CN116196314B - Application of RI-1 or salt thereof in preparation of medicine for preventing and treating gastrointestinal diseases - Google Patents

Application of RI-1 or salt thereof in preparation of medicine for preventing and treating gastrointestinal diseases Download PDF

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Publication number
CN116196314B
CN116196314B CN202310487172.5A CN202310487172A CN116196314B CN 116196314 B CN116196314 B CN 116196314B CN 202310487172 A CN202310487172 A CN 202310487172A CN 116196314 B CN116196314 B CN 116196314B
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salt
use according
colitis
dosage form
medicament
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CN116196314A (en
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冼惠芳
黄婉明
张玉霞
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Guangzhou Women and Childrens Medical Center
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Guangzhou Women and Childrens Medical Center
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of RI-1 or a salt thereof in preparation of medicines for preventing and treating gastrointestinal diseases. The invention discloses the application of RI-1 or the salt thereof in preparing the medicine for preventing and treating gastrointestinal diseases for the first time, the RI-1 can obviously inhibit the expression of inflammatory factors IL-1 beta under the stimulation of LPS, thereby inhibiting the activation of downstream inflammatory signals, and the purposes of preventing and treating the gastrointestinal diseases such as colonitis, inflammatory bowel diseases and the like are achieved by inhibiting the protein level of IL-1 beta and gamma H2AX in colon tissues, enhancing the expression level of MUC2 in intestinal tracts of mice, restoring colon crypt and prolonging the colon length.

Description

Application of RI-1 or salt thereof in preparation of medicine for preventing and treating gastrointestinal diseases
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of RI-1 or a salt thereof in preparation of medicines for preventing and treating gastrointestinal diseases.
Background
Gastrointestinal disorders, such as non-infectious gastrointestinal disorders, are a generic term for a variety of inflammatory disorders of the digestive tract, and may affect populations of various ages, according to different classification angles, including, for example, inflammatory gastrointestinal disorders (e.g., inflammatory bowel disease (inflammatory bowel disease, hereinafter sometimes abbreviated IBD)), allergic gastrointestinal disorders (e.g., food allergies), and functional gastrointestinal disorders, among others. Is also particularly common among infants and is a major medical problem affecting the healthy growth of children. The clinical manifestations are repeated abdominal pain and distention, hematemesis and hematochezia, diarrhea and constipation, appetite reduction, malnutrition and various systemic complications, and death occurs when the symptoms are serious. The pathogenesis of gastrointestinal disorders, such as non-infectious gastrointestinal disorders, is currently unknown, in that the naming of the disease subtype is mainly based on the site of involvement, clinical manifestation, causative factors or the number of certain cell types present, rather than the pathogenesis.
Treatment of gastrointestinal disorders is currently symptomatic based on the different possible causes, including allergen avoidance, enteral nutrition, inhibition of inflammatory responses by glucocorticoid, immunosuppressant and biologic agents, etc. These drugs may cause toxic side effects affecting organ function, increased risk of infection, and risk of inducing malignant tumors such as lymphoma after long-term administration. These risks are particularly significant for pediatric patients, particularly in children in the growth phase.
Gastrointestinal diseases such as non-infectious gastrointestinal diseases, which cause acute attacks and sustained chronic subclinical inflammatory reactions or recurrent attacks of the diseases, seriously affect the physical health and growth and development of vast patients, especially children, and bring about great economic burden to families and society.
Disclosure of Invention
The object of the first aspect of the present invention is to provide the use of RI-1 or a salt thereof for the manufacture of a medicament for the prevention and treatment of gastrointestinal disorders.
The object of the second aspect of the present invention is to provide the use of a combination of a first medicament and a second medicament for the manufacture of a medicament for the prevention and treatment of gastrointestinal disorders.
The object of the third aspect of the present invention is to provide a pharmaceutical composition.
The object of the fourth aspect of the present invention is to provide a method for controlling gastrointestinal diseases.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided the use of RI-1 or a salt thereof in the manufacture of a medicament for the prevention and treatment of gastrointestinal disorders.
The RI-1 has the chemical name of 3-chloro-1- (3, 4-dichlorophenyl) -4- (4-morpholinyl) -1H-pyrrole-2, 5-dione, the molecular weight of 361.61 and the chemical formula of C 14 H 11 Cl 3 N 2 O 3 The CAS number is 415713-60-9.
Preferably, the salt comprises at least one of a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid. Preferred examples of the metal salt include: alkali metal salts, e.g., sodium salts, potassium salts, and the like; alkaline earth metal salts, e.g., calcium salts, magnesium salts, barium salts, and the like; and (3) an aluminum salt. Preferred examples of salts with organic bases include salts with: trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N' -dibenzylethylenediamine, and the like. Preferred examples of salts with inorganic acids include: salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of the salt with an organic acid include salts with the following organic acids: formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferred examples of the salt with a basic amino acid include salts with the following basic amino acids: arginine, lysine, ornithine, and the like. Preferred examples of salts with acidic amino acids include salts with the following acidic amino acids: aspartic acid, glutamic acid, and the like.
Preferably, the gastrointestinal disease comprises an infectious gastrointestinal disease and/or a non-infectious gastrointestinal disease.
Preferably, the infectious gastrointestinal disease comprises infectious enteritis and/or infectious gastritis.
Preferably, the infectious enteritis is caused by pathogens such as viruses, bacteria, parasites, etc.
Preferably, the infectious gastritis is caused by a pathogen such as a virus, a bacterium, a parasite, or the like.
Preferably, the non-infectious gastrointestinal disease comprises at least one of an inflammatory gastrointestinal disease, an allergic gastrointestinal disease, a functional gastrointestinal disease, a gastrointestinal tumor.
Preferably, the inflammatory gastrointestinal disease comprises at least one of inflammatory bowel disease, gastroenteritis, colitis.
Preferably, the inflammatory bowel disease comprises at least one of undefined inflammatory bowel disease (Undefined Inflammatory boweldisease), proctitis, ulcerative colitis, crohn's disease, and undifferentiated colitis; further comprising at least one of ulcerative colitis, crohn's disease and undifferentiated colitis.
Preferably, the gastroenteritis comprises at least one of superficial gastritis, ulcerative gastritis, chronic gastroenteritis, esophageal stricture, intestinal stricture.
Preferably, the colitis comprises at least one of acute colitis, chronic colitis.
Preferably, the allergic gastrointestinal disorder comprises a food allergy induced gastrointestinal disorder, for example: eosinophilic esophagitis, eosinophilic gastroenteritis, eosinophilic colitis, non-eosinophilic colitis, food protein-induced enterocolitis syndrome, food protein-induced enteropathy, food protein-induced rectal colitis, nonspecific chronic colitis, necrotizing enterocolitis, megacolon-related preoperative inflammation, and the like.
Preferably, the functional gastrointestinal disorder comprises irritable bowel syndrome.
Preferably, the gastrointestinal tumor comprises at least one of a gastric tumor, a duodenal tumor, a gastric stromal tumor, a duodenal stromal tumor, a small intestinal tumor, a colon cancer.
Preferably, the gastrointestinal diseases described in the present invention are a generic term for various inflammatory diseases of the digestive tract, and relate to the gastrointestinal tract such as stomach, duodenum, small intestine, colon, etc., including: non-infectious and infectious gastrointestinal diseases, such as inflammatory, allergic, and functional gastrointestinal diseases and gastrointestinal tumors, and the like. Stomach diseases such as acute and chronic gastritis, gastric ulcer, gastric polyp, erosive gastritis, peptic ulcer, gastric tumor, duodenal tumor, gastric stromal tumor, duodenal stromal tumor, etc. Small intestine diseases such as small intestine tumor, mesenteric lymphadenitis, interstitial lesions, etc. Colon diseases such as colitis, ulcerative colitis, crohn's disease, tuberculosis of the intestines, polyps of the colon, colon cancer, etc.
The method specifically comprises the following steps: inflammatory gastrointestinal diseases, for example, inflammatory bowel disease, colitis, undifferentiated colitis, crohn's Disease (CD), ulcerative Colitis (UC), undefined inflammatory bowel disease (Undefined Inflammatory boweldisease), acute colitis, chronic colitis, proctitis, and the like; gastroenteritis, for example, superficial gastritis, ulcerative gastritis, chronic gastroenteritis, esophageal stricture, intestinal stricture, and the like; allergic gastrointestinal disorders, such as those caused by food allergy, such as eosinophilic esophagitis, eosinophilic gastroenteritis, eosinophilic colitis, non-eosinophilic colitis, food protein induced enterocolitis syndrome, food protein induced enteropathy, food protein induced rectal colitis, nonspecific chronic colitis, necrotizing enterocolitis, megacolon-related preoperative and postsurgical inflammation. Preferably colitis, proctitis, undifferentiated colitis, crohn's disease, ulcerative colitis, acute colitis, chronic colitis; functional gastrointestinal disorders. The gastrointestinal disorders described above include both infectious and non-infectious. In the present invention, non-infectious gastrointestinal diseases including colitis, inflammatory bowel disease, such as Crohn's Disease (CD), ulcerative Colitis (UC), undefined inflammatory bowel disease, food allergy induced gastrointestinal diseases, such as eosinophilic esophagitis, eosinophilic gastroenteritis, eosinophilic colitis, non-eosinophilic colitis, food protein induced enterocolitis syndrome, food protein induced intestinal diseases, food protein induced rectal colitis, non-specific chronic colitis, necrotizing enterocolitis, megacolon-related preoperative inflammation, more preferably inflammatory bowel disease, such as colitis (e.g. undifferentiated colitis), proctitis, crohn's disease, ulcerative colitis, chronic colitis, acute colitis, eosinophilic colitis, non-eosinophilic colitis. In the present invention, colitis is intended to cover various forms of colitis; IBD is intended to cover crohn's disease, ulcerative colitis, undifferentiated/undefined IBD, and the like.
Preferably, the dosage form of the medicament is a child-resistant dosage form or an adult-resistant dosage form.
Preferably, the child is a newborn within 28 days of birth, an infant within 1 year of age, a child between 1 and 6 years of age, or a child over 6 and under 18 years of age.
Preferably, the adult is a gestational female adult, a perinatal female adult or a lactating female adult.
Preferably, the dosage form is selected from the group consisting of a gastrointestinal dosage form, and a parenteral dosage form.
Preferably, the parenteral administration form includes at least one of powder, tablet, granule, capsule, sustained release preparation, solution, dry suspension, effervescent tablet, emulsion, suspension, syrup, drop, and chewable tablet.
Preferably, the parenteral administration type includes injection administration type (e.g., injection, including intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and intracavity injection); respiratory tract administration type (such as spray, aerosol, powder spray, etc.); skin administration forms (such as topical solutions, lotions, liniments, ointments, plasters, pastes, patches, etc., mucosal administration forms (such as eye drops, nasal drops, ophthalmic ointments, gargle, sublingual tablets, adhesive tablets, film patches, etc.), and luminal administration forms (such as suppositories, aerosols, effervescent tablets, drops, dripping pills, etc., for use in the rectum, vagina, urethra, nasal cavity, auditory canal, etc.).
Preferably, the medicament is an oral medicament or an injection.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier, and/or any one or more of the second active ingredients.
Preferably, the second active ingredient comprises at least one of nicotinamide, resveratrol, vitamin C, vitamin E, vitamin a, folic acid, coenzyme Q10, lipoic acid, glutathione, dipyridamole.
Preferably, the subject to which the medicament is administered is an animal; further preferably, the animal is a mammal; still more preferably, the animal is selected from the group consisting of humans, cats, cattle, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; still further preferably, the animal is a human, including minors, adults, and geriatric; most preferably, the animal is an infant, a young child or a child.
Preferably, as the active ingredient of the prepared medicament, the mass content of RI-1 or a salt thereof in the medicament is 1 to 20%, preferably 1 to 10%, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%.
In a second aspect of the invention, there is provided the use of a combination of a first medicament and a second medicament for the preparation of a combination medicament for the treatment of gastrointestinal disorders; the first medicament comprises RI-1 or a salt thereof and the second medicament comprises an antioxidant substance and/or a PDE inhibitor (phosphodiesterase inhibitor).
Preferably, the gastrointestinal disorder is a gastrointestinal disorder in the use of the first aspect of the invention.
Preferably, the RI-1 or salt thereof is RI-1 or salt thereof in the use of the first aspect of the present invention.
Preferably, the antioxidant substance comprises at least one of nicotinamide, resveratrol, vitamin C, vitamin E, vitamin a, folic acid, coenzyme Q10, lipoic acid, glutathione.
Preferably, the PDE inhibitors include, but are not limited to, PDE1 inhibitors, PDE2 inhibitors, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE6 inhibitors, PDE7 inhibitors, PDE8 inhibitors, PDE9 inhibitors, PDE10 inhibitors, PDE11 inhibitors, or inhibitors having inhibitory effects on a plurality of members of the family, and drugs having inhibitory effects on other members of the phosphodiesterase family, and the like.
Preferably, the PDE inhibitor in the second medicament is dipyridamole.
Preferably, the first and second drugs are present independently or in combination.
Preferably, the dosage form of the first medicament is a child-resistant dosage form or an adult-resistant dosage form.
Preferably, the dosage form of the second medicament is a child-resistant dosage form or an adult-resistant dosage form.
Preferably, the child is a newborn within 28 days of birth, an infant within 1 year of age, a child between 1 and 6 years of age, or a child over 6 and under 18 years of age.
Preferably, the adult is a gestational female adult, a perinatal female adult or a lactating female adult.
Preferably, the dosage form of the first drug is selected from the group consisting of a gastrointestinal dosage form, and a parenteral dosage form.
Preferably, the dosage form of the second drug is selected from the group consisting of a gastrointestinal dosage form, and a parenteral dosage form.
Preferably, the parenteral administration form includes at least one of powder, tablet, granule, capsule, sustained release preparation, solution, dry suspension, effervescent tablet, emulsion, suspension, syrup, drop, and chewable tablet.
Preferably, the parenteral administration type includes injection administration type (e.g., injection, including intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and intracavity injection); respiratory tract administration type (such as spray, aerosol, powder spray, etc.); skin administration forms (such as topical solutions, lotions, liniments, ointments, plasters, pastes, patches, etc., mucosal administration forms (such as eye drops, nasal drops, ophthalmic ointments, gargle, sublingual tablets, adhesive tablets, film patches, etc.), and luminal administration forms (such as suppositories, aerosols, effervescent tablets, drops, dripping pills, etc., for use in the rectum, vagina, urethra, nasal cavity, auditory canal, etc.).
Preferably, the first medicament is an oral medicament or an injection.
Preferably, the second medicament is an oral medicament or an injection.
Preferably, the first medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the second medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the first and second agents are administered simultaneously, separately or sequentially.
Preferably, the subject to which the first medicament is administered is an animal; further preferably, the animal is a mammal; still more preferably, the animal is selected from the group consisting of humans, cats, cattle, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; still further preferably, the animal is a human, including minors, adults, and geriatric; most preferably, the animal is an infant, a young child or a child.
Preferably, the subject to which the second medicament is administered is an animal; further preferably, the animal is a mammal; still more preferably, the animal is selected from the group consisting of humans, cats, cattle, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; still further preferably, the animal is a human, including minors, adults, and geriatric; most preferably, the animal is an infant, a young child or a child.
In a third aspect of the invention, there is provided a combination comprising a first medicament and a second medicament; the first medicament comprises RI-1 or a salt thereof and the second medicament comprises an antioxidant substance and/or a PDE inhibitor (phosphodiesterase inhibitor).
Preferably, the combination is used for the prevention and treatment of gastrointestinal diseases.
Preferably, the gastrointestinal disorder is a gastrointestinal disorder in the use of the first aspect of the invention.
Preferably, the RI-1 or salt thereof is RI-1 or salt thereof in the use of the first aspect of the present invention.
Preferably, the antioxidant substance comprises at least one of nicotinamide, resveratrol, vitamin C, vitamin E, vitamin a, folic acid, coenzyme Q10, lipoic acid, glutathione.
Preferably, the PDE inhibitors include, but are not limited to, PDE1 inhibitors, PDE2 inhibitors, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE6 inhibitors, PDE7 inhibitors, PDE8 inhibitors, PDE9 inhibitors, PDE10 inhibitors, PDE11 inhibitors, or inhibitors having inhibitory effects on a plurality of members of the family, and drugs having inhibitory effects on other members of the phosphodiesterase family, and the like.
Preferably, the PDE inhibitor in the second medicament is dipyridamole.
Preferably, the first and second drugs are present independently or in combination.
Preferably, the dosage form of the first medicament is a child-resistant dosage form or an adult-resistant dosage form.
Preferably, the dosage form of the second medicament is a child-resistant dosage form or an adult-resistant dosage form.
Preferably, the child is a newborn within 28 days of birth, an infant within 1 year of age, a child between 1 and 6 years of age, or a child over 6 and under 18 years of age.
Preferably, the adult is a gestational female adult, a perinatal female adult or a lactating female adult.
Preferably, the dosage form of the first drug is selected from the group consisting of a gastrointestinal dosage form, and a parenteral dosage form.
Preferably, the dosage form of the second drug is selected from the group consisting of a gastrointestinal dosage form, and a parenteral dosage form.
Preferably, the parenteral administration form includes at least one of powder, tablet, granule, capsule, sustained release preparation, solution, dry suspension, effervescent tablet, emulsion, suspension, syrup, drop, and chewable tablet.
Preferably, the parenteral administration type includes injection administration type (e.g., injection, including intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and intracavity injection); respiratory tract administration type (such as spray, aerosol, powder spray, etc.); skin administration forms (such as topical solutions, lotions, liniments, ointments, plasters, pastes, patches, etc., mucosal administration forms (such as eye drops, nasal drops, ophthalmic ointments, gargle, sublingual tablets, adhesive tablets, film patches, etc.), and luminal administration forms (such as suppositories, aerosols, effervescent tablets, drops, dripping pills, etc., for use in the rectum, vagina, urethra, nasal cavity, auditory canal, etc.).
Preferably, the first medicament is an oral medicament or an injection.
Preferably, the second medicament is an oral medicament or an injection.
Preferably, the first medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the second medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the first and second agents are administered simultaneously, separately or sequentially.
Preferably, the subject to which the first medicament is administered is an animal; further preferably, the animal is a mammal; still more preferably, the animal is selected from the group consisting of humans, cats, cattle, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; still further preferably, the animal is a human, including minors, adults, and geriatric; most preferably, the animal is an infant, a young child or a child.
Preferably, the subject to which the second medicament is administered is an animal; further preferably, the animal is a mammal; still more preferably, the animal is selected from the group consisting of humans, cats, cattle, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; still further preferably, the animal is a human, including minors, adults, and geriatric; most preferably, the animal is an infant, a young child or a child.
In a fourth aspect of the invention, there is provided a method of controlling gastrointestinal disorders, administering to a subject an effective amount of a 1) or a 2):
a1 RI-1 or a salt thereof;
a2 A combination according to the third aspect of the invention.
Preferably, the RI-1 or salt thereof is RI-1 or salt thereof in the use of the first aspect of the present invention.
The beneficial effects of the invention are as follows:
the invention discloses the application of RI-1 or the salt thereof in preparing the medicine for preventing and treating gastrointestinal diseases for the first time, the RI-1 can obviously inhibit the expression of inflammatory factors IL-1 beta under the stimulation of LPS, thereby inhibiting the activation of downstream inflammatory signals, and the purposes of preventing and treating the gastrointestinal diseases such as colonitis, inflammatory bowel diseases and the like are achieved by inhibiting the protein level of IL-1 beta and gamma H2AX in colon tissues, enhancing the expression level of MUC2 in intestinal tracts of mice, restoring colon crypt and prolonging the colon length.
Further, the present invention provides a combination comprising a first agent and a second agent; the first drug comprises RI-1 or a salt thereof, and the second drug comprises an antioxidant substance; the combination of the first medicine and the second medicine has synergistic effect in preventing and treating colonitis, inflammatory bowel disease and other gastrointestinal tract diseases.
Drawings
FIG. 1 is a graph showing the effect of RI-1 on the expression level of inflammatory factor IL-1β under LPS stimulation in example 1.
FIG. 2 is a graph showing the effect of RI-1 on colon length in mice in the DSS colitis induced model in example 2.
FIG. 3 is a graph showing the effect of RI-1 on the expression levels of mouse colon crypt and MUC2 in a DSS colitis model in example 2.
FIG. 4 is a graph showing the effect of RI-1 on IL-1β and γH2AX protein levels in colon tissue of mice in a DSS colitis model in example 2.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The materials, reagents and the like used in this example are commercially available ones unless otherwise specified.
The following examples use nicotinamide as a positive control in patent CN 113398130A "use of nicotinamide for preventing and treating gastrointestinal dysfunction".
Example 1 RI-1 inhibition of downstream inflammatory Signal activation
In THP-1 cell-induced macrophages (using 100ng/mL phorbol 12-myristate-13-acetate (PMA), THP-1 cells were induced to differentiate into macrophages for 48 h), while the experimental group was treated with RI-1 (final concentration: 20. Mu.M) and LPS (final concentration: 100 ng/mL) (model group was treated with LPS (final concentration: 100 ng/mL), the positive control group was treated with Nico (Nicotinamide; final concentration: 20. Mu.M) and LPS (final concentration: 100 ng/mL), and the blank control group was treated with no LPS, RI-1 and Nico) for 6 hours (each treatment was repeated 3 times). Cell culture supernatants were collected and assayed for expression levels of inflammatory factor IL-1β by ELISA as shown in FIG. 1: RI-1 significantly inhibits the expression of inflammatory factor IL-1 beta under LPS stimulation, thereby inhibiting the activation of downstream inflammatory signals, and the effect of RI-1 is relatively better than that of positive medicine nicotinamide.
Example 2 RI-1 for the prevention and/or treatment of colitis
The experimental method comprises the following steps: in the case of normal feeding, wild-type mice of the experimental group were given 3 days (RI-1:10 mg/kg, once daily; nico:20mg/kg, once daily; vehicle: similar to the volume of drug injection, once daily) by intraperitoneal injection in advance before molding with DSS. The drinking water of the experimental groups DSS-RI-1, DSS-Nico and DSS-Vehicle is changed into 3% DSS water for continuous feeding, meanwhile, the intraperitoneal injection of medicines (RI-1:10 mg/kg; nico:20 mg/kg; vehicle: similar to the injection volume of medicines once a day) is continuously carried out once a day, and the blank control group is continuously fed by using the drinking water. During the molding process, mice were weighed, stool morphology scored, and hematochezia degree scored at fixed times per day. Mice were sacrificed on day 7 of DSS feeding and the colon was taken for photographic recording of length, representative pictures and length statistics are shown in fig. 2: RI-1 can effectively prolong colon length of mice in a DSS colitis model, and has effects of preventing and treating colitis; then, the distal colon ring of the mice was cut and fixed with 4% Paraformaldehyde (PFA) for 24 hours, after tissue fixation, the mice were embedded and sectioned (3 μm), and the sections were stained with hematoxylin-eosin (HE), immunofluorescent staining was performed for MUC2 protein (MUC 2 is mucin secreted by goblet cells of the intestinal tract, and has an important protective effect on the intestinal tract), and the HE results and the immunofluorescent staining results for MUC2 are shown in fig. 3: the colon crypt of the mice controlled by RI-1 is recovered well, the MUC2 expression is obviously enhanced compared with the model group in the intestinal tract of the mice controlled by administration, which indicates that the intestinal barrier of the mice controlled by administration is being reconstructed well, and the control effect of RI-1 is better than that of nicotinamide (as can be seen from the figure, RI-1 is closer to the blank control group); meanwhile, immunofluorescent staining is carried out on IL-1 beta and gamma H2AX protein levels, and statistical analysis is carried out, and the immunofluorescent staining and statistical results of IL-1 beta and gamma H2AX protein levels are shown in FIG. 4: can inhibit IL-1 beta and gamma H2AX protein level in colon tissue of mouse effectively.
As can be seen from the experimental results of this example 2, administration of RI-1 can effectively relieve symptoms of DSS-induced colitis model, has a significant inhibitory effect on inflammatory factors in the process, and significantly enhances the level of protective protein, and by combining with the mechanism that RI-1 shown in example 1 can effectively resist inflammation, it is demonstrated that RI-1 can prevent and/or treat gastrointestinal diseases, especially inflammatory gastrointestinal diseases, including colitis (including acute and chronic colitis), inflammatory bowel diseases (including ulcerative colitis, crohn's disease, undifferentiated/undefined inflammatory bowel disease), and the like.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (16)

  1. Use of RI-1 or a salt thereof for the manufacture of a medicament for the prevention and treatment of gastrointestinal diseases, including at least one of inflammatory bowel disease, colitis, said RI-1 having the chemical name 3-chloro-1- (3, 4-dichlorophenyl) -4- (4-morpholinyl) -1H-pyrrole-2, 5-dione.
  2. 2. The use according to claim 1, characterized in that:
    the inflammatory bowel disease comprises at least one of undefined inflammatory bowel disease, proctitis, ulcerative colitis, crohn's disease, and undifferentiated colitis.
  3. 3. The use according to claim 1, characterized in that:
    the colitis comprises at least one of acute colitis and chronic colitis.
  4. 4. A use according to any one of claims 1 to 3, characterized in that:
    the dosage form of the medicament comprises a child-applicable dosage form or an adult-applicable dosage form.
  5. 5. The use according to claim 4, characterized in that:
    the children include newborns within 28 days of birth, infants within 1 year of age, infants between 1 and 6 years of age, or children over 6 and under 18 years of age.
  6. 6. The use according to claim 4, characterized in that: the adult comprises a gestational female adult, a perinatal female adult or a lactating female adult.
  7. 7. A use according to any one of claims 1 to 3, characterized in that: the salt includes at least one of a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid.
  8. 8. A use according to any one of claims 1 to 3, characterized in that:
    the dosage form of the medicine is selected from a gastrointestinal tract administration dosage form or a parenteral tract administration dosage form.
  9. 9. The use according to claim 8, characterized in that:
    the gastrointestinal tract administration type preparation comprises at least one of powder, tablet, granule, capsule, sustained release agent, solution, emulsion, suspension, syrup and drop.
  10. 10. The use according to claim 8, characterized in that:
    the gastrointestinal tract administration type preparation comprises at least one of dry suspension, chewable tablet and effervescent tablet.
  11. 11. The use according to claim 8, characterized in that: the parenteral administration type includes injection administration type, respiratory administration type, skin administration type, mucosa administration type or cavity administration type.
  12. 12. A use according to any one of claims 1 to 3, characterized in that:
    the dosage form of the medicine is selected from oral medicine or injection.
  13. 13. A use according to any one of claims 1 to 3, characterized in that:
    the mass content of the RI-1 or the salt thereof in the medicine is 1-20%.
  14. 14. The use according to claim 13, characterized in that:
    the mass content of the RI-1 or the salt thereof in the medicine is 1% -10%.
  15. 15. Use according to any one of claims 1 to 3, wherein the medicament further comprises a pharmaceutically acceptable carrier, and/or any one or more of the second active ingredients.
  16. 16. The use according to claim 15, wherein the second active ingredient comprises at least one of nicotinamide, resveratrol, vitamin C, vitamin E, vitamin a, folic acid, coenzyme Q10, lipoic acid, glutathione, dipyridamole.
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