CN110841023B

CN110841023B - Pharmaceutical composition for treating Alzheimer disease

Info

Publication number: CN110841023B
Application number: CN201911321394.XA
Authority: CN
Inventors: 黎明全; 李玉娟; 王冰梅; 关树文; 刘立影; 刘聪
Original assignee: Changchun University of Chinese Medicine
Current assignee: Changchun University of Chinese Medicine
Priority date: 2019-12-19
Filing date: 2019-12-19
Publication date: 2021-11-02
Anticipated expiration: 2039-12-19
Also published as: CN110841023A

Abstract

The invention relates to a pharmaceutical composition for treating Alzheimer disease, belonging to the field of traditional Chinese medicines. The traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 8-12 parts of scutellaria baicalensis, 6-10 parts of coptis chinensis, 10-20 parts of phellodendron, 8-12 parts of gardenia, 6-12 parts of tortoise-plastron glue, 10-20 parts of fructus alpiniae oxyphyllae and 8-16 parts of wine-processed rhubarb. The invention has unique compatibility and strict prescription, has the effects of clearing away heat and toxic material, replenishing essence and nourishing marrow, and is suitable for amnesia, dull expression, reaction retardation, reversed speech, dry throat and mouth, dark urine and dry stool, red tongue with yellow coating and wiry and rapid pulse caused by the Alzheimer disease. Clinical trial research shows that the Chinese medicinal composition has high safety in clinical application, can obviously improve symptoms and has small side effect.

Description

Pharmaceutical composition for treating Alzheimer disease

Technical Field

The invention belongs to the field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition for treating Alzheimer disease.

Background

Alzheimer's Disease (AD) is a degenerative disease of the nervous system that is occult from disease to progressive memory loss and dementia. In recent years, the mortality rate of alzheimer's disease has been on an increasing trend year by year, and thus, effective prevention and treatment of alzheimer's disease has been imminent.

The pathological mechanism of alzheimer's disease is not well understood, and the academic accepted pathological mechanisms mainly include amyloid deposition of a β, neurofibrillary tangles of tau protein, oxidative stress, neuroinflammatory mechanisms, neurovascular injury, and the like. Amyloid a β is derived primarily from the hydrolysis of Amyloid Precursor Protein (APP). The breakdown pathways for APP include the "secretase breakdown pathway" and the "lysosomal breakdown pathway". Normally the secretase breakdown pathway is the major breakdown pathway, and only part of APP is cleaved via the lysosomal breakdown pathway. When external factors act or APP changes, the APP is mainly cracked through a lysosome decomposition pathway to generate a large amount of A beta, so that a large amount of A beta amyloid is deposited, and toxic effects are generated. Excessive concentrations of a β, β sheets and fiber formation are the basis for neurotoxic effects. the component of tau neurofibrillary tangles is abnormally phosphorylated tau protein that forms aggregates in paired double helix-like structures. Normally, tau protein has the effect of stabilizing cellular microtubules, and when it is highly phosphorylated, tau protein loses its binding to stabilized microtubules, causing nerve fibers to degenerate, resulting in AD.

Only 5 of the current western medicines for treating alzheimer disease are approved by FDA to be on the market, namely donepezil, galantamine, rivastigmine, tacrine and memantine, however, these medicines can only delay the progression of the disease and cannot treat alzheimer disease fundamentally.

Tacrine is the first generation acetylcholinesterase inhibition that promotes cholinergic neurotransmission, allowing the receptor to be stimulated for a prolonged period of time, and although approved by the FDA for marketing, it is less used because of its severe hepatotoxicity. While a new study has found that tacrine isoform Kojo tacrine (KT2D), which has inhibitory effects on acetylcholinesterase, has antioxidant properties, has a significant neuroprotective effect on a β, and is less toxic to the liver than tacrine, a large amount of clinical trial data is still required to determine its clinical properties. Donepezil maintains cognition, has better overall sexual function, relatively less adverse reaction, is taken 1 time a day, has good curative effect-economic benefit, and is the only drug which is approved by FDA and used for treating various degrees of severity AD at present. The rivastigmine is used for treating mild and moderate AD caused by Parkinson, and has higher safety for patients needing various drug combinations. Excitatory amino acid receptor antagonists are the first FDA-approved drugs for the treatment of moderate to severe dementia, representing the drug memantine. Memantine can improve cognitive function, daily life ability, comprehensive ability and psychobehavioral symptoms, and especially has certain therapeutic effect on psychobehavioral abnormalities such as delusion and horror of patients with moderate and severe AD. The memantine and the cholinesterase inhibitor are combined to treat moderate and severe AD, so that the cognitive function and the daily life ability can be effectively improved, and the incidence rate of adverse reactions is not increased.

Disclosure of Invention

The invention provides a pharmaceutical composition for treating Alzheimer's disease, which has the effects of clearing heat, removing toxicity, replenishing essence and nourishing marrow, and has the advantages of high safety, small side effect and the like.

Alzheimer's disease is also known in Chinese medicine as "dementia", "amnesia", "dementia", etc. Su Wen & Ting tiao Lun mentioned: "blood flowing downward and qi flowing upward and disharmony and forgetfulness" indicates that reverse disorder of qi and blood can lead to "forgetfulness". Qing, Wang Qing ren (correction of medical forest) considers that: the "the old has no memories and the brain becomes empty", and "Nei Jing Yi" (the essence and meaning of the Nei Jing) considers that "the old has kidney essence deficiency and marrow source deficiency, which makes the marrow sea not sufficient, and the mind is unclear and the disease is dull ". Kidneys store essence, essence is filled in brain, and brain is the fu-organ of spirit, indicating that the spirit is mainly thought agile and normal in cognition.

The pharmaceutical composition is prepared by taking the coptis detoxification decoction as a basic prescription and adding tortoise plastron glue, fructus alpiniae oxyphyllae and wine rhubarb. In the formula, the coptis chinensis is used as a monarch drug to purge heart fire and middle-jiao fire; the scutellaria baicalensis is used as a ministerial drug for clearing away lung heat and purging the fire in the upper-jiao, and the phellodendron amurense is used as an adjuvant drug for purging the fire in the lower-jiao; in the formula, the three yellows are used for purging the fire of the three cokes, and the cape jasmine is used as a guiding drug for purging the fire and relieving restlessness, so that heat can be discharged from urine and urine; the wine rhubarb is good at clearing heat and toxicity in the upper-jiao blood system, has the efficacy of purging heat and relaxing bowels, and is capable of purging fire heat on one hand and guiding pathogenic factors out from the lower part on the other hand, so that the heat pathogenic factors are easier to eliminate. The tortoise-plastron glue is an emotional product of blood and meat, and has three functions in the formula: the aged has the effects of replenishing essence and nourishing marrow to nourish brain and marrow due to kidney essence deficiency and brain and marrow malnutrition; kidney essence deficiency failing to nourish the tendons and vessels, and being apt to soreness and weakness of the waist and knees, and kidney-tonifying and bone-strengthening effects, and strengthening the bones and muscles; the tortoise plastron glue has the effects of clearing heat and nourishing yin, and prevents the coptis chinensis, the scutellaria baicalensis and the phellodendron amurense from damaging yin due to excessive heat clearing; the kidney is the innate root, the spleen and the stomach are the acquired root, the spleen and the kidney are weakened day by day after the old, and the sharpleaf galangal fruit can warm and tonify the yang of the spleen and the kidney and nourish the innate and acquired root to ensure that the brain and marrow are filled.

The coptis chinensis is a monarch drug in the formula and has the effects of clearing heat, drying dampness, purging fire and removing toxicity, and one of the main components in the coptis chinensis is berberine. Berberine can treat AD by accelerating the degradation of a β and reducing the production of a β. Experimental research shows that the berberine can obviously improve the learning and memory abilities of dementia model mice, and shows that the berberine has a protective effect on the damage of Abeta. In addition, the berberine also has the functions of reducing the level of phosphorylated Tau protein, reducing the tangle of neuron fibers and protecting brain cells so as to achieve the aim of preventing and treating AD.

The radix Scutellariae is a ministerial drug, and has effects of clearing heat, eliminating dampness, clearing pathogenic fire, removing toxic substances, cooling blood, stopping bleeding, and preventing miscarriage. The main chemical component of scutellaria is baicalin, which can prevent mitochondrial enzyme reduction induced by Abeta and reduce apoptotic neurons, and has a certain effect of oxidative stress.

The cortex phellodendri is an adjuvant drug in the formula, and has the effects of clearing heat, eliminating dampness, purging fire, removing steam, detoxifying and treating sore. Through network pharmacology investigation, HO-1 is a cytoprotective enzyme resisting oxidative stress, and phellodendron amurense can prevent and treat AD by regulating the activity of HO-1. Meanwhile, the methanol extract of the golden cypress can effectively inhibit the generation and the release of inflammatory factors and NO in microglia cells, and has the effect of resisting neurodegenerative change.

The colla Plastri Testudinis is solid gum prepared by decocting carapax et Plastrum Testudinis with water and concentrating. Salty, sweet and cool in nature and flavor, enter liver and kidney heart channels, and have the functions of nourishing yin, clearing heat, tonifying kidney, strengthening bone, replenishing essence and nourishing marrow.

Fructus Alpinae Oxyphyllae is dry mature fruit of Alpinia oxyphylla of Zingiberaceae. It is pungent and warm in nature and taste. It enters spleen and kidney meridians, and has effects of warming kidney, stopping nocturnal emission, reducing urination, warming spleen, stopping diarrhea, and controlling saliva. Researches show that the fructus alpiniae oxyphyllae leaching liquor has higher effects of eliminating hydrogen peroxide and hydroxyl radical activity so as to protect nerve cells and prevent AD.

The wine-processed rhubarb has the effects of purging and eliminating accumulation, clearing heat and purging fire, has the effect of resisting oxidative stress and can relieve the injury of cerebral ischemia reperfusion.

Fructus Gardeniae has effects of clearing heat-fire, relieving restlessness, clearing heat, promoting diuresis, cooling blood, and removing toxic substance. The main chemical component of gardenia is geniposide. In the research of AD rats, the geniposide is found to improve the learning and memory ability of AD model rats and effectively inhibit the pathological changes of the hippocampal cells of the AD model rats.

The invention is a proved prescription summarized by a large amount of clinical practices of the inventor, has strict formula, definite curative effect and safe medicament dosage, and is prepared from the following raw material medicaments in part by weight:

8-12 parts of scutellaria baicalensis, 6-10 parts of coptis chinensis, 10-20 parts of phellodendron, 8-12 parts of gardenia, 6-12 parts of tortoise-plastron glue, 10-20 parts of fructus alpiniae oxyphyllae and 8-16 parts of wine-processed rhubarb;

preferably:

10 parts of scutellaria baicalensis, 10 parts of coptis chinensis, 15 parts of golden cypress, 10 parts of gardenia, 10 parts of tortoise-plastron glue, 15 parts of fructus alpiniae oxyphyllae and 10 parts of wine-processed rhubarb.

The medicine can be prepared into any conventional oral preparation by adopting a conventional method of a traditional Chinese medicine preparation.

The invention has the advantages that:

the invention has unique compatibility and strict prescription, has the effects of clearing away heat and toxic material, replenishing essence and nourishing marrow, and is suitable for amnesia, dull expression, reaction retardation, reversed speech, dry throat and mouth, dark urine and dry stool, red tongue with yellow coating and wiry and rapid pulse caused by the Alzheimer disease. Clinical trial research shows that the Chinese medicinal composition has high safety in clinical application, can obviously improve symptoms and has small side effect.

Detailed Description

Example 1

The traditional Chinese medicine composition is prepared from the following traditional Chinese medicine raw materials in parts by weight:

8 parts of scutellaria baicalensis, 6 parts of coptis chinensis, 10 parts of phellodendron, 8 parts of gardenia, 6 parts of tortoise-plastron glue, 10 parts of fructus alpiniae oxyphyllae and 8 parts of wine-processed rhubarb;

making into traditional Chinese medicine powder according to conventional method.

Example 2

10 parts of scutellaria baicalensis, 8 parts of coptis chinensis, 15 parts of phellodendron, 10 parts of gardenia, 9 parts of tortoise-plastron glue, 15 parts of fructus alpiniae oxyphyllae and 12 parts of wine-processed rhubarb;

Example 3

12 parts of scutellaria baicalensis, 10 parts of coptis chinensis, 20 parts of phellodendron, 12 parts of gardenia, 12 parts of tortoise-plastron glue, 20 parts of fructus alpiniae oxyphyllae and 16 parts of wine-processed rhubarb;

Example 4

10 parts of scutellaria baicalensis, 10 parts of coptis chinensis, 15 parts of phellodendron, 10 parts of gardenia, 10 parts of tortoise-plastron glue, 15 parts of fructus alpiniae oxyphyllae and 10 parts of wine-processed rhubarb;

The effects of the present invention will be further described by clinical trials.

1.1 general data

Cases were selected from 124 cases of alzheimer disease from month 8 in 2018 to month 8 in 2019, diagnosed in my campus of patients 60-80 years old.

1.2 diagnostic criteria

The diagnosis standard refers to AD diagnosis standard proposed by American National Institute of Aging (NIA) and Alzheimer's disease (AA) in 2011.

1.3 inclusion criteria

(1) Patients who meet the NIA-AA diagnostic criteria proposed by the American National Institute for Aging (NIA) and the Alzheimer's disease society (AA) in 2011; (2) brain atrophy is shown by CT or MRI on the head.

1.4 exclusion criteria

(1) Cognitive disorders can be explained by other psychiatric disorders (e.g., major depressive disorder, schizophrenia, liver and kidney insufficiency, hypothyroidism, alcoholism, etc.); (2) (ii) a disease that interferes with the assessment of cognitive function; (3) those with severe complications of the center of gravity, liver, kidney and hematopoietic system; (4) drugs for dementia not relevant to this study are being taken.

1.5 grouping method

The total number of patients was 124, and 60 of western medicine symptomatic treatment groups (control group) and 64 of the middle medicine treatment groups (observation group) were included.

1.6 methods of treatment

As a control group, donepezil hydrochloride tablets (Weizi pharmaceutical Co., Ltd., standard: 5 mg/tablet) were administered in an initial amount of 5mg, and the clinical response of the patients was evaluated one month and then the amount was increased to 10 mg. The observation group gives the medicine powder (10 parts of radix scutellariae, 10 parts of coptis chinensis, 15 parts of phellodendron, 10 parts of gardenia, 10 parts of tortoise-plastron glue, 15 parts of fructus alpiniae oxyphyllae and 10 parts of wine-processed rhubarb). The treatment course is 3 months.

1.7 Observation index and therapeutic index

The basic information data includes sex, age, disease course, smoking and drinking. The therapeutic index includes ADL, ADAS-cog, MMSE score. The evaluation work of the above scales is completed by the same group of doctors.

1.8 statistical methods

Statistical analysis of the data was performed using SPSS 25.0.

2 results of the study

2.1 comparison of general data of two groups of patients

The comparison P of the sex, age, course of disease, smoking and drinking of the two groups of patients is more than 0.05, and the difference has no statistical significance.

TABLE 1 comparison of general data for two groups of patients

2.2 Pre-and post-treatment ADL score comparison of two groups of patients

After treatment, both groups had a decrease in ADL score compared to pre-treatment (P < 0.05), and the observed group was lower than the control group (P < 0.05).

TABLE 2 comparison of ADL scores before and after treatment in two groups of patients

Note: comparison of control group with observation group after treatment^＊P＜0.05。

2.3 comparison of ADAS-cog scores before and after treatment in two groups of patients

After treatment, ADAS-cog scores were reduced in both groups compared to the pretreatment group (P < 0.05), and the observed group was superior to the control group (P < 0.05).

TABLE 3 comparison of ADAS-cog scores before and after treatment in two groups of patients

2.4 comparison of mental State Scale assessment in two groups of patients

The MMSE score after treatment was higher in both groups than before treatment (P < 0.05), and the observed group was higher than the control group (P < 0.05).

TABLE 4 simplified mental State Scale score comparison for two groups of patients

2.5 comparison of incidence of adverse reactions in two groups

The incidence of adverse reactions of two groups of patients during the treatment period is not obviously different, and P is more than 0.05.

TABLE 5 comparison of adverse event incidence during two groups of treatments

Typical cases

Example 1

Initial diagnosis: patient, female, 66 years old, visit in 2017 month 10. Amnesia and slow response appeared 2 years ago, and in severe cases, the patients had taken the medicine by mistake and lost 2 times. Dull expression, speech disorder, thought, irritability and anorexia. A red tongue with a thin coating and a wiry pulse. The ADAS-cog scale score was 39 points; ADL scale score of 43 points; the simple intelligent state checklist is divided into 15 points. Head CT indicates multiple lacunar infarction; brain atrophy. The donepezil hydrochloride tablet of 5mg is orally taken at once, and then the donepezil hydrochloride tablet is stopped taking due to insomnia. Alzheimer's disease is diagnosed. The traditional Chinese medicine diagnoses dementia which belongs to the syndrome of hyperactivity of heart and liver fire. It is indicated for clearing heat and removing toxicity, replenishing essence and nourishing marrow. 10g of medicinal scutellaria baicalensis, 10g of coptis chinensis, 15g of golden cypress, 10g of gardenia, 10g of tortoise plastron glue, 15g of fructus alpiniae oxyphyllae and 12g of wine-processed rhubarb. Taken 2 times daily in the morning and evening with 100ml of warm water.

And (3) return diagnosis: after 30 days, the patient turns good, forgetfulness is relieved, the patient is willing to exchange, and appetite is strengthened earlier. The biggest change of the family members who complain about the patients is that the patients take the medicines on time, and the medicines are taken more correctly. According to the patient's condition, 15g of Sharen is added to regulate the function of the stomach. Taking the medicine for 2 months to consolidate the treatment.

Three diagnoses: the patient can make a double-visit after taking the medicine for 2 months, so that the amnesia is improved, the communication capacity is enhanced, and the appetite is normal. And (4) scale evaluation: the ADAS-cog scale scored 33 points; ADL scale score 26 points; the simple intelligent state check table is divided into 21 points. The above should be continued to enhance the therapeutic effect. Patients complain of stable illness after 3 months of follow-up visit, and the condition of loss does not appear yet.

Example 2

Initial diagnosis: patients, male, 72 years old, visit 2018 in 2 months. The main complaints are: hypomnesis and slow response for more than 1 year. The current symptoms are as follows: hypomnesis, slow response, restlessness, irritability, soreness and weakness of the waist and knees, bitter taste, dry mouth, poor sleep, dry stool. Red tongue with yellow coating and wiry and rapid pulse. History of the past: the patient has a hypertension history of 5 years, the maximum blood pressure is 170/100mmHg, and the self-statement control is good. Head MRI shows: cortical brain atrophy. The ADAS-cog scale score was 39 points; ADL scale score 40 points; the simple intelligent status check table is 18 points. And (3) Western diagnosis: alzheimer's disease. Traditional Chinese medicine diagnosis: dementia and fire syndrome due to yin deficiency. Therapeutic method: clearing away heat and toxic material, invigorating kidney and replenishing marrow. The prescription consists of the following components: 12g of scutellaria baicalensis, 12g of coptis chinensis, 12g of golden cypress, 15g of gardenia, 12g of tortoise plastron glue, 15g of fructus alpiniae oxyphyllae and 8g of wine-processed rhubarb. Taken 2 times a day, 100ml in the morning and evening.

And (3) return diagnosis: after 20 days, the memory of the patient is slightly better than that of the patient before, the patient has vexation, irritability, soreness and weakness of waist and knees, dry mouth and bitter taste and has the same symptoms as before. The upper part is taken after the first time.

Three diagnoses: the doctor visits the patient in 2018 in 5 months. The memory of the patient is better than before, the reaction capability is stronger than before, the vexation and irritability are less likely to appear, and the dry mouth and bitter mouth are obviously better. The ADAS-cog scale scored 30 points; ADL scale score 25 points; the simple intelligent status check table 22 points. The patient is advised to continue taking the medicine to consolidate the curative effect after the symptoms are improved.

Example 3

Initial diagnosis: the patient, male, was aged 76 years, and visited the clinic in 2019 month 3. The main complaints are: memory decline is more than 2 years. The current symptoms are as follows: hypomnesis, slow response, hypocalculation, flushing, conjunctival congestion, palpitation, restlessness, poor sleep and normal stool and urine. A red tongue with yellow and greasy coating and a wiry pulse. Head MRI shows: bilateral cerebral radiation coronary, basal ganglia zone lacunar cerebral infarction, partial softening focus; senile brain atrophy. The ADAS-cog scale scored 38 points; ADL scale score of 43 points; the simple intelligent state checklist is divided into 15 points. And (3) Western diagnosis: alzheimer's disease. Traditional Chinese medicine diagnosis: dementia, syndrome of hyperactivity of heart-liver fire. Therapeutic method: clearing away heat and toxic material, tonifying kidney and replenishing marrow. The prescription consists of the following components: 12g of scutellaria baicalensis, 10g of coptis chinensis, 16g of golden cypress, 15g of gardenia, 15g of tortoise-plastron glue, 15g of fructus alpiniae oxyphyllae and 10g of wine-processed rhubarb. Taken 2 times a day in the morning and evening with 100ml of warm water. At the same time, family members of the patient are required to buy the oral calculation card to train the calculation capability of the patient.

And (3) return diagnosis: after 30 days, the memory of the patient is improved, the face red and the eyes red are relieved, and the palpitation and uneasiness are relieved. 15g of rhubarb and the rest of the medicines are unchanged.

Three diagnoses: the doctor visits 7 months in 2019. The memory of the patient is improved more than before, and the patient has red face and eyes, palpitation and uneasiness. The ADAS-cog scale scored 30 points; ADL scale score 27 points; the simple intelligent state check table is divided into 21 points. The patient is advised to take the medicine once every other day to consolidate the curative effect.

Claims

1. The pharmaceutical composition for treating the Alzheimer disease is characterized by being prepared from the following raw material medicines in parts by weight:

8-12 parts of scutellaria baicalensis, 6-10 parts of coptis chinensis, 10-20 parts of phellodendron, 8-12 parts of gardenia, 6-12 parts of tortoise-plastron glue, 10-20 parts of fructus alpiniae oxyphyllae and 8-16 parts of wine-processed rhubarb.

2. The pharmaceutical composition for treating alzheimer's disease according to claim 1, which is prepared from the following raw material medicines in parts by weight:

3. The pharmaceutical composition according to claim 1 or 2, for the treatment of alzheimer's disease, wherein: the traditional Chinese medicine preparation is prepared into any conventional oral preparation by a conventional method.