Application of Tablet for treating dyspepsia in preparation of medicine for improving alteration of intestinal flora

Abstract

The invention relates to the technical field of biological medicine, in particular to application of Xiaoming tablets in preparation of a medicine for improving intestinal flora imbalance. The tablet is prepared from 20 to 30 parts of rhizoma acori graminei, 30 to 40 parts of semen cassiae, 30 to 40 parts of herba cistanche, 30 to 40 parts of radix puerariae, 30 to 40 parts of semen celosiae, 40 to 50 parts of radix codonopsis, 30 to 40 parts of fructus viticis, 40 to 50 parts of fructus lycii, 30 to 40 parts of semen plantaginis, 40 to 50 parts of radix paeoniae alba, 20 to 30 parts of fructus corni, 20 to 30 parts of liquorice root, 60 to 70 parts of semen cuscutae, 1 to 10 parts of rhizoma cimicifugae, 30 to 40 parts of nux prinsepiae, 30 to 40 parts of flos chrysanthemi, 30 to 40 parts of flos buddlejae, 30 to 40 parts of rhizoma chuanxiong, 30 to 40 parts of wine-processed rhizoma polygonati, 60 to 70 parts of radix rehmanniae The technical scheme of the invention has the advantages of wider clinical application range, good curative effect, low cost and small side effect.

Description

Technical Field

[0001] The present application relates to the field of biomedicine technology, and in particular to the use of Zhanyanming tablets in the preparation of drugs for improving intestinal flora imbalance. Background Art

[0002] The intestinal flora is a complex ecological community of trillions of parasites in the human intestine. Through their collective metabolic activities and interactions with the host, they affect the host's normal physiological activities and disease susceptibility. Intestinal microorganisms participate in the body's immune regulation and nutritional metabolism, and are closely related to aging.

[0003] In the intestines of healthy adults, there are five most abundant bacterial phyla, namely Bacteroidetes, Firmicutes, Actinomycetes, Proteus and Verrucosa, among which Bacteroidetes and Firmicutes are the most common. Not all intestinal flora are beneficial to the human body. For example, Bifidobacterium and Lactobacillus are called beneficial bacteria. Bacteria such as Staphylococcus aureus and hemolytic Streptococcus are called pathogenic bacteria by competitively inhibiting the growth and reproduction of beneficial bacteria. In addition, there is a class of bacteria that are harmful to the human body only under specific conditions, such as Escherichia coli and Proteus, called conditional pathogens. When the parasitic position of these bacteria in the intestine or the surrounding environment changes, they will proliferate rapidly, breaking the balance of intestinal flora and causing various clinical diseases, which is intestinal flora imbalance.

[0004] At present, the methods for regulating intestinal flora mainly include probiotic preparations, prebiotic preparations, fecal microbiota transplantation and traditional Chinese medicine treatment. Probiotic preparations are mainly beneficial bacteria for the human body, that is, beneficial bacteria in the intestines that have physiological and immune functions. They can be live bacteria, dead bacteria, components or products. Probiotics require strict storage conditions and are relatively expensive. In addition, some patients with probiotic treatment of intestinal flora imbalance experience adverse reactions such as abdominal distension, constipation, and migraine after taking probiotics. Prebiotic preparations refer to substances that can selectively stimulate or promote the colonization, growth or activation of one or several physiological bacteria in the host intestinal mucosa. Prebiotics are not effective when used alone and do not have an inhibitory effect on conditional pathogens and pathogens. Fecal microbiota transplantation refers to the transplantation of functional flora in the feces of healthy people into the gastrointestinal tract of patients to rebuild intestinal flora with normal functions, thereby treating intestinal flora imbalance. However, the exact efficacy of fecal microbiota transplantation on flora imbalance is still unclear, and there is a risk of multi-drug resistant bacteria infection and death. Compared with the first three methods, TCM has been fully developed in the treatment of intestinal flora imbalance, and the theoretical system is becoming more mature. The principle of TCM's yin-yang balance in treating diseases is consistent with the theory of ecological balance of intestinal flora. TCM can change the overall function of intestinal flora by adjusting the types and number of dominant flora, interfere with the body's absorption and utilization of substances, and thus affect the body's health status. At the same time, TCM needs the intestinal flora to decompose and metabolize drugs in order to make the effective ingredients in the drugs available for treatment.

[0005] At present, there have been many clinical cases reporting the good therapeutic effects of traditional Chinese medicine on diseases accompanied by intestinal dysbiosis. However, since traditional Chinese medicine treatment emphasizes holistic treatment and syndrome differentiation and treatment, different traditional Chinese medicine formulas are provided for different diseases in the reported cases. Therefore, patients with dysbiosis but whose symptoms are not yet clear cannot arbitrarily refer to and adopt publicly available treatment methods.

[0006] The traditional Chinese medicine compound (with the corresponding trade name "Zhanyanming Tablets") composed of Acorus calamus, Cassia seed, Cistanche deserticola, Pueraria root, Amaranthus fruit, Codonopsis pilosula, Vitex rotundifolia, Lycium barbarum, Plantago seed, White peony root, Cornus officinalis, Licorice, Cuscuta seed, Cimicifuga heracleifolia, Semen rutinae, Chrysanthemum, Buddismia odorata, Ligusticum chuanxiong, Polygonatum sibiricum, Rehmannia root, Phellodendron chinense and Astragalus has the effects of nourishing the liver and kidneys, removing cataracts and improving eyesight. It is clinically used for early-stage and middle-aged and senile cataracts. The ingredients of the prescription are mild and the side effects are small. Developing its further medical uses will help expand the scope of application of traditional Chinese medicine and greatly shorten the development time and research costs. Summary of the invention

[0007] The present application unexpectedly discovered the excellent regulating effect of Zhanyanming tablets in improving intestinal flora imbalance during a series of activity studies on the tablets. Based on this, the present application provides the use of the tablets in the preparation of a drug for improving intestinal flora imbalance. The tablets include: 20-30 parts of Acorus calamus, 30-40 parts of Cassia seed, 30-40 parts of Cistanche deserticola, 30-40 parts of Pueraria root, 30-40 parts of Atractylodes lancea, 40-50 parts of Codonopsis pilosula, 30-40 parts of Rhizoma Cibotii, 40-50 parts of Vitex rotundifolia, 40-50 parts of Lycium barbarum, 30-40 parts of Plantago seed, 40-50 parts of White Peony Root, 20-30 parts of Cornus officinalis, 20-30 parts of Licorice, 60-70 parts of Cuscuta seed, 1-10 parts of Cimicifuga heracleifolia, 30-40 parts of Rhizoma Cynomorii, 30-40 parts of Chrysanthemum, 30-40 parts of Buddismia, 30-40 parts of Ligusticum chuanxiong, 30-40 parts of Polygonatum sibiricum, 60-70 parts of Rehmannia root, 30-40 parts of Phellodendron chinense and 40-50 parts of Astragalus.

[0008] The technical solution of the present application is conducive to expanding the scope of clinical application, and has the advantages of good efficacy, low cost and few side effects.

[0009] In one embodiment, the eye-changing tablets include: 22 parts of Acorus calamus, 30 parts of Cassia seed, 37 parts of Cistanche deserticola, 37 parts of Pueraria root, 30 parts of Amaranthus aquatica, 48 parts of Codonopsis pilosula, 30 parts of Vitex rotundifolia, 48 parts of Lycium barbarum, 37 parts of Plantago seed, 45 parts of White Peony Root, 24 parts of Cornus officinalis, 22 parts of Licorice, 61 parts of Cuscuta seed, 7 parts of Cimicifuga heracleifolia, 37 parts of Rhizoma Cynomorii, 37 parts of Chrysanthemum, 37 parts of Buddlejac, 30 parts of Ligusticum chuanxiong, 37 parts of Polygonatum sibiricum, 61 parts of Rehmannia root, 30 parts of Phellodendron chinense and 48 parts of Astragalus.

[0010] In one embodiment, the intestinal flora imbalance includes:

[0011] The relative abundance of Bacteroidetes and Verrucomicrobia increased, and the relative abundance of Firmicutes decreased; and / or,

[0012] A decrease in the ratio between Firmicutes and Bacteroidetes; and / or,

[0013] The relative abundance of vadinBB60 group of Clostridiales and Ruminococcaceae decreased, and the relative abundance of Muribaculaceae increased; and / or,

[0014] Increased relative abundance of Enterobacter spp.; and / or,

[0015] The relative abundance of Eubacterium xylanophilum and Oscillatory Spirillum decreased.

[0016] In one embodiment, the intestinal flora imbalance is caused by an intestinal disease, and the Chinese medicine composition is used to prepare a medicine for preventing and treating the intestinal disease.

[0017] In one embodiment, the intestinal disease includes at least one of megacolon, colitis and constipation.

[0018] In one embodiment, the drug is a solid preparation.

[0019] In one embodiment, the solid preparation is selected from ordinary tablets, dispersible tablets, sustained-release tablets, capsules, granules or powders.

[0020] In one embodiment, the medicine contains an effective amount of the Chinese medicine composition.

[0021] In one embodiment, the subject of the drug is a mammal.

[0022] In one embodiment, the subject of the drug is a mouse or a human.

[0023] The application of the Zhanyanming tablets of the present application in the preparation of drugs for improving intestinal flora imbalance overcomes the defect that the existing traditional Chinese medicine treatment is limited to the treatment of specific diseases and causes intestinal flora imbalance. It can exert multi-target effects through multiple groups, intervene in the dominant flora in the intestine, adjust the intestinal flora structure, and improve intestinal flora imbalance. It is more widely and convenient to use in clinical practice.

[0024] The Zhanyanming tablets in the technical solution of the present application are composed of 22 kinds of pure plant medicines, have small toxic and side effects, are not likely to cause drug dependence in patients, are low in cost, can be widely promoted, and provide an effective and low-side effect treatment method for adjusting the intestinal microecology and improving intestinal flora imbalance in clinical Chinese medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0026] Figure 1 The PCA analysis results of the Beta diversity of the intestinal flora of mice in different groups (NC group, BCA group, and ZYMT group) in Example 1 of the present application;

[0027] Figure 2 This is a heat map of the relative abundance of different intestinal flora phyla of mice in different groups (NC group, BCA group, ZYMT group) in Example 1 of the present application;

[0028] Figure 3 It is a bar chart showing the relative abundance of key intestinal flora phyla of mice in different groups (NC group, BCA group, and ZYMT group) in Example 1 of the present application. Bacteroidota abundance refers to the relative abundance of Bacteroidetes, Verrucomicrobiota abundance refers to the relative abundance of Verrucomicrobia, and Firmicutes abundance refers to the relative abundance of Firmicutes.

[0029] Figure 4 This is a heat map of the relative abundance of different intestinal flora families of mice in different groups (NC group, BCA group, and ZYMT group) in Example 1 of the present application;

[0030] Figure 5 It is a bar chart showing the relative abundance of the key intestinal flora families of mice in different groups (NC group, BCA group, and ZYMT group) in Example 1 of the present application. Muribaculaceae abundance refers to the relative abundance of Muribaculaceae family, Ruminococcaceae abundance refers to the relative abundance of Ruminococcaceae family, and Clostridia_vadinBB60_groupabundance refers to the relative abundance of the vadinBB60 group of the Clostridia order;

[0031] Figure 6 This is a heat map of the relative abundance of different intestinal flora genera in different groups of mice (NC group, BCA group, ZYMT group) in Example 1 of the present application;

[0032] Figure 7This is a bar chart of the relative abundance of key intestinal flora genera in different groups of mice (NC group, BCA group, ZYMT group) in Example 1 of the present application. Muribaculum abundance refers to the relative abundance of Eubacterium, [Eubacterium]_xylanophilum_group abundance refers to the relative abundance of Eubacterium xylanophilum, and Oscillibacter abundance refers to the relative abundance of Oscillibacter. DETAILED DESCRIPTION

[0033] The present application will be further described below in conjunction with the embodiments and examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. In addition, it should be understood that after reading the content taught in the present application, those skilled in the art may make various changes or modifications to the present application, and these equivalent forms also fall within the protection scope of the claims attached to the present application.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0035] the term

[0036] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0037] Herein, "BCA" refers to benzalkonium chloride. In a specific experiment, the subjects were treated in the form of a benzalkonium chloride solution, and the mass concentration of the benzalkonium chloride solution was generally 0.2%.

[0038] "PCA analysis" refers to the use of variance decomposition to reflect the differences between multiple groups of data on a two-dimensional or three-dimensional coordinate graph. The coordinate axes are two or three eigenvalues ​​that can best reflect the variance. For example, the more similar the sample composition is, the closer the distance reflected in the PCA graph is.

[0039] The phyla, families and genera of bacteria that appear in this article and their English names are as follows:

[0040] Bacteroidota: Bacteroidetes.

[0041] Verrucomicrobiota: Verrucomicrobiota.

[0042] Firmicutes: Firmicutes.

[0043] Clostridia_vadinBB60_group: Clostridiales vadinBB60 group.

[0044] Ruminococcaceae: Ruminococcaceae, whose main fermentation metabolite is acetic acid, the abundance of this genus has been shown to be positively correlated with intestinal motility.

[0045] Muribaculaceae: (also known as Mucispirillum) is a bacterial family that includes some intestinal commensal bacteria that produce intestinal mucus. It was previously classified as part of the Bacteroidaceae family. The bacteria in this family play important physiological functions in the intestine, such as participating in food digestion and nutrient absorption, regulating the immune system, etc.; Muribaculaceae is a newly established bacterial family name, formerly known as the S24-7 family, which is mainly related to various dietary treatments, host conditions or rodent colonization processes.

[0046] Muribaculum: Enterobacterium muribae;

[0047] Eubacterium: Eubacterium is an important intestinal bacterium found in the colon of healthy people. It is one of the core bacterial genera of the human intestinal microbiota and plays an important role in the body's nutritional metabolism and maintaining intestinal balance.

[0048] [Eubacterium]_xylanophilum_group: Eubacterium xylanophilum belongs to the family Lachnospiraceae of the phylum Firmicutes. Its horizontal abundance is positively correlated with the degree of intestinal homeostasis, and its presence is related to the production of branched-chain amino acids and short-chain fatty acids.

[0049] Oscillibacter: Oscillibacter is associated with reduced cholesterol levels in feces and plasma. It has the ability to metabolize cholesterol, including glycosylation and dehydrogenation. Bacteria of this genus can metabolize cholesterol in the intestine, thereby helping to lower host cholesterol levels and the risk of cardiovascular disease, and is beneficial to lipid balance and cardiovascular health.

[0050] F / B: The ratio of the relative abundance of Firmicutes to Bacteroidota. Abnormal values ​​of this ratio reflect potential pathological changes. For example, abnormal increases in the abundance of specific Firmicutes or Bacteroidota species lead to obesity and intestinal inflammation, respectively.

[0051] The term "and / or" used in this article includes any one of two or more related listed items, and also includes any and all combinations of related listed items, and the arbitrary and all combinations include any two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0052] Herein, "preferred", "preferable", "better", etc. are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute limitations on the scope of protection of this application.

[0053] In the present application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0054] In the present application, the terms "first", "second", "third", etc. in "the first aspect", "the second aspect", "the third aspect", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0055] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0056] In the present application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges included therein.

[0057] In this application, "prevention and treatment" includes concepts such as prevention, treatment, and auxiliary treatment.

[0058] In the present application, a "composition" may be a combination of multiple substances, and further, may be used in combination, or may be a mixture of the combination.

[0059] In the present application, "effective amount" refers to the dosage of the component corresponding to the term in a subject to achieve the treatment, prevention, alleviation and / or relief of a specific disease, condition and / or symptom. In the present application, unless otherwise specified, it refers to the dosage to achieve the treatment, prevention, alleviation and / or relief of intestinal ischemia-reperfusion injury.

[0060] In the present application, "subject" is an animal, preferably a mammal, more preferably a human, and the subject includes but is not limited to food consumers, health product users and patients with diseases, disorders and / or symptoms. The subject in the present application is preferably a mammal. The term "mammal" mainly refers to warm-blooded vertebrate mammals, including but not limited to: such as cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice (such as rats, mice), pigs, cattle, sheep, horses, humans, etc., preferably primates, more preferably humans. Taking the subject of steviol bioside as an example, it refers to an animal that receives steviol bioside or its composition to treat, prevent, alleviate and / or relieve diseases, disorders, symptoms.

[0061] In the present application, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" mainly refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, cattle, sheep, horses, humans, etc., preferably primates, more preferably humans.

[0062] In the present application, "pharmaceutical composition" refers to a composition that has a pharmaceutical preventive and / or therapeutic effect and can be used in medicine.

[0063] As used herein, "drug" includes any agent, compound, composition or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The scope of the physiological and / or pharmacological effects produced by the "drug" in vivo is not particularly limited, and may be systemic effects or may only produce effects locally. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances, or an inert substance that does not interact.

[0064] As used herein, "therapeutically effective amount" refers to the amount of a pharmaceutically active ingredient that will elicit a biological or medical response in an individual to a disease, disorder and / or symptom, for example, the amount of a compound of the present application that brings about a physiologically and / or pharmacologically positive effect in an individual, wherein the physiologically and / or pharmacologically positive effect includes but is not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression or preventing disease, etc.

[0065] As used herein, "pharmaceutically acceptable" refers to those ligands, materials, compositions and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0066] In this application, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with drug administration. Each substance must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, etc. Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; and (21) other non-toxic compatible substances used in pharmaceutical formulations. In the present application, "pharmaceutically acceptable carrier" can be selected from the following range: including but not limited to mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine ​​hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium sodium EDTA, carbonates, acetates, phosphates or aqueous solutions of monovalent alkali metals, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinyl pyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, phospholipid materials, kaolin, talc, calcium stearate, magnesium stearate.

[0067] The first aspect of the present application

[0068] In the first aspect of the present application, there is provided a use of a Zhanyanming tablet (also referred to as Chinese medicine composition I) in the preparation of a drug (also referred to as drug II) for improving intestinal flora imbalance. This method overcomes the defect that traditional Chinese medicine treatment requires specific compatibility for specific diseases, has a wider range of applications, and is more convenient for clinical use.

[0069] In the present application, unless otherwise specified, reference to "Chinese medicine composition I" refers to a Chinese medicine composition comprising the following components: Acorus calamus, Cassia seed, Cistanche deserticola, Pueraria root, Amaranthus aquatica, Codonopsis pilosula, Vitex rotundifolia, Lycium barbarum, Plantago seed, White peony root, Cornus officinalis, Licorice, Cuscuta seed, Cimicifuga heracleifolia, Semen raphanii, Chrysanthemum, Buddleja buddleja, Ligusticum chuanxiong, Polygonatum sibiricum, Rehmannia root, Phellodendron chinense and Astragalus.

[0070] Specifically, the weight proportions of each component are: 20-30 parts of Acorus calamus, 30-40 parts of Cassia seed, 30-40 parts of Cistanche deserticola, 30-40 parts of Pueraria root, 30-40 parts of Amaranthus aquatica, 40-50 parts of Codonopsis pilosula, 30-40 parts of Vitex rotundifolia, 40-50 parts of Lycium barbarum, 30-40 parts of Plantago seed, 40-50 parts of White Peony Root, 20-30 parts of Cornus officinalis, 20-30 parts of Licorice, 60-70 parts of Cuscuta seed, 1-10 parts of Cimicifuga heracleifolia, 30-40 parts of Rhizoma Cynomorii, 30-40 parts of Chrysanthemum, 30-40 parts of Buddlejac, 30-40 parts of Ligusticum chuanxiong, 30-40 parts of Polygonatum sibiricum, 60-70 parts of Rehmannia root, 30-40 parts of Phellodendron chinense and 40-50 parts of Astragalus.

[0071] In one embodiment, the Chinese medicine composition includes: 22 parts of Acorus calamus, 30 parts of Cassia seed, 37 parts of Cistanche deserticola, 37 parts of Pueraria root, 30 parts of Amaranthus aquatica, 48 parts of Codonopsis pilosula, 30 parts of Vitex rotundus, 48 ​​parts of Lycium barbarum, 37 parts of Plantago seed, 45 parts of White Peony Root, 24 parts of Cornus officinalis, 22 parts of Licorice, 61 parts of Cuscuta seed, 7 parts of Cimicifuga heracleifolia, 37 parts of Semen Polygoni Multiflori, 37 parts of Chrysanthemum, 37 parts of Buddleja buddleja, 30 parts of Ligusticum chuanxiong, 37 parts of Polygonatum odoratum, 61 parts of Rehmannia root, 30 parts of Phellodendron chinense and 48 parts of Astragalus.

[0072] In one embodiment, the Chinese medicine composition specifically refers to Zhanyanming tablets.

[0073] Intestinal flora imbalance, also known as intestinal microbial imbalance, refers to the imbalance caused by changes in the type, quantity, proportion or distribution of normal microbial communities in the intestine due to various reasons. This imbalance may lead to a variety of gastrointestinal and extraintestinal diseases, causing symptoms such as diarrhea, abdominal pain, and bloating.

[0074] Common causes of intestinal flora imbalance include improper eating habits, abuse of antibiotics, and aging. For example, long-term use of antibiotics can reduce the flora that is sensitive to antibiotics, leading to overgrowth of drug-resistant bacteria. In addition, bad eating habits may disrupt the balance of intestinal flora. The decrease in the number of beneficial bacteria and the increase in harmful bacteria in the intestines of the elderly may also lead to flora imbalance. Intestinal flora imbalance is also associated with a variety of diseases, including but not limited to inflammatory bowel disease (IBD), type 2 diabetes (T2DM), autoimmune diseases, mental illness, intestinal cancer, irritable bowel syndrome (IBS), chronic fatigue syndrome, etc.

[0075] In one embodiment, intestinal flora imbalance includes:

[0076] The relative abundance of Bacteroidota and Verrucomicrobiota increased, and the relative abundance of Firmicutes decreased; and / or,

[0077] A decrease in the ratio between Firmicutes and Bacteroidota; and / or,

[0078] The relative abundance of the vadinBB60 group of the Clostridiales and the Ruminococcaceae family decreased, while the relative abundance of the Muribaculaceae family increased; and / or,

[0079] Increased relative abundance of Muribaculum; and / or,

[0080] The relative abundance of Eubacterium xylanophilum and Oscillibacter decreased.

[0081] In one embodiment, the intestinal flora imbalance is caused by an intestinal disease, and the Chinese medicine composition is used to prepare a medicament for preventing and treating the intestinal disease.

[0082] In one embodiment, the intestinal disease includes at least one of megacolon, colitis and constipation.

[0083] In some embodiments, drug II is a solid preparation.

[0084] In some embodiments, the solid preparation is selected from ordinary tablets, dispersible tablets, sustained-release tablets, capsules, granules or powders.

[0085] In some embodiments, drug II contains an effective amount of traditional Chinese medicine composition I.

[0086] In some embodiments, the drug II comprises: (a) a Chinese medicine composition I; and (b) a pharmaceutically acceptable excipient and / or a pharmaceutically acceptable carrier. In some embodiments, the drug II comprises: a Chinese medicine composition I and a pharmaceutically acceptable excipient. In some embodiments, the drug II comprises a Chinese medicine composition I and a pharmaceutically acceptable carrier. In some embodiments, the drug II comprises a Chinese medicine composition I, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable carrier.

[0087] In some embodiments, drug II is a blinding pill.

[0088] Zhanyanming Tablets are included in the 2020 edition of the Chinese Pharmacopoeia. They have the effects of nourishing the liver and kidneys, removing cataracts and improving eyesight. They are suitable for eye diseases such as dry eyes, visual fatigue, cataracts and other vision-related diseases.

[0089] In some embodiments, in drug II, the mass percentage of traditional Chinese medicine composition I is 85% to 90%, and examples of the mass percentage are 85%, 86%, 87%, 88%, 89%, 90%, etc.

[0090] In some embodiments, the subject of Drug II is a mammal.

[0091] In some embodiments, the subject of Drug II is a mouse or a human.

[0092] In some embodiments, drug II exerts multi-target effects through multiple groups, intervenes in the dominant flora in the intestine, adjusts the structure of the intestinal flora, and improves intestinal flora imbalance.

[0093] The definition of intestinal dysbiosis is given above.

[0094] The second aspect of the present application

[0095] The second aspect of the present application provides a method for preventing and treating intestinal flora imbalance, comprising administering a therapeutically effective amount of Chinese medicine composition I to a patient in need thereof. That is, administering a therapeutically effective amount of Chinese medicine composition I to the patient.

[0096] Mode of administration

[0097] There is no particular limitation on the dosage form and administration method of the Zhanyanming tablet (Chinese medicine composition I) of the present application.

[0098] Representative routes of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration, inhalation.

[0099] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, sugar pills, capsules, pills and granules may be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the above-mentioned excipients.

[0100] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, specifically, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices. For example, the suspension may contain a suspending agent, specifically, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methylate and agar or mixtures of these substances.

[0101] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0102] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants, which are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required under sterile conditions.

[0103] It is to be understood that the medicine of the present application embodiment can be added with different pharmaceutically acceptable adjuvants to be prepared into suitable clinical dosage forms, and these clinical dosage forms include but are not limited to the dosage forms described above. These pharmaceutically acceptable adjuvants include but are not limited to diluents, wetting agents, adhesives, disintegrants, lubricants, color and flavor regulators, solvents, solubilizers, cosolvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, local analgesics, pH regulators, isotonic or isotonic regulators, etc. Further: diluents, such as starch, sucrose, cellulose, inorganic salts, etc.; wetting agents, such as water, ethanol, etc.; binders, such as starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol, etc.; disintegrants, such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium dicarboxymethyl cellulose, cross-linked polyvinylpyrrolidone, surfactants, and paternal disintegrants, etc.; lubricants, such as talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, micro-powdered silica gel, polyethylene glycol, etc.; color and flavor regulators, such as pigments, flavors, sweeteners, Flavoring agents, adhesives, deodorants, etc., such as fuchsin and xylitol; solvents, such as water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, ethyl acetate, etc.; solubilizers, such as Tweens, sorbents, polyoxyethylene fatty alcohol ethers, soaps, sulfates, sulfonates, etc.; cosolvents, such as organic acids (such as citric acid) and their salts, amide and amine compounds, inorganic salts, polyethylene glycol, povidone, glycerol, etc.; emulsifiers, such as spans, tweens, sorbents, benzyls, glycerol fatty acid esters, high fatty acid salts, sulfates, sulfonates, gum arabic, tragacanth gum, gelatin, pectin, phospholipids, agar, sodium alginate, hydroxides, silicon dioxide, bentonite, etc.; suspending agents, such as glycerol, syrup, gum arabic, tragacanth gum, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, thixotropic glue, etc.; antioxidants, such as sulfites, pyrosulfites, bisulfites, ascorbic acid, gallic acid and its esters, etc.; metal complexing agents, such as disodium ethylenediaminetetraacetic acid, polycarboxylic acid compounds, etc.; inert gases, such as Nitrogen, carbon dioxide, etc.; preservatives, such as parabens, organic acids and their salts (such as sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils, etc.; local analgesics, such as benzyl alcohol, chlorobutanol, lidocaine and procaine, etc.; pH adjusters, such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphates, acetates, citric acid, citrate, etc.; isotonic or isotonic adjusters, such as glucose, sodium chloride, sodium citrate, sorbitol and xylitol, etc.It can be understood that the diluent described in the embodiments of the present application can also be called a filler, which plays the same role in the pharmaceutical preparation; the water described in the embodiments of the present application is water that meets the requirements of the medicine, such as water for injection, purified water, etc., and the oil is oil for injection; the preservative described in the embodiments of the present application can also be called an antibacterial agent, which plays a role in inhibiting the growth of microorganisms and prolonging the shelf life in the preparation; the lubricant described in the embodiments of the present application contains a flow aid, an anti-adhesive agent, etc.; the sugar described in the embodiments of the present application can be powdered sugar or syrup, and the type of sugar is not limited to glucose; the flavors described in the embodiments of the present application include but are not limited to flavors.

[0104] In some embodiments, the administration frequency is 1 to 3 times / day, for example, once / day, twice / day, or three times / day.

[0105] In some embodiments, the dosage administered is 1.2 g / kg / day.

[0106] In some embodiments, the Chinese medicine composition I is administered orally.

[0107] In some embodiments, the Chinese medicine composition I is administered by intragastric administration.

[0108] In this article, "gastric administration" refers to the direct delivery of liquids, suspensions, semi-fluids, etc. into the stomach through a catheter through the oral cavity or nasal cavity and esophagus. In some embodiments, the dosage is: 1.2 mL of saline solution of the drug composition I is administered by gavage per kg body weight (the Chinese medicine composition I is added to saline solution, prepared at 1 g / mL, shaken, and dissolved at room temperature).

[0109] The "Chinese medicine composition I" in the second aspect of the present application can be selected from including but not limited to the Chinese medicine composition I described above, and reference can be made to the first aspect of the present application.

[0110] In some embodiments, the Chinese medicine composition I is a solid preparation. In some embodiments, the solid preparation is selected from ordinary tablets, dispersible tablets, sustained-release tablets, capsules, granules or powders.

[0111] In some embodiments, the patient is human or mouse.

[0112] In some embodiments, the patient is a human.

[0113] In some embodiments, the patient is a mouse.

[0114] The third aspect of the present application

[0115] The third aspect of the present application provides a Chinese medicine composition I for preventing and treating intestinal flora imbalance.

[0116] The "Chinese medicine composition I" in the third aspect of the present application can be selected from including but not limited to the Chinese medicine composition I described above, and reference can be made to the first aspect of the present application.

[0117] The following are some specific embodiments.

[0118] For experimental parameters not specified in the following specific embodiments, reference is made to the instructions given in the present application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by manufacturers.

[0119] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources, or can be prepared by those skilled in the art according to known methods.

[0120] The drug Zhanyanming Tablets (National Medicine Standard No. Z44022460) used in the following specific examples was provided by Guangzhou Baiyunshan Zhongyi Pharmaceutical Co., Ltd.

[0121] Example 1

[0122] 1. Experimental Methods

[0123] 1.1 Fifteen 6-8-week-old C57BL / 6J mice were randomly divided into three groups: control group (NC group), model group (BCA group), and ZYMT group (ZYMT group), with 5 mice in each group. The mice in the ZYMT group were given ZYMT at a rate of 1.2 g per kg body weight per day by intragastric administration of ZYMT solution (ZYMT solution was 1 g / mL ZYMT in saline), while the NC group and BCA group were given the same volume of saline by intragastric administration.

[0124] 1.2 Model construction method: Both the BCA group and the ZYMT group were constructed using the following method.

[0125] (1) Prepare 0.2% benzalkonium chloride solution: Wrap the wall of a 15 ml centrifuge tube with tin foil to protect it from light; weigh 0.03 g of benzalkonium chloride powder into the 15 ml centrifuge tube; add 15 ml of sterile double distilled water; after mixing, 0.2% benzalkonium chloride solution (BCA) is prepared.

[0126] (2) Place the mouse on an iron rack, pull the mouse's tail back with the right hand, gently lift the skin on the back of the mouse's neck with the left hand to expose both eyes, lift the mouse and clamp the tail with the left ring finger and little finger to completely control the mouse; at the same time, use a pipette in the right hand to drop 5 μL of the prepared 0.2% benzalkonium chloride (BCA) into both eyes, once in the morning and once in the evening for 14 days, thereby inducing dry eyes and intestinal flora imbalance; the control group mice were given 5uL of sterile double-distilled water drops in the same way for 14 days.

[0127] 1.3 After modeling and treatment intervention, mouse feces were collected for 16S rRNA gene sequencing to analyze the effect of the Zhanyanming tablets on the intestinal microecology of mice.

[0128] 2. Experimental results

[0129] 2.1 Effect of Zhanyanming tablets on intestinal flora of mice

[0130] 2.1 PCA analysis of the effect of Zhanyanming tablets on the Beta diversity of intestinal flora in mice

[0131] Beta diversity is the degree of diversity among organisms, that is, comparing the differences between samples in different groups. Figure 1 The PCA analysis results of the Beta diversity of intestinal flora of mice in different groups (NC group, BCA group, and ZYMT group) are shown in Table 1. Figure 1 It can be seen that the inter-group difference between the BCA model group and the NC group was very obvious, indicating that the intestinal flora diversity of the model mice was significantly changed after the administration of BCA, while the distance between the ZYMT intervention group (ZYMT) and the NC group was close, indicating that the administration of ZYMT can effectively regulate the intestinal flora of mice and improve it to a level close to normal.

[0132] 2.2 Effect of Zhanyanming tablets on the relative abundance of bacterial phyla in the intestinal flora of mice

[0133] Cluster analysis was performed on the relative abundance of intestinal flora of mice in different groups, and a heat map was obtained as shown in the figure. Figure 2 , the bar chart is as follows Figure 3 .according to Figure 2 and Figure 3 It can be seen that compared with the control group, the proportion of Bacteroidota and Verrucomicrobiota in the intestine of the BCA model group was significantly increased, and the proportion of Firmicutes was significantly decreased; compared with the model group, after intervention with the Zhanyanming tablets, the levels of Bacteroidetes, Verrucomicrobiota and Firmicutes showed a significant correction, the abundance of Bacteroidetes and Verrucomicrobiota decreased significantly, and the abundance of Firmicutes increased significantly, and the differences were statistically significant.

[0134] according to Figure 3 The F / B value was calculated from the data. The F / B value of the NC group was 0.605251681, the F / B value of the BCA group was 0.19124995, and the F / B value of the ZYMT group was 0.398555209. It can be seen that the (F / B) ratio of the BCA model group was significantly reduced. Compared with the model group, the (F / B) ratio was restored to a normal level after intervention with the blinding film.

[0135] 2.3 Effect of Zhanyanming tablets on the relative abundance of bacterial families in the intestinal flora of mice

[0136] Cluster analysis was performed on the relative abundance of bacterial families in the mouse intestinal flora to obtain a heat map as shown in Figure 4 , the bar chart is as follows Figure 5 .according to Figure 4 and Figure 5 It can be seen that the relative abundance of Clostridia vadinBB60 group (Clostridia_vadinBB60_group) and Ruminococcaceae in the intestinal flora disorder model group caused by BCA decreased significantly. After the administration of Zhanyanming tablets, the levels of these three bacterial families showed a significant correction, and the difference was statistically significant; compared with the control group, the relative abundance of Muribaculaceae in the intestinal flora disorder model group caused by BCA increased significantly, and after the administration of Zhanyanming tablets, the relative abundance of Muribaculaceae showed a significant decrease, and the difference was statistically significant.

[0137] 2.4 Effect of Zhanyanming tablets on the relative abundance of bacterial genus levels in the intestinal flora of mice

[0138] Cluster analysis was performed on the relative abundance of the genus level of the mouse intestinal flora to obtain a heat map as shown in Figure 6 , the bar chart is as follows Figure 7 .according to Figure 6 and Figure 7 It can be seen that the relative abundance of Muribacillus Muribaculum in the intestinal flora disorder model group caused by BCA was significantly increased; after the administration of Zhanyanming tablets, the relative abundance of Muribacillus Muribaculum showed a significant decrease, and the difference was statistically significant; compared with the control group, the relative abundance of [Eubacterium]_xylanophilum_group (p<0.05) and Oscillibacter (p=0.058) in the intestinal flora disorder model group caused by BCA was significantly decreased, and after the administration of Zhanyanming tablets, the relative abundance of [Eubacterium]_xylanophilum_group (p<0.05) and Oscillibacter (p=0.051) showed a significant correction.

[0139] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited with all contents and all purposes. When the cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0140] The technical features of the above-mentioned implementation modes and examples can be combined in any appropriate manner. To make the description concise, not all possible combinations of the technical features in the above-mentioned implementation modes and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0141] The above-described embodiments only express several implementation methods of the present application, but they cannot be understood as limiting the scope of the patent application. It should be pointed out that, for those of ordinary skill in the art, without departing from the concept of the present application, several variations and improvements can also be made, which all belong to the protection scope of the present application. In addition, it should be understood that after reading the above-mentioned teaching content of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by those skilled in the art on the basis of the technical solutions provided in the present application through logical analysis, reasoning or limited experiments are all within the protection scope of the claims attached to the present application. Therefore, the protection scope of the patent of the present application shall be based on the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. The use of Zhanyanming tablets in the preparation of a drug for improving intestinal flora imbalance, characterized in that: The eye-changing tablets include: 20-30 parts of Acorus calamus, 30-40 parts of Cassia seed, 30-40 parts of Cistanche deserticola, 30-40 parts of Pueraria root, 30-40 parts of Amaranthus aquatica, 40-50 parts of Codonopsis pilosula, 30-40 parts of Vitex rotundifolia, 40-50 parts of Lycium barbarum, 30-40 parts of Plantago seed, 40-50 parts of White Peony Root, 20-30 parts of Cornus officinalis, 20-30 parts of Licorice, 60-70 parts of Cuscuta seed, 1-10 parts of Cimicifuga heracleifolia, 30-40 parts of Rhizoma Cynomorii, 30-40 parts of Chrysanthemum, 30-40 parts of Buddlejac, 30-40 parts of Ligusticum chuanxiong, 30-40 parts of Polygonatum sibiricum, 60-70 parts of Rehmannia root, 30-40 parts of Phellodendron chinense and 40-50 parts of Astragalus.

2. The use according to claim 1, characterized in that: The eye-changing tablets include: 22 parts of Acorus calamus, 30 parts of Cassia seed, 37 parts of Cistanche deserticola, 37 parts of Pueraria root, 30 parts of Amaranthus aquatica, 48 parts of Codonopsis pilosula, 30 parts of Vitex rotundus, 48 ​​parts of Lycium barbarum, 37 parts of Plantago seed, 45 parts of White Peony Root, 24 parts of Cornus officinalis, 22 parts of Licorice, 61 parts of Cuscuta seed, 7 parts of Cimicifuga heracleifolia, 37 parts of Rhizoma Cynomorii, 37 parts of Chrysanthemum, 37 parts of Buddlejac, 30 parts of Ligusticum chuanxiong, 37 parts of Polygonatum sibiricum, 61 parts of Rehmannia root, 30 parts of Phellodendron amurense and 48 parts of Astragalus.

3. The use according to claim 1 or 2, characterized in that: The intestinal flora imbalance includes: The relative abundance of Bacteroidetes and Verrucomicrobia increased, and the relative abundance of Firmicutes decreased; and / or, A decrease in the ratio between Firmicutes and Bacteroidetes; and / or, The relative abundance of vadinBB60 group of Clostridiales and Ruminococcaceae decreased, and the relative abundance of Muribaculaceae increased; and / or, Increased relative abundance of Enterobacter spp.; and / or, The relative abundance of Eubacterium xylanophilum and Oscillatory Spirillum decreased.

4. The use according to claim 1 or 2, characterized in that: The intestinal flora imbalance is caused by intestinal diseases, and the traditional Chinese medicine composition is used to prepare medicines for preventing and treating the intestinal diseases.

5. The use according to claim 4, characterized in that: The intestinal disease includes at least one of megacolon, colitis and constipation.

6. The use according to any one of claims 1, 2 and 5, characterized in that The medicine is a solid preparation.

7. The use according to claim 6, characterized in that: The solid preparation is selected from ordinary tablets, dispersible tablets, sustained-release tablets, capsules, granules or powders.

8. The use according to any one of claims 1, 2 and 5, characterized in that The medicine contains an effective amount of the traditional Chinese medicine composition.

9. The use according to any one of claims 1, 2 and 5, characterized in that The subject of the drug is a mammal.

10. The use according to claim 9, characterized in that: The subject is a mouse or a human.

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