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CN117018000B - Application of 4-cholestene-3-one in preparing medicine for preventing or treating inflammatory bowel disease - Google Patents

Application of 4-cholestene-3-one in preparing medicine for preventing or treating inflammatory bowel disease Download PDF

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Publication number
CN117018000B
CN117018000B CN202311100673.XA CN202311100673A CN117018000B CN 117018000 B CN117018000 B CN 117018000B CN 202311100673 A CN202311100673 A CN 202311100673A CN 117018000 B CN117018000 B CN 117018000B
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inflammatory bowel
cholesten
bowel disease
preventing
mice
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CN117018000A (en
Inventor
胡显镜
荣光宏
袁霞
张章
李俊
张冬梅
桂平
王凯亮
刘小叶
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Dongguan Southeast Central Hospital Dongguan Southeast Traditional Chinese Medicine Medical Service Center
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Dongguan Southeast Central Hospital Dongguan Southeast Traditional Chinese Medicine Medical Service Center
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs 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

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses application of 4-cholesten-3-one in preparing medicines for preventing or treating inflammatory bowel disease. The effect of 4-cholesten-3-one on mice body weight changes, fecal viscosity and fecal hemorrhage, disease Activity Index (DAI), and colon length was calculated by modeling sodium dextran sulfate (DSS) induced Inflammatory Bowel Disease (IBD) mice. The result shows that 4-cholesten-3-one has remarkable treatment effect on DSS induced colonitis, and provides a new medicament for clinically treating IBD.

Description

Application of 4-cholesten-3-one in preparation of medicines for preventing or treating inflammatory bowel disease
Technical Field
The invention relates to the technical field of medicines, in particular to application of 4-cholesten-3-one in preparing medicines for preventing or treating inflammatory bowel diseases.
Background
Inflammatory bowel disease (Inflammatory Bowel Disease, IBD) is a chronic, non-specific, inflammatory bowel disease caused mainly by the gut microbiota and immune system disorders, including Crohn's Disease (CD) and ulcerative colitis (ulcerative colitis, UC). The current treatments for IBD rely primarily on traditional therapeutic agents including 5-aminosalicylic acid, glucocorticoids, immunomodulators, and the like. Traditional drugs have poor control efficacy for partially moderately severe patients and have serious side effects. Thus, finding a positive and effective therapeutic regimen for IBD is a clinical problem that needs to be addressed urgently.
The steroid compound is used as a second large class of medicine next to antibiotics, plays an important role in medicine, is widely used for treating cardiovascular diseases, anti-tumor, anti-infection, anti-allergy and the like, and 4-cholesten-3-one is a precondition substance of a series of steroid hormone medicines, is a metabolic intermediate product of intestinal bacteria, participates in lipid metabolism, can be directly used as a medicine, has a certain health care function and potential medicinal value, and can be used for inhibiting fat accumulation in human bodies, treating liver diseases and preventing skin keratinization. However, no report on the preparation of medicines for preventing or treating inflammatory bowel disease by using 4-cholesten-3-one is currently known.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of 4-cholesten-3-one in preparing a medicament for preventing or treating inflammatory bowel disease, and to provide a novel medicament for treating inflammatory bowel disease clinically.
Inflammatory bowel disease (Inflammatory bowel disease, IBD) as described herein includes ulcerative colitis and crohn's disease.
The 4-cholesten-3-one can be used in combination with other medicines for preventing and treating inflammatory bowel diseases, and can also be used as the only active ingredient.
The invention detects the weight change, the fecal viscosity and the fecal hemorrhage of mice by inducing an IBD mouse model by dextran sodium sulfate (Dextran Sulfate Sodium, DSS), calculates the disease activity Index (DISEASE ACTIVITY Index, DAI), and observes the influence of 4-cholesten-3-one (4 CTL 3) on the colon length of the mice. The results show that the 4-cholesten-3-one has no obvious reversal effect on the weight loss caused by the enteritis, the DAI is calculated by observing the viscosity and the bleeding condition of the feces of the mice every day, the DAI score of a model group is found to be obviously higher than that of a 4CTL3 group, and the colon length of the mice is measured, and the 4CTL3 is found to obviously prolong the colon length of the IBD mice. The results show that 4-cholesten-3-one (4 CTL 3) has remarkable treatment effect on DSS induced colonitis and can obviously improve IBD symptoms.
The medicine contains effective content of 4-cholesten-3-one and pharmaceutically acceptable carrier. The medicine for preventing or treating inflammatory bowel disease can be prepared into a proper dosage form by a conventional method in the field. The pharmaceutically acceptable carrier is selected from pharmaceutically acceptable suspensions. The medicament may thereby be formulated in a form suitable for administration of a clinical pharmaceutical formulation.
Preferably, the dosage form of the medicament is a suspension.
Compared with the prior art, the invention has the following excellent effects:
The invention provides a new application of 4-cholesten-3-one in preparing medicines for preventing or treating inflammatory bowel diseases, and the result shows that 4-cholesten-3-one has remarkable treatment effect on colitis induced by DSS by establishing a dextran sodium sulfate (Dextran Sulfate Sodium, DSS) induced IBD mouse model, can obviously improve IBD symptoms, and provides a new medicine for clinically treating IBD.
Drawings
FIG. 1 shows the effect of 4CTL3 on the weight of mice with colon inflammation, *** P <0.001 (model group VS blank group), ### P <0.001 (4 CTL3 group VS model group).
FIG. 2 shows the effect of 4CTL3 on the disease activity index of mice with colitis, *** P <0.001 (model group vs blank group), ## P <0.01 (4 CTL3 group vs model group).
FIG. 3 shows the effect of 4CTL3 on colon length in colon inflammatory mice, *** P <0.001 (model VS blank), ##P<0.01,### P <0.001 (5-ASA, 4CTL3 VS model).
Detailed Description
The present invention will be further illustrated by the following examples, which are not intended to limit the scope of the invention.
EXAMPLE 1 therapeutic Effect of 4-cholesten-3-one on mouse IBD
1. Materials and methods
1.1 Medicaments
(+) -4-Cholesten-3-one (4 CTL 3) was purchased from sigma (CAS: 601-57-0), prepared as a suspension using 5% CMCNA, and sulfasalazine (lot: J2212276) was purchased from Shanghai Ala Biochemical technologies Co. Dextran sodium sulfate was purchased from MP Biomedicals (lot: S7980).
1.2 Instruments
MTB1000D electronic balance (Shenzhen Mobil electronic Co., ltd.)
1.3 Animals
C57BL/6 mice (purchased from medical laboratory animal center, guangdong province, license number SCXK (Yue) 2022-0002 Yue license 2006A 018) were male, and had a body weight of 19-21g. Mice were kept in the university of medical science laboratory animal center, guangdong, 12 hours light/dark, free diet.
1.4 Method
After 7 days of adaptive feeding (24-25 ℃ C., humidity 70-75%,12 hours light/dark) with standard diet and water, the mice were randomly divided into 4 groups of 6 animals each, including control group, model group, 5-ASA group (200 mg/kg), 4CTL3 group (50 mg/kg). The 4CTL3 group was prophylactically orally administered for 5 days, the model group was continuously orally administered purified water for 5 days (from day 0 to day 5), mice were free to drink 2.5% dss at day 5, and the blank group was continuously administered purified water for 7 days (from day 5 to day 12). Mice were observed daily and recorded for body weight, fecal consistency, and fecal bleeding. On day 12, anesthetized mice were sacrificed after blood collection. The length was measured from colon tissue of the mice.
According to the Disease Activity Index (DAI), the disease activity index score (no loss record 0 score, 1% -5% loss record 1 score, 5% -10% loss record 2 score, 10% -5% loss record 3 score, and more than 15% loss record 4 score) is determined according to the weight loss condition, the fecal viscosity (normal stool score 0 score, soft stool score 1 score, thin wet stool score 2 score, diarrhea dry stool score 3 score, diarrhea wet stool score 4 score) and the fecal bleeding (no blood record 0 score, slight blood record 1 score, occult blood record 2 score, bleeding record less than 3 score and major bleeding record 4 score) of the IBD mice are determined. DAI calculation dai= (weight loss score + fecal viscosity score + fecal blood level score)/3
1.5 Statistical methods
The results were analyzed using Graphpad prism7.0 statistical analysis software. Each set of data x- ±sd represents that the sample-to-sample comparison uses a t-test.
2. Results
2.1 Effect of 4CTL3 on IBD mouse body weight
Experimental results indicate that 4CTL3 had no significant effect on the body weight caused by IBD, and that 4CTL3 group had significant differences (P < 0.001) compared to the body weight of the model group, and that the model group had significant differences (P < 0.001) compared to the body weight of the blank group. The results are shown in Table 1 and FIG. 1.
Table 1.4CTL3 influence on the weight of mice with colon inflammation (x- + -SD N=6)
*** P <0.001 (model VS blank), ### P <0.001 (4 CTL3 VS model).
2.2 Influence of 4CTL3 on the disease Activity index of mice with colon inflammation
After 4CTL3 treatment, the IBD mice had significantly reduced diarrhea, rectal bleeding and weight loss symptoms and significantly reduced DAI scores. The 4CTL3 group had significant differences (P < 0.01) compared to the model group DAI, the 4CTL3 group DAI values were significantly lower than the model group, and the model group had significant differences (P < 0.010) compared to the blank group DAI. The results are shown in Table 2 and FIG. 2.
Table 2.4CTL3 influence on the disease Activity index of mice with colon inflammation (x- + -SD N=6)
*** P <0.001 (model group vs blank group), ## P <0.01 (4 CTL3 group vs model group).
2.3 Effect of 4CTL3 treatment on colon length
The colon length was significantly shortened in the model group compared to the blank group (P < 0.001), whereas the colon length shortening was significantly reversed 12 days after 4CTL3 treatment, and the 4CTL3 group was significantly different from the model group colon length (P < 0.001). The results are shown in Table 3 and FIG. 3.
Table 3.4CTL3 Effect on colon length in mice with colon inflammation (x- + -SD N=6)
*** P <0.001 (model VS blank), ##P<0.01,### P <0.001 (5-ASA, 4CTL3 VS model).
In conclusion, by establishing a dextran sodium sulfate induced IBD mouse model, the 4CTL3 group is significantly different from the model group in terms of DAI score and colon length 2 index evaluation, so that the conclusion can be drawn that the 4CTL3 has significant therapeutic effect on DSS induced colitis, can significantly improve IBD symptoms, and provides a new medicament for clinical treatment of IBD.

Claims (5)

1.4-胆甾烯-3-酮在制备预防或治疗炎症性肠病药物中的应用;所述炎症性肠病为溃疡性结肠炎和克罗恩病。1. Use of 4-cholestene-3-one in the preparation of drugs for preventing or treating inflammatory bowel disease; the inflammatory bowel disease is ulcerative colitis and Crohn's disease. 2.根据权利要求1所述的应用,其特征在于,所述4-胆甾烯-3-酮和其他防治炎症性肠病的药物联合应用。2. The use according to claim 1, characterized in that the 4-cholesten-3-one is used in combination with other drugs for preventing and treating inflammatory bowel disease. 3.根据权利要求1所述的应用,其特征在于,所述4-胆甾烯-3-酮是作为唯一活性成分使用。3. The use according to claim 1, characterized in that the 4-cholesten-3-one is used as the only active ingredient. 4.根据权利要求1所述的应用,其特征在于,所述药物包含有效含量的4-胆甾烯-3-酮和药学上可接受的载体。4. The use according to claim 1, characterized in that the drug comprises an effective amount of 4-cholesten-3-one and a pharmaceutically acceptable carrier. 5.根据权利要求1所述的应用,其特征在于,所述药物的剂型为混悬剂。5. The use according to claim 1, characterized in that the dosage form of the drug is a suspension.
CN202311100673.XA 2023-08-29 2023-08-29 Application of 4-cholestene-3-one in preparing medicine for preventing or treating inflammatory bowel disease Active CN117018000B (en)

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CN102083849A (en) * 2008-07-30 2011-06-01 特罗福斯公司 Novel cholest-4-en-3-one oxime derivatives, pharmaceutical compositions containing same, and preparation method
EP3777865A1 (en) * 2018-03-29 2021-02-17 Morinaga Milk Industry Co., Ltd. Anti-aging composition

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DE69818673T2 (en) * 1997-07-17 2004-08-05 F. Hoffmann-La Roche Ag DIHOMO-SECO-CHOLESTAN COMPOUNDS WITH TWO UNSATURATED BINDINGS IN THE SIDE CHAIN
US6998392B2 (en) * 2003-04-02 2006-02-14 Mti Meta Tech Inc. Formulation to treat or prevent parasitic infection
CN101484001A (en) * 2006-04-07 2009-07-15 顺天生物科技股份有限公司 Anthracene dione compound
WO2010045180A1 (en) * 2008-10-13 2010-04-22 Metabolon, Inc. Biomarkers for inflammatory bowel disease and methods using the same
WO2018011691A1 (en) * 2016-07-12 2018-01-18 Nestec S.A. Competitive immunoassay methods
CN120732855A (en) * 2020-03-18 2025-10-03 伊莱利利公司 Fanisolide X receptor agonists for the treatment of disease

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
CN102083849A (en) * 2008-07-30 2011-06-01 特罗福斯公司 Novel cholest-4-en-3-one oxime derivatives, pharmaceutical compositions containing same, and preparation method
EP3777865A1 (en) * 2018-03-29 2021-02-17 Morinaga Milk Industry Co., Ltd. Anti-aging composition

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