WO2020051973A1 - 伏龙肝在制备防治过敏性疾病、精神类疾病、代谢类疾病和内分泌紊乱疾病药物中的应用 - Google Patents

伏龙肝在制备防治过敏性疾病、精神类疾病、代谢类疾病和内分泌紊乱疾病药物中的应用 Download PDF

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WO2020051973A1
WO2020051973A1 PCT/CN2018/110877 CN2018110877W WO2020051973A1 WO 2020051973 A1 WO2020051973 A1 WO 2020051973A1 CN 2018110877 W CN2018110877 W CN 2018110877W WO 2020051973 A1 WO2020051973 A1 WO 2020051973A1
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allergic
diseases
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周东蕊
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Southeast University
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to a new use of Fulonggan, and particularly relates to the application of Fulonggan in the preparation of medicines for preventing and treating allergic diseases, mental diseases, metabolic diseases and endocrine disorders.
  • Allergic diseases can occur at all ages, from newborns to the elderly.
  • the main types of allergic diseases are skin allergic reactions, respiratory allergic reactions, gastrointestinal allergic reactions, and anaphylactic shock.
  • the common diseases are as follows: allergic dermatitis, allergic rhinitis, allergic asthma, allergic purpura, anaphylactic shock , Allergic bowel disease, etc.
  • allergic dermatitis includes drug rash, contact dermatitis, eczema, urticaria, skin scratches, food allergies and environmental factors causing allergies.
  • Allergic bowel disease mainly refers to allergic colitis, ulcerative colitis and Crohn's disease.
  • the treatment of allergic diseases mainly uses antihistamines and hormonal drugs, and antihistamines such as chlorpheniramine, astemazine, mink, and caritamide.
  • Antihistamines have side effects, and long-term use can cause drowsiness, fatigue, and mental retardation.
  • Hormone drugs such as adrenocortical hormones, such as prednisone, dexamethasone, cyclophosphamide, and azathioprine. Commonly used hormones can seriously damage internal organs such as the liver and kidneys, and also affect children's growth and development.
  • the purpose of the present invention is to thoroughly study the efficacy of Fulonggan through a large number of experimental screenings and develop its new clinical efficacy.
  • the technical solutions adopted by the present invention are:
  • Fulonggan in the preparation of medicines for the prevention and / or treatment of allergic diseases, mental diseases, metabolic diseases and diseases related to endocrine disorders.
  • the allergic diseases include allergic dermatitis, allergic rhinitis, allergic asthma, allergic purpura, anaphylactic shock, allergic bowel disease, and the like.
  • Allergic dermatitis includes drug rash, contact dermatitis, eczema, urticaria, skin scratches, food allergies and environmental factors causing allergic dermatitis; allergic bowel disease includes allergic colitis, ulcerative colitis and Crohn disease.
  • the mental illness includes depression, autism or Alzheimer's disease.
  • the metabolic diseases include high blood pressure, diabetes or obesity.
  • the diseases related to endocrine disorders include acne, irregular menstruation in women, sleep disorders, dry stool and constipation.
  • Fulonggan in the preparation of medicines for improving the immunity of the body, increasing the diversity of intestinal microorganisms, and promoting the growth of various probiotics.
  • fulongan and a pharmaceutically acceptable carrier can be prepared into oral preparations or external preparations.
  • the medicament can be in solid or fluid form for oral administration, and can also be made into an externally applied paste preparation or powder.
  • the fulong liver provided by the present invention can increase the type and quantity of probiotics, especially the type and quantity of actinomycetes.
  • the Fulonggan provided by the invention can reduce the influence of antibiotics on the intestinal microecology, and promote the intestinal microecology to restore balance as soon as possible after antibiotics are used.
  • the fulongan provided by the present invention can be taken alone, or mixed with any food and medicine-food homologous food, as well as traditional Chinese medicine or western medicine with no antagonistic effect.
  • the present invention has the following beneficial effects:
  • the oxides and various inorganic ions contained in Fulong liver provided by the present invention can regulate the intestinal microecological structure and composition; the contained oxides and inorganic ions play a role in various probiotics in the intestinal microstate Nutrition.
  • the fulong liver provided by the present invention has the effect of further stimulating the development of various immune cells by regulating the intestinal microecology; the various oxides and ions contained in fulong liver are essential nutrients for a variety of probiotics to support probiotics
  • the growth of bacteria, probiotics can further stimulate the development of immune cells, further maintain immune balance, and achieve the role of prevention and treatment of allergic diseases.
  • the plurality of nutritional probiotics of the present invention stimulate immune cell development to produce immune factors. These immune factors further regulate the development of children's brain and nerves, and therefore have the function of regulating neural development.
  • the nutritional multiple probiotics metabolites can regulate human endocrine activities to prevent and treat various diseases caused by endocrine disorders.
  • Autism research subjects 50 children with autism were recruited as study subjects. The patients were diagnosed according to the diagnostic criteria for children with autism in the US Manual of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). There were 36 cases and 14 girls. Among these subjects, there were 16 children with mild autism, 18 children with moderate autism, and 16 children with severe autism. The subjects were randomly divided into two groups, the treatment group and the control group, with 25 people in each group, 8 patients with mild patients, 9 patients with moderate patients, and 8 patients with severe patients.
  • DSM-IV US Manual of Diagnostic and Statistical Manual of Mental Disorders
  • Treatment method The treatment group received oral Fulonggan capsules 3 times a day, 2 capsules each time, and mixed with food. After 3 months of treatment, the treatment effect was evaluated. The control group was given a starch placebo. During the medication, the patient normally participated in rehabilitation treatment and normal diet. At the same time, high-throughput sequencers were used to detect changes in intestinal microbes before and after treatment.
  • Results The results showed that the values of the CARS and ABC scales in the treatment group before and after treatment were significantly different (P ⁇ 0.05), while the scores in the control group did not change significantly before and after treatment. Compared with the control group, the CARS and ABC scale scores in the treatment group were significantly reduced after treatment, and the differences were significant (P ⁇ 0.05). The results are shown in Table 1. After treatment, the social adaptation DQ, language DQ, and personal social DQ of the children in the treatment group were significantly higher than those in the control group, and the differences were significant (P ⁇ 0.05). The results are shown in Tables 1 and 2.
  • Intestinal microbial changes 16s rRNA was analyzed by high-throughput sequencing. The results showed that the diversity of intestinal microbial diversity in the treatment group increased significantly (P ⁇ 0.01). Random Forests analysis showed (Table 3). The number and type of actinomycetes increased significantly (P ⁇ 0.01).
  • auxiliary materials are high-quality dry barley flour and wheat flour, and the mixing ratio of Fulonggan flour, barley flour and wheat flour is Fulonggan flour: barley flour: wheat flour at a ratio of 3: 1: 1 (mass ratio). It is made into capsules, and each capsule contains The medicine is 0.5-0.55 g, and it is ready for use after preparation.
  • Treatment method The treatment group takes Fulonggan capsules 3 times a day, and the dosage is 4 capsules / time, which can be taken together with food. After 3 months of treatment, the treatment effect was evaluated. The control group was given a starch placebo. At the same time, high-throughput sequencers were used to detect changes in intestinal microorganisms.
  • Asthma control score 25 points for complete control of asthma, 20-24 points for good control of asthma, and ⁇ 20 points for uncontrolled asthma.
  • Scoring criteria for rhinitis symptoms A. Evaluate the symptoms of patients according to the scoring criteria for allergic rhinitis according to the Pocket Reference for Allergic Rhinitis Management 2009. The scores of rhinitis symptoms before and after treatment were completed by the same experienced doctor.
  • RQLQ score scale score before and after treatment.
  • Treatment method The treatment group received the above-mentioned fulongan tablets orally three times a day, three times a day, two tablets each time.
  • the control group was treated with conventional methods. After 6 months of treatment, the treatment effect was evaluated.
  • Preparation of preparation Crush fulongan and autoclave it for later use.
  • the auxiliary materials are high-quality dry barley flour and soybean flour, and the mixing ratio of fulonggan flour, corn flour and soybean flour is fulongan flour: barley flour: soybean flour at a ratio of 1: 1: 1 (mass ratio).
  • the weight of each tablet is 0.5 g.
  • Exclusion criteria 1 acute coronary syndrome (ACS); 2 acute stroke event within 1 month; 3 secondary hypertension, hypertension crisis; 4 patients with secondary dyslipidemia; 5 high in grades II and above Patients with blood pressure; 6 Type I diabetes and type II diabetes with acute metabolic disorders; 7 Within 3 months of trauma or surgery; 8 Within 1 month of acute infectious disease; 9 Patients with obvious reasons who cannot cooperate with completion.
  • ACS acute coronary syndrome
  • 2 acute stroke event within 1 month
  • 3 secondary hypertension, hypertension crisis 4 patients with secondary dyslipidemia
  • 6 Type I diabetes and type II diabetes with acute metabolic disorders 7 Within 3 months of trauma or surgery; 8 Within 1 month of acute infectious disease; 9 Patients with obvious reasons who cannot cooperate with completion.
  • Treatment method The treatment group received 2 fulongan tablets orally 3 times a day.
  • the control group was treated with conventional methods or automatically abandoned treatment with any drug. After 12 weeks of treatment, the effect of treatment was evaluated.
  • Symptom observation Observe dizziness, headache, palpitations, insomnia, and tinnitus.
  • Efficacy criteria were significant: after treatment, the diastolic blood pressure decreased by 10 mmHg and decreased to normal or more than 20 mmHg, and the systolic blood pressure decreased to normal. Effective: After treatment, the diastolic blood pressure did not drop to 10mmHg, but it has fallen to the normal range, or decreased by 10-19mmHg. If it is systolic hypertension, the systolic blood pressure decreases by 30mmHg. Ineffective: The blood pressure drop after treatment did not reach the effective standard.
  • Criteria for judging the efficacy of symptoms 1 markedly effective: marked improvement in clinical symptoms with a reduction of ⁇ 70%; 2 effective: clinical improvement, with a reduction in symptoms of ⁇ 30%; 3 ineffective: no significant improvement in clinical symptoms, or even exacerbation, with a reduction in symptoms of ⁇ 30 %.
  • Preparation of preparation Crush fulongan and autoclave it for later use.
  • the auxiliary materials are high-quality corn flour, soy flour and wheat flour, and the mixing ratio is fulongan flour: corn flour: soy flour: wheat flour: 2: 1: 1: 1: 1 (mass ratio). 0.5 grams, spare after making.
  • Type II diabetes 80 patients were randomly divided into a treatment group and a control group. Forty patients in the treatment group were 20 males and 20 females, aged 35 to 65 years, with an average age of (44.3 ⁇ 9.5) years. The course of disease was 1 to 10 years, with an average (5.3 ⁇ 2.8) years. The control group included 40 cases, 20 males and 20 females, aged 36 to 65 years, with an average (43.9 ⁇ 7.9) years of age. The course of 1 to 10 years with an average (4.7) ⁇ 1.9) years. There was no significant difference in gender, age, and duration of disease between the two groups of patients. The selected cases all met the criteria for diagnosing diabetes (referring to the 1998 ADA criteria for diagnosing diabetes) and were diagnosed as type 2 diabetes outpatients of TCM.
  • TCM syndrome differentiation can have 3 of the following empirical evidence and 2 of the false evidence.
  • Empirical evidence fat eating, stomach fullness, hiccup rot, odor in the mouth, foul stool, fullness of pain in the ribs, irritability and anxiety, elimination of good hunger, constipation, drinking thirst, irregular menstruation, heavy limbs , Sticky mouth, or swollen limbs in the hands, sticky appetite, irritability, upset mouth, dry stool.
  • Deficiency syndrome dry mouth, thirst, drink more, eat more and be hungry, five upset and hot, soft waist and knees, dizziness and tinnitus.
  • Treatment method 80 outpatients keep the original treatment plan and diet exercise program unchanged. From the day of observation, the treatment group received 4 fulongan tablets orally once a day. The control group was treated with conventional methods. The drug was stopped for 10 days after 90 days of treatment, and then the treatment effect was evaluated.
  • Efficacy assessment of hypoglycemic effect After 90 days of treatment, observe the treatment effect 10 days after stopping the drug.
  • the curative effect standard is markedly effective: fasting blood glucose ⁇ 7.0mmol / L after treatment, or 2h post-prandial blood glucose ⁇ 7.8mmol / L, or a decrease in glycemia by more than 30% compared with before treatment; Effective: fasting blood glucose ⁇ 8.3mmol / L after treatment Or 2h postprandial blood glucose is less than 11.0mmol / L, or the hypoglycemic range is decreased by 10% to 30% compared with that before treatment; ineffective: those whose blood glucose drop does not reach the above standard after treatment. Calculate the effective rate based on the total number of significant and effective cases.
  • Intestinal microbial changes 16s rRNA was analyzed by high-throughput sequencing. The results showed that the diversity of intestinal microorganisms in the treatment group increased significantly (P ⁇ 0.01). Random Forests analysis showed (Table 12). The number and type of actinomycetes increased significantly (P ⁇ 0.01).
  • Preparation of preparation Crush fulongan and autoclave it for later use.
  • the auxiliary materials are high-quality dry corn flour and soybean flour, and the mixing ratio of fulonggan flour, corn flour and soybean flour is fulonggan flour: corn flour: soy flour at 2: 1: 1 (mass ratio).
  • the weight of each tablet is 0.5 g.
  • Treatment method The treatment group received oral Fulonggan preparation daily, 2 capsules per day. The control group was treated with conventional methods. After 4 weeks of treatment, the treatment effect was evaluated.
  • Group N cure Improve invalid Number of valid cases Efficient therapy group 40 25 10 5 35 87.5% Control group 40 3 6 31 9 22.5%
  • Preparation of preparation Crush fulongan and autoclave it for later use.
  • the auxiliary materials are high-quality dry bran, corn flour and soybean flour, and the mixing ratio of fulonggan flour, bran, corn flour and soybean flour is 1: 1: 1: 1: 1: 1.
  • Mass ratio made into tablets, each tablet weight is 0.5 grams, ready for use.
  • depression subjects selection 70 patients volunteers all met the diagnostic criteria for depression ("Chinese Classification and Diagnostic Criteria for Mental Disorders", 3rd Edition). The subjects were randomly divided into observation groups, a total of 35 cases, 15 male patients and 20 female patients, aged 18 to 60 years, with an average (44.2 ⁇ 12.4) years of age and an average course of disease (14.6 ⁇ 7.8) months; 35 patients in the control group There were 14 male patients and 21 female patients, aged 18 to 59 years, with an average (44.5 ⁇ 10.7) years of age and an average course of disease (15.7 ⁇ 8.7) months. There were no statistical differences in the age, gender, and disease duration between the two groups of patients.
  • Treatment method Before the administration, subjects in the observation group and the control group were given a washing period of 2 weeks to avoid the effects of other depression drugs on this study. In the observation group, except for paroxetine treatment, voron liver preparation was taken orally 3 times a day, 2 capsules each time. The control group was treated with paroxetine. After 12 weeks of treatment, the effect of treatment was evaluated.
  • HAMD Hamilton Depression Scale
  • comparative analysis were used at different periods of treatment. Before treatment, the HAMD scores of the two groups of patients were basically equal, and there was no statistical significance between the groups. . At 4 weeks, 6 weeks, 10 weeks, and 12 weeks after treatment, the HAMD score of the observation group was significantly improved compared with the control group, and the difference between the groups was statistically significant (P ⁇ 0.05), as shown in Table 15.
  • Intestinal microbial changes 16s rRNA was analyzed by high-throughput sequencing. The results showed that the diversity of intestinal microbial diversity in the treatment group increased significantly (P ⁇ 0.01). Random Forests analysis showed that The number and type of actinomycetes increased significantly (P ⁇ 0.01).
  • the total number of cases is less than 40, and Fisher's exact probability method is used.
  • auxiliary materials are high-quality dry corn flour, Fulonggan traditional Chinese medicine powder, and the mixing ratio with Fulonggan powder: Fulonggan powder: corn flour is 1: 1 (mass ratio). It is made into tablets, each tablet weight is 0.5 g. After the backup.
  • Treatment method The treatment group received the above-mentioned fulongan tablets orally twice a day, 2 tablets each time.
  • the control group was treated with conventional methods. After 1 month of treatment, the treatment effect was evaluated.
  • Intestinal microbial changes 16s rRNA was analyzed by high-throughput sequencing. The results showed that the diversity of intestinal microorganisms in the treatment group increased significantly (P ⁇ 0.01). Random Forests analysis showed (Table 19). The number and type of actinomycetes increased significantly (P ⁇ 0.01).

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Abstract

伏龙肝在制备预防和/或治疗过敏性疾病、精神类疾病、代谢类疾病和内分泌紊乱相关疾病药物中的用途；伏龙肝在制提高机体免疫力、提高倡导微生物的多样性与促进多种益生菌生长的药物中的用途。

Description

伏龙肝在制备防治过敏性疾病、精神类疾病、代谢类疾病和内分泌紊乱疾病药物中的应用 技术领域
本发明涉及伏龙肝的新用途，具体涉及伏龙肝在制备防治过敏性疾病、精神类疾病、代谢类疾病和内分泌紊乱疾病药物中的应用。
背景技术
过敏性疾病从新生儿到老年人的各个年龄阶段都可能发生。过敏性疾病主要类型有皮肤过敏反应、呼吸道过敏反应、消化道过敏反应及过敏性休克等，常见疾病有如下几种：过敏性皮炎，过敏性鼻炎，过敏性哮喘，过敏性紫癜，过敏性休克，过敏性肠病等。其中过敏性皮炎包括药疹、接触性皮炎、湿疹、荨麻疹、皮肤划痕症、食物过敏与环境因素引起过敏。过敏性肠病主要是指过敏性结肠炎、溃疡性结肠炎和克罗恩病。
近年来，过敏性疾病的发病率逐年升高，比如婴儿湿疹发病率天津市大港区妇幼保健院2007年对新生儿的调查显示发病率为75.6％；2013年重庆市一家医院的调查研究结果为64.8％；2011年北京市门诊调查研究发现42日龄儿童湿疹发病率已达57.3％。目前全球约有3亿哮喘患者，其中每年约有一千五百万人因为该病而丧失劳动能力，中国目前己有2000万的哮喘患者。我国大城市居民过敏性鼻炎的发病率已经上升到了10-19％。其他过敏性疾病(如过敏性皮炎、食品过敏等)的发病率也逐年升高。因此，给社会带来了沉重的经济负担和造成巨大的经济损失，已经成为严重的公共卫生问题。
过敏性疾病的治疗主要采用抗组胺类药物和激素类药物，抗组胺类药物如扑尔敏、息斯敏、敏克、开瑞坦等。抗组胺药物都有副作用，长期使用会使人嗜睡、疲倦、脑力迟钝。激素类药物，如主要有肾上腺皮质激素，如强的松、地塞米松以及环磷酰胺、硫唑嘌呤等，常用激素会严重损伤肝脏、肾脏等内部器官，还会影响儿童的生长发育。
此外，随着人们生活方式的改变，多种精神类疾病、代谢类疾病与内分泌失调症也逐年增多，对人类的健康具有重要影响。
发明内容
发明目的：本发明的目的是通过大量实验筛选，深入研究伏龙肝的功效，开发其新的临床功效。
为解决上述技术问题，本发明采用的技术方案是：
伏龙肝在制备预防和/或治疗过敏性疾病、精神类疾病、代谢类疾病和内分泌紊乱相关疾病药物中的应用。
所述的过敏性疾病包括过敏性皮炎、过敏性鼻炎、过敏性哮喘、过敏性紫癜、过敏性休克、过敏性肠病等。
所述的过敏性皮炎包括药疹、接触性皮炎、湿疹、荨麻疹、皮肤划痕症、食物过敏与环境因素引起过敏皮炎；过敏性肠病包括过敏性结肠炎、溃疡性结肠炎和克罗恩病。
所述的精神类疾病包括抑郁症、孤独症或老年痴呆疾病。
所述的代谢类疾病包括血压高、糖尿病或肥胖症。
所述的内分泌紊乱相关疾病包括青春痘、女性月经不调症、睡眠障碍、大便干燥和便秘。
伏龙肝在制备提高机体免疫力、提高肠道微生物的多样性与促进多种益生菌生长的药物中的应用。
本发明可将伏龙肝与药学上可接受的载体制备成口服制剂或外用制剂。所述的药物可以口服的固体或流体形式，也可以制成外用涂抹膏状制剂或散剂。
本发明提供的伏龙肝可增加益生菌的种类与数量，尤其是增加放线菌门细菌的种类和数量。
本发明提供的伏龙肝可降低抗生素对于肠道微生态的影响，促进肠道微生态用过抗生素后尽快恢复平衡。
作为本发明的一种改进，本发明提供的伏龙肝可以单独服用，也可以与任意食品和药食同源食品，以及无对抗作用的中药或西药混合在一起服用。
本发明较现有技术相比，具有的有益效果如下：
1)本发明提供的伏龙肝含有的氧化物和多种无机离子，具有调节肠道微生态结构与组成作用；所含有的氧化物和无机离子对肠道微态中多种益生菌起着营养作用。
2)本发明提供的伏龙肝通过调节肠道微生态，有进一步刺激多种免疫细胞发育的作用；伏龙肝含有的多种氧化物和离子作为多种益生菌的必需营养物，支持益生菌的生长，益生菌可以进一步刺激免疫细胞的发育，进一步维持免疫平衡，达到预防与治疗过敏性疾病的作用。
3)本发明营养的多种益生菌通过刺激免疫细胞的发育，产生免疫因子，这些免疫因子进一步调节儿童大脑和神经的发育，因此具有调节神经发育的功能。
4)本发明营养的多种益生菌代谢产物，可以调节人体内分泌活动，达到预防与治疗内分 泌紊乱引起的多种疾病。
具体实施方式
下面对本发明的较佳实施例进行详细阐述，以使本发明的优点和特征能更易于被本领域技术人员理解，从而对本发明的保护范围做出更为清楚明确的界定。
实施例1：
治疗孤独症
(1)制剂制备：伏龙肝粉碎，高压灭菌备用。辅料为优质干玉米粉与麸皮，伏龙肝粉∶玉米粉∶麸皮为2∶1∶1(质量比)，制成胶囊，每个胶囊中含药0.5-0.55克，制好后备用。
(2)孤独症研究对象：招募孤独症患儿50例作为研究被试，患者通过美国精神障碍诊断和统计手册(DSM-IV)儿童孤独症的诊断标准来确诊，年龄小于3.5岁，其中男孩36例，女孩14例。在这些被试中，轻度自闭症患儿16例，中度自闭症患儿18例，重度自闭症患儿16例。实验对象随机分为两组，治疗组和对照组，每组25人，轻度患者8例、中度患者9例，重度患者8例。
(3)治疗方法：治疗组口服伏龙肝胶囊，每天3次，每次2粒，与食物混合一起服用。用药3个月后进行治疗效果评测。对照组服用淀粉安慰剂。用药期间，患者正常参加康复治疗和正常饮食。同时采用高通量测序仪检测肠道微生物治疗前后的变化。
(4)治疗效果评价：治疗前后采用CARS量表、ABC量表、Gesell发育量表(社会适应DQ、个人社交DQ、语言DQ)，采用问卷形式对孤独症儿童的各项进行评测。采集的数据采用SPSS 18.0软件进行统计分析。
(5)结果：结果显示治疗组治疗前后CARS量表、ABC量表数值差异显著(P＜0.05)，而对照组治疗前后评分无明显变化。治疗后治疗组与对照组比较，CARS、ABC量表评分均明显降低，差异显著(P＜0.05)，结果见表1。治疗后治疗组患儿社会适应DQ、语言DQ、个人社交DQ值与对照组比较均明显升高，差异显著(P＜0.05)。结果见表1和表2。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表3)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表1 CARS量表、ABC量表评分比较(分，
Figure PCTCN2018110877-appb-000001
)
Figure PCTCN2018110877-appb-000002
Figure PCTCN2018110877-appb-000003
表2 Gesell发育量表评分(分，
Figure PCTCN2018110877-appb-000004
)
Figure PCTCN2018110877-appb-000005
表3.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000006
Figure PCTCN2018110877-appb-000007
实施例2伏龙肝治疗过敏性哮喘合并过敏性鼻炎患者的实验研究
(1)制剂制备：将伏龙肝粉碎，高压灭菌备用。辅料为优质干大麦粉与小麦粉，伏龙肝粉、大麦粉与小麦粉混合比例为伏龙肝粉∶大麦粉∶小麦粉为3∶1∶1(质量比)，制成胶囊，每个胶囊中含药0.5-0.55克，制好后备用。
(2)过敏性哮喘合并过敏性鼻炎被试选择：60例过敏哮喘合并过敏性鼻炎患者随机分成治疗组和对照组。治疗组30例，男16例，女14例，年龄5～54岁，平均28.5±11.5岁。病程1～15年，平均(7±6.5)年；对照组30例，男15例，女15例，年龄5～55岁，平均(29.5±12.5)岁；病程1～15年，平均(7±5.5)年。两组被试患者性别、年龄、病程无统计学差异。入选病例均符合过敏性哮喘和过敏性鼻炎诊断标准(过敏性哮喘诊断标准：参考中华医学会呼吸病学分会哮喘学组制定的《支气管哮喘防治指南(2008)》)。
(3)治疗方法：治疗组服用伏龙肝胶囊，每天3次，用量4粒/次，可与食物混合一起服用。用药3个月后进行治疗效果评测。对照组服用淀粉安慰剂。同时采用高通量测序仪进行肠道微生物变化的检测。
(4)治疗效果评价：治疗3个月后，观察治疗效果。
①哮喘控制评分标准：哮喘完全控制评分为25分，哮喘控制良好评分为20～24分，哮喘未控制评分为＜20分。
②鼻炎症状评分标准：A.参照《过敏性鼻炎处理袖珍参考2009》中的过敏性鼻炎评分标准评价患者的症状。治疗前后鼻炎症状评分均由同一名经验丰富的医生来完成。
B. RQLQ评分量表：治疗前后进行评分。
③血清总IgE检测：空腹静脉血，试剂盒检测IgE含量。
④过敏性鼻炎疗效评价指标：改善率按[(治疗前总分-治疗后总分)/治疗前总分]*100％计算，其中，显效≥51％；有效≤50％，≥21％；无效≤20％。
⑤总有效率：有效：哮喘评分为25分，同时，过敏性鼻炎疗效评价指标≥51％；好转：哮喘评分为20～24分，同时过敏性鼻炎疗效评价指标≤50％，≥21％；无效：哮喘＜20分，同时过敏性鼻炎疗效评价指标≤20％。
(5)结果：采集的数据采用SPSS 18.0软件进行统计分析。结果显示，伏龙肝胶囊制剂治疗的有效率达96.67％，显著高于对照(16.67％)，结果见表4和表5。
(6)肠道微生物的变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道 微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表6)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表4.治疗前后两组患者观察指标比较(分，
Figure PCTCN2018110877-appb-000008
)
Figure PCTCN2018110877-appb-000009
表5.两组患者治疗总效果比较(例)
组别 例数 有效 好转 无效 总有效率
治疗组 30 22 5 3 90％
对照组 30 3 2 25 16.67％
P值         ＜0.001
注：经卡方检验：df＝1，X 2＝32.411，P＜0.001。
表6.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000010
Figure PCTCN2018110877-appb-000011
实施例3伏龙肝治疗湿疹的实验研究
(1)制剂制备：将伏龙肝粉碎，高压灭菌备用。辅料为优质干玉米粉和黄豆粉，伏龙肝中药粉、玉米粉与黄豆粉混合比例为伏龙肝粉∶玉米粉∶黄豆粉为2∶1∶1(质量比)，压片制成片剂，每个片剂重量为0.5克，制好后备用。
(2)成人湿疹被试选择：120例患者随机分成治疗组和对照组。治疗组60例，男30例，女30例，年龄16～65岁，平均(45.3±8.3)岁。病程1～30年，平均(15.5±6.8)年；对照组60例，男30例，女20例，年龄16～66岁，平均(45.9±7.9)岁；病程1～30年，平均(15.2±8.9)年。两组被试患者性别、年龄、病程无统计学差异。入选病例均符合湿疹诊断标准。
(3)治疗方法：治疗组每天口服三次上述伏龙肝片剂，每天3次，每次2片。对照组采用常规方法处理。用药6个月后进行治疗效果评测。
(4)治疗效果评价：治疗6个月后，停药后9个月，观察治疗效果。疗效标准治愈：皮疹全部消退，瘙痒症状消失；显效：皮疹消退80％以上，瘙痒症状明显减轻；好转：皮肤消退50％，瘙痒症状未减轻；无效：皮疹消退不明显，瘙痒症状未减轻或无效。以治愈、显效病例数合计计算有效率。
(5)结果：结果显示治疗有效率，见表7。根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表8)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表7两组患者治疗总效果比较(例)
组别 N 治愈 显效 好转 无效 有效例数 有效率
治疗组 60 45 10 2 3 55 91.67％
对照组 60 3 7 6 44 10 16.67％
P值             P＜0.001
注：经卡方检验：df＝1，X 2＝67.972，P＜0.001。
表8随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000012
实施例4伏龙肝降血压功能实验研究
(1)制剂制备：将伏龙肝粉碎，高压灭菌备用。辅料为优质干大麦粉和黄豆粉，伏龙肝粉、玉米粉与黄豆粉混合比例为伏龙肝粉∶大麦粉∶黄豆粉为1∶1∶1(质量比)，制成片剂，每个压片重量为0.5克，制好后备用。
(2)高血压病人选择：60例符合I级高血压患者，随机分成治疗组和对照组。治疗组30例，男15例，女15例，年龄35～60岁，平均(49.3±7.3)岁。对照组30例，男15例，女15例，年龄35～61岁，平均(50.1±8.4)岁。两组被试患者性别、年龄、病程无统计学差异。被试未用药物或者停用降压药1周后，签署知情同意书。
入选病例均符合中医症候诊断标准(中华人民共和国药品监督局(2002)指定《中药新药临床研究指导原则》阴虚阳亢型主症)，并符合1999年WHO/SH四次高血压指南诊断标准： 非药物状态下2次或2次以上非同日重复血压测定所得平均值：收缩压140mmHg和/或舒张压90mmHg，一级高血压140～159/90～99，根据高血压指南要求需要药物治疗的。
排除标准：①急性冠脉综合征(ACS)；②急性脑卒中事件1个月内；③继发性高血压，高血压危象；④继发性血脂异常患者；⑤II级及II级以上高血压患者；⑥I型糖尿病和II型糖尿病合并急性代谢紊乱；⑦外伤或手术3个月内；⑧急性感染性疾病1个月内；⑨患者有明显的原因，不能配合完成者。
(3)治疗方法：治疗组每天口服3次伏龙肝片剂，每次2粒。对照组采用常规方法处理或自动放弃用任何药物治疗。用药12周后进行治疗效果评测。
(4)治疗效果评价：治疗时间为12周，停药后4周，评价治疗效果。体征观察：治疗前1d及治疗开始后1、4、7d，以后2次/周，固定时间(上午8：00-10：00；下午15：00-17：00)监测血压，每周测两次取平均值，被测者安静休息10分钟，取坐位右上肢血压。
症状观察：观察眩晕、头痛、心悸、失眠、耳鸣。
疗效标准显效：治疗后舒张压下降10mmHg并下降到正常或下降20mmHg以上，收缩压降到正常。有效：治疗后舒张压下降未达到10mmHg，但己降到正常范围，或下降10-19mmHg，如为收缩期高血压，收缩压下降30mmHg。无效：治疗后血压下降未达到有效标准。
症状疗效判定标准：①显效：临床症状明显改善积分减少≥70％；②有效：临床有所好转，症状积分减少≥30％；③无效：临床症状无明显改善，甚或加重，症状积分减少≤30％。
(5)结果：结果显示治疗有效率，见表9。根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表10)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表9两组患者治疗1个月后疗效比较(n，％)
组别 N 显效 有效 无效 有效例数 有效率
治疗组 30 20 7 3 27 90％
对照组 30 3 3 24 6 20％
注：经卡方检验：df＝1，X 2＝29.697，P＜0.001。
表10随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000013
实施例5伏龙肝降血糖功能研究
(1)制剂制备：将伏龙肝粉碎，高压灭菌备用。辅料为优质玉米粉、黄豆粉与小麦粉，混合比例为伏龙肝粉∶玉米粉∶黄豆粉∶小麦粉为2∶1∶1∶1(质量比)，制成片剂，每个压片重量为0.5克，制好后备用。
(2)II型糖尿病被试选择：80例患者随机分成治疗组和对照组。治疗组40例，男20例，女20例，年龄35～65岁，平均(44.3±9.5)岁。病程1～10年，平均(5.3±2.8)年；对照组40例，男20例，女20例，年龄36～65岁，平均(43.9±7.9)岁；病程1～10年，平均(4.7±1.9)年。两组被试患者性别、年龄、病程无统计学差异。入选病例均符合糖尿病诊断的标准(参照1998年ADA关于糖尿病诊断的标准)，确诊为2型糖尿病中医科门诊患者。
中医辨证具备以下实证中3项和虚证中2项即可。
实证：嗜食肥甘，胃脘胀满，呃逆嗳腐，口中异味，大便秽臭，胁肋胀满疼痛，易怒焦虑、消谷善饥、便秘、大渴引饮，月经不调，肢体沉重，口中黏腻，或手胀肢肿，纳呆便黏，急躁易怒，心烦口苦，大便干结。虚证：口干、口渴多饮、多食易饥，五心烦热、腰膝酸软、眩晕耳鸣。
(3)治疗方法：80例门诊患者保持原治疗方案和饮食运动方案不变。自观察之日起，治疗组每天口服1次伏龙肝片剂，每次4粒。对照组采用常规方法处理。用药90天后停用10天，然后进行治疗效果评测。
(4)降糖疗效评定：治疗90天后，停药后10天观察治疗效果。疗效标准为显效：治疗后空腹血糖＜7.0mmol/L，或餐后2h血糖＜7.8mmol/L，或降糖幅度较治疗前下降30％以上； 有效：治疗后空腹血糖＜8.3mmol/L，或餐后2h血糖＜11.0mmol/L，或降糖幅度较治疗前下降10％～30％；无效：治疗后血糖下降未达上述标准者。以显效、有效病例数合计计算有效率。
(5)结果：结果显示治疗有效率，见表11。根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表12)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表11两组患者治疗9个月后疗效比较(n，％)
组别 N 显效 有效 无效 有效例数 有效率
治疗组 40 26 11 3 37 92.5％
对照组 40 3 2 35 5 12.5％
注：经卡方检验：df＝1，X 2＝51.328，P＜0.001。
表12随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000014
实施例6伏龙肝治疗青春痘功能研究
(1)制剂制备：将伏龙肝粉碎，高压灭菌备用。辅料为优质干玉米粉和黄豆粉，伏龙肝 粉、玉米粉与黄豆粉混合比例为伏龙肝粉∶玉米粉∶黄豆粉为2∶1∶1(质量比)，制成片剂，每个压片重量为0.5克，制好后备用。
(2)青春痘患者被试选择：80例患者随机分成治疗组和对照组。治疗组40例，男25例，女15例，年龄13～20岁，平均(14.3±3.4)岁。病程1～4年；对照组40例，男24例，女16例，年龄13～20岁，平均(15.1±4.1)岁；病程1～4年。两组被试患者性别、年龄、病程无统计学差异。入选病例为有经验的皮肤科医师诊断为青春痘。
(3)治疗方法：治疗组每天口服伏龙肝制剂，每天2粒。对照组采用常规方法处理。用药4周后进行治疗效果评测。
(4)治疗效果评价：根据《中医病症诊断疗效标准》结合临床拟定。治愈：皮肤损害消退，自觉症状消失好转；好转：自觉症状明显减轻，皮损消退30％以上；未愈：皮损及症状均无变化或消退不及30％。以治愈、好转病例数合计计算有效率。
(5)结果：结果显示治疗有效率，见表13。根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表14)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表13两组患者治疗4周后疗效比较(n，％)
组别 N 治愈 好转 无效 有效例数 有效率
治疗组 40 25 10 5 35 87.5％
对照组 40 3 6 31 9 22.5％
注：经卡方检验：df＝1，X 2＝34.141，P＜0.001。
表14.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000015
Figure PCTCN2018110877-appb-000016
实施例7伏龙肝辅助治疗抑郁症功能研究
(1)制剂制备：将伏龙肝粉碎，高压灭菌备用。辅料为优质干麸皮、玉米粉和黄豆粉，伏龙肝粉、麸皮、玉米粉与黄豆粉混合比例为伏龙肝粉∶麸皮∶玉米粉∶黄豆粉为1∶1∶1∶1(质量比)，制成片剂，每个压片重量为0.5克，制好后备用。
(2)抑郁症被试选择：70例患者志愿者均符合抑郁症疾病的诊断标准(《中国精神障碍分类与诊断标准》，第3版)。将被试随机分为观察组，共35例，男性患者15例，女性患者20例，年龄18～60岁，平均(44.2±12.4)岁，平均病程(14.6±7.8)月；对照组35例，男性患者14例，女性患者21例，年龄18～59岁，平均(44.5±10.7)岁，平均病程(15.7±8.7)月。两组患者在年龄、性别、病程等指标，无统计学差异。
(3)治疗方法：给药前，观察组与对照组被试均设清洗期2周，避免其他抑郁药物对本研究的影响。观察组除采用帕罗西汀治疗外，每天口服3次伏龙肝制剂，每次2粒。对照组采用帕罗西汀治疗。用药12个周后进行治疗效果评测。
(4)治疗效果评价：治疗不同时段，采用汉密顿抑郁量表(Hamilton Depression Scale，HAMD)评分和比较分析，治疗前，两组患者的HAMD评分均基本相当，组间差异无统计学意义。而治疗后4周、6周、10周、12周，观察组较对照组患者的HAMD评分出现了明显改善，组间差异具有统计学意义(P＜0.05)，见表15。
表15两组患者的HAMD指标评分情况
Figure PCTCN2018110877-appb-000017
组别 被试数量 治疗前 治疗4周 治疗6周 治疗10周 治疗12周
观察组 35 27.14±5.17 15.76±4.23 11.89±5.89 10.17±3.77 8.74±5.79
对照组 35 26.85±4.75 21.37±5.47 16.78±4.31 13.69±3.85 10.22±4.96
t   0.244 -4.800 -3.964 -3.865 -1.148
P   0.808 ＜0.001 ＜0.001 ＜0.001 0.255
(5)两组患者的不良反应发生情况比较：治疗期间，两组患者均出现了口干、出汗、恶心、呕吐、体重增加、食物模糊等不良反应，但是，观察组不良反应发生率均明显低于对照组患者，其中，出汗、口干、恶心呕吐、体重增加、视物模糊、头疼等不良反应的发生率组 间具有统计学差异，见表16。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表17)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表16两组患者治疗期间发生不良反应情况对比
组别 出汗 口干 恶心呕吐 体重增加 视物模糊 头晕 便秘/腹泻 头疼
观察组 1 3 3 1 1 0 0 2
对照组 7 16 12 7 7 5 5 7
P 0.055 0.01 0.001 0.055 0.055 0.468 0.468 0.151
注：总例数小于40，采用的是Fisher确切概率法。
表17.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000018
实施例8伏龙肝治疗功能性便秘研究
(1)制剂制备：将伏龙肝粉碎，高压灭菌备用。辅料为优质干玉米粉，伏龙肝中药粉、与玉米粉混合比例为伏龙肝粉∶玉米粉为1∶1(质量比)，制成片剂，每个压片重量为0.5克，制好后备用。
(2)功能性便秘被试选择：100例患者随机分成治疗组和对照组。治疗组50例，男20例，女30例，年龄16～71岁，平均(43.5±9.4)岁。病程1～10年，平均(5.5±2.8)年；对照组50例，男29例，女21例，年龄16～70岁，平均(44.9±8.9)岁；病程1～10年，平均(5.1 ±3.9)年。两组被试患者性别、年龄、病程无统计学差异。入选病例均符合功能性便秘诊断标准(罗马II标准)。
(3)治疗方法：治疗组每天口服2次上述伏龙肝片剂，每次2片。对照组采用常规方法处理。用药1个月后进行治疗效果评测。
(4)治疗效果评价：参照《中医病症诊断疗效标准》中的成人便秘疗效标准制定。(1)治愈：1天内排便1次，便质正常，排便通畅，1个月内无复发；(2)显效：2天内排便1次，便质趋于正常，排便通畅，1个月内无复发；(3)有效：3天内排便1次，便质转润，排便欠畅；(4)无效：临床症状无明显改善。以治愈、显效病例数合计计算有效率。
(5)结果：结果显示治疗有效率，见表18。根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表19)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表18两组患者治疗1个月后疗效比较(n，％)
组别 N 治愈 显效 有效 无效 有效例数 有效率
治疗组 50 35 8 3 4 46 92％
对照组 50 9 5 10 26 24 48％
注：经卡方检验：df＝1，X 2＝23.048，P＜0.001。
表19.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2018110877-appb-000019
Figure PCTCN2018110877-appb-000020
上述实施例仅为本发明的优选技术方案，而不应视为对于本发明的限制，本发明的保护范围应以权利要求记载的技术方案，包括权利要求记载的技术方案中技术特征的等同替换方案为保护范围，即在此范围内的等同替换改进，也在本发明的保护范围之内。

Claims (10)

  1. 伏龙肝在制备预防和/或治疗过敏性疾病、精神类疾病、代谢类疾病和内分泌紊乱相关疾病药物中的应用。
  2. 伏龙肝在制备提高机体免疫力、提高肠道微生物的多样性与促进多种益生菌生长的药物中的应用。
  3. 根据权利要求1所述的应用，其特征在于，所述的过敏性疾病包括过敏性皮炎、过敏性鼻炎、过敏性哮喘、过敏性紫癜、过敏性休克、过敏性肠病等。
  4. 根据权利要求3所述的应用，其特征在于，所述的过敏性皮炎包括药疹、接触性皮炎、湿疹、荨麻疹、皮肤划痕症、食物过敏与环境因素引起过敏皮炎；过敏性肠病包括过敏性结肠炎、溃疡性结肠炎和克罗恩病。
  5. 根据权利要求1所述的应用，其特征在于，所述的精神类疾病包括抑郁症、孤独症或老年痴呆疾病。
  6. 根据权利要求1所述的应用，其特征在于，所述的代谢类疾病包括血压高、糖尿病或肥胖症。
  7. 根据权利要求1所述的应用，其特征在于，所述的内分泌紊乱相关疾病包括青春痘、女性月经不调症、睡眠障碍、大便干燥和便秘。
  8. 根据权利要求1所述的应用，其特征在于，将伏龙肝与药学上可接受的载体制备成口服制剂或外用制剂。
  9. 根据权利要求2所述的应用，其特征在于，伏龙肝增加放线菌门细菌的种类和数量。
  10. 根据权利要求2所述的应用，其特征在于，伏龙肝可降低抗生素对于肠道微生态的影响，促进肠道微生态用过抗生素后尽快恢复平衡。
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