CN116650458A - Application of sodium crotonate in preparing medicament for treating ulcerative colitis - Google Patents
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- CN116650458A CN116650458A CN202310878199.7A CN202310878199A CN116650458A CN 116650458 A CN116650458 A CN 116650458A CN 202310878199 A CN202310878199 A CN 202310878199A CN 116650458 A CN116650458 A CN 116650458A
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- GOCYQQKRJUGVRU-SQQVDAMQSA-M sodium;(e)-but-2-enoate Chemical compound [Na+].C\C=C\C([O-])=O GOCYQQKRJUGVRU-SQQVDAMQSA-M 0.000 title claims abstract description 26
- 206010009900 Colitis ulcerative Diseases 0.000 title claims abstract description 25
- 201000006704 Ulcerative Colitis Diseases 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 239000000463 material Substances 0.000 claims description 10
- 239000002552 dosage form Substances 0.000 claims description 4
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- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical group C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 9
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
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- NCEXYHBECQHGNR-UHFFFAOYSA-N chembl421 Chemical compound C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 3
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- OQXLFPHHAAAVKQ-UHFFFAOYSA-L disodium;3,4,5-trioxocyclopentene-1,2-diolate Chemical compound [Na+].[Na+].[O-]C1=C([O-])C(=O)C(=O)C1=O OQXLFPHHAAAVKQ-UHFFFAOYSA-L 0.000 description 2
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- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
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- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an application of sodium crotonate in preparing a medicament for treating ulcerative colitis, and discloses an application of sodium crotonate in preparing a medicament for treating ulcerative colitis. The experimental result shows that the sodium crotonate can effectively improve DAI score, colon length, pathological tissue score and the like of the ulcerative colitis model mouse, and has obvious treatment effect on ulcerative colitis. Therefore, sodium crotonate has a prospect of being developed into a medicament for treating ulcerative colitis.
Description
Technical Field
The invention belongs to the field of medicines, and relates to application of sodium crotonate in preparation of a medicine for treating ulcerative colitis.
Background
Ulcerative colitis (ulcerative colitis, UC), also known as chronic nonspecific ulcerative colitis or idiopathic ulcerative colitis, is a common chronic intestinal disease, and is also a multi-factor, multi-layered, nonspecific inflammation of unknown cause. Lesions are mainly in the mucous membrane and submucosa of the colon and are continuously and diffusely distributed, and most of lesions involve the rectum and sigmoid colon. The main clinical manifestations are abdominal pain, diarrhea, mucopurulent bloody stool, tenesmus and the like, and part of patients have extra-intestinal manifestations such as joint diseases, hepatobiliary diseases and eye and skin injuries; the duration of the disease is not healed, and the weight is not equal; the age range of onset is mainly 20-50 years old, but there is no significant sex difference. Epidemiological statistics at home and abroad show that the incidence and the prevalence of UC all show obvious increasing trend, and are listed by the world-guard organization as one of the modern refractory diseases, and the etiology, pathogenesis and therapeutic drugs thereof are always research hot spots.
There is currently no report of sodium crotonate for the treatment of UC.
Disclosure of Invention
The invention aims to provide an application of sodium crotonate in preparing a medicament for treating ulcerative colitis.
The above object of the present invention is achieved by the following technical scheme:
use of sodium crotonate for preparing a medicament for treating ulcerative colitis.
Further, the medicine takes sodium crotonate as an active ingredient, and pharmaceutically acceptable auxiliary materials are added to prepare a pharmaceutically acceptable dosage form.
Still further, the auxiliary material is a solid or semi-solid auxiliary material.
Still further, the dosage forms include tablets, capsules, injections.
The beneficial effects are that:
experimental results show that the sodium crotonate can effectively improve DAI score, colon length, pathological tissue score and the like of the ulcerative colitis model mouse, and has obvious treatment effect on ulcerative colitis. Therefore, sodium crotonate has a prospect of being developed into a medicament for treating ulcerative colitis.
Drawings
FIG. 1 is a weight line graph of mice in each group.
Fig. 2 shows DAI scoring results for each group of mice.
FIG. 3 shows the results of colon length measurement and organ index calculation for each group of mice.
FIG. 4 shows the results of colonoscopy and histological scoring of mice in each group; wherein: a is colon pathological section diagram of each group of mice, and B is histological scoring result of each group of mice.
FIG. 5 shows the levels of cytokines IFN-gamma, TNF-alpha, IL-2, IL-6, IL-9, IL-17A, IL-4 and IL-10 in the serum of each group of mice; wherein: A. b, C, D, E, F, G, H is the content of IFN-gamma, TNF-alpha, IL-2, IL-6, IL-9, IL-17A, IL-4 and IL-10, respectively, in the serum of different groups of mice.
Detailed Description
The following describes the essential aspects of the invention in detail with reference to the drawings and examples, but is not intended to limit the scope of the invention.
1. Experimental materials and methods
1. Grouping, modeling and administration
Materials: c57BL/6 mice; dextran Sodium Sulfate (DSS); 0.5% cmc-Na solution; sodium crotonate (Croconic Acid Disodium Salt) was purchased from Shanghai source leaf with CAS number 14379-00-1.
C57BL/6 mice are selected as experimental objects and purchased from Jiangsu Huazhuanuo medical science and technology Co., ltd, the week age is 7-8 weeks, and the experiment is carried out after the weight reaches about 20g after the mice are adaptively fed for about one week in a pharmacological laboratory of a hospital in Jiangsu province.
The animals were randomized into a blank group (Control), model group (DSS), sodium crotonate group (NaCr), and sulfasalazine group (SASP), with 8 mice per group.
The experimental period was 7 days, the mice in the blank group were given normal water for 7 days, and the other groups were given aqueous DSS solution containing 3% for seven days starting on the first day for modeling Ulcerative Colitis (UC). Drug administration intervention starting from day 1 of modeling: sodium crotonate group was given 20mg/kg of sodium crotonate by gavage, sulfasalazine group (positive control group) was given 200mg/kg of sulfasalazine by gavage, the solvents were all 0.5% CMC-Na solution by mass concentration, and the blank group and model group were given the same dose of 0.5% CMC-Na solution by gavage. Mice were sacrificed by cervical scission on day 7 of feeding.
2. Weight measurement
On the first day of the initial formal experiment, the weights of the mice were weighed at the same time point every day and recorded in a table, and all weights were sorted after the end of the experiment on day 7, and a line graph was made to feed back the severity of the disease of the mice with the weights.
3. Determination of Disease Activity Index (DAI) score
During the experiment, the quality change, fecal character and hematochezia of the mice are recorded every day, and the Disease Activity Index (DAI) score is measured. DAI is obtained by adding the weight loss rate fraction, the stool character fraction and the hematochezia fraction, and the score is between 0 and 12. The scoring criteria are as follows: 1) Weight loss score: no weight loss, 0 point; 5% -9% of the weight is reduced, and 1 min of the weight is reduced; the weight is reduced by 10 to 14 percent and is divided into 2 parts; 15% -20% of the weight is reduced, and 3 minutes is required; the reduction is more than 20 percent and the weight is 4 minutes. 2) Stool trait scoring: normally, score 0; loosening and 1 minute; semi-forming thin, 2 minutes; not forming thin, and dividing into 3; water sample was drained and 4 minutes. 3) Fecal blood score: negative (-) hematochezia, 0 minutes; weak positive of hematochezia (+), 1 minute; positive hematochezia (++), 2 minutes; positive hematochezia ((+ ++), 3 minutes; blood stool was visually observed, 4 minutes. All DAI scores were sorted at the end of the 7 th day experiment and made into a line graph as an indicator reflecting the severity of the disease in the mice.
4. Determination of serum inflammation index content
Materials: legendplex TM Multi-Analyte FlowAssay Kit。
The method comprises the following steps: after the 7 th experiment is finished, the mouse orbital venous plexus is used for taking blood, the supernatant is centrifugally taken, and the supernatant is stored in a refrigerator at the temperature of minus 80 ℃ for standby, so that repeated freezing and thawing are avoided. Serum samples were thawed on ice and the processing steps were performed according to the LEGENDplex multifactorial kit instructions using a Cytoflex flow cytometer (beckmann coulter, germany, g Lei Feier d). The data were analyzed by Legendplex V8.0 software (Biolegend).
5. Determination of colon length
After the mice were sacrificed on day 7, the mice were dissected, their livers, spleens and thymus were weighed, and organ indexes were calculated; the colon part is taken and placed on white paper, the length is measured by a ruler, and the disease severity is recorded by taking the colon length as one aspect.
6. Colonoscopy and histological scoring
Materials: 4% paraformaldehyde; ethylenediamine tetraacetic acid EDTA; HE dye liquor; a neutral resin; xylene; ethanol
The method comprises the following steps: after the experimental mice are killed, a colon with about 1cm long and containing a lesion part is cut and fixed on 4% paraformaldehyde, EDTA is used for decalcification, paraffin is embedded, and the section is 4-5 mu m (longitudinal cutting), and conventional xylene, ethanol of each grade and distilled water are dewaxed to water; HE staining. Hematoxylin staining nuclei and eosin staining cytoplasm; and (3) sealing the sheet with neutral resin, and observing pathological histological changes by an optical microscope. The histological scoring criteria for colon sections are divided into 2 aspects of epithelial lesions and mucositis cell infiltration: epithelial lesions were rated 5: 0 grade, no damage; grade 1, small number of goblet cells lost; level 2, loss of a large number of cupped cells; grade 3, small amount of crypt disappear and a large amount of cup-shaped cells are lost; the 4-order large number of crypts disappeared. Inflammatory infiltrates were graded 5: 0 level, no infiltration; 1, soaking to the bottom of the recess; grade 2, infiltrating into the mucosal layer; grade 3, massive infiltration of mucosal myolayers with edema; grade 4, infiltration into submucosa. The sum of the above 2 part scores is the histological score.
7. Data processing
The results of the experiments are expressed in (mean+ -SEM) and were compared between two groups using Student's t, one-way ANOVA and post hoc inspection. * P <0.05 has a statistically significant difference, P <0.01 has a statistically significant difference, and P <0.001 has a statistically significant difference.
2. Experimental results
1. Weight measurement results
The weight line diagram of each group of mice is shown in fig. 1, the weight of the mice in the blank group has no obvious change in the experimental period, and compared with the mice in the blank group, the weight of the mice in the model group has obvious descending trend in the experimental period; compared with the model group, the weight reduction trend of the sodium crotonate group and the sulfasalazine group mice in the experimental period is effectively controlled.
2. Disease Activity Index (DAI) scoring results
The DAI score results for each group of mice are shown in fig. 2, with significantly higher DAI scores for the model group of mice compared to the blank group; the DAI scores were significantly reduced in the sodium crotonate group and the sulfasalazine group mice compared to the model group.
3. Colon length measurement results and organ index calculation results
The results of the colon length measurement and the organ index calculation of the mice in each group are shown in fig. 3, and compared with the blank group, the colon length and the thymus index of the mice in the model group are obviously reduced; the colon length of the sodium crotonate group and sulfasalazine group mice was significantly increased compared to the model group. The liver index and spleen index of the mice in the model group are significantly increased compared with the blank group; compared with the model group, the liver index and spleen index of the mice in the sodium crotonate group and the sulfasalazine group are obviously reduced.
4. Colonoscopy and histological scoring results
The results of colon pathology section and histological scoring of each group of mice are shown in fig. 4, and compared with the blank group, the colon of the model group of mice has obvious lesions and inflammatory infiltration is enhanced; compared with the model group, the colon lesions of the mice in the sodium crotonate group and the sulfasalazine group are obviously relieved, and the inflammatory infiltration is improved.
5. Determination of serum inflammation index content
The levels of cytokines IFN-gamma, TNF-alpha, IL-2, IL-6, IL-9, IL-17A, IL-4 and IL-10 in the serum of each group of mice are shown in FIG. 5, wherein IL-4 and IL-10 are a family of anti-inflammatory factors, and the remainder are pro-inflammatory factors. Compared with the blank group, the serum of the mice in the model group has obviously increased content of the proinflammatory factors and obviously reduced content of the anti-inflammatory factors. Compared with the model group, the contents of the pro-inflammatory factors and the anti-inflammatory factors in the serum of the mice of the sodium crotonate group and the sulfasalazine group are adjusted back to different degrees.
In conclusion, the sodium crotonate can effectively improve DAI score, colon length, pathological tissue score and the like of the ulcerative colitis model mouse, and has obvious treatment effect on ulcerative colitis.
The above-described embodiments serve to describe the substance of the present invention in detail, but those skilled in the art should understand that the scope of the present invention should not be limited to this specific embodiment.
Claims (4)
1. Use of sodium crotonate for preparing a medicament for treating ulcerative colitis.
2. The use according to claim 1, wherein the medicament is prepared into a pharmaceutically acceptable dosage form by adding pharmaceutically acceptable auxiliary materials into sodium crotonate serving as an active ingredient.
3. Use according to claim 2, characterized in that: the auxiliary materials are solid or semisolid auxiliary materials.
4. Use according to claim 2, characterized in that: the dosage forms comprise tablets, capsules and injections.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310878199.7A CN116650458A (en) | 2023-07-18 | 2023-07-18 | Application of sodium crotonate in preparing medicament for treating ulcerative colitis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310878199.7A CN116650458A (en) | 2023-07-18 | 2023-07-18 | Application of sodium crotonate in preparing medicament for treating ulcerative colitis |
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| Publication Number | Publication Date |
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| CN116650458A true CN116650458A (en) | 2023-08-29 |
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|---|---|---|---|
| CN202310878199.7A Pending CN116650458A (en) | 2023-07-18 | 2023-07-18 | Application of sodium crotonate in preparing medicament for treating ulcerative colitis |
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| Country | Link |
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- 2023-07-18 CN CN202310878199.7A patent/CN116650458A/en active Pending
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