Application of enteritis preparation in preparation of medicine for treating or preventing diarrhea-type irritable bowel syndrome

Abstract

The invention belongs to the field of application of traditional Chinese medicine preparations, and particularly relates to application of an enteritis preparation in preparation of a medicine for treating or preventing diarrhea-type irritable bowel syndrome. The traditional Chinese medicine composition can be used for preparing medicines for treating diarrhea-type irritable bowel syndrome caused by liver-qi impairing spleen syndrome, spleen-stomach weakness syndrome, spleen-kidney yang deficiency syndrome or large intestine damp-heat syndrome, and is used for reducing diarrhea, stomachache or frequency of defecation and changing the conventional technical prejudice of enteritis preparation for clearing heat, promoting diuresis and promoting the circulation of qi. The invention further provides application of the enteritis preparation in preparation of a medicine for treating or preventing diarrhea-type irritable bowel syndrome combined with liver dysfunction or fatty liver diseases, a medicine for treating or preventing mood anxiety diseases or a medicine for reducing urine protein, and a foundation is laid for development of new application of the enteritis preparation. Clinical data is adopted to support the technical effect, and the safety and effectiveness of the enteritis preparation for the new application are proved.

Description

Technical Field

[0001] The invention belongs to the application field of traditional Chinese medicine preparations, and particularly relates to the use of a Changyanning preparation in preparing a medicine for treating or preventing diarrhea-type irritable bowel syndrome. Background Art

[0002] Irritable bowel syndrome (IBS) is a common functional bowel disease. The Western medical diagnostic criteria for IBS (Rome IV criteria): recurrent abdominal pain, with an average of at least 1 day a week in the past 3 months, accompanied by at least 2 of the following: 1) related to defecation; 2) accompanied by changes in the frequency of defecation; 3) accompanied by changes in stool characteristics (appearance). The relevant symptoms have appeared for at least 6 months, and the above diagnostic criteria have been met in the past 3 months. The "2020 Chinese Expert Consensus on Irritable Bowel Syndrome" defines IBS as: abdominal pain, bloating or abdominal discomfort as the main symptoms, related to defecation or accompanied by changes in bowel habits such as frequency and (or) stool characteristics, and no organic diseases that can explain these symptoms have been found through routine clinical examinations.

[0003] According to the different stool characteristics of patients, IBS is divided into four subtypes using the Bristol Stool Characteristics Scale, namely IBS with predominant diarrhea (IBS-D), IBS with predominant constipation (IBS-C), IBS with mixed bowel habits (IBS-M), and IBS unclassified (IBS-U). 1) IBS-D: >25% of bowel movements are Bristol stool pattern type 6 or 7, and <25% of bowel movements are Bristol stool pattern type 1 or 2; 2) IBS-C: >25% of bowel movements are Bristol stool pattern type 1 or 2, and <25% of bowel movements are Bristol stool pattern type 6 or 7; 3) IBS-M: >25% of bowel movements are Bristol stool pattern type 1 or 2, and >25% of bowel movements are Bristol stool pattern type 6 or 7; 4) IBS-U: Patients meet the diagnostic criteria for IBS, but their bowel habits cannot be accurately classified into any of the above 3 types, so they are called indeterminate.

[0004] The TCM disease classification in the Expert Consensus on Diagnosis and Treatment of Irritable Bowel Syndrome (2024) (Journal of Traditional Chinese Medicine, 2024, (18): 105-113.) includes liver depression and spleen deficiency syndrome, spleen deficiency and dampness syndrome, spleen and kidney yang deficiency syndrome, large intestine dampness and heat syndrome for IBS-D, and liver depression and qi stagnation syndrome, large intestine dryness and heat syndrome, yin deficiency and dryness of intestine syndrome, spleen and kidney yang deficiency syndrome, lung and spleen qi deficiency syndrome for IBS-C. Clinical treatment should follow the principle of syndrome differentiation and treatment, and individualized treatment should be carried out according to the different clinical manifestations of patients with IBS-D, IBS-C, IBS-M and IBS-U. The article lists different Chinese patent medicines for the treatment of IBS-D. Tongxiening Granules and Qizhiweitong Granules are used to suppress the liver and strengthen the spleen to treat the liver depression and spleen deficiency syndrome of IBS-D; Ginseng Jianpi Tablets and Shenling Baizhu Granules are used to strengthen the spleen and eliminate dampness to treat the spleen deficiency and dampness syndrome of IBS-D; Sishen Pills and Guben Yichang Tablets are used to warm the spleen and kidney to treat the spleen and kidney yang deficiency syndrome of IBS-D; Gegenqinlian Pills and Xianglian Tablets are used to clear heat and remove dampness to treat the large intestine damp-heat syndrome of IBS-D. According to the "Expert Consensus on TCM Diagnosis and Treatment of Irritable Bowel Syndrome (2017)" (Journal of Traditional Chinese Medicine, 2017, (18): 89-95), the TCM classification of IBS-D includes five types, namely, spleen deficiency and dampness obstruction syndrome with spleen deficiency and excessive dampness, spleen and stomach dampness-heat syndrome with spleen and stomach invaded by dampness and heat, liver qi stagnation affecting spleen qi, spleen and kidney yang deficiency syndrome with insufficient spleen and kidney yang, and cold and heat syndrome. IBS-D with spleen and stomach damp-heat syndrome is caused by internal accumulation of dampness and heat, which blocks the spleen and stomach qi.

[0005] In addition, the Technical Guidelines for Clinical Research on New Chinese Medicines for Irritable Bowel Syndrome, released in December 2017, differs from the expert consensus on the TCM classification of IBS-D. IBS-D is divided into liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, spleen and kidney yang deficiency syndrome, and large intestine damp-heat syndrome. The selection of TCM syndromes should comply with the principle of corresponding prescriptions and syndromes, and the TCM syndrome diagnostic criteria should be selected according to authoritative and recognized principles. The standards recently proposed by the Spleen and Stomach Disease Branch of the Chinese Association of Traditional Chinese Medicine, the Digestive System Disease Professional Committee of the Chinese Association of Integrated Traditional Chinese and Western Medicine, or other relevant industry guidelines can be referred to. It can be seen that the TCM syndrome of IBS-D is complex, and targeted medication is required according to the typical symptoms and different clinical manifestations of the classification, otherwise the purpose of treatment cannot be achieved.

[0006] Typical symptoms of IBS include abdominal pain, diarrhea, constipation, etc., depending on its classification. It may be combined with upper gastrointestinal symptoms such as heartburn, epigastric pain, early satiety, nausea, and postprandial fullness, and may also be accompanied by extra-intestinal symptoms such as fatigue, headache, chest tightness, hot flashes, palpitations, back pain, frequent urination, urgency, and decreased libido. IBS is defined by the Rome IV diagnostic criteria as a common disease caused by dysfunctional gut-brain interaction, suggesting that psychological states such as anxiety and depression cannot be ignored in the onset and treatment of IBS. Therefore, during the treatment process, attention should be paid not only to the improvement of the patient's intestinal symptoms, but also to the changes in the patient's mental state. However, the drugs currently used in the clinic to treat IBS are mainly symptomatic treatments such as relieving abdominal pain and changing bowel movement patterns, such as iludorline, loperamide, and alosetron. The results of many clinical studies have found that taking tricyclic antidepressants can improve abdominal pain symptoms in some IBS patients, and it is independent of the effect on depression and thus improves the intestinal symptoms of IBS patients. Achieving emotional anxiety relief and improvement in intestinal symptoms alone can help improve the overall cure rate of IBS patients.

[0007] The Changyanning preparation is composed of Herba Dijinjin, Herba Goldenrods (Yellow-hair ...

[0008] CN102579638B "A Chinese medicine pill for treating gastroenteritis and irritable bowel syndrome and its preparation method and application" (publication date: 2012.07.18) discloses a Chinese medicine pill prepared from Herba Euphorbiae, Herba Lycopodii, Camphora roots, Elsholtzia ciliata and Liquidambar leaves as raw materials. The preparation method is as follows: the above five Chinese medicine raw materials are decocted with water twice, 10 times the amount of water is added each time, and the decoctions are decocted for 2 hours, the decoctions are combined, filtered, and the filtrate is concentrated under reduced pressure at 80°C to a clear paste with a relative density of 1.20 at 80°C, 2438mL of 95% ethanol is added, stirred, allowed to stand for 12 hours, filtered, and the filtrate is concentrated under reduced pressure at 80°C to a clear paste with a relative density of 1.25 at 80°C, 249g of starch is added, mixed, and pilled with refined honey: water in a ratio of 1:1 as an adhesive, dried at 60°C, polished, bagged, and packaged to obtain a total of 1000g. The patent also does not disclose that the above-mentioned Chinese medicine pills have the effect of alleviating emotional anxiety.

[0009] "Clinical Observation on the Treatment of Irritable Bowel Syndrome with Changyanning Granules Combined with Compound Glutamine Enteric-coated Capsules" (Practical Clinical Integration of Traditional Chinese and Western Medicine, 2022, 22(15): 49-51.) Two kinds of traditional Chinese medicine preparations were used to treat IBS, and the quality of life scale (IBS-QOL) was statistically evaluated before and after treatment. The scale consists of 8 sections: anxiety, behavioral disorders, body thoughts, picky eating, health worries, social reactions, sexual behavior, and interpersonal relationships, with a total of 34 items. The lower the score, the worse the quality of life. After treatment, the IBS-QOL score of the study group was higher than that of the control group (P<0.05), but it did not show that Changyanning Granules alone could treat emotional anxiety. Summary of the invention

[0010] The present invention provides a use of a Changyanning preparation in the preparation of a drug for treating or preventing diarrhea-type irritable bowel syndrome. IBS-D has complex TCM syndromes, and different TCM syndromes have different clinical manifestations. The Changyanning preparation provided by the present invention can be used to treat IBS-D liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, spleen and kidney yang deficiency syndrome, or large intestine damp-heat syndrome. Clinical trial results show that the Changyanning preparation has a therapeutic effect on abnormal liver function or fatty liver disease; it can reduce urine protein content; and the Changyanning preparation can relieve emotional anxiety alone, achieving the treatment of emotional anxiety before intestinal symptoms are relieved.

[0011] The present invention is achieved through the following technical solutions:

[0012] The use of the Changyanning preparation in the preparation of drugs for the treatment or prevention of diarrhea-type irritable bowel syndrome, the types of diarrhea-type irritable bowel syndrome include liver qi invading spleen syndrome, spleen and stomach weakness syndrome, spleen and kidney yang deficiency syndrome or large intestine damp-heat syndrome, wherein the Changyanning preparation can reduce diarrhea, abdominal pain or bowel movement frequency in patients with the above diarrhea-type irritable bowel syndrome.

[0013] The present invention also provides the use of the Changyanning preparation in preparing the treatment or prevention of diarrhea-type irritable bowel syndrome combined with abnormal liver function or fatty liver disease, wherein the type of diarrhea-type irritable bowel syndrome is liver qi invading spleen syndrome, spleen and stomach deficiency syndrome or large intestine damp-heat syndrome.

[0014] The present invention also provides the use of the Changyanning preparation in preparing a medicine for treating or preventing emotional anxiety diseases, wherein the emotional anxiety diseases are diarrhea-type irritable bowel syndrome combined with emotional anxiety.

[0015] Preferably, the type of diarrhea-predominant irritable bowel syndrome is spleen and stomach deficiency syndrome.

[0016] The present invention also provides the use of the Changyanning preparation in preparing a medicine for reducing urine protein.

[0017] Preferably, the drug is used to treat or prevent diarrhea-type irritable bowel syndrome combined with high urine protein. The types of diarrhea-type irritable bowel syndrome are liver qi invading spleen syndrome, spleen and stomach deficiency syndrome or large intestine damp-heat syndrome.

[0018] Preferably, the Changyanning preparation is made of the following medicinal materials in parts by weight: 500-1300 parts of Herba Euphorbiae Ichthyophthirius, 650-1700 parts of Herba Cibotii, 500-1300 parts of Cinnamomum camphora roots, 250-640 parts of Elsholtzia ciliata, and 250-640 parts of Acer truncatum odoratum leaves.

[0019] From the perspective of traditional Chinese medicine, the causes and symptoms of liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, spleen and kidney yang deficiency syndrome, and large intestine damp-heat syndrome are all different. According to the diagnostic criteria of the "Technical Guidelines for Clinical Research on New Chinese Medicines for Irritable Bowel Syndrome" (2017), the specific criteria are as follows:

[0020] (1) Liver Qi invading the spleen syndrome

[0021] Main symptoms: ① Abdominal pain is followed by diarrhea, and the pain is relieved after diarrhea; ② The attack is related to mood changes.

[0022] Secondary symptoms: ① intestinal rumbling and flatulence; ② fullness and pain in the chest and flanks; ③ abdominal distension and discomfort.

[0023] Tongue and pulse: pale red or dark tongue, thin white fur; thready and fine pulse.

[0024] Syndrome type determination: 2 main symptoms plus 1 to 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0025] (2) Spleen and stomach weakness syndrome

[0026] Main symptoms: ① Loose stools after meals; ② Fear of raw and cold food.

[0027] Secondary symptoms: ① abdominal distension and intestinal rumbling; ② easy sweating; ③ poor appetite; ④ fatigue and laziness.

[0028] Tongue and pulse: pale tongue, or with teeth marks, white tongue coating; thready and weak pulse.

[0029] Syndrome type determination: 2 main symptoms plus 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0030] (3) Spleen and Kidney Yang Deficiency

[0031] Main symptoms: ① Ejaculation at dawn; ② Cold pain in the abdomen, which is relieved by warmth.

[0032] Secondary symptoms: ① Weakness in waist and knees; ② Undigested food in stool; ③ Cold body and limbs.

[0033] Tongue and pulse: The tongue is pale and fat with teeth marks on the edges, and the tongue coating is white and smooth; the pulse is deep and fine.

[0034] Syndrome type determination: 2 main symptoms plus 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0035] (4) Large Intestine Damp-Heat Syndrome

[0036] Main symptoms: ① Abdominal pain and diarrhea; ② Urgent or uncomfortable diarrhea.

[0037] Secondary symptoms: ① abdominal discomfort; ② thirst without desire to drink; ③ dry and sticky mouth; ④ burning sensation in the anus.

[0038] Tongue and pulse: red tongue with yellow and greasy coating; slippery and rapid pulse.

[0039] Syndrome type determination: 2 main symptoms plus 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0040] Clinical statistics of the above four syndromes show that large intestine damp-heat syndrome accounts for the largest proportion, while spleen and kidney yang deficiency syndrome accounts for the smallest proportion.

[0041] The selection of TCM symptoms should comply with the principle of prescription-syndrome correspondence. Different syndromes have different main symptoms, secondary symptoms, and tongue and pulse. As mentioned in the background, the expert consensus recommends the principle of syndrome differentiation and treatment for Chinese patent medicines, such as the treatment of liver depression and spleen deficiency syndrome in IBS-D by suppressing the liver and supporting the spleen, the treatment of spleen deficiency and dampness in IBS-D by strengthening the spleen and eliminating dampness, and the treatment of spleen and kidney yang deficiency syndrome in IBS-D by warming and tonifying the spleen and kidney. The Changyanning preparation has the effects of clearing heat and removing dampness and promoting qi, which is different from the drugs required for syndrome differentiation and treatment of liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, and spleen and kidney yang deficiency syndrome. In addition, when the Changyanning preparation is used for the four types of IBS-D syndromes, it reduces the indicators of abnormal liver function or fatty liver, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP); reduces the urine protein content; and relieves emotional anxiety before the improvement of intestinal symptoms, and can be used to treat diarrhea-type irritable bowel syndrome with emotional anxiety.

[0042] The beneficial effects of the present invention are:

[0043] (1) It provides the therapeutic uses of Changyanning preparation in different TCM syndromes of diarrhea-type irritable bowel syndrome, changing the technical prejudice that Changyanning preparation is only suitable for the treatment of large intestine damp-heat syndrome.

[0044] Syndrome is a summary of the pathological reflection of the body at a certain stage in the development of the disease, including the location, cause, nature and relationship between the positive and negative factors of the lesion. IBS-D is divided into liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, spleen and kidney yang deficiency syndrome and large intestine damp-heat syndrome according to the different locations, causes, nature and relationship between the positive and negative factors of the disease. Traditional Chinese medicine treatment adopts the principle of syndrome differentiation and treatment, and it is necessary to determine the corresponding treatment method according to the results of different syndrome differentiation. Changyanning preparation has the effect of clearing heat and removing dampness, and can be used to treat large intestine damp-heat syndrome, but for liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, spleen and kidney yang deficiency syndrome, heat-clearing and dampness-removing drugs are still used, which is different from the theory and conventional treatment methods of traditional Chinese medicine syndrome differentiation and treatment. The present invention uses clinical trial data to confirm that Changyanning preparation can be used to treat IBS-D liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, spleen and kidney yang deficiency syndrome, which changes the technical prejudice that the use of heat-clearing and dampness-removing drugs is limited to the corresponding symptoms, and expands the scope of application of Changyanning preparation.

[0045] The results of clinical trials showed that Changyanning preparation can be used to treat 4 types of IBS-D syndromes. The V6 (after 8 weeks of medication) weekly response rate in IBS-D large intestine damp-heat syndrome was 75.68%, which was twice that of the placebo control group, and the difference between the groups was statistically significant (p<0.01); in the treatment of IBS-D spleen and stomach deficiency syndrome, the V6 weekly response rate was 76.32%, which was twice that of the placebo control group, and the difference between the groups was statistically significant (p<0.01); in the treatment of IBS-D liver qi invading spleen syndrome, the V6 weekly response rate was 75.00%, which was 1.6 times that of the placebo control group, and the difference between the groups was statistically significant (p<0.05); in the treatment of IBS-D spleen and kidney yang deficiency syndrome, the V6 weekly response rate was 69.23%, which was twice that of the placebo control group, and the difference between the groups was statistically significant (p<0.05).

[0046] In addition, the onset time of the Changyanning preparation for different syndromes is different. The Changyanning preparation has the fastest onset of effect in the treatment of IBS-D large intestine damp-heat syndrome, with symptoms improving 2 weeks after medication; in the treatment of IBS-D spleen and stomach deficiency syndrome and IBS-D spleen and kidney yang deficiency syndrome, symptoms improved 6 weeks after medication; in the treatment of IBS-D liver qi invading spleen syndrome, symptoms improved 8 weeks after medication.

[0047] Table 1 V6 week response of four syndrome types

[0048]

[0049] (2) Changyanning preparations can treat emotional anxiety or treat emotional anxiety combined with IBS-D spleen and stomach deficiency syndrome. Before the intestinal symptoms improve, Changyanning preparations can improve the patient's anxiety symptoms.

[0050] In the IBS-QOL trial of the Changyanning preparation for the treatment of IBS-D with spleen and stomach deficiency syndrome, the anxiety score of the IBS-QOL index at V4-V2 of the experimental group was reduced by 6.8 compared with the control group, indicating that the effect of Changyanning tablets in improving anxiety at the V4 observation point was 117.44% higher than that of the placebo; the health anxiety score of the IBS-QOL index at V4-V2 of the experimental group was reduced by 2.88 compared with the control group, indicating that the effect of Changyanning tablets in improving health anxiety at the V4 observation point was 32.14% higher than that of the placebo, see Table 13 for details.

[0051] Combined with the weekly response rate of the spleen and stomach deficiency syndrome subgroup in Table 7, it can be found that the response rate of Changyan Ning tablets in week V3 is similar to that of the control group, indicating that Changyan Ning tablets are not effective in treating intestinal symptoms at the V3 observation point. The response rate in week V4 is lower than that in V3, but anxiety and health worries were improved at V4, indicating that Changyan Ning tablets can treat emotional anxiety alone, rather than relieving emotional anxiety by treating intestinal symptoms. It can be seen from the response rates of Changyan Ning tablets in weeks V5 and V6 that Changyan Ning tablets can treat intestinal symptoms of IBS-D spleen and stomach deficiency syndrome. The diagnostic criteria for IBS-D spleen and stomach deficiency syndrome do not use anxiety or mood changes as syndrome diagnosis conditions, so emotional anxiety and IBS-D spleen and stomach deficiency syndrome are two diseases. The test results show that the Changyan Ning preparation can relieve emotional anxiety alone, or emotional anxiety combined with IBS-D spleen and stomach deficiency syndrome.

[0052] (3) The Changyanning preparation can be used to reduce urine protein, treat or prevent IBS-D combined with high urine protein, and lay the foundation for the development of new uses for the Changyanning preparation.

[0053] Clinical studies on different syndromes of IBS-D have found that Changyanning preparations can also be used to treat IBS-D combined with high urine protein, corresponding to IBS-D syndromes including liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, and large intestine damp-heat syndrome. Typical cases 1 to 4 show that Changyanning preparations reduce bowel movement frequency and NRS pain index, while urine protein changes from weak positive to negative, and urine red blood cells and urine white blood cells decrease, achieving simultaneous improvement of urinary system function and treatment of intestinal diseases.

[0054] (4) Changyanning preparations can be used to improve abnormal liver function and treat or prevent IBS-D combined with abnormal liver function or fatty liver disease.

[0055] Clinical studies on different syndromes of IBS-D have found that Changyanning preparations can also be used to treat IBS-D combined with abnormal liver function or fatty liver disease, and the corresponding IBS-D syndromes include liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, and large intestine damp-heat syndrome. After treatment with Changyanning preparations, patients' bowel movement frequency and abdominal pain were reduced, and alanine aminotransferase and aspartate aminotransferase indicators returned to normal levels or tended to normal, achieving improvement in liver function and treatment of intestinal diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 It is the Bristol stool quality scale. Type 1 is dry pellets, one by one dry fecal balls (difficult to pass); Type 2 is dry block, like sausage, but full of lumps; Type 3 is hard strips, like sausage or snake, but with cracks on the surface; Type 4 is soft stool in strips, like sausage, smooth and soft; Type 5 is loose soft stool, soft small lumps, clear edges (easy to pass); Type 6 is mushy, with irregular edges, porridge-like stool; Type 7 is watery stool, without solid components. DETAILED DESCRIPTION

[0057] A multicenter, randomized, double-blind, placebo-controlled trial of Changyanning tablets in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D).

[0058] The Changyanning preparation is prepared from the following medicinal materials in parts by weight: 500-1300 parts of Herba Euphorbiae Ichthyophthirius, 650-1700 parts of Herba Cibotii, 500-1300 parts of Cinnamomum camphora roots, 250-640 parts of Elsholtzia ciliata, and 250-640 parts of Liquidambar formosana leaves.

[0059] 1. Research subjects

[0060] 1.1 Sample size

[0061] A total of 240 subjects were enrolled in this study. Qualified subjects were randomly assigned to the experimental group or the control group (placebo group) in a 1:1 ratio, including 120 subjects in the experimental group and 120 subjects in the control group.

[0062] 1.2 Diagnostic criteria

[0063] 1.2.1 Western medicine diagnostic criteria for IBS

[0064] The diagnosis of IBS should meet the Rome IV diagnostic criteria. The typical clinical manifestations of IBS are recurrent abdominal pain, which occurs at least 1 day a week in the past 3 months, accompanied by 2 or more of the following: 1) related to defecation; 2) accompanied by changes in defecation frequency during the attack; 3) accompanied by changes in stool characteristics (appearance) during the attack. Symptoms must have appeared for at least 6 months before diagnosis and have persisted for the past 3 months.

[0065] 1.2.2 Subtype diagnostic criteria

[0066] For IBS-D, >25% of bowel movements should be Bristol stool type 6 or 7, and <25% of bowel movements should be Bristol stool type 1 or 2.

[0067] 1.2.3 TCM Syndrome Diagnostic Criteria

[0068] According to the Technical Guidelines for Clinical Research of New Chinese Medicines for Irritable Bowel Syndrome (2017), the diagnostic criteria are as follows:

[0069] (1) Liver Qi invading the spleen syndrome

[0070] Main symptoms: ① Abdominal pain is followed by diarrhea, and the pain is relieved after diarrhea; ② The attack is related to mood changes.

[0071] Secondary symptoms: ① intestinal rumbling and flatulence; ② fullness and pain in the chest and flanks; ③ abdominal distension and discomfort.

[0072] Tongue and pulse: pale red or dark tongue, thin white fur; thready and fine pulse.

[0073] Syndrome type determination: 2 main symptoms plus 1 to 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0074] (2) Spleen and stomach weakness syndrome

[0075] Main symptoms: ① Loose stools after meals; ② Fear of raw and cold food.

[0076] Secondary symptoms: ① abdominal distension and intestinal rumbling; ② easy sweating; ③ poor appetite; ④ fatigue and laziness.

[0077] Tongue and pulse: pale tongue, or with teeth marks, white tongue coating; thready and weak pulse.

[0078] Syndrome type determination: 2 main symptoms plus 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0079] (3) Spleen and Kidney Yang Deficiency

[0080] Main symptoms: ① Ejaculation at dawn; ② Cold pain in the abdomen, which is relieved by warmth.

[0081] Secondary symptoms: ① Weakness in waist and knees; ② Undigested food in stool; ③ Cold body and limbs.

[0082] Tongue and pulse: The tongue is pale and fat with teeth marks on the edges, and the tongue coating is white and smooth; the pulse is deep and fine.

[0083] Syndrome type determination: 2 main symptoms plus 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0084] (4) Large Intestine Damp-Heat Syndrome

[0085] Main symptoms: ① Abdominal pain and diarrhea; ② Urgent or uncomfortable diarrhea.

[0086] Secondary symptoms: ① abdominal discomfort; ② thirst without desire to drink; ③ dry and sticky mouth; ④ burning sensation in the anus.

[0087] Tongue and pulse: red tongue with yellow and greasy coating; slippery and rapid pulse.

[0088] Syndrome type determination: 2 main symptoms plus 2 secondary symptoms, or 1 main symptom plus 3 secondary symptoms, and diagnosis is made with reference to the tongue and pulse.

[0089] 1.3 Inclusion criteria

[0090] Patients who meet the following six criteria can be included in this study:

[0091] (1) Meet the Rome IV diagnostic criteria for IBS-D;

[0092] (2) Aged between 18 and 65 (inclusive), regardless of gender;

[0093] (3) IBS-SSS score >75 points;

[0094] (4) The average abdominal pain score in the week (7 days) before enrollment was ≥3 points (the most severe abdominal pain score in the past 24 hours, using an 11-level (0-10) pain numeric rating scale, NRS-11); and at least one stool type (Bristol stool scale) was type 6 or 7 for ≥2 days;

[0095] (5) Patients who voluntarily accept the treatment plan of this project and sign the informed consent form.

[0096] Table 2 IBS-SSS Assessment Scale

[0097]

[0098]

[0099] *Note: The maximum total score for each item is 500 points, and a total score greater than 75 points is one of the inclusion criteria.

[0100] 1.4 Exclusion criteria

[0101] Patients who meet one or more of the following criteria should be excluded:

[0102] (1) Patients with severe or unstable heart, liver, kidney, immune, endocrine system diseases or malignant tumors;

[0103] (2) Those whose intellectual disability, mental disorder, language impairment, etc. affect data collection;

[0104] (3) Patients with organic gastrointestinal lesions or malignant tumors, such as pancreatitis, intestinal adenoma (excluding those who have undergone polypectomy for more than half a month), intestinal diverticula, colon or rectal cancer, inflammatory bowel disease, intestinal tuberculosis, etc.;

[0105] (4) Other diseases that affect digestive tract motility (such as poorly controlled hyperthyroidism, poorly controlled diabetes, chronic renal insufficiency, nervous system diseases, etc.);

[0106] (5) Combined with non-intestinal diseases of the digestive system such as tuberculous peritonitis, cholelithiasis, cirrhosis, and chronic pancreatitis;

[0107] (6) Those who are allergic to the components of the drug being studied;

[0108] (7) Pregnant or lactating women, and female patients who have plans to have children in the near future;

[0109] (8) Those who have undergone abdominal or pelvic surgery that affects digestive function, such as cholecystectomy;

[0110] (9) Patients with positive fecal occult blood test;

[0111] (10) During the screening period, it is impossible to stop taking drugs that affect gastrointestinal motility and function, including parasympathetic inhibitors such as atropine and belladonna; muscle relaxants such as succinylcholine; antidiarrheal drugs such as loperamide and smectite;

[0112] (11) Patients who used probiotics (except those who consumed yogurt) or antibiotics within 8 weeks before administration;

[0113] (12) Use of IBS medications (except polyethylene glycol and loperamide) within 14 days before administration;

[0114] (13) Regular drinkers within 6 months before screening, that is, those who drank more than 14 units of alcohol per week (1 unit = 360 mL of beer or 45 mL of 40% alcohol liquor or 150 mL of wine);

[0115] (14) Participated in or are currently participating in other clinical trials within 1 month before screening;

[0116] (15) The researchers believe that there are patients who are not suitable for inclusion.

[0117] 2. Experimental drugs and administration methods

[0118] Experimental group: oral administration of Changyanning tablets (manufacturer: Jiangxi Kangenbei Chinese Medicine Co., Ltd., batch number: 2205060), 4 tablets / time, 3 times / day, treatment course of 8 weeks, and follow-up for 4 weeks after the end of treatment.

[0119] Control group: oral Changyanning tablets simulated placebo (manufacturer: Jiangxi Kangenbei Chinese Medicine Co., Ltd., valid for 24 months, batch number: 20220502), which has the same appearance, smell, taste, specifications and packaging as Changyanning tablets, and meets the requirements of placebo in placebo randomized controlled clinical trials. The oral method, course of treatment and follow-up are the same as those of the experimental group.

[0120] 3. Outcome indicators and safety

[0121] 3.1 Main efficacy indicators

[0122] 3.1.1 Response rate at week 8 after enrollment

[0123] The definition of a weekly respondent is one that satisfies both of the following:

[0124] ① Abdominal pain intensity: The most severe abdominal pain score in the past 24 hours, the weekly average value decreased by at least 30% compared with the baseline;

[0125] ② Stool characteristics: The number of days per week with type 6 or type 7 stool characteristics at least once decreased by at least 50% compared with baseline.

[0126] The intensity of abdominal pain was evaluated using a pain numeric rating scale (0-10), with patients rating their "worst abdominal pain in the past 24 hours" every day. 0 points: no pain; 1-3 points: mild pain (pain does not affect sleep); 4-6 points: moderate pain; 7-9 points: severe pain (inability to fall asleep or awakening from sleep due to pain); 10 points: severe pain.

[0127] The stool characteristics were assessed with reference to the Bristol stool characteristics scale (see attached). Figure 1 shown.

[0128] Evaluation time: Visit 6.

[0129] 3.2 Secondary efficacy indicators

[0130] 3.2.1 Response rate at week 2, week 4, week 6, and week 12 after enrollment

[0131] The definition of a weekly respondent is one that satisfies both of the following:

[0132] ① Abdominal pain intensity: The most severe abdominal pain score in the past 24 hours, the weekly average value decreased by at least 30% compared with the baseline;

[0133] ② Stool characteristics: The number of days per week with type 6 or type 7 stool characteristics at least once decreased by at least 50% compared with baseline.

[0134] Evaluation time: Visit 3, Visit 4, Visit 5, Visit 7.

[0135] 3.2.2 IBS-QOL

[0136] The IBS-QOL scale is a special scale for IBS patients compiled by Patrick et al. through reviewing literature and interviewing clinical IBS patients. It is used to evaluate the quality of life of patients. The scale contains 34 items, each of which is divided into five levels: asymptomatic, mild, moderate, severe, and severe, with a score of 1-5. According to the content of the scale, it is divided into 8 dimensions, namely anxiety (Q1), behavioral disorders (Q2), body consciousness (Q3), health worries (Q4), food avoidance (Q5), social function (Q6), opposite sex concept (Q7) and interpersonal relationship (Q8). The score of each dimension is converted to a range of 0-100 points. The higher the score, the worse the patient's quality of life.

[0137] The conversion formula is: Conversion score = (actual score - minimum possible score) ÷ possible score range × 100.

[0138] This outcome indicator was mainly evaluated at Visit 2, Visit 4, Visit 6, and Visit 7.

[0139] 3.3 Safety indicators

[0140] (1) Routine examination: routine blood test, routine urine test, and routine stool test, performed at visit 2 and visit 6; the urine routine examination indicators include urine protein (PRO), urine red blood cells (BLD), and urine white blood cells (LEU);

[0141] (2) Biochemical indices: liver function including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP); renal function including blood urea nitrogen (BUN) and creatinine (Cr), performed at visit 2 and visit 6;

[0142] (3) electrocardiogram, performed at visit 2 and visit 6;

[0143] (4) Adverse reaction log: patients should record any adverse reaction such as rash, constipation or other special symptoms at any time.

[0144] 3.4 Timing of outcome measurement

[0145] The clinical trial data collection of Changyanning Tablets is divided into a screening period and a treatment period. The screening period corresponds to visit 1 (V1), the treatment period is divided into visits 2 to 6, corresponding to V2 to V6, and the observation period corresponds to visit 7 (V7). The V3 measurement point is the first measurement point after medication, corresponding to 14±4d after medication, V4 to V6 and so on, and the total medication is 8 weeks.

[0146] Table 3 Data collection and measurement time points for the clinical trial of Changyanning Tablets

[0147]

[0148] *: Screening period is defined as 7 days before randomization. Telephone follow-up is available at Visit 3 and Visit 5.

[0149] a. Vital signs: temperature, pulse, respiration, blood pressure;

[0150] b. Routine blood test: red blood cell count (RBC), hemoglobin (HGB), white blood cell count (WBC), platelet count (PLT), neutrophil percentage (NEUT%). c. Routine urine test: urine protein (PRO), urine red blood cells (BLD), urine white blood cells (LEU).

[0151] d. Liver function test indicators include: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).

[0152] e. Renal function test indicators include: blood urea nitrogen (BUN), urea (UREA), and creatinine (Cr).

[0153] f. Routine stool examination and occult blood test: color, texture, red blood cells, white blood cells and occult blood test.

[0154] 4. Statistical analysis

[0155] 4.1 Statistical principles

[0156] A two-sided test was used, the test level for statistical significance was set at 0.05, and p < 0.05 was considered to be statistically significant.

[0157] 4.2 Analysis methods

[0158] Descriptive analysis: The mean is given for measurement data; the frequency distribution and corresponding percentage are given for count data; and the frequency distribution and corresponding percentage are given for rank data.

[0159] Comparison between groups: t test was used.

[0160] 5. Statistical analysis results

[0161] 5.1 Completion of the test

[0162] A total of 240 subjects were enrolled in this study, and 228 subjects actually completed the trial. Among them, 4 subjects withdrew from the experimental group and 1 was lost to follow-up, 4 subjects withdrew from the control group and 3 were lost to follow-up, and there was no statistically significant difference in the number of subjects who did not complete the trial and the reasons between the groups. The order of enrollment of 2 subjects was wrong, resulting in incorrect trial grouping, and the analysis was based on the intention-to-treat (ITT) principle. 2 patients did not take medication after enrollment, 1 patient seriously violated the inclusion criteria, 16 patients used prohibited drugs, 2 patients violated the randomization scheme, 2 patients met the exclusion criteria, 8 patients missed the primary efficacy index at visit 6, and 6 patients had poor medication compliance. In summary, 237 patients were included in the full analysis set (FAS set) of this study. There was no statistically significant difference between the groups in the number and reasons for excluding subjects in each data set.

[0163] There were 5 patients in the experimental group and 10 patients in the control group with medication compliance <80% or >120%, and there was no statistically significant difference between the groups.

[0164] 5.2 Baseline case characteristics

[0165] There was no statistical difference in age and gender between the control group and the treatment group.

[0166] Table 4 Comparison of demographic data

[0167]

[0168] There are four types of TCM syndromes, with large intestine damp-heat syndrome accounting for 33.33%, spleen and stomach weakness syndrome accounting for 27.43%, liver qi invading the spleen syndrome accounting for 24.89%, and spleen and kidney yang deficiency syndrome accounting for 14.35%. There was no statistical difference in the distribution of each syndrome among the groups.

[0169] Table 5 Distribution of TCM syndrome types

[0170]

[0171] 5.3 Effectiveness Analysis

[0172] 5.3.1 Week Response Rate

[0173] The response rate of the V3 week in the IBS-D large intestine damp-heat syndrome test group was 29.73%, which was 2.5 times that of the control group, and the difference between the groups was statistically significant (p<0.05). As the medication cycle was prolonged, the response rate of the V4 to V6 weeks in the test group gradually increased. After 8 weeks of medication (V6), the response rate was greater than 75%, which was more than 2 times that of the control group, and the difference between the groups was statistically significant (p<0.001). After 4 weeks of discontinuation of medication (V7), the response rate was still greater than 70%, and the symptoms did not recur. The test results show that Changyanning Tablets can be used to treat IBS-D large intestine damp-heat syndrome, and it takes effect 14±4d (V3) after medication, the treatment effect is stable, and there is no recurrence after discontinuation of medication.

[0174] Table 6 Weekly response rate of large intestine damp-heat syndrome subgroup

[0175]

[0176] The V3-week response rate of the experimental group of IBS-D spleen and stomach deficiency syndrome was 28.95%, which was close to 25.93% in the control group, and there was no statistically significant difference between the groups; the V4-week response rate was 26.32%, which was higher than 14.81% in the control group, and there was no statistically significant difference between the groups. The weekly response rates of the experimental group and the control group at the V4 observation point were lower than those at the V3 observation point, which may be related to the development of the disease, whether the drug treatment is symptomatic, and the degree of data dispersion within the group. Combining the V5 and V6 observation points can more objectively evaluate whether the drug is effective. The V4-week response rate of the experimental group was lower than that of V3. Combined with the therapeutic effect that the V5-week response rate increased to 65.79% and the V6-week response rate increased to 76.32%, it can be inferred that the Changyanning tablets were not effective at the V3 observation point (14±4d after medication) and the V4 observation point (28±4d after medication). The test results show that Changyanning tablets can be used to treat IBS-D with spleen and stomach deficiency syndrome. The effect is effective 42±4 days after medication, the treatment effect is stable, and there is no recurrence after medication discontinuation.

[0177] Table 7 Weekly response rate of spleen and stomach deficiency syndrome subgroups

[0178]

[0179]

[0180] The response rate of the IBS-D liver qi invading spleen syndrome test group at week V3 was 34.37%, which was higher than 22.22% in the control group, and the difference between the groups was not statistically significant; the response rate at week V4 was 50.00%, which was twice that of the control group, and the difference between the groups was not statistically significant. The response rate at week V6 was 75.00%, and the response rate in the control group was 48.15%, and the difference between the groups was statistically significant. Combined with the trend of the response rate from week V3 to week V6, it was found that the onset of the V3 and V4 observation points was not obvious. The experimental results show that Changyanning tablets can be used to treat IBS-D liver qi invading spleen syndrome, which takes effect 60±4d after medication, the treatment effect is stable, and there is no recurrence after discontinuation of medication.

[0181] Table 8 Weekly response rate of liver qi invading spleen syndrome subgroups

[0182]

[0183] The response rate of the IBS-D spleen and kidney yang deficiency group at week V3 was 38.46%, which was close to 38.10% in the control group, and there was no statistically significant difference between the groups; the response rate at week V4 was 61.54%, which was close to 57.14% in the control group, and there was no statistically significant difference between the groups; the response rate at week V5 was 76.92%, which was about 2 times that of the control group, and there was a statistically significant difference between the groups. The results of the experiment showed that Changyanning tablets can treat IBS-D spleen and kidney yang deficiency, but the effect was not obvious at the V3 and V4 observation points. It took effect 42±4d after medication, the treatment effect was stable, and the weekly response rate continued to decrease after discontinuation of medication. The small sample size and intra-group differences of spleen and kidney yang deficiency may affect the test results.

[0184] Table 9 Weekly response rate of spleen and kidney yang deficiency subgroups

[0185]

[0186] 5.3.2 IBS-QOL scale score and each dimension score

[0187] The IBS-QOL scale analyzes the patient's emotions from eight aspects, including anxiety, behavioral disorders, body consciousness, health worries, food avoidance, social function, opposite sex concepts, and interpersonal relationships, and evaluates the effects of drugs on different dimensions. The score of each dimension is converted to a range of 0-100 points. The higher the score, the worse the patient's quality of life. The greater the reduction in the score, the better the treatment effect. The number of cases in the experimental group and the control group is different, so the difference in the scores of each dimension of IBS-QOL in the same group is used for comparison to reduce the probability of statistical errors caused by the amount of data. V4-V2 scores and V6-V2 scores are negative, indicating that the drug is effective; the smaller the negative number, the better the treatment effect.

[0188] The emotional data of the experimental group and the control group of IBS-D large intestine damp-heat syndrome are shown in Tables 10 and 11. V2 is the baseline data, and V4 and V6 are the data of 4 weeks and 8 weeks of medication. There are differences in the scores of each dimension of the two groups of data. Among them, the scores of V4 and V6 in the experimental group are lower than those in the control group, that is, the experimental group has a therapeutic effect. The V4-V2 score was used for longitudinal comparison between the experimental group and the control group. After 4 weeks of medication, the anxiety score of the IBS-QOL index in the experimental group was reduced by 1.61 compared with the control group, indicating that the effect of Changyan Ning tablets on improving anxiety after 4 weeks of medication was 31.82% higher than that of the placebo; in addition, the treatment effects of behavioral disorders, health worries, food avoidance, social function and interpersonal relationships were improved to varying degrees compared with the control group. Combined with the weekly response rate of the large intestine damp-heat syndrome subgroup in Table 6, it can be found that the weekly response rate of V3 in the experimental group was 2.5 times that of the control group, and the difference between the groups was statistically significant (p<0.05), indicating that the intestinal symptoms began to ease 14±4d after medication, and the corresponding emotions may be improved due to the relief of intestinal symptoms.

[0189] Table 10 Scores of each dimension of the observation point of IBS-QOL scale for large intestine damp-heat syndrome

[0190]

[0191] Table 11 Comparison of changes in IBS-QOL indicators of large intestine damp-heat syndrome

[0192]

[0193] The emotional data of the IBS-D spleen and stomach deficiency syndrome experimental group and the control group are shown in Tables 12 and 13. The scores of the V4 and V6 experimental groups were lower than those of the control group, that is, the treatment effect of Changyan Ning tablets was better. The V4-V2 score was used for longitudinal comparison between the experimental group and the control group. The anxiety score of the IBS-QOL index of V4-V2 in the experimental group was 6.8 lower than that in the control group, indicating that the effect of Changyan Ning tablets on improving anxiety after 4 weeks of medication was 117.44% higher than that of placebo; the health anxiety score of the IBS-QOL index of V4-V2 in the experimental group was 2.88 lower than that of the control group, indicating that the effect of Changyan Ning tablets on improving health anxiety after 4 weeks of medication was 32.14% higher than that of placebo. In addition, all IBS-QOL indicators in the experimental group were improved to varying degrees compared with the control group.

[0194] Combined with the weekly response rate of the spleen and stomach deficiency syndrome subgroup in Table 7, it can be found that the weekly response rate of Changyan Ning tablets V3 is similar to that of the control group, indicating that Changyan Ning tablets are not effective in treating intestinal symptoms at V3. The weekly response rate of V4 is lower than that of V3, but anxiety and health worries were improved at V4, indicating that Changyan Ning tablets can treat emotional anxiety alone, rather than relieving emotional anxiety by treating intestinal symptoms. As mentioned above, IBS-D spleen and stomach deficiency syndrome is not caused by emotional anxiety, and Changyan Ning preparations can relieve emotional anxiety alone, or emotional anxiety combined with IBS-D spleen and stomach deficiency syndrome.

[0195] Table 12 Scores of each dimension of the IBS-QOL scale for spleen and stomach deficiency syndrome

[0196]

[0197] Table 13 Comparison of changes in IBS-QOL indicators of spleen and stomach deficiency syndrome

[0198]

[0199] The emotional data of the IBS-D liver qi invading spleen syndrome test group and the control group are shown in Tables 14 and 15. The V4-V2 score was used for longitudinal comparison between the test group and the control group. The anxiety score of the IBS-QOL index of V4-V2 in the test group was 4.12 lower than that in the control group, indicating that the effect of Changyan Ning tablets on improving anxiety after 4 weeks of medication was 67.10% higher than that of the placebo; the health anxiety score of the IBS-QOL index of V4-V2 in the test group was 1.66 higher than that in the control group, indicating that the effect of placebo on improving health anxiety at the V4 observation point was better than that of Changyan Ning tablets. In addition, the IBS-QOL indicators of behavioral disorders, body consciousness, food avoidance, social function, opposite sex concept, and interpersonal relationships in the test group were all improved to varying degrees compared with the control group.

[0200] Combined with the weekly response rate of the liver qi invading spleen syndrome subgroup in Table 8, it can be found that there is no statistically significant difference between the weekly response rate of Changyanning tablets at V3 and V4 observation points and the control group, indicating that Changyanning tablets are not effective in treating intestinal symptoms at V3 and V4. Combined with the weekly response rate of Changyanning tablets at V5, it can be seen that Changyanning tablets can treat intestinal symptoms of liver qi invading spleen syndrome IBS-D. As mentioned above, the onset of IBS-D liver qi invading spleen syndrome is related to mood changes, and Changyanning preparations can alone relieve anxiety and the liver qi invading spleen syndrome IBS-D disease caused by it.

[0201] Table 14 Scores of each dimension of the IBS-QOL scale for liver qi invading spleen syndrome observation points

[0202] IBS-QOL indicators Experimental Group Control group IBS-QOL indicators Experimental Group Control group IBS-QOL indicators Experimental Group Control group V2 Anxiety 25.49 21.88 V4 Anxiety 15.23 15.74 V6 Anxiety 10.21 10.30 V2 Behavioral Disorders 27.57 26.06 V4 Behavioral disorders 16.07 20.24 V6 Behavioral Disorders 11.87 14.95 V2 Body Awareness 18.95 15.74 V4 Body Awareness 11.72 12.96 V6 Body Awareness 9.93 11.81 V2 Health Concerns 33.07 32.41 V4 Health Concerns 25.78 23.46 V6 Health Concerns 20.64 19.75 V2 Food Avoidance 36.98 34.26 V4 Food Avoidance 25.52 30.56 V6 Food Avoidance 21.81 23.77 V2 Social Features 19.53 13.66 V4 Social Function 12.11 14.58 V6 Social Function 9.71 7.41 V2 Heterosexual Concept 10.16 8.33 V4 Opposite Sex Concept 6.25 9.26 V6 Opposite Sex Concept 3.00 8.33 V2 Interpersonal Relationships 15.36 10.49 V4 Interpersonal Relationships 7.29 9.57 V6 Interpersonal Relationships 4.62 7.72 V2 IBS-QOL total score 36.83 33.77 V4 IBS-QOL total score 27.73 29.77 V6 IBS-QOL total score 23.99 25.27

[0203] Table 15 Comparison of changes in IBS-QOL indicators in liver qi invading spleen syndrome

[0204]

[0205] The emotional data of the IBS-D spleen and kidney yang deficiency test group and control group are shown in Tables 16 and 17. The longitudinal comparison of the test group and the control group using V4-V2 and V6-V2 scores showed that the test group had higher scores in anxiety, body consciousness, health anxiety, food avoidance, and interpersonal relationships than the placebo group. The small sample size of spleen and kidney yang deficiency and intra-group differences may affect the test results.

[0206] Table 16 Scores of each dimension of the IBS-QOL scale for spleen and kidney yang deficiency

[0207]

[0208]

[0209] Table 17 Comparison of changes in IBS-QOL indicators in spleen and kidney yang deficiency syndrome

[0210]

[0211] 5.3.3 Typical Cases

[0212] (1) IBS-D combined with elevated urine protein, urine white blood cells, and urine red blood cells

[0213] 1) Case 1: No. 045

[0214] Female, 48 years old. Chief complaint: abdominal pain, diarrhea, and changes in bowel habits occurred in December 2022. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, she was diagnosed with IBS-D large intestine damp-heat syndrome. The patient denied previous medical history. She had concurrent diseases such as high urine protein, dermatitis, osteoporosis, mild fatty liver, and high urine white blood cells. The disease started in October 2023 and was not treated during the enrollment period. Oral administration of 4 tablets of Enteritis Ning tablets / time, 3 times / day, for a course of 8 weeks. Follow-up was conducted for 4 weeks after the end of treatment. The subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, liver and kidney function, and blood routine were normal, and the frequency of bowel movements decreased.

[0215] The frequency of bowel movements and abdominal pain are shown in Table 18. V1 and V2 are the screening period and the baseline period, respectively, and are the controls before medication; V6 is the control after 8 weeks of treatment. After 8 weeks of treatment, the frequency of bowel movements in this case decreased by 46%, urine protein turned from weak positive to negative, urine white blood cells and urine red blood cells were reduced to normal ranges, and the pain index did not improve. The test results show that the Changyanning preparation can reduce the frequency of bowel movements in patients with IBS-D large intestine damp-heat syndrome, and at the same time treat combined diseases with high urine protein and high urine white blood cells.

[0216] Table 18 Defecation frequency and abdominal pain in cases 1 to 4

[0217]

[0218] Table 19 Urine routine test results for case 1

[0219]

[0220]

[0221] *Note: Data from different hospitals vary, which does not affect the results.

[0222] 2) Case 2: No. 172

[0223] Male, 46 years old. Chief complaint: abdominal pain, diarrhea, and changes in bowel habits in 2015. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, he was diagnosed with IBS-D spleen and stomach weakness syndrome. The patient confirmed a history of previous surgery for intussusception and had gastritis complications. The disease started in August 2014 and was not treated during the enrollment period. Oral Changyanning tablets 4 tablets / time, 3 times / day, the course of treatment was 8 weeks, and follow-up was conducted for 4 weeks after the end of treatment. The subjects completed the clinical study according to the protocol requirements. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, liver and kidney function, and blood routine were normal, the frequency of bowel movements decreased, and the NRS pain index decreased.

[0224] The frequency of bowel movements and abdominal pain are shown in Table 18. After 8 weeks of treatment, the frequency of bowel movements decreased by 20%, the NRS pain index decreased by 35%, and the urine protein index in the urine routine test turned negative. The test results show that the Changyanning preparation can reduce the frequency of bowel movements and abdominal pain index in patients with IBS-D spleen and stomach deficiency syndrome, and treat concurrent diseases with high urine protein.

[0225] Table 20 Urine routine test results for case 2

[0226] Visit index Test value* Range lower limit Upper limit of range Range Units Clinical significance V1: Screening period (D-9±2-D0) Urine protein 0.3 / <0.15 g / l abnormal V1: Screening period (D-9±2-D0) Urine red blood cells 3.20 0<＝ <＝13.1 pcs / ul normal V1: Screening period (D-9±2-D0) Urine white blood cells 2.90 0<＝ <＝9.2 pcs / ul normal V6: Treatment period (D60±4d) Urine protein Negative / <0.15 g / l normal V6: Treatment period (D60±4d) Urine red blood cells 1.80 0<＝ <＝13.1 pcs / ul normal V6: Treatment period (D60±4d) Urine white blood cells 0.30 0<＝ <＝9.2 pcs / ul normal

[0227] *Note: Data from different hospitals vary, which does not affect the results.

[0228] 3) Case 3: No. 009

[0229] Male, 30 years old. The main complaint was abdominal pain, diarrhea, and changes in bowel habits in 2023. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, he was diagnosed with IBS-D large intestine damp-heat syndrome. The patient denied previous medical history and had fatty liver and proctitis. The disease started in January 2024 and was not treated during the enrollment period. Oral Enteritis Ning tablets 4 tablets / time, 3 times / day, for 8 weeks, followed up for 4 weeks after the end of treatment, and the subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, liver and kidney function, and blood routine were normal. The frequency of bowel movements did not decrease, and the NRS pain index decreased.

[0230] The frequency of bowel movements and abdominal pain are shown in Table 18. After 8 weeks of treatment, the frequency of bowel movements did not decrease, but the NRS pain index decreased by 24%; the weak positive urine protein turned negative. The test results show that the Changyanning preparation can relieve abdominal pain in patients with IBS-D large intestine damp-heat syndrome and treat concurrent diseases with high urine protein.

[0231] Table 21 Urine routine test results of case 3

[0232]

[0233]

[0234] *Note: Data from different hospitals vary, which does not affect the results.

[0235] 4) Case 4: No. 022

[0236] Female, 58 years old. Complaints of abdominal pain, diarrhea, and changes in bowel habits in 2020. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, she was diagnosed with IBS-D liver qi invading spleen syndrome. The patient denied previous medical history. She had thyroid nodules, uterine leiomyoma, hyperlipidemia, external hemorrhoids, chest pain, chest tightness, chronic nephritis, and right liver cysts. The disease started from June 2021 to December 2023 and was not treated during the enrollment period. Oral Enteritis Ning tablets 4 tablets / time, 3 times / day, for 8 weeks, followed up for 4 weeks after the end of treatment, and the subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, liver and kidney function, and blood routine were normal, the frequency of bowel movements decreased, and the NRS pain index decreased.

[0237] The frequency of bowel movements and abdominal pain are shown in Table 18. After 8 weeks of treatment, the frequency of bowel movements decreased by 20%, the NRS pain index decreased by 78%, and the weak positive urine protein turned negative. The results of the experiment showed that the Changyanning preparation can relieve the frequency of bowel movements and abdominal pain in patients with IBS-D liver qi invading spleen syndrome, and treat the concurrent diseases with high urine white blood cells.

[0238] Table 22 Urine routine test results for case 4

[0239] Visit index Test value* Range lower limit Upper limit of range Range Units Clinical significance V1: Screening period (D-9±2-D0) Urine protein +- Negative Negative / abnormal V1: Screening period (D-9±2-D0) Urine red blood cells 10 0<＝ <＝17 / uL normal V1: Screening period (D-9±2-D0) Urine white blood cells 0 0<＝ <＝28 / uL normal V6: Treatment period (D60±4d) Urine protein Negative Negative Negative / normal V6: Treatment period (D60±4d) Urine red blood cells 4 0<＝ <＝17 / uL normal V6: Treatment period (D60±4d) Urine white blood cells 0 0<＝ <＝28 / uL normal

[0240] *Note: Data from different hospitals vary, which does not affect the results.

[0241] (2) IBS-D combined with fatty liver and abnormal liver function

[0242] 1) Case 5: No. 027

[0243] Male, 49 years old. Complaints of abdominal pain, diarrhea, and changes in bowel habits in 2022. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, he was diagnosed with IBS-D large intestine damp-heat syndrome. The patient denied previous medical history. He had mild fatty liver, calcification foci in the left liver, and cholesterol crystals in the gallbladder wall. The disease started in May 2023 and was not treated during the enrollment period. Oral Enteritis Ning tablets 4 tablets / time, 3 times / day, for 8 weeks, followed up for 4 weeks after the end of treatment, and the subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, urine routine, and blood routine were normal, the frequency of bowel movements decreased, and the frequency of bowel movements and NRS pain index continued to decrease after discontinuation of the drug, without rebound.

[0244] The frequency of bowel movements and abdominal pain are shown in Table 23. After 8 weeks of treatment, the frequency of bowel movements decreased by 60%, the NRS pain index decreased by 92%, the alanine aminotransferase and aspartate aminotransferase index decreased, and one of the indicators returned to normal. The results of the experiment showed that the Changyanning preparation can relieve abdominal pain in patients with IBS-D large intestine damp-heat syndrome, reduce the frequency of bowel movements, and treat fatty liver complications.

[0245] Table 23 Defecation frequency and abdominal pain in cases 5 to 9

[0246]

[0247] Table 24 Liver and kidney function of case 5

[0248] Visit index Test value* Range lower limit Upper limit of range unit Clinical significance V1: Screening period (D-9±2-D0) ALT 80 9<＝ <＝50 U / L Associated with fatty liver V1: Screening period (D-9±2-D0) Aspartate aminotransferase 44 15<＝ <＝40 U / L Associated with fatty liver V1: Screening period (D-9±2-D0) Alkaline phosphatase 88 45<＝ <＝125 U / L normal V1: Screening period (D-9±2-D0) Urea nitrogen / / / — Not checked V1: Screening period (D-9±2-D0) Urea 5.80 3.10<＝ <＝8.00 mmol / L normal V1: Screening period (D-9±2-D0) Creatinine 87 57<＝ <＝97 μmol / L normal V6: Treatment period (D60±4d) ALT 64 9<＝ <＝50 U / L Associated with fatty liver V6: Treatment period (D60±4d) Aspartate aminotransferase 36 15<＝ <＝40 U / L normal V6: Treatment period (D60±4d) Alkaline phosphatase 93 45<＝ <＝125 U / L normal V6: Treatment period (D60±4d) Urea nitrogen / / / — Not checked V6: Treatment period (D60±4d) Urea 7.50 3.10<＝ <＝8.00 mmol / L normal V6: Treatment period (D60±4d) Creatinine 91 57<＝ <＝97 μmol / L normal

[0249] *Note: Data from different hospitals vary, which does not affect the results.

[0250] 2) Case 6: No. 151

[0251] Female, 58 years old. Complaints of abdominal pain, diarrhea, and changes in bowel habits in 2021. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, she was diagnosed with IBS-D liver qi invading spleen syndrome. The patient denied previous medical history and had fatty liver comorbidities. The disease started in July 2023 and was not treated during the enrollment period. Oral administration of Enteritis Ning tablets 4 tablets / time, 3 times / day, for 8 weeks, and follow-up for 4 weeks after the end of treatment. The subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, urine routine, and blood routine were normal, the frequency of bowel movements decreased, and the NRS pain index decreased.

[0252] The frequency of bowel movements and abdominal pain are shown in Table 23. After 8 weeks of treatment, the frequency of bowel movements decreased by 33%, the NRS pain index decreased by 65%, and the alanine aminotransferase index decreased to normal. The test results show that Changyanning preparation can relieve abdominal pain in patients with IBS-D liver qi invading spleen syndrome, reduce the frequency of bowel movements, and treat fatty liver complications.

[0253] Table 25 Liver and kidney function of case 6

[0254]

[0255]

[0256] *Note: Data from different hospitals vary, which does not affect the results.

[0257] 3) Case 7: No. 083

[0258] Male, 43 years old. Complaints of abdominal pain, diarrhea, and changes in bowel habits in February 2023. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, he was diagnosed with IBS-D spleen and stomach weakness syndrome. The patient denied previous medical history. He had elevated alanine aminotransferase, elevated aspartate aminotransferase, and elevated glutamyl transferase. The disease started in October 2023 and was not treated during enrollment. The subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, urine routine, and blood routine were normal, the frequency of bowel movements decreased, and the frequency of bowel movements and the NRS pain index continued to decrease after discontinuation of the drug, without rebound.

[0259] The frequency of bowel movements and abdominal pain are shown in Table 23. After 8 weeks of treatment, the frequency of bowel movements did not improve significantly, and the NRS pain index did not improve; however, the alanine aminotransferase and aspartate aminotransferase indexes decreased, and one of the indicators returned to normal. The test results show that Changyanning preparations can treat liver function abnormalities such as elevated alanine aminotransferase and aspartate aminotransferase combined with IBS-D spleen and stomach deficiency syndrome.

[0260] Table 26 Liver and kidney function of case 7

[0261] Visit index Test value* Range lower limit Upper limit of range unit Clinical significance V1: Screening period (D-9±2-D0) ALT 126.7 5<＝ <＝50 U / L Abnormal, related to comorbidity V1: Screening period (D-9±2-D0) Aspartate aminotransferase 82.6 5<＝ <＝50 U / L Abnormal, related to comorbidity V1: Screening period (D-9±2-D0) Alkaline phosphatase 64.5 40<＝ <＝150 U / L normal V1: Screening period (D-9±2-D0) Urea nitrogen / NA NA / Not checked V1: Screening period (D-9±2-D0) Urea 4.01 2.6<＝ <＝8.2 mmol / L normal V1: Screening period (D-9±2-D0) Creatinine 101.1 41<＝ <＝132.6 μmol / L normal V6: Treatment period (D60±4d) ALT 82.3 5<＝ <＝50 U / L Abnormal, related to comorbidity V6: Treatment period (D60±4d) Aspartate aminotransferase 49.0 5<＝ <＝50 U / L normal V6: Treatment period (D60±4d) Alkaline phosphatase 63.8 40<＝ <＝150 U / L normal V6: Treatment period (D60±4d) Urea nitrogen / NA NA / Not checked V6: Treatment period (D60±4d) Urea 3.43 2.6<＝ <＝8.2 mmol / L normal V6: Treatment period (D60±4d) Creatinine 113.8 41<＝ <＝132.6 μmol / L normal

[0262] *Note: Data from different hospitals vary, which does not affect the results.

[0263] 4) Case 8: No. 084

[0264] Male, 46 years old. The main complaint was abdominal pain, diarrhea, and changes in bowel habits in January 2023. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, he was diagnosed with IBS-D spleen and stomach weakness syndrome. The patient denied previous medical history. He had elevated alanine aminotransferase and aspartate aminotransferase and other diseases. The disease started in November 2023 and was not treated during the enrollment period. Oral Enteritis Ning tablets were taken, and the subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, urine routine, and blood routine were normal, and the frequency of stool and NRS pain index did not improve.

[0265] The defecation frequency and abdominal pain are shown in Table 23. The results showed that after 8 weeks of treatment, the defecation frequency and NRS pain index did not improve, but the alanine aminotransferase and aspartate aminotransferase indexes decreased to normal. The test results showed that the Changyanning preparation can treat liver function abnormalities such as elevated alanine aminotransferase and aspartate aminotransferase combined with IBS-D spleen and stomach deficiency syndrome.

[0266] Table 27 Liver and kidney function of case 8

[0267] Visit index Test value* Range lower limit Upper limit of range unit Clinical significance V1: Screening period (D-9±2-D0) ALT 88.5 5<＝ <＝50 U / L Abnormal, related to comorbidity V1: Screening period (D-9±2-D0) Aspartate aminotransferase 56.7 5<＝ <＝50 U / L Abnormal, related to comorbidity V1: Screening period (D-9±2-D0) Alkaline phosphatase 68.1 40<＝ <＝150 U / L normal V1: Screening period (D-9±2-D0) Urea nitrogen / NA NA / Not checked V1: Screening period (D-9±2-D0) Urea 5.53 2.6<＝ <＝8.2 mmol / L normal V1: Screening period (D-9±2-D0) Creatinine 92.9 41<＝ <＝132.6 μmol / L normal V6: Treatment period (D60±4d) ALT 39.3 5<＝ <＝50 U / L normal V6: Treatment period (D60±4d) Aspartate aminotransferase 29.3 5<＝ <＝50 U / L normal V6: Treatment period (D60±4d) Alkaline phosphatase 59.4 40<＝ <＝150 U / L normal V6: Treatment period (D60±4d) Urea nitrogen / NA NA / Not checked V6: Treatment period (D60±4d) Urea 5.07 2.6<＝ <＝8.2 mmol / L normal V6: Treatment period (D60±4d) Creatinine 99.6 41<＝ <＝132.6 μmol / L normal

[0268] *Note: Data from different hospitals vary, which does not affect the results.

[0269] 5) Case 9: No. 158

[0270] Male, 37 years old. The main complaint was abdominal pain, diarrhea, and changes in bowel habits in 2020. The symptoms appeared for at least 6 months and persisted for nearly 3 months. After relevant examinations, he was diagnosed with IBS-D large intestine damp-heat syndrome. The patient denied previous medical history and had fatty liver comorbidities. The disease started in August 2023 and was not treated during the enrollment period. Oral Enteritis Ning tablets were taken, and the subjects completed the clinical study as required by the protocol. During V1 to V7, vital signs such as blood pressure, respiration, pulse, body temperature, electrocardiogram, urine routine, and blood routine were normal, the frequency of bowel movements decreased, and there was no rebound in the frequency of bowel movements after stopping the medication.

[0271] The frequency of bowel movements and abdominal pain are shown in Table 23. After 8 weeks of treatment, the frequency of bowel movements did not improve, but the NRS pain index decreased by 16%; the alanine aminotransferase and aspartate aminotransferase indexes decreased, and the urea index increased, with 2 of the indexes returning to normal. The results of the experiment showed that the Changyanning preparation can relieve abdominal pain in patients with IBS-D large intestine damp-heat syndrome and treat fatty liver complications at the same time.

[0272] Table 28 Liver and kidney function of case 9

[0273]

[0274]

[0275] *Note: Data from different hospitals vary, which does not affect the results.

Claims

1. Use of the Changyanning preparation in the preparation of a drug for treating or preventing diarrhea-type irritable bowel syndrome, wherein the types of diarrhea-type irritable bowel syndrome include liver qi invading spleen syndrome, spleen and stomach deficiency syndrome, spleen and kidney yang deficiency syndrome, or large intestine damp-heat syndrome.

2. The use according to claim 1, characterized in that The treatment or prevention of diarrhea-predominant irritable bowel syndrome includes reducing diarrhea, abdominal pain or stool frequency.

3. The use according to claim 1, characterized in that The Changyanning preparation is used in preparing a medicine for treating or preventing diarrhea-type irritable bowel syndrome combined with abnormal liver function or fatty liver disease.

4. The use according to claim 3, characterized in that The types of diarrhea-type irritable bowel syndrome are liver qi invading spleen syndrome, spleen and stomach deficiency syndrome or large intestine damp-heat syndrome.

5. Use of the Changyanning preparation in the preparation of drugs for treating or preventing emotional anxiety diseases.

6. The use according to claim 5, characterized in that The emotional anxiety disease is a disease of diarrhea-type irritable bowel syndrome combined with emotional anxiety, and the type of diarrhea-type irritable bowel syndrome is spleen and stomach deficiency syndrome.

7. Use of the Changyanning preparation in the preparation of a drug for reducing urine protein.

8. The use according to claim 7, characterized in that The medicine is used for treating or preventing diarrhea-type irritable bowel syndrome combined with high urine protein.

9. The use according to claim 8, characterized in that The types of diarrhea-type irritable bowel syndrome are liver qi invading spleen syndrome, spleen and stomach deficiency syndrome or large intestine damp-heat syndrome.

10. The use according to any one of claims 1 to 9, characterized in that: The Changyanning preparation is prepared from the following medicinal materials in parts by weight: 500-1300 parts of Herba Euphorbiae Ichthyophthirius, 650-1700 parts of Herba Cibotii, 500-1300 parts of Cinnamomum camphora roots, 250-640 parts of Elsholtzia ciliata, and 250-640 parts of Liquidambar formosana leaves.

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