Application of Zhongwinning in preparation of medicine for treating irritable bowel syndrome
By using the drugs prepared by Zhongwuning, the problem of poor treatment of irritable bowel syndrome in the prior art was solved, the sensory threshold of rats with high visceral sensitivity was significantly improved, the symptoms of IBS were alleviated, and diarrhea was reduced and diarrhea was reduced. The severity of constipation-type symptoms provides a new treatment for irritable bowel syndrome.
Patent Information
- Application Number
- CN202411489744.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-24
- Publication Date
- 2024-12-31
AI Technical Summary
There is a lack of effective drugs for the treatment of irritable bowel syndrome in the prior art, and the existing drugs are poorly relieved of abdominal discomfort symptoms and have adverse reactions, such as bloating and drug dependence caused by anticholiner drugs.
Liquid, solid or semi-solid preparations are prepared by using Zhongwuning or its pharmaceutically acceptable salt as active ingredient, combined with commonly used pharmaceutically acceptable excipients or auxiliary ingredients, for the treatment of irritable bowel syndrome.
Zhongwuning can increase the sensory threshold for colorectal dilation in rats with high visceral sensitivity, significantly alleviate IBS symptoms, reduce the loose stool rate of diarrhea irritable bowel syndrome, increase the frequency of defecation and feces content of constipation irritable bowel syndrome The amount of water has good therapeutic prospects.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of new drug applications, and in particular relates to the application of Zhongwuning in preparing drugs for treating irritable bowel syndrome. Background Art
[0002] Irritable bowel syndrome (IBS) is a common functional bowel disease in clinical practice. IBS is diagnosed based on the Rome IV standard and is divided into constipation-type irritable bowel syndrome, diarrhea-type irritable bowel syndrome, mixed irritable bowel syndrome and uncertain irritable bowel syndrome according to bowel habits. The typical symptoms of IBS mainly include abdominal pain, diarrhea, constipation, etc. depending on its type. Its clinical manifestations are mainly reflected in chronic intermittent or persistent abdominal hyperalgesia and changes in intestinal emptying habits, often accompanied by gastrointestinal symptoms such as heartburn, early satiety, nausea, vomiting, etc., and may also have other systemic symptoms such as fatigue, back pain, palpitations, dyspnea, frequent urination, urgency, sexual dysfunction, etc. Some patients are accompanied by obvious anxiety and depression tendencies, and often have no specific clinical signs.
[0003] Since the etiology of IBS is unclear and the pathogenesis is complex, although there are many treatment methods, the efficacy is not certain. It is currently believed that increased visceral sensitivity is one of the most important pathophysiological characteristics of IBS, and is the basis for the symptoms of IBS patients and the reason for the diversity of symptoms. Visceral hypersensitivity refers to the increased sensitivity of visceral tissues to stimulation. Visceral sensitivity is generally assessed by the volume threshold or pressure threshold that causes various sensations. In the gastrointestinal tract, intraluminal balloon dilation is particularly commonly used. The intestine sensitized by intestinal tract manifestations is a decrease in pain threshold, that is, the so-called hyperalgesia. Even stimuli that do not cause pain under normal physiological conditions can induce pain, that is, allodynia.
[0004] There is currently no clear and effective drug treatment for IBS. There are many drugs on the market for the treatment of IBS, including anticholinergic drugs, antibiotics, antidepressants and anti-inflammatory drugs. Although there are many drugs to choose from, the symptoms of abdominal discomfort are still not well relieved. In addition, many drugs have adverse reactions. For example, although anticholinergic drugs can relieve abdominal pain and stop diarrhea, they are prone to cause abdominal distension, and long-term use will lead to drug dependence, which will increase the stubbornness of constipation.
[0005] Mesaconine (CAS NO.: 6792-09-2; molecular formula: C 24 H 39NO9) is a new type of alkaloid with medicinal value. It has a clear chemical structure and can be obtained by raw material extraction or chemical synthesis. Zhongwu Ning has a significant effect on improving cardiac function and can effectively prevent and treat acute heart failure caused by myocardial ischemia-reperfusion injury. However, there is no report on the treatment of irritable bowel syndrome with Zhongwu Ning. Summary of the invention
[0006] In view of the above-mentioned deficiencies in the prior art, the purpose of the present invention is to provide an application of Zhongwu Ning in the preparation of drugs for the treatment of irritable bowel syndrome. Studies have confirmed that Zhongwu Ning can increase the sensory threshold of visceral hypersensitive rats to rectal distension, can effectively improve the visceral hypersensitivity of irritable bowel syndrome model rats, can significantly alleviate IBS symptoms, and has certain application prospects for the treatment of IBS.
[0007] In order to achieve the above object, the solution adopted by the present invention is:
[0008] Application of Zhongwuning or its pharmaceutically acceptable salt in preparing medicine for treating irritable bowel syndrome.
[0009] Furthermore, in a preferred embodiment of the present invention, irritable bowel syndrome includes diarrhea-type, constipation-type, mixed-type and indeterminate irritable bowel syndrome.
[0010] Furthermore, in a preferred embodiment of the present invention, the irritable bowel syndrome drug is a preparation prepared with Zhongwu Ning or a pharmaceutically acceptable salt thereof as an active ingredient and adjuvants or auxiliary ingredients commonly used in pharmacy.
[0011] Furthermore, in a preferred embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt.
[0012] Furthermore, in a preferred embodiment of the present invention, the dosage form of the preparation includes a liquid preparation, a solid preparation or a semisolid preparation.
[0013] The beneficial effects of the application of Zhongwuning provided by the present invention in preparing a drug for treating irritable bowel syndrome are:
[0014] (1) This application first discovered the use of Zhongwu Ning in the preparation of drugs for the treatment of irritable bowel syndrome. Studies have shown that Zhongwu Ning can increase the sensory threshold of visceral hypersensitive rats to rectal distension, effectively improve the visceral hypersensitivity of irritable bowel syndrome model rats, and significantly relieve IBS symptoms, and has certain application prospects for the treatment of IBS;
[0015] (2) The present application has confirmed through research that Zhongwu Ning can significantly reduce the loose stool rate of rats with diarrhea-type irritable bowel syndrome, and can significantly increase the defecation frequency and fecal water content of rats with constipation-type irritable bowel syndrome, and has certain therapeutic prospects for diarrhea-type and constipation-type irritable bowel syndrome. DETAILED DESCRIPTION
[0016] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.
[0017] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.
[0018] Example 1 Behavioral (intestinal sensitivity) experiment on visceral hypersensitivity IBS rat model
[0019] 1. Experimental Materials
[0020] Experimental animals: SD rats, SPF grade, provided by Chengdu Dashuo Biotechnology Co., Ltd., female, body weight 170-210g. Production license number: SCXK (Chuan) 2015-030, fully nutritious, caged, in an environment with room temperature of 18-25°C, relative humidity of 50-60%, artificial 12h day / night cycle lighting, cages cleaned regularly every day, rats free access to food and water.
[0021] Main raw materials and reagents: Zhong Wu Ning (provided by Good Doctor Pharmaceutical Group Co., Ltd., referred to as ZWN), trimebutine maleate capsules, prepared into 0.003g / ml solution with distilled water before use.
[0022] 2. Experimental methods
[0023] 2.1 Animal grouping: Forty newborn rats were randomly divided into 4 groups: Zhongwuning group, positive drug control group, model group and blank control group, with 10 rats in each group.
[0024] 2.2 Modeling method: After SD rats were purchased, they were raised individually until the rats gave birth, and the birth date was recorded. On the 8th, 10th, and 12th days after birth, the young male rats received percutaneous transluminal coronary angioplasty balloon colon stimulation with a pressure of 60 mmHg for 1 min, once a day, for a total of 3 times; the control group: a balloon catheter was inserted into the anus, but it was not expanded.
[0025] 2.3 Administration method: Rats were gavaged starting on the 60th day after birth. The Zhonguning group was gavaged with 2 mg / kg Zhonguning, the positive drug control group was gavaged with 2 ml / 100 g of trimebutine maleate solution, and the model group and blank control group were both given 2 ml / 100 g of normal saline. Each group was dosed twice a day, and gavage lasted for 10 days.
[0026] 2.4 Measurement indicators and methods:
[0027] After the rats were gavaged, they were fasted for 12 hours and placed in a self-made transparent glass cage. After the rats adapted, the balloon was inserted through the anus about 6-8 cm, the catheter was tied to the rat's tail with tape to fix the balloon, and air was injected into the balloon to give different pressure stimulations.
[0028] The abdominal muscle retraction reflex of rats to rectal balloon distension was observed at 10, 20, 40, 60, and 80 mmHg pressures, and each rectal distension lasted for 20 seconds. The rats' responses to rectal distension under different pressures were observed, and semi-quantitative behavioral scores were performed based on their response records. At the same time, the number of abdominal muscle contractions of rats within 3 minutes of each distension of the rectal balloon at different pressures was recorded, with an interval of 30 minutes each time. Each pressure value was tested 3 times, and the average value was taken for scoring. The higher the score of the abdominal wall retraction reflex test, the higher the visceral sensitivity.
[0029] Judgment criteria: rats have no behavioral response to colon distension: 0 points: rats have no behavioral response to rectal distension; 1 point: the body is still and the head movement is reduced during rectal distension, which is defined as the initial perception threshold; 2 points: the abdominal muscles contract slightly during rectal distension, but the abdominal muscles are not lifted off the table, which is defined as the pain sensitivity threshold; 3 points: the abdominal muscles contract strongly and lift off the table during rectal distension, which is defined as the pain threshold; 4 points: the pelvis is lifted and the body is arched during rectal distension, which is defined as the maximum pain tolerance capacity threshold.
[0030] 2.5 Statistical methods: The experimental data were analyzed using SPSS10.0 statistical software. The data results were expressed as mean ± standard deviation (x±s). One-way ANOVA was used for analysis, and the differences between the groups were compared using t-test. P<0.05 was considered statistically significant.
[0031] 3. Experimental results
[0032] (1) Comparison of the threshold scores of the abdominal withdrawal reflex test under different pressure stimulations in each group of rats after treatment is shown in Table 1:
[0033] Table 1 Threshold scores of abdominal withdrawal reflex test under different pressure stimulations in rats after treatment (points, x±s, n=10)
[0034] Group No. 10 mmHg 20 mmHg 40 mmHg 60 mmHg 80 mmHg Model Group 0.71±0.21 1.68±0.48 2.51±0.52 3.62±0.44 3.82±0.32 Blank control group <![CDATA[0 ** ]]> <![CDATA[0.20±0.32 ** ]]> <![CDATA[0.56±0.38 ** ]]> <![CDATA[2.65±0.41 * ]]> <![CDATA[3.21±0.36 ** ]]> Zhongwuning Group <![CDATA[0.09±0.23 * ]]> <![CDATA[0.64±0.44 ** ]]> <![CDATA[1.78±0.62 * ]]> <![CDATA[2.74±0.38 * ]]> <![CDATA[3.72±0.30 * ]]> Positive drug control group <![CDATA[0.07±0.34 * ]]> <![CDATA[0.58±0.56 ** ]]> <![CDATA[1.68±0.54 * ]]> <![CDATA[2.62±0.46 * ]]> <![CDATA[3.60±0.33 * ]]>
[0035] Note: Compared with the model group, *P<0.05, **P<0.01.
[0036] The results in Table 1 show that the model group rats showed a decrease in visceral distension tolerance after adulthood, and the threshold score of the abdominal wall withdrawal reflex test was statistically different from that of the blank control group. The visceral hypersensitivity of the rats in the positive drug control group after treatment was improved, which was statistically significant compared with the model group; the abdominal wall withdrawal reflex test threshold score of the Zhongwuning group at different pressures was close to that of the drug control group, and was statistically significant compared with the model group.
[0037] (2) Comparison of the number of abdominal muscle contractions of rats in each group under different pressure stimulations is shown in Table 2:
[0038] Table 2 Comparison of the number of abdominal muscle contractions under different pressure stimulations in rats after treatment (times, x±s, n=10)
[0039] Group No. 10 mmHg 20 mmHg 40 mmHg 60 mmHg 80 mmHg Model Group 7.24±1.22 15.32±1.46 15.68±1.33 16.24±0.76 16.54±1.58 Blank control group <![CDATA[0.07±0.24 ** ]]> <![CDATA[0.08±0.22 ** ]]> <![CDATA[7.48±0.64 ** ]]> <![CDATA[11.52±1.14 ** ]]> <![CDATA[12.66±1.14 ** ]]> Zhongwuning Group <![CDATA[1.46±0.22 ** ]]> <![CDATA[3.91±0.38 ** ]]> <![CDATA[8.43±0.38 ** ]]> <![CDATA[14.21±1.34 * ]]> <![CDATA[14.88±0.92 * ]]> Positive drug control group <![CDATA[1.24±0.28 ** ]]> <![CDATA[3.72±0.42 ** ]]> <![CDATA[7.82±0.42 ** ]]> <![CDATA[13.62±1.22 * ]]> <![CDATA[14.37±0.88 * ]]>
[0040] Note: Compared with the model group, *P<0.05, **P<0.01
[0041] The results in Table 2 show that compared with the model group, the number of abdominal wall contractions under different pressure stimuli in the rats in the positive drug control group after treatment was significantly reduced, indicating that the visceral sensitivity was significantly reduced, which was statistically significant compared with the model group; although the number of abdominal wall contractions under different pressure stimuli in the Zhongwuning group was more than that in the positive drug control group, it was also significantly reduced compared with the model group, and was statistically significant compared with the model group.
[0042] The above results show that in the visceral hypersensitivity rat model of irritable bowel syndrome established by chronic acetic acid stimulation of the colon, the abdominal wall withdrawal reflex test score of the visceral hypersensitive rats can be significantly reduced after treatment with Zhongwu Ning, indicating that Zhongwu Ning can increase the sensory threshold of visceral hypersensitive rats to rectal distension, and can effectively improve the visceral hypersensitivity of irritable bowel syndrome model rats, and has certain application prospects in the treatment of irritable bowel syndrome.
[0043] Example 2 Rats with diarrhea-type irritable bowel syndrome
[0044] 1. Experimental Materials
[0045] Experimental animals: Male Wistar rats, weighing 180-220 g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., with animal production license number SCXK (Beijing) 2016-0011 and animal use license number SYXK (Beijing) 2019-0003.
[0046] Main raw materials and reagents: Zhongwuning (provided by Good Doctor Pharmaceutical Group Co., Ltd., referred to as ZWN), 0.8 mg / mL pinaverium bromide suspension.
[0047] 2. Experimental methods
[0048] 2.1 Animal grouping: 40 rats were randomly divided into 4 groups: Zhongwuning group, positive drug control group (pinaverium bromide suspension), model group and blank control group, with 10 rats in each group.
[0049] 2.2 Modeling method: After the rats were divided into groups, each group was fasted but not watered for 24 hours. After the rats were lightly anesthetized with ether, a 6-Fr double-lumen catheter (8 cm from the anus) was inserted through the anus. Except for the blank control group, 1 mL of 4% acetic acid solution was injected and retained in the colon for 30 seconds. Then, 1 mL of phosphate buffer was injected into each group to flush the colon, the catheter was slowly pulled out, and the rats were returned to the cage to move freely and eat and drink water.
[0050] 2.3 Administration method: Each group was given different drugs. The Zhongwuning group was gavaged with 4 mg / kg Zhongwuning, the positive drug control group was gavaged with 1 mL, 0.8 mg / mL pinaverium bromide suspension, and the model group and the blank group were gavaged with the same volume of sodium carboxymethyl cellulose aqueous solution, once a day for a total of 5 days.
[0051] 2.4 Measurement indicators and methods:
[0052] On the 7th day, the stress defecation of rats in each group was observed. Before the experiment, rats in each group were fasted for 24 hours but not water. After mild ether anesthesia, the front shoulders, front upper limbs and chest were bound with wide tape, and the front upper limbs were restricted from scratching the head and face, but their activities were not restricted. They were placed in a metabolic cage and taken out after being restrained for 1 hour. The number of hard stools, soft stools and unformed stools was recorded respectively, and the percentage was calculated.
[0053] 3. Experimental results
[0054] (1) The percentages of hard stools, soft stools, and unformed stools are shown in Table 3:
[0055] Table 3 Percentage of hard stool, soft stool and unformed stool in each group of rats
[0056] Group No. Percentage of hard stools / % Soft stool percentage / % Unformed stool percentage / % Model Group 13.33％ 22％ 64.67％ Blank control group <![CDATA[81.67% ** ]]> <![CDATA[18.33% ** ]]> 0 Zhongwuning Group <![CDATA[42.24% ** ]]> 35.62％ <![CDATA[22.14% ** ]]> Positive drug control group <![CDATA[55.38% ** ]]> 30％ <![CDATA[14.62% ** ]]>
[0057] Note: Compared with the model group, *P<0.05, **P<0.01.
[0058] The results in Table 3 show that compared with the model group, the loose stool rate of rats in the positive drug control group after treatment was significantly reduced, and the hard stool rate was significantly increased, which was statistically significant compared with the model group; the loose stool rate of rats in the Zhongwuning group after treatment was also significantly reduced, and the hard stool rate was significantly increased, which was statistically significant compared with the model group.
[0059] Example 3 Rats with constipation-type irritable bowel syndrome
[0060] 1. Experimental Materials
[0061] Experimental animals: Male Wistar rats, weighing 180-220 g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., with animal production license number SCXK (Beijing) 2016-0011 and animal use license number SYXK (Beijing) 2019-0003.
[0062] Main raw materials and reagents: Zhongwuning (provided by Good Doctor Pharmaceutical Group Co., Ltd., referred to as ZWN), 0.8 mg / mL pinaverium bromide suspension.
[0063] 2. Experimental methods
[0064] 2.1 Animal grouping: 20 rats were randomly divided into 4 groups: Zhongwuning group, positive drug control group (pinaverium bromide suspension), model group and blank control group, with 5 rats in each group.
[0065] 2.2 Modeling method: Rats were randomly divided into groups and each group was housed separately in separate cages. To eliminate the influence of biological rhythm, gavage was started at 13:00. All groups ate and drank normally before and after gavage.
[0066] 2.3 Administration method: Each group was given different drugs. The Zhongwuning group was gavaged with 4 mg / kg Zhongwuning, the positive drug control group was gavaged with 1 mL, 0.8 mg / mL pinaverium bromide suspension, and the model group and the blank group were gavaged with the same volume of sodium carboxymethyl cellulose aqueous solution, once a day for a total of 5 days.
[0067] 2.4 Measurement indicators and methods:
[0068] On the 15th and 20th day, the feces of rats in each group were collected. The rats in each group were placed in a metabolic cage, and the feces were collected for 6-24 hours, and the feces count was recorded. The feces pellets were placed in a 10mL centrifuge tube, and the initial weight of the feces was recorded. The feces were dried at 80℃ under vacuum to a constant weight, and the final weight of the feces was recorded.
[0069] Feces moisture content (%) = (feces weight before drying - feces weight after drying) / feces weight before drying × 100%.
[0070] 3. Experimental results
[0071] (1) The defecation frequency and feces water content of rats in each group at 15 days and 20 days are shown in Table 4:
[0072] Table 4 Defecation frequency and feces water content of rats in each group
[0073]
[0074]
[0075] Note: Compared with the blank group, **P<0.01; Compared with the model group, ##P<0.01.
[0076] The results in Table 4 show that compared with the model group, the defecation frequency and fecal water content of rats in the positive drug control group after treatment increased significantly, which was statistically significant compared with the model group; the defecation frequency and fecal water content of rats in the Zhongwuning group after treatment also increased significantly, which was statistically significant compared with the model group.
[0077] In summary, the present invention provides the use of Zhongwu Ning in the preparation of drugs for treating irritable bowel syndrome. Studies have shown that Zhongwu Ning can effectively improve visceral hypersensitivity in rats with irritable bowel syndrome models, reduce pain thresholds, and reverse the weakening of intestinal motility. At the same time, Zhongwu Ning can also significantly reduce the loose stool rate of rats with diarrhea-type irritable bowel syndrome, and significantly increase the defecation frequency and fecal water content of rats with constipation-type irritable bowel syndrome, significantly relieve IBS symptoms, and has certain therapeutic prospects for IBS.
[0078] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. Use of Zhongwuning or its pharmaceutically acceptable salt in preparing a drug for treating irritable bowel syndrome.
2. The use according to claim 1, characterized in that: The irritable bowel syndrome includes diarrhea-type, constipation-type, mixed-type and indeterminate irritable bowel syndrome.
3. The use according to claim 1, characterized in that: The irritable bowel syndrome drug is a preparation prepared by taking Zhongwuning or its pharmaceutically acceptable salt as an active ingredient and adding auxiliary materials or auxiliary ingredients commonly used in medicine.
4. The use according to claim 3, characterized in that: The pharmaceutically acceptable salt is an inorganic salt or an organic salt.
5. The use according to claim 3, characterized in that: The dosage form of the preparation includes a liquid preparation, a solid preparation or a semisolid preparation.