Application of eight-treasure pill in preparation of medicine for preventing or treating radiation enteritis

Abstract

The invention provides an application of eight-treasure pill in preparation of a medicine for preventing or treating radiation enteritis. Through clinical tests, the clinical curative effect of the Babaodan capsule for preventing and treating radiation enteritis is verified, meanwhile, the mechanism of the Babaodan capsule for treating radiation enteritis is defined, and clinical research data and a theoretical basis are provided for clinical prevention and treatment of radiation enteritis through the Babaodan capsule.

Description

Technical Field

[0001] The invention belongs to medical technology, in particular to the field of new drug indications, and specifically relates to the use of Babaodan in preparing drugs for preventing or treating radiation enteritis. Background Art

[0002] Radiation enteritis, also known as intestinal radiation injury, refers to intestinal inflammation that occurs after radiotherapy for pelvic or abdominal tumors. It can affect the small intestine, colon, and rectum, with the rectum being more common. According to clinical statistics, the incidence of radiation enteritis in patients who have received radiotherapy for pelvic tumors is as high as 20% (Wang Menglei, Yang Ze, Research Progress in Traditional Chinese Medicine Treatment of Radiation Enteritis [J], Journal of Practical Traditional Chinese Medicine, 2020, 05:685-687). Therefore, the prevention and treatment of radiation enteritis has become an important issue in tumor radiotherapy.

[0003] The effects of radiotherapy on the intestine can be divided into two aspects. First, it is manifested as a widespread suppression of the original intestinal flora, as well as the overgrowth of a few species of bacteria such as Staphylococcus, Proteus and Candida albicans. The endotoxin (LPS) produced by them can activate the NF-kB and MAPK signaling pathways, causing a large amount of Th1 secretion, promoting delayed inflammatory response in the intestine, and thus leading to the occurrence of enterogenic infection (Bi Yinghui, Experimental study on the repair effect of Actovegin on the intestine of rats with acute radiation enteritis and its mechanism of action [D], Shandong University, 2007).

[0004] Secondly, the effect of radiation on the intestine is manifested as an impact on the intestinal mucosal barrier. The intestinal mucosal barrier has poor tolerance to radiation. The energy effect of radiation can cause the water in the cell tissue to produce oxygen free radicals (ROS), thereby destroying the helical structure of DNA and leading to cell necrosis; low concentrations of ROS can act as second messengers to activate signaling pathways such as NF-kB, ERK / MAPK, and P13K / AKT, causing the transcription and expression of proinflammatory factors and apoptotic factors, and the dynamic balance between proinflammatory factors and anti-inflammatory factors is destroyed, ultimately leading to a cascade effect of mucosal inflammation (Chen Yang, Study on the Mechanism of Gegenqinlian Decoction Intervention in Acute Enteritis Model Rats Based on Intestinal Flora [D], Shanghai University of Traditional Chinese Medicine, 2019).

[0005] Babaodan is mainly made of precious medicinal materials such as bezoar, snake gall, antelope horn, pearl, Panax notoginseng, musk, etc. It contains a variety of effective ingredients such as taurine, musk ketone, taurocholic acid, saponins and flavonoids. The main drug is natural bezoar, which is cool in nature and bitter in taste. It can soothe the liver and calm the nerves, clear away heat and detoxify. Its main active ingredient is taurine. It contains bilirubin and bile acid, which can dilate capillaries and relax bile duct smooth muscles, and has the effects of benefiting the liver and gallbladder and promoting the recovery of hepatitis; the assistant drug is snake gall, which is cool in nature and slightly bitter in taste, clears away heat and detoxifies, relieves pain and improves eyesight. It contains more than 12 kinds of bile acids, mainly ursodeoxycholic acid, which has the effect of dissolving bile salt stones; the adjuvant drug is pearl, which is cold in nature and salty in taste, calms the heart and calms the nerves, astringes and promotes muscle growth, clears the liver and removes cataracts; the adjuvant drug is antelope horn, which has the effects of relieving fever, resisting viruses and enhancing immune function; the guiding drug is natural musk, which is warm in nature and pungent in taste, can promote blood circulation and dissipate blood stasis, reduce swelling and relieve pain. Its main ingredients are musk ketone and polypeptides, which can alleviate the symptoms of hepatitis; the guiding drug is Panax notoginseng, whose main active ingredient is Panax notoginseng total glycosides, which has the effects of scavenging free radicals, activating the sulfhydryl enzyme system, and protecting the stability of liver cell membranes and other liver protection and antioxidant effects.

[0006] However, there is no report on the use of Babaodan in the prevention or treatment of radiation enteritis. Summary of the invention

[0007] The purpose of the present invention is to provide the use of Babaodan in preparing a medicine for preventing or treating radiation enteritis.

[0008] The Babaodan mentioned above is the Babaodan capsule produced by Xiamen Traditional Chinese Medicine Factory Co., Ltd., with the national medicine approval number Z10940006. Its main ingredients include bezoar, snake gall, antelope horn, pearl powder, Panax notoginseng, musk, etc.

[0009] The invention discloses for the first time the use of Babaodan in preparing medicines for preventing or treating radiation enteritis.

[0010] In some embodiments, the drug may be in the form of a solid, semisolid, or liquid.

[0011] In some embodiments, the drug preparation can be an aqueous solution, a non-aqueous solution, a suspension, a lozenge, a capsule, a tablet, a granule, a pill or a powder.

[0012] In some embodiments, the medicament may include one or more pharmaceutically acceptable excipients.

[0013] In some embodiments, the pharmaceutically acceptable excipient may include an excipient, a filler, or a diluent.

[0014] In some embodiments, the drug may include 0.01-99.99% of Babaodan and 99.99-0.01% of pharmaceutically acceptable excipients based on the total mass of the drug.

[0015] In some embodiments, the drug can be administered orally or by injection.

[0016] In some embodiments, Babaodan can alleviate symptoms such as diarrhea, bloody and mucous stools, abdominal pain, and tenesmus.

[0017] In some embodiments, Babaodan can significantly reduce VRS scores, and significantly improve KPS scores and quality of life scores (SF-36).

[0018] In some embodiments, Babaodan can significantly reduce malondialdehyde (MDA) levels and significantly increase superoxide dismutase (SOD) levels.

[0019] In some embodiments, Babaodan can significantly increase the levels of Lactobacillus, Bifidobacterium and Escherichia coli in the intestinal flora.

[0020] In some embodiments, Babaodan can significantly increase CD3 + and CD4 + / CD8 + The inventors have verified the clinical efficacy of Babaodan Capsules in preventing and treating radiation enteritis through clinical trials, and clarified the mechanism of Babaodan Capsules in treating radiation enteritis, providing clinical research data and theoretical basis for Babaodan Capsules in clinical prevention and treatment of radiation enteritis. DETAILED DESCRIPTION

[0021] Hereinafter, the present invention will be described in detail by way of examples. However, the examples provided herein are only for illustrative purposes and are not intended to limit the present invention.

[0022] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0023] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0024] Example

[0025] Purpose of the test:

[0026] (I) To observe the overall efficacy of Babaodan Capsule in the prevention and treatment of acute radiation enteritis during pelvic tumor radiotherapy;

[0027] (II) Study on the mechanism of Babaodan capsule in treating radiation enteritis

[0028] Trial design: Prospective randomized, double-blind controlled clinical study

[0029] Inclusion criteria:

[0030] (1) Age 18 to 70 years old;

[0031] (2) Patients with pelvic tumors who are preparing to receive radiotherapy;

[0032] (3) The patient meets the diagnostic criteria for acute radiation enteritis in the "Chinese Expert Consensus on the Diagnosis and Treatment of Radiation Proctitis", and the radiation injury classification meets grade 1 or 2;

[0033] (4) good general condition, KPS>60 points;

[0034] (5) expected survival period > 6 months;

[0035] (6) Be able to understand and voluntarily sign a written informed consent, which must be signed before any trial-specified procedures are performed;

[0036] (7) Subjects must be willing and able to complete the study procedures and follow-up examinations.

[0037] Exclusion criteria:

[0038] (1) Those who are allergic to Chinese medicine;

[0039] (2) Those with serious underlying diseases such as cardiovascular, cerebrovascular, lung, liver, and kidney diseases;

[0040] (3) Patients with metastasis or recurrence of intestinal cancer;

[0041] (4) Patients with other intestinal diseases such as Crohn's disease, ulcerative colitis, chronic amoebic dysentery, and those who have undergone intestinal fistula in the past;

[0042] (5) Patients with intestinal obstruction, perforation, etc. who urgently need surgery;

[0043] (6) Currently receiving chemotherapy or other traditional Chinese medicine treatment or enema treatment;

[0044] (7) Pregnant or breastfeeding women.

[0045] Sample size: A total of 120 subjects were included. Among them, 60 patients with pelvic tumors who were preparing for radiotherapy and 60 patients with confirmed acute radiation enteritis were randomly divided into a treatment group and a control group at a ratio of 1:1. The subjects were stratified and randomized based on the radiation injury grade (grade 1; grade 2).

[0046] Trial Drugs:

[0047] 1.Babaodan Capsules (National Medicine Approval No. Z10940006), produced by Xiamen Traditional Chinese Medicine Factory Co., Ltd.

[0048] (1) Single packaging specification: 0.3g / pill, 6 pills / plate × 2 plates / small box;

[0049] (2) Formula ingredients: in vitro cultured bezoar, snake gall, antelope horn, pearl, Panax notoginseng, artificial musk, etc.;

[0050] (3) Storage conditions: sealed, in a cool and dry place;

[0051] (4) Shelf life: 36 months.

[0052] 2. Babaodan Capsule Simulator: Produced by Xiamen Traditional Chinese Medicine Factory Co., Ltd., its main ingredients are starch and pigment. The smell and color of its contents are basically similar to those of Babaodan Capsules, and the packaging specifications are exactly the same as those of Babaodan Capsules.

[0053] Test treatment:

[0054] Subjects will be randomly assigned to the treatment group or control group in a 1:1 ratio on a double-blind basis. Subjects will be stratified and randomized based on the radiation injury grade (grade 1; grade 2).

[0055] Treatment group: All subjects were given fluid replacement, anti-infection, anti-diarrhea, hemostasis, nutritional support, semi-liquid diet, and retention enema. On this basis, the subjects were given Babaodan capsules, and one course of treatment was every 2 weeks.

[0056] Control group: All subjects were given treatments such as fluid replacement, anti-infection, anti-diarrhea, hemostasis, nutritional support, semi-fluid diet, and retention enema. On this basis, the subjects were given Babaodan capsule simulation medicine, and one course of treatment was every 2 weeks.

[0057] Try to ensure that the subjects with the same stratification factors receive the same degree of treatment, such as fluid replacement, anti-infection, anti-diarrhea, hemostasis, nutritional support, semi-liquid diet, etc. The retention enema time is also kept consistent.

[0058] Effectiveness evaluation indicators:

[0059] A prospective, randomized, double-blind, controlled trial was conducted. Patients with pelvic tumors who were about to undergo radiotherapy or had been diagnosed with acute radiation enteritis were selected as the research subjects and randomly assigned to the treatment group or the control group in a 1:1 ratio. The subjects were stratified and randomized based on the radiation injury grade (grade 1; grade 2).

[0060] The two groups of subjects had their baseline determined before treatment, and the treatment lasted for 4 weeks. After 4 weeks of treatment, the efficacy-related indicators were evaluated. The observation indicators were:

[0061] (1) Comparison of TCM syndrome scores.

[0062] (2) Changes in Vienna proctoscopy score (VRS), inflammatory bowel disease quality of life index (IBDQ), and Karnofsky performance status (KPS) scores before treatment and 4 weeks after treatment compared with baseline.

[0063] (3) The levels of oxygen free radicals in venous blood and the levels of tumor necrosis factor and inflammatory factors (including IL-6, IL-1β, TNF-α, and IFN-γ) in intestinal mucosal tissue before and 4 weeks after treatment.

[0064] (4) Changes in the distribution of intestinal flora before and 4 weeks after treatment;

[0065] (5) Comparison of T lymphocyte subsets, an indicator of immune function, before and 4 weeks after treatment.

[0066] (6) Safety evaluation indicators: mainly include body temperature, blood pressure, pulse, respiration, blood routine + CRP, liver and kidney function, stool and urine routine, electrolytes, electrocardiogram, myocardial enzymes, etc.

[0067] Test procedure:

[0068] 1. Follow the principle of informed consent, strictly control the inclusion and exclusion criteria, and screen 120 subjects, including 60 patients with pelvic tumors preparing for radiotherapy and 60 patients with confirmed acute radiation enteritis. They will be randomly divided into a control group or a treatment group according to the random number table method, with 60 subjects in each group. The subjects will be stratified and randomized based on the radiation injury grade (grade 1; grade 2).

[0069] 2. Screening period:

[0070] Complete the following assessment items within 1 week before the first dose:

[0071] 2.1 Collect blood biochemistry (including liver and kidney function and electrolytes), blood routine + CRP, urine routine, and myocardial enzyme samples from the subjects, and check the electrocardiogram, body temperature, respiration, blood pressure, and pulse.

[0072] 2.2 According to the "Guidelines for Clinical Research of New Chinese Medicines", the TCM syndrome score of the patient was evaluated one day before enrollment, including mucus, pus and blood in the stool, diarrhea, tenesmus, and abdominal pain. According to the severity of the symptoms, the symptoms were divided into 4 levels: normal, mild, moderate, and severe. The main symptoms (mucus, pus and blood in the stool, diarrhea) were assigned 0, 2, 4, and 6 points respectively, and the secondary symptoms (tenesmus, abdominal pain) were assigned 0, 1, 2, and 3 points respectively. The higher the score, the more serious the patient's condition.

[0073] 2.3 Venous blood was collected and allowed to stand for 2 hours. The blood samples were centrifuged at 2500 rpm for 15 minutes. The supernatant was collected and stored at -20°C. Malondialdehyde (MDA) and superoxide dismutase (SOD) ELISA kits were used for detection.

[0074] 2.4 The Vienna proctoscopic score (VRS), inflammatory bowel disease quality of life index (IBDQ) and Karnofsky performance status (KPS) were completed through colonoscopy.

[0075] 2.5 After colonoscopy, fresh irradiated intestinal mucosal tissue was obtained, and part of it was added with an appropriate amount of PBS for homogenization. After centrifugation, the supernatant was obtained and the content of tumor necrosis factor and inflammatory factor in the intestinal mucosal tissue was detected by ELISA kit.

[0076] 2.6 Comparison of T lymphocyte subsets: About 3 mL of fasting venous blood was drawn and flow cytometry was used to measure the CD3 T lymphocyte subsets. + 、CD4 + 、CD4 + / CD8 + level.

[0077] 3. Instruct the subjects to have a light diet one day before administration. Before administration on the first day, collect stool samples and freeze them at -20℃ for subsequent testing.

[0078] 4. Treatment period: Both groups of subjects received treatment for 4 consecutive weeks.

[0079] Treatment group: Take Babaodan capsules with warm water, three times a day, 2 capsules each time. Retention enema method: The enema solution temperature is 38-40℃, empty the bowels and bladder at night, lie on the left side, raise the buttocks, and drip the enema solution at 60 drops / minute. After the enema, lie on the left side for 5 minutes, lie flat for 5 minutes, lie on the right side for 5 minutes, and finally lie flat, and keep it overnight as much as possible.

[0080] Control group: This group was given Babaodan capsules simulant medicine, three times a day, 2 capsules each time. The retention enema method was the same as the treatment group.

[0081] Both groups of subjects were given treatments such as fluid replacement, anti-infection, anti-diarrhea, hemostasis, nutritional support, and semi-liquid diet.

[0082] 5. After 4 weeks of treatment, complete the following tests:

[0083] 5.1 Collect blood biochemistry (including liver and kidney function and electrolytes), blood routine + CRP, urine routine, and myocardial enzyme samples from the subjects, and check the electrocardiogram, body temperature, respiration, blood pressure and pulse.

[0084] 5.2 Refer to the "Guidelines for Clinical Research of New Chinese Medicines" and evaluate the TCM syndrome score of the patient after 4 weeks of treatment, including mucus, pus and blood in the stool, diarrhea, tenesmus, and abdominal pain. According to the severity of the symptoms, the score is divided into 4 levels: normal, mild, moderate, and severe. The main symptoms (mucus, pus and blood in the stool, diarrhea) are assigned 0, 2, 4, and 6 points respectively, and the secondary symptoms (tenesmus, abdominal pain) are assigned 0, 1, 2, and 3 points respectively. The higher the score, the more serious the patient's condition.

[0085] 5.3 Collect venous blood, let the blood sample stand for 2 hours, centrifuge it at 2500 rpm for 15 minutes, take the supernatant, store it at -20℃, and detect it with malondialdehyde (MDA) and superoxide dismutase (SOD) ELISA kits.

[0086] 5.4 The Vienna proctoscopic score (VRS), inflammatory bowel disease quality of life index (IBDQ) and Karnofsky performance status (KPS) were completed through colonoscopy.

[0087] 5.5 After colonoscopy, fresh irradiated intestinal mucosal tissue was obtained, part of which was added with an appropriate amount of PBS for homogenization. After centrifugation, the supernatant was collected and the content of tumor necrosis factor and inflammatory factor in the intestinal mucosal tissue was detected by ELISA kit.

[0088] 5.6 Collect stool samples and extract DNA from them together with the stool retained during the screening period. Perform PCR amplification and purification, and perform III-umine sequencing to obtain the corresponding community abundance information, and compare and analyze the changes in intestinal flora.

[0089] 5.7 Comparison of T lymphocyte subsets: About 3 mL of fasting venous blood was drawn and T lymphocyte subsets CD3 were measured using flow cytometry. + 、CD4 + 、CD4 + / CD8 + level.

[0090] Note: 1. During the experiment, meals will be arranged uniformly and eating on your own is prohibited.

[0091] 2. Randomization: SAS software generates random numbers and groups, and the random allocation scheme is stored in a sealed, light-proof envelope. Patients are divided into groups according to the allocation scheme in the envelope in the order of inclusion.

[0092] 3. Blind method: Blind the efficacy evaluators and statistical analysts.

[0093] Statistical analysis:

[0094] Statistical analysis was performed by a blinded statistician using the SPSS26.0 software package. All statistical tests were bilateral, and the difference was considered statistically significant when the p value was less than 0.05. The measurement data were described by mean ± standard deviation, median, maximum value, and minimum value, and the count data and rank data were described by number of cases and percentage. The analysis method for inter-group comparison was selected according to the data distribution characteristics: measurement data were analyzed by one-way analysis of variance (normal distribution) or non-parametric test (non-normal distribution); count data were analyzed by one-way analysis of variance. Compared with the baseline value, the measurement data were analyzed by paired t test or non-parametric test, and the count data were analyzed by rank sum test.

[0095] Linear regression analysis was used to evaluate the factors affecting the efficacy and to analyze the correlation between the patient's age, gender and other baseline conditions and the efficacy.

[0096] The Vienna colonoscopy score (VRS), inflammatory bowel disease quality of life index (IBDQ), Karnofsky performance score (KPS), oxygen free radical level in venous blood, tumor necrosis factor and inflammatory factor content in intestinal mucosal tissue, distribution of intestinal flora, and CD3 T lymphocyte subsets before and 4 weeks after treatment were compared and analyzed. + 、CD4 + 、CD4 + / CD8 + level, change from baseline.

[0097] Test results:

[0098] 1. General Information

[0099] The control group (n = 60): 32 males and 28 females; aged 31 to 64 years old, with an average age of (47.57 ± 16.43) years old. The study group (n = 60): 33 males and 27 females; aged 32 to 64 years old, with an average age of (48.63 ± 15.37) years old. There was no significant difference in the general data between the two groups (P > 0.05), and they were comparable.

[0100] 2. Comparison of TCM syndrome scores

[0101] According to the "Guidelines for Clinical Research of New Chinese Medicines", the TCM syndrome scores of patients were evaluated one day before enrollment and four weeks after treatment, including mucus, pus and blood in stool, diarrhea, tenesmus, and abdominal pain. According to the severity of symptoms, the symptoms were divided into four levels: normal, mild, moderate, and severe. The main symptoms (mucus, pus and blood in stool, diarrhea) were assigned 0, 2, 4, and 6 points respectively, and the secondary symptoms (tenesmus, abdominal pain) were assigned 0, 1, 2, and 3 points respectively. The higher the score, the more serious the patient's condition.

[0102] Before treatment, there was no significant difference in the scores of diarrhea, bloody and mucous stool, abdominal pain and tenesmus between the two groups. After 4 weeks of treatment, the scores of diarrhea, bloody and mucous stool, abdominal pain and tenesmus in the two groups were lower than those before treatment, and the scores in the observation group were lower than those in the control group.

[0103] Table 1 Comparison of TCM syndrome scores (points)

[0104]

[0105] Note: Compared with the group before treatment, *p<0.05; compared with the control group after treatment, **p<0.01

[0106] 3. Comparison of Vienna colonoscopy VRS score, Karnofsky performance score (KPS) and quality of life index (SF-36)

[0107] There was no significant difference in VRS score, KPS score and SF-36 between the two groups before treatment. After 4 weeks of treatment, VRS score decreased significantly, and the treatment group was significantly lower than the control group; while KPS score and SF-36 increased significantly, and the treatment group was significantly higher than the control group.

[0108] Table 2 Comparison of Vienna colonoscopy VRS score, Karnofsky performance score (KPS) and quality of life index (SF-36)

[0109]

[0110] Note: Compared with the group before treatment, *p<0.05; compared with the control group after treatment, **p<0.01

[0111] 4. Comparison of MDA and SOD levels in venous blood

[0112] After 4 weeks of treatment, MDA in both groups was significantly lower than before treatment, while SOD was significantly higher. Moreover, after treatment, the improvement in the treatment group was better than that in the control group.

[0113] Table 3 MDA and SOD levels in venous blood

[0114]

[0115] Note: Compared with the group before treatment, *p<0.05; compared with the control group after treatment, **p<0.01

[0116] 5. Comparison of serum tumor necrosis factor and inflammatory factor levels

[0117] Before treatment, there was no significant difference in the levels of IL-6, IL-1β, TNF-α, and CRP between the two groups. After 4 weeks of treatment, the levels of IL-6, IL-1β, TNF-α, and CRP in the treatment group were significantly lower than those in the control group.

[0118] Table 4 Comparison of serum tumor necrosis factor and inflammatory factor levels

[0119]

[0120] Note: Compared with the group before treatment, *p<0.05; compared with the control group after treatment, **p<0.05

[0121] 6. Comparison of intestinal flora levels

[0122] The results in Table 5 show that before treatment, there was no statistically significant difference in the levels of Lactobacillus, Bifidobacterium, and Escherichia coli in the intestinal flora of the two groups of patients, and they were comparable. After 4 weeks of treatment, the levels of Lactobacillus, Bifidobacterium, and Escherichia coli in the intestinal flora of the two groups of patients increased compared with before treatment, and the increase in the treatment group was significantly better than that in the control group.

[0123] Table 5 Comparison of intestinal flora levels (log 10 CFU / g)

[0124]

[0125] Note: Compared with the group before treatment, *p<0.05; compared with the control group after treatment, **p<0.05

[0126] 7 Immune function indicators Comparison of T lymphocyte subsets

[0127] T lymphocyte subsets CD3 in the two groups before treatment + 、CD4 + 、CD4 + / CD8 + After 4 weeks of treatment, the levels of CD4 + There was no significant change in the level compared with before treatment, but CD3 + and CD4 + / CD8 + The level was significantly increased compared with that before treatment, and the increase in the treatment group was significantly greater than that in the control group.

[0128] Table 6 Comparison of immune function indicators T lymphocyte subsets

[0129]

[0130] Note: Compared with the group before treatment, *p<0.05; compared with the control group after treatment, **p<0.05.

Claims

1. Use of Babaodan in preparing a medicine for preventing or treating radiation enteritis.

2. The use according to claim 1, wherein The drug is in the form of solid, semisolid or liquid.

3. The use according to claim 2, wherein The drug preparation is an aqueous solution, a non-aqueous solution, a suspension, a lozenge, a capsule, a tablet, a granule, a pill or a powder.

4. The use according to claim 1, wherein The medicament includes one or more pharmaceutically acceptable excipients.

5. The use according to claim 4, wherein The pharmaceutically acceptable excipients include excipients, fillers or diluents.

6. The use according to claim 4 or 5, wherein Based on the total mass of the medicine, the medicine comprises 0.01 to 99.99% of Babaodan and 99.99 to 0.01% of pharmaceutically acceptable excipients.

7. The use according to claim 1, wherein The administration route of the drug is oral administration or injection administration.

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