clinical study on the treatment of apoplexy by new Chinese medicine (2002 edition) established by the department of health and disease prevention and control of the department of China, and the department of neurology of the China. Recovery period: onset is 2 weeks to 6 months.
Inclusion criteria: meets Western diagnosis standard of apoplexy and Chinese medicine differentiation standard; the patient is under 80 years of age; in the recovery period, 2 weeks to 6 months after the onset of the disease; the vital signs of the patient are stable, the consciousness is clear, and the patient can be matched with the patient for completing the treatment; sleep disorders; the patient has nerve function defects such as language disorder, limb dysfunction and the like, and the patient has no peripheral nerve injury or traumatic disease on the affected limb; patients were all the first onset.
Exclusion criteria: patients with severe symptoms or patients with unstable disease conditions; patients with other secondary changes; dysfunctions such as hemopoiesis, heart, liver, kidney, etc.; disabled people exist before the disease occurs; combining other nervous system disease patients; women in gestation or lactation.
2. Observation index
And (3) observing the indexes: (1) clinical effectiveness: basic cure: the NIHSS score is reduced by 90-100 percent; the effect is shown: the NIHSS score is reduced by 46-89%; the method is effective: the NIHSS score is reduced by 18 to 45 percent; invalidation: NIHSS scores decreased below 18%, or even increased. Total effective rate= (number of basic cure cases + number of significant cases + number of effective cases)/total case number x 100%. (2) Insomnia Severity Index (ISI): the higher the score, the heavier the sleep disorder, the total score of 0 to 28 points, the score of 0 to 7 points to no clinically significant insomnia, the score of 8 to 14 points to subthreshold insomnia, the score of 15 to 21 points to moderately severe clinical insomnia, and the score of 22 to 28 points to severely clinical insomnia; (3) National institutes of health stroke scale score (NIHSS): the method comprises 11 items of consciousness level, gaze, visual field, eyeball level movement, face appearance, upper limb movement, lower limb movement, ataxia, sensation, language, dysarthria neglect, wherein each item has 0, 1 and 2 grades, the total score is 0-46, and the higher the score is, the more serious the nerve damage is. For evaluating the neurological recovery of a patient. (4) simplified Fugl-Meyer motor function score (FMA): score in terms of score, score in upper limb 34 and score in lower limb 66. For evaluating motor function of a patient, a higher score indicates a better motor function; (5) improved barchel index (MBI): the total score is 100 points, and the lower the score is, the worse the activity of daily life is; (6) Chinese medicine symptom score: referring to the guidelines of clinical research on new Chinese medicine, the Chinese medicine is used for grading and scoring hemiplegia, facial distortion, slurred speech, hypoesthesia, pale complexion, shortness of breath and hypodynamia, spontaneous perspiration, swelling of limbs, and the like according to the non-scale (0 score), the scale (1 score), the scale (2 score) and the scale (3 score).
3. Results
3.1 Total effective rate comparison
After 8 weeks of treatment, the total effective rate of the test group reaches 87.5%, the total effective rate of the control group is 67.9%, and the difference between the two has statistical significance (P is less than 0.05). See table 4.
Table 4 comparison of clinical efficacy scores for two groups of patients
3.2ISI score comparison
The difference in the inter-group comparison of ISI scores of the two groups of patients prior to treatment is not statistically significant; the ISI score of the treated test group decreased and the ISI score of the control group did not change significantly. The ISI score was lower in the experimental group than in the control group, and the difference was statistically significant (P < 0.05). The ISI score change (absolute value of post-treatment-pre-treatment difference) was statistically significant (P < 0.05) in the experimental group over the control group. The invention can obviously improve sleep disorder of ischemic stroke patients, and the yang-tonifying five-returning decoction has no obvious effect of improving sleep disorder. See table 5.
Table 5 comparison of ISI scores for two groups of patients
a: p <0.05 compared to prior to treatment in this group; b: p <0.05 compared to the contemporaneous control group.
3.3NIHSS score comparison
NIHSS scores of the two groups of patients before treatment, and the comparison difference between the groups has no statistical significance; the score decreased after 8 weeks of treatment for both groups of patients compared to pre-treatment, the comparison difference being statistically significant (P < 0.05); after 8 weeks of treatment, the test group NIHSS score was lower than the control group, the difference was statistically significant (P < 0.05). The NIHSS score change (absolute value of the post-treatment-pre-treatment difference) was higher in the test group than in the control group, and the difference was statistically significant (P < 0.05). The invention and the yang-tonifying five-returning decoction can improve the neurological deficit of ischemic stroke patients, and the curative effect of the invention is better than that of the yang-tonifying five-returning decoction. See table 6.
Table 6 two groups of patients NIHSS score comparison
a: p <0.05 compared to prior to treatment in this group; b: p <0.05 compared to the contemporaneous control group.
3.4 comparison of FMA scores before and after treatment for two groups of patients
FMA scores of the two groups of patients before treatment, and the comparison difference between the groups has no statistical significance; the scores increased 8 weeks after treatment for both groups of patients compared to pre-treatment, the differences being statistically significant (P < 0.05); post-treatment test group FMA scores were higher than control group, and differences were statistically significant (P < 0.05). The FMA score variation (post-treatment-pre-treatment difference) was statistically significant (P < 0.05) for the test group over the control group. The invention and the yang-tonifying five-returning decoction can improve the exercise function of ischemic stroke patients, and the curative effect of the invention is stronger than that of the yang-tonifying five-returning decoction. See table 7.
Table 7 comparison of FMA scores for two groups of patients
a: p <0.05 compared to prior to treatment in this group; b: p <0.05 compared to the contemporaneous control group.
3.5 MBI score comparison of two groups of patients before and after treatment
The MBI scores of the two groups of patients before treatment have no statistical significance in comparison difference between the groups; the scores increased 8 weeks after treatment for both groups of patients compared to pre-treatment, the differences being statistically significant (P < 0.05); post-treatment test group MBI scores were higher than control group, and differences were statistically significant (P < 0.05). The MBI score change (post-treatment-pre-treatment difference) was statistically significant (P < 0.05) in the test group over the control group. The invention and the yang-tonifying five-returning decoction can improve the daily living activity of ischemic stroke patients, and the curative effect of the invention is stronger than that of the yang-tonifying five-returning decoction. See table 8.
Table 8 comparison of MBI scores at different time points for two groups of patients
a: p <0.05 compared to prior to treatment in this group; b: p <0.05 compared to the contemporaneous control group.
3.6 comparison of Chinese medicine symptoms score before and after treatment of two groups of patients
The Chinese medicine symptom score of the two groups of patients before treatment has no statistical significance in comparison difference between the groups; the scores were reduced after 8 weeks of treatment for both groups of patients compared to pre-treatment, the differences being statistically significant (P < 0.05); the post-treatment test group had a lower symptom score than the control group, and the difference was statistically significant (P < 0.05). The traditional Chinese medicine symptom score variation (absolute value of difference between treatment and pre-treatment) of the test group is higher than that of the control group, and the difference has statistical significance (P is less than 0.05), so that the traditional Chinese medicine symptom of ischemic stroke patients can be improved by the Chinese medicine symptom score variation and the pre-treatment score variation, and the traditional Chinese medicine symptom score variation and the pre-treatment score variation are better than those of the traditional Chinese medicine symptom score variation and the pre-treatment score variation of the control group. See table 9.
Table 9 comparison of Chinese medicine symptom scores for two groups of patients/>
a: p <0.05 compared to prior to treatment in this group; b: p <0.05 compared to the contemporaneous control group.
3.7 Security analysis
In the whole test process, the occurrence rate of the two groups of adverse events is low, and the two groups of adverse events have no difference in statistical significance, so that the safety and effectiveness of the medicament are proved. The results are shown in Table 10.
Table 10 comparative incidence of adverse reactions (example/%)
4. Conclusion(s)
Experiments prove that the invention has high clinical effective rate, can obviously reduce the ISI, NIHSS and Chinese medicine symptom scores of patients with qi deficiency and blood stasis type stroke convalescence, and raise FMA and MBI scores, which proves that the invention can improve the nerve functions of the patients, improve the sleep quality and improve the exercise and daily life activity ability. In addition, the research result also shows that the invention has no obvious side effect, is safe and reliable, and has practical clinical significance and popularization value.
(seventh) pharmacodynamic study
1. Materials and methods
1.1 laboratory animals and test subjects
SPF-grade healthy male SD rats 120, weight 220-250 g, purchased from Leston Jingda laboratory animals Co., hunan province, eligibility number: SCXK (Hunan) 2019-0004, adapted for 7 days, free diet.
Test article: the invention relates to a granule dry paste powder, which is produced by manufacturers: jinzhengtang pharmaceutical Co., ltd., lot number: z031822003. Naoxintong capsule, manufacturer: shaanxi step size pharmaceutical Co., ltd., lot number: 220107.
1.2 reagents and apparatus
MCAO wire bolt (the institute of laboratory equipment, the department of campaigns, the Tianjin city); ZH-Morris water maze (Anhua Zhenghua Co.); snowflake ice machine (SIMAG SPR 80); ultrasonic cell disruption instrument (Ningbo Xinzhi organism JY 92-11N); a multifunctional enzyme-labeled instrument (Tecan Austria GmbH); vortex mixer (SCILOGEX D1008E); an electrothermal constant temperature incubator (Japan ASONE ICV-450); low temperature refrigerated high speed centrifuge (Hunan instrument H1650-W); digital display pendulum shaking table (Servicebio DS-S100); magnetic stirrer (Servicebio MS-PB); vertical electrophoresis apparatus (Servicebio SVE-2); transfer electrophoresis apparatus (Servicebio SVT-2); ultra-thin microtomes (Leica UC 7); transmission electron microscopy (hitachi HT 7700); a forward fluorescence microscope (Nikon Eclipse Ci-L); chloral hydrate (microphone C804539-100G); toluidine blue staining (Biosharp); 4% paraformaldehyde (Servicebio); an electron microscope fixing solution (Servicebio G1102) full-automatic tissue embedding machine; SOD kit (Irireotide E-BC-K020-M); MDA kit (Irireotide E-BC-K025-M); ECL luminescence (melem); ANTI-BETA TUBULIN RABBIT PAB (Servicebio GB 11017); ANTI-tnfα rabit PAB (Servicebio GB 11188); ANTI-BAX rabit PAB (Servicebio GB 114122); ANTI-ICAM1 RABBIT (Bioss BS-0608R); the method comprises the steps of carrying out a first treatment on the surface of the ANTI-Caspase-3RABBIT PAB (Bioss BS-0081R); ANTI-IL-6RABBIT PAB (Bioss BS-6309R).
1.3 animal grouping and dosing design
The method comprises the steps of randomly grouping 120 healthy SD rats into a normal group, a sham operation group, a model group, a low, medium and high dose group and a brain heart through positive group, randomly dividing 10 normal groups and sham operation groups respectively by adopting a twice random grouping method, copying the MCAO reperfusion models of the rest 100 rats, dividing the nerve defect score of the rats into 1-3 into inclusion standards, eliminating the non-nerve defect symptom or symptom excess rats, randomly grouping again, and finally completing experiments smoothly by 10 normal groups, 10 sham operation groups, 8 model groups, 9 low dose groups, 8 medium dose groups, 10 high dose groups and 9 positive drug groups.
The test object used in the experiment is the dry paste powder of the granule, and the dry paste powder of the granule is converted according to the feeding amount, wherein 1g of the dry paste powder of the granule is equivalent to 4.16g of crude drug; the clinical dosage of the dry paste powder of the granule is 27.63g a day, the weight of an adult is calculated as 60kg, and the calculated clinical dosage is 27.63 g/60 kg=0.46 g/kg. The equivalent dose in rats was 2.88g/kg. The specific conversion formula is that the daily extract dosage/adult weight is 6.25. I.e. the equivalent dose of rats in human clinical dose is 2.88g/kg.
Early pre-experiments show that the dosage of the granule dry paste powder is set as the clinical dosage of a human, namely 2.88g/kg when a dosage gradient is set because the limit of the stomach-filling amount is influenced by excessive weakness after the rat is molded; the low dose is 1/2 of the clinical dose of human, namely 1.44g/kg; the high dose is 1.5 times of the clinical dosage of the human, namely 4.32g/kg. And in the Naoxintong positive group, the Naoxintong capsules are disassembled, then are packaged and re-weighed, and the stomach is irrigated at the dosage of 0.5g/kg, which is equivalent to the conventional dosage for clinical people.
The test substance is prepared on the same day, and the following steps are carried out:
low dose group liquor: accurately weighing 7.2g of a test object, pouring the test object into a beaker with proper size, adding about 40mL of distilled water, placing the beaker into an ultrasonic instrument, carrying out ultrasonic treatment at 60 ℃ for at least 30min, fully dissolving the test object, finally, fixing the volume to 50mL by using distilled water, and slightly shaking the test object uniformly to obtain the dry paste powder suspension of the granule with the concentration of 0.144 g/mL.
Medium dose group liquor: 14.4g of the tested object is accurately weighed, poured into a beaker with proper size, added with about 40mL of distilled water, placed into an ultrasonic instrument, subjected to ultrasonic treatment at 60 ℃ for at least 30min, fully dissolved, finally fixed to 50mL by distilled water, and gently shaken uniformly to obtain the dry paste powder suspension of the granule with the concentration of 0.288 g/mL.
High dose group liquor: accurately weighing 21.6g of a tested object, pouring the tested object into a beaker with proper size, adding about 40mL of distilled water, placing the beaker into an ultrasonic instrument, carrying out ultrasonic treatment at 60 ℃ for at least 30min, fully dissolving the tested object, finally, fixing the volume to 50mL by using distilled water, and gently shaking the mixture uniformly to obtain the dry paste powder suspension of the granule with the concentration of 0.432 g/mL.
Brain heart dredging positive group medicine liquid: accurately weighing 2.5g of the test object, pouring into a beaker with proper size, adding about 40mL of distilled water, placing into an ultrasonic instrument, performing ultrasonic treatment at 60 ℃ for at least 30min, fully dissolving, finally fixing the volume to 50mL by using distilled water, and gently shaking to obtain the brain-heart-dredging suspension with the concentration of 0.05 g/mL.
1.4 preparation of rat model with qi deficiency and blood stasis syndrome
The rats of each group were fed normal diet and had free diet. Except for the normal group, the rats in each group adopt a sleep deprivation method to replicate the qi deficiency and blood stasis syndrome of the rats. The experiment adopts a platform water environment method (platform technique), also called a water surface platform method and a water environment small platform method, which is a modeling method for carrying out sleep deprivation on experimental animals by placing the experimental animals on one or more narrow small platforms, wherein the platforms are arranged in a box with water at the bottom. The water environment small platform boxes used in the experiment are provided with 6 small platforms (diameter is 9cm, height is 9 cm) in each box, water depth is 7cm, 6 rats are placed, the rats are covered by a wire gauze with a trough, water bottles are inserted into the water boxes, the rats can eat and drink water freely during the experiment, the rats are taken out and put back into a squirrel cage after sleep deprivation for 18h (16:00 a day to 10:00 a day) every day, normal eating and drinking water is carried out, and sleep is continuously deprived for 21 days. Normal rats were fed normal diet and had free diet.
1.5 preparation of rat model with cerebral infarction
Except for the sham operation group, the rats with qi deficiency and blood stasis syndrome of the other groups are used for preparing an acute ischemic cerebral apoplexy model by adopting a modified middle cerebral artery embolism method (Zea Longa method). The rats are anesthetized by injecting 8% chloral hydrate into the abdominal cavity, the skin is incised on the right side of the middle of the neck, the left common carotid artery of the rats is exposed by blunt separation of subcutaneous tissue, the bifurcation of the internal and external carotid arteries is separated from the distal end along the common carotid artery, a standby line is placed under the common carotid artery and the external carotid artery, the proximal end of the common carotid artery and the external carotid artery are ligated, and the internal carotid artery is clamped by an arterial clamp. A small opening is cut at a position about 4mm away from the bifurcation of the common carotid artery, and a round-head end bolt wire of the MCAO nylon wire is inserted from the small opening and enters the internal carotid artery to slight resistance. Ligating internal carotid artery, suturing, cutting off the redundant part of the suppository line to leave about 1cm outside the skin, inserting the suppository for 2 hours, and pulling out the suppository inserted into the cranium to finish ischemia reperfusion operation. The sham operation group is operated as above, but only the common carotid artery and the external carotid artery are ligated, and no plug wire is used.
1.6 Observation index and method
1.6.1 serological test for the correlation of rat syndromes
Blood is taken from tail vein after 1 day and 14 days respectively after the traditional Chinese medicine is dried, serum is separated at 4 ℃ by a high-speed centrifuge, and the serum ATP and ADP levels of rats in each group are detected by a biochemical kit.
1.6.2 neurological deficit scoring
Rat neurological functions were scored using a 5-score scoring method established by Bederson et al. 0 point: no neurological symptoms; 1, the method comprises the following steps: when the tail is lifted and suspended, the contralateral forelimb of the rat presents internal rotation of the shoulder, abduction of the elbow and close to the chest wall; 2, the method comprises the following steps: the rat is placed on a smooth plane, the shoulder of the pushing operation moves to the opposite side, and the resistance is reduced; 3, the method comprises the following steps: dumping or turning around to the opposite side of the operation when the rat walks; 4, the following steps: no voluntary activity occurs.
1.6.3 Water maze experiments
The water maze experiment is divided into two stages of a positioning navigation experiment and a space exploration experiment. Positioning navigation experiments: after 14 days of traditional Chinese medicine intervention in each group of rats, each group of rats was subjected to a water maze experiment. Positioning navigation experiments the rats were respectively watered from 4 quadrants, the duration was recorded as escape latency if they climbed back to the platform within 90s, and the escape latency was defined as 90s if the rats did not find the platform within 90s. During the experiment, 7 groups of rats were subjected to two water maze tests at a fixed time in the morning with a 7d period. (II) space exploration experiment: after the space exploration experiment is finished, the platform is removed, the rat is put into water, and the number of times of passing through the area where the original platform is located in 90s of the rat is observed and recorded.
1.6.4 rat cerebral cortex infarction area HE staining
3 rats were randomly selected for each group, and 200mL of 4% paraformaldehyde solution was administered for cardiac perfusion, and brain tissue was harvested from the broken ends. And (3) dehydrating by using a totally-enclosed tissue dehydrator, embedding paraffin by using a fully-automatic tissue embedding device, and slicing at the coronal position with the thickness of 5 mu m. After brain tissue sections are dried, HE staining is carried out, and the regional tissue structure of cerebral cortex infarction and the morphological change condition of neurons of the rat are observed under a light microscope.
Determination of MDA and SOD molecular content level in 1.6.5 rat serum
The dry paste powder of the granule of the invention is used for inhibiting lipid peroxidation and scavenging excessive free radicals in the ischemia reperfusion process of rats by detecting the level of Malondialdehyde (MDA) and superoxide dismutase (SOD) in the serum of the rats by using an enzyme-linked immunosorbent assay (Elisa method).
1.6.6 determination of Caspase-3, ICAM-1, IL-6, TNF-alpha protein levels in rat brain tissue
Protein expression levels of apoptosis related factors Caspase-3, inflammatory response related factors ICAM-1, IL-6 and TNF-alpha in rat brain tissues are detected by Western Blot (Western Blot), and the improvement effect of the brain-strengthening and vein relaxing particles on inflammatory response and apoptosis after cerebral ischemia reperfusion injury of rats is explored.
2. Results
2.1 effects of the invention on serum ATP and ADP levels of rats with qi deficiency and blood stasis syndrome
Compared with the normal group, on the 1 st day of cerebral infarction model establishment, the ATP of rats in the other groups is obviously reduced, the ADP is obviously increased, and the difference has statistical significance (P < 0.05); after 14 days of administration of the traditional Chinese medicine, ATP starts to rise significantly and ADP starts to drop significantly compared with the normal group, and the difference has statistical significance (P < 0.05), wherein the amplitude of ATP rise and ADP drop is respectively high dose group, positive medicine, medium dose group, low dose group and model group from large to small. The results are shown in Table 11.
TABLE 11 detection results of serum ATP and ADP levels in rats of each group
a: p <0.05 compared to the normal group; b: p <0.05 compared to model set; c: p >0.05 compared to model group.
2.2 neurological deficit scoring
The model group and the administration group have statistically significant differences in neurological deficit score (P < 0.05) compared to the normal group on the first day of modeling, the traditional Chinese medicine intervention groups have no statistically significant differences in neurological deficit score (P > 0.05) compared to the model group, the traditional Chinese medicine intervention groups have statistically significant differences in neurological deficit score (P < 0.05) compared to the normal group on the 14 th day of traditional Chinese medicine intervention, the traditional Chinese medicine intervention groups have significantly reduced scores compared to the model group, and the differences have statistically significant differences (P < 0.05). Compared with the positive medicine, the difference of the neurological deficit scores of the high, medium and low dose groups has no statistical significance (P > 0.05), and is shown in Table 12.
Table 12 group rat neurological deficit score/>
a: p <0.05 compared to the normal group; b: p <0.05 compared to model set; c: p >0.05 compared to model group.
2.3 Water maze experiments
Positioning navigation experiment
Comparing 1-5 times of water maze positioning navigation experiments of rats in each group, the escape latency of rats in the model group and the traditional Chinese medicine group is obviously increased, and the rats have statistical difference (P < 0.05); compared with the model group, the first 2 experiments of the traditional Chinese medicine intervention group have longer incubation period, and the difference has no statistical significance (P is more than 0.05); the experimental results on days 3-5 show that the escape latency of the traditional Chinese medicine intervention group is obviously shortened, and the comparison model group has statistical difference (P < 0.05). See Table 13 for details.
Table 13 comparison of Morris water maze escape latency time for rats of each group
a: p <0.05 compared to the normal group; b: p <0.05 compared to model group.
(II) space exploration experiment
Comparing the space exploration experimental results of the rats of each group, comparing the model groups, and obviously increasing the times of crossing the platform by each traditional Chinese medicine intervention group, thereby having statistical significance (P < 0.05); compared with the normal group, the times of crossing platforms of the other groups are obviously reduced, and the method has statistical significance (P < 0.05); the number of times of crossing the platform is slightly more than that of other traditional Chinese medicine intervention groups in the brain heart through positive group, and the brain heart through positive group has no statistical significance (P is more than 0.05). The specific trajectories of the space exploration experiments of the rats in each group are shown in figure 1.
Positioning navigation experiments show that after the water maze platform is removed, normal group rat searches are mainly concentrated in target quadrants and pass through the target platform for a plurality of times. The model group rat searching strategy is edge type without purpose, the searching time in the target quadrant is short, and the number of times of crossing the target platform is small. The rats of the low, medium and high doses and the brain heart positive control group of the other granules are all in the target quadrant for long exploration time, long swimming distance and more times of crossing the platform. The invention has stronger improving effect on the learning and memory ability of the cerebral ischemia rats.
2.4 hippocampal Nib counts
Compared with the normal group, the number of the nikovia bodies in the hippocampus of the rats in the model group and the traditional Chinese medicine intervention group is obviously reduced, and the difference has statistical significance (P < 0.05); compared with the model group, the invention has the advantages that the number of the nikovia bodies in the hippocampus of the rats in the low, medium and high dose groups is obviously increased, and the difference has statistical significance (P < 0.05); the invention has the advantages that the number of the nikovia bodies in the hippocampus of the rats in the low, medium and high dose groups is increased compared with that in the Naoxintong positive group, and the difference has no statistical significance (P is more than 0.05). The difference of the number of the nikovia bodies in the hippocampus of the rats in the low, medium and high dose groups has no statistical significance (P is more than 0.05). The results are shown in Table 14, FIG. 2.
TABLE 14 Nib body count [ (]n＝3)
a: p <0.05 compared to the normal group; b: p <0.05 compared to model group.
2.5 detection of SOD and MDA molecular level of rat brain tissue of each group
The rats of each group were bled from the tail vein 14 days after the stomach lavage of the traditional Chinese medicine, and the levels of SOD and MDA molecules in the serum of each group of rats were detected by an Elisa method. The results show that the serum SOD level of rats in the model group is obviously reduced compared with that of rats in the normal group, and the difference has statistical significance (P < 0.05); comparing the model group, the serum SOD level of the rats in the low, medium and high dose groups of the invention is obviously increased, and the difference has statistical significance (P < 0.05); compared with the normal group, the MDA content of the serum malondialdehyde of the rats in the model group is obviously reduced, and the difference has statistical significance (P < 0.05); comparing the model group, the serum malondialdehyde MDA content of the rats in the low, medium and high dose groups is obviously increased, and the difference has statistical significance (P < 0.05); the invention is suggested to have a certain resistance to lipid peroxidation in the cerebral ischemia reperfusion process of rats, can effectively remove excessive free radicals in injured brain tissues, and can play a certain neuroprotection role, and the specific table is shown in Table 15.
Table 15 serum SOD and MDA concentrations before and after intervention in each group of rats />
a: p <0.05 compared to the normal group; b: p <0.05 compared to model group.
2.6 rat brain tissue related protein level detection
Caspase-3 is one of the most important apoptosis genes in human body, and cell adhesion molecules (ICAM 1) can specifically bind to the receptor thereof, so that the adhesion between leucocytes, inflammatory cells and the like and endothelial cells is enhanced to promote the occurrence of inflammatory reaction; interleukin 6 (IL-6) and induces intracellular signaling cascades that cause the production of inflammatory cytokines, promoting the occurrence of inflammatory responses; tumor necrosis factor (TNF- α) promotes the adhesion of neutrophils to endothelial cells, thereby stimulating a localized inflammatory response in the body.
And detecting the expression level of Caspase-3 protein in the brain tissue of the rat after the traditional Chinese medicine dry process in each group by using a western blot method. The result shows that compared with the normal group, the Caspase-3 protein expression level of the other cerebral infarction model groups is increased, and the difference has statistical significance (P < 0.05); the mean decrease in Caspase-3 protein expression levels in the low, medium and high dose and brain heart communication groups of the present invention was compared with the model group, and the specific results of the differences with statistical significance (P < 0.05) are shown in FIGS. 3 and 4.
Western blot results show that compared with a normal group, the expression levels of ICAM1, IL-6 and TNF-alpha proteins of the other cerebral infarction model groups are all increased, and the difference has statistical significance (p < 0.05); comparing the model group, the expression level of ICAM1, IL-6 and TNF-alpha protein in the low, medium and high dose groups is reduced, and the difference has statistical significance (P < 0.05); the specific results of the invention, which are statistically significant (P < 0.05) in the low, medium and high dose groups and the brain heart communication groups, are shown in FIGS. 5 and 6, wherein the comparison difference between ICAM1, IL-6 and TNF-alpha protein expression level groups is shown in the invention.
3. Conclusion(s)
The invention has better curative effect in treating ischemic stroke rats with qi deficiency and blood stasis, and the rats after the invention are dried can improve the energy metabolism condition of cerebral infarction rats with qi deficiency and blood stasis, improve the learning memory and cognitive ability of cerebral infarction rats and obviously shorten the positioning navigation experiment incubation period of cerebral infarction rats; the function of the rat is improved to a certain extent; the detection result on the molecular level shows that the invention can obviously reduce the concentration of rat serum Malondialdehyde (MDA) and superoxide dismutase (SOD), and has good effects of inhibiting lipid peroxidation and scavenging excessive free radicals. Meanwhile, the invention has certain regulation and control effects on related apoptosis factors and inflammatory factors, and has good neuroprotection effect. The invention with low, medium and high doses, which is set in the study, has no obvious dose-effect relationship in the influence on rats with ischemic stroke with qi deficiency and blood stasis.
The foregoing examples merely illustrate embodiments of the invention and are described in more detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present patent is to be determined by the appended claims.
Claims (4)
1. The traditional Chinese medicine composition with the functions of activating blood and soothing nerves is characterized by comprising the following raw materials in parts by weight: 10-50 parts of astragalus membranaceus, 3-20 parts of angelica sinensis, 3-20 parts of ligusticum wallichii, 3-20 parts of peach kernel, 3-20 parts of safflower, 10-30 parts of spina date seed, 3-20 parts of earthworm and 5-25 parts of poria cocos.
2. The traditional Chinese medicine composition with the function of activating blood circulation and soothing nerves according to claim 1 is characterized by comprising the following raw materials in parts by weight: 4-8 parts of astragalus membranaceus, 1-3 parts of angelica sinensis, 1-3 parts of ligusticum wallichii, 1-3 parts of peach kernel, 1-3 parts of safflower, 3-5 parts of spina date seed, 1-3 parts of earthworm and 2-4 parts of poria cocos.
3. The traditional Chinese medicine composition with the function of activating blood circulation and soothing nerves according to claim 2 is characterized by comprising the following raw materials in parts by weight: 6 parts of astragalus membranaceus, 2 parts of angelica sinensis, 2 parts of ligusticum wallichii, 2 parts of peach kernel, 2 parts of safflower, 4 parts of spina date seed, 2 parts of earthworm and 3 parts of poria cocos.
4. A method for preparing the traditional Chinese medicine composition with the function of activating blood circulation and soothing nerves according to any one of claims 1 to 3, which is characterized by comprising the following steps:
(1) Weighing the raw materials according to the proportion, adding water for decocting twice, adding 8 times of water for soaking for 30 minutes for 60 minutes for the first time, adding 6 times of water for decocting for 30 minutes for the second time, filtering, and combining the filtrates;
(2) Concentrating the filtrate under reduced pressure to obtain extract with relative density of about 1.10-1.15 (65-75 ℃);
(3) Spray drying the extract to obtain dry extract powder;
(4) Taking dry paste powder, adding a proper amount of maltodextrin, and uniformly mixing;
(5) Granulating with granulating device, packaging and sealing to obtain the final product.
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Non-Patent Citations (3)
| Title |
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| 王建伟;郭蓉娟;王嘉麟;贺立娟;刘向哲;王建华;: "中风病气虚血瘀证用药规律文献研究", 中医杂志, no. 01, pages 74 - 78 * |
| 王建芬;刘涓;史曼;乔剑锋;郝建勋;: "补阳还五汤在缺血性脑卒中患者中的应用", 临床合理用药杂志, no. 31, pages 85 - 86 * |
| 陈更福: "活血化瘀为主治疗缺血性脑卒中41例临床观察", 河北中医, no. 05, pages 18 * |
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