CN117205214B - Application of dextromethorphan in preparing medicine for treating ulcerative colitis - Google Patents
Application of dextromethorphan in preparing medicine for treating ulcerative colitis Download PDFInfo
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Abstract
The key point of the application of dextromethorphan in preparing medicines for treating ulcerative colitis belongs to the field of biological pharmacy, and aims to solve the problems of treating ulcerative colitis, crohn's disease, irritable bowel syndrome and other inflammatory bowel diseases, wherein the medicines comprise dextromethorphan with the content of about 10ng/kg per day, and experimental data show that dextromethorphan can be used for preventing or treating the intestinal inflammation.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to application of dextromethorphan, and particularly relates to application of dextromethorphan in preparation of a medicament for treating ulcerative colitis or preparation of an intestinal antioxidant stress medicament.
Background
Ulcerative colitis is a chronic inflammatory intestinal disease, and has the clinical manifestations of symptoms such as abdominal pain, bloody diarrhea, hypodynamia, weight loss and the like, the disease course is long, and repeated attacks bring great pain to patients. At present, the cause of ulcerative colitis is not completely clear, and various factors such as heredity, environment, immunity and the like are involved. Aiming at the clinical treatment of inflammatory intestinal diseases, mainly drug treatment is mainly carried out, and commonly used drugs comprise four types: aminosalicylic acids, glucocorticoids, immunosuppressants and biologicals. These drugs have limited therapeutic effects and have certain side effects. Even with new biological agents, it is reported that about two-thirds of ulcerative colitis patients fail to reach or maintain the remission state of the disease after 1 year, with recurrence or exacerbation. Thus, the need for additional treatment options for patients with ulcerative colitis remains unmet and new therapeutic agents need to be developed.
Dextromethorphan is a codeine isomer of levomaleic, an over-the-counter central antitussive agent that is widely used clinically. Dextromethorphan functions as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and a sigma-1 receptor agonist. Dextromethorphan has wide pharmacological effects, and researches show that dextromethorphan has anti-inflammatory and cytoprotective effects on sepsis mice. Furthermore, the U.S. FDA approval of dextromethorphan in combination with bupropion was made 2022 for the treatment of major depressive disorder in adults, anxiety disorders caused by alzheimer's disease, and smoking cessation. Previous studies by the inventor of the application also show that dextromethorphan and sodium valproate have better treatment effect on refractory epilepsy, and the studies are recorded in CN116265016A, a composition of a drug named as an epilepsy disease, and a Chinese patent application publication document of the application for preparing the drug for treating the epilepsy disease. Currently, dextromethorphan is mainly applied to treatment of central nervous system diseases, and the treatment effect on ulcerative colitis has not been reported yet.
Disclosure of Invention
The invention aims to provide application in preparing medicines for treating intestinal inflammation. The embodiment of the invention provides the application of the medicine, and experimental data show that the invention has a therapeutic effect on intestinal inflammation, especially ulcerative colitis, not only expands the medicine selection for treating ulcerative colitis, but also further expands the application range of dextromethorphan.
In a first aspect, some embodiments of the application provide the use of dextromethorphan in the manufacture of a medicament for treating intestinal inflammation.
In some embodiments, dextromethorphan is included in the medicament at a level of about 10ng/kg per day.
In some embodiments, the medicament is any one of an oral formulation, an injectable formulation.
In some embodiments, the oral formulation comprises any of a tablet, capsule, powder, granule, or film coated tablet, and the injectable formulation comprises any of an intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, or intraluminal injection dosage form.
In some embodiments, the medicament further comprises a pharmaceutically acceptable excipient.
In some embodiments, the drug for treating intestinal inflammation comprises an intestinal antioxidant stress drug.
In some embodiments, the drug for treating intestinal inflammation comprises one of a drug for treating colitis, a drug for treating ulcerative colitis, a drug for treating crohn's disease, or a drug for treating irritable bowel syndrome.
Medicine for treating intestinal inflammation.
In a second aspect, some embodiments of the application provide a medicament for treating intestinal inflammation, comprising dextromethorphan and pharmaceutically acceptable excipients.
In some embodiments, dextromethorphan is included in the medicament at a level of about 10ng/kg per day.
In some embodiments, treating the intestinal inflammation comprises one of colitis, treating ulcerative colitis, crohn's disease, or irritable bowel syndrome.
Compared with the prior art, the invention has the following beneficial effects: the dextromethorphan serving as the old medicine for treating the nervous system diseases has a treatment effect on ulcerative colitis, and is specifically expressed in the following steps:
(1) Reducing weight loss in ulcerative colitis mice;
(2) Increasing colon length in ulcerative colitis mice;
(3) Reducing the disease activity index of ulcerative colitis mice;
(4) Increasing intestinal wall tight junction protein, increasing intestinal mucus secretion, decreasing intestinal wall permeability;
(5) Reducing the level of intestinal oxidative stress;
(6) Reducing leukocyte infiltration;
(7) Improving dysbacteriosis of intestinal canal.
Experimental data in the examples show that the invention provides more scope for drug selection for treating ulcerative colitis, and also expands the range of use of dextromethorphan.
Drawings
FIG. 1 is a graph of the results provided in example 1 of the present invention, wherein a is a weight change experimental plot and a DAI scoring plot, b is a colon length experimental plot, and c is a HE staining experimental plot.
FIG. 2 is a graph of the results provided in example 2 of the present invention, wherein a is a FITC-dextran experiment, b is an Aristolochia blue staining experiment, and c is a ZO-1 experiment.
FIG. 3 is a graph showing the results provided in example 3 of the present invention, wherein a is an 8-OHdG experiment, b is a catalase experiment, c is a malondialdehyde experiment, d is a myeloperoxidase experiment, and e is a superoxide dismutase experiment.
FIG. 4 is a graph of the results provided in example 4 of the present invention, where a is the CD45 experiment and b is the F4/80 experiment.
FIG. 5 is a graph of the results provided in example 5 of the present invention, where a is a graph of a portal horizontal species relative abundance experiment and b is a graph of a generic horizontal species relative abundance experiment.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The term "treatment" means the delivery of a therapy aimed at reducing the severity or frequency of symptoms, eliminating symptoms or underlying causes, preventing the occurrence of symptoms or underlying causes thereof, or ameliorating or remediating damage due to a disorder or disease. In certain embodiments, "treatment" includes prophylactic treatment, i.e., administration is effective to reduce the likelihood of a patient developing a disease. The application provides an application of dextromethorphan in preparing a medicine for treating intestinal inflammation, wherein the intestinal inflammation refers to colonitis, particularly ulcerative colitis, crohn's disease or one of irritable bowel syndrome or other diseases belonging to intestinal inflammation. According to the use in some embodiments of the application, the medicament comprises dextromethorphan at a level of 10ng/kg per day.
According to the use in some embodiments of the application, the medicament is an oral formulation or an injectable formulation. The oral preparation comprises tablets, capsules, powder, granules and film coated tablets. The injection preparation comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and intracavity injection.
The dextromethorphan disclosed by the invention can be used for preparing a medicine for treating the anti-oxidative stress injury of the intestinal tract, increasing the intestinal wall tight junction protein, reducing the intestinal wall permeability, improving the intestinal flora, increasing the mucous secretion of intestinal epithelial goblet cells, reducing the activation of colonic macrophages, and can be used for treating intestinal inflammation by integrating the effects. Dextromethorphan of the present invention can be used as a single active ingredient for the preparation of a medicament for the treatment of intestinal inflammation, the above effects and therapeutic purposes of which are demonstrated by the following examples.
The experimental reagent of the invention comprises a modeling and administration reagent and consumable material, and specifically comprises
Dextromethorphan (Supelco, PHR 1018)
Immune combined dyeing reagent box SP-9000 (Beijing Zhonghua Jinqiao biotechnology Co., ltd.)
Concentrated DAB chromogenic reagent kit ZLI-9032 (Beijing China fir golden bridge biotechnology Co., ltd.)
Dextran sodium sulfate (MP Biomedicals, U.S.A.)
A Li Xinlan dyeing liquor (Beijing Solaibao science and technology Co., ltd.)
8-OHdGC antibody (Abcam, U.S.A.)
CD45 antibody (Abcam, U.S.A.)
ZO-1 antibody (Abcam, U.S.A.)
FITC-dextran (Shanghai Ala Biochemical technology Co., ltd.)
Example 1 dextromethorphan improvement Dextran Sodium Sulfate (DSS) induced ulcerative colitis
(1) Animal grouping and model for producing chronic ulcerative colitis
Wild type C57/BL6J male mice (6-8 weeks old) were kept under standardized conditions at 22-24℃and 20% humidity, and were free to receive standard diet and water for 12 hours on a light-dark cycle. After 7 days of adaptive feeding, the mice were grouped into 10 groups, each group and mode of administration being shown in fig. 1a, including Normal (control), dss+veccle (enteritis model), dss+ ULDM (dextromethorphan-treated), dss+5-ASA (5-ASA drug-treated).
The method for establishing the chronic enteritis model comprises the following steps: on days 1-7, mice consumed 1% dss solution, and on days 8-17 was changed to 0.5% dss solution, and on days 18-24 was changed to 1% dss solution, and on days 24-34 was changed to 0.5% dss solution. It is applied to enteritis model group, dextromethorphan treatment group and 5-ASA drug treatment group.
The dextromethorphan treatment group was also given 10ng/kg dextromethorphan subcutaneous injections daily. The 5-ASA drug treatment group was also given 50mg/kg of 5-ASA per day for gastric lavage. The control group did not drink DSS solution daily, but was injected with the same volume of physiological saline as dextromethorphan in the dextromethorphan-treated group. Mice were weighed daily and stool shape was recorded. Mice were euthanized for 35 days of the experiment and fecal samples, colonic tissue samples, and blood samples were taken.
(2) Measuring disease activity index: disease severity was assessed by daily measurement of body weight, fecal viscosity, and fecal bleeding scores. The weight loss (score: 0, none; 1,1-5%, 2,5-10%, 3, 10-20%, 4, more than 20%) and the fecal blood (score: 0, negative hematoma; 2, positive hematoma; 4, major bleeding) and fecal consistency (score: 0, well-shaped particles 2, thin stool; 4, diarrhea) were calculated; measuring colon length: opening abdominal cavity to separate out colon, naturally laying, and measuring intestine length; colon tissue HE staining: colon tissue was taken, fixed in 4% pfa for 24 hours, paraffin embedded, cut into 5 μm sections, stained with conventional HE, blocked, and photographed under a microscope for observation.
Experimental results: as can be seen from fig. 1 a-b, dextromethorphan is capable of significantly improving loss of body weight in DSS-colitis mice, reducing disease activity index, and reducing colon length shortening. As can be seen from fig. 1c, HE staining results showed a significant reduction in colon histological damage, reduced crypt structural damage, reduced submucosal edema, and reduced inflammatory cell infiltration in the dextromethorphan-treated mice as compared to the enteritis model mice.
Example 2 dextromethorphan increases Dextran Sodium Sulfate (DSS) ulcerative colitis mice intestinal wall barrier function
(1) FITC-dextran detection of intestinal wall permeability
Taking 34 th mice of each experimental group, firstly, stopping water for run out of grain hours, and then, on the next day, filling the stomach according to the weight of 40mg FITC-dextran (sigma-Aldrich 3-5 kDA)/100 g; after 4 hours, serum of the mice is collected, and the fluorescence intensity is detected by a multifunctional enzyme-labeled instrument, wherein excitation light is 485nm; the emitted light was 528nm.
(2) Colon alisxin blue staining
5 Μm sections of colon wax were taken and placed in an oven at 60℃to bake the slices for 1 hour. After taking out, the slices are soaked in xylene I and xylene II for 10 minutes in turn for dewaxing, and then soaked in absolute ethyl alcohol I, absolute ethyl alcohol II, 95% ethyl alcohol, 85% ethyl alcohol, 75% ethyl alcohol and 50% ethyl alcohol for 5 minutes respectively for hydration. Wash with PBS for 15 min. Adding the acid solution of the Li Xinlan to soak for 3 minutes, and flushing with running water. The dye solution of Gaa Li Xinlan is added for 30 minutes and washed with running water. Adding the nuclear solid red staining solution for counterstaining for 5 minutes, and flushing with running water. Sequentially soaking slices in 50% ethanol, 75% ethanol, 85% ethanol, 95% ethanol, absolute ethanol I and absolute ethanol II for 5 min respectively, dehydrating, and soaking in xylene I and xylene II for 10 min for transparency. The slides were blocked with neutral gum and coverslips. Observed under a microscope and photographed.
(3) Tight junction protein expression assay
The 5 μm colonic paraffin sections were placed in an oven at 60℃to bake the sections for 1 hour. After taking out, the slices are soaked in xylene I and xylene II for 10 minutes in turn for dewaxing, and then soaked in absolute ethyl alcohol I, absolute ethyl alcohol II, 95% ethyl alcohol, 85% ethyl alcohol, 75% ethyl alcohol and 50% ethyl alcohol for 5 minutes respectively for hydration. Wash with PBS for 15 min. Adding sodium citrate buffer solution, and heating in boiled water bath for 15min to repair antigen. Then cooled to room temperature and washed with PBS for 15 minutes. The endogenous peroxidase of the sample was washed off by adding 1%H 2O2 solutions, and after 1 hour, washed with PBS for 15 minutes. The serum blocking solution was added for 1 hour. Adding 1:250 dilution of abcam ZO-1 primary antibody, overnight followed by washing with PBS for 15 min. Biotin secondary antibody was added and after 1 hour, washed with PBS for 15 minutes. Avidin three antibodies were added and washed with PBS for 15 minutes after 1 hour. Sequentially soaking the slices in 50% ethanol, 75% ethanol, 85% ethanol, 95% ethanol, absolute ethanol I and absolute ethanol II for 5 minutes respectively, and then soaking in xylene I and xylene II for 10 minutes for dehydration. The slides were blocked with neutral gum and coverslips. Observed under a microscope and photographed.
Experimental results: as can be seen from fig. 2a, dextromethorphan treatment significantly reduced the amount of FITC-dextran from the intestinal tract into the blood of the experimental mice compared to the enteritis model group; as can be seen from fig. 2b, the colonic acid mucus in the enteritis model group was significantly reduced, and the colonic acid mucus in the dextromethorphan treatment group was increased; as can be seen from fig. 2c, the colon tight junction protein was significantly reduced in the enteritis model group and significantly increased in the dextromethorphan-treated group. This suggests that dextromethorphan treatment can increase the barrier function of the colon of enteritis mice.
Example 3 dextromethorphan reduces Dextran Sodium Sulfate (DSS) ulcerative colitis mice intestinal oxidative stress injury
(1) Colonic 8-OHdG immunohistochemistry
Experimental procedure conventional immunohistochemical procedure, given 1: 8-OhdGC (Abcam) primary antibody diluted at 100 was incubated overnight at 4 ℃. Other immunohistochemistry was performed as above MuC.
(2) Oxidative stress-related enzyme assay
Enzyme-linked immunosorbent assay (ELISA) analyzes the effect of activities of colon tissue-associated oxidative stress-related enzymes such as superoxide dismutase (SOD), catalase (CAT), myeloperoxidase (MPO) and Malondialdehyde (MDA).
Experimental results: as can be seen from FIG. 3 a, the oxidative stress markers 8-OhdG were significantly increased in the colon epithelium of mice in the enteritis model group compared to the control group. Compared with enteritis model group, dextromethorphan treatment group can obviously reduce 8-OhdG expression. Indicating that dextromethorphan is capable of reducing the level of oxidative stress in colonic epithelial cells. As can be seen from fig. 3 b-e, the detection results of enzymes related to colon oxidative stress show that catalase and superoxide dismutase are reduced compared with the enteritis model group, and the dextromethorphan treatment can increase the activity of the two enzymes. Myeloperoxidase and malondialdehyde were increased in enteritis mice, whereas dextromethorphan treatment was able to decrease both, suggesting that dextromethorphan was able to ameliorate colonic oxidative stress injury in enteritis mice.
Example 4 dextromethorphan reduces Dextran Sodium Sulfate (DSS) ulcerative colitis mouse inflammatory cell infiltration
Colon leukocyte marker CD45 and macrophage marker F4/80 immunohistochemistry
Experimental procedure conventional immunohistochemical procedure, given 1:100 dilutions of CD45 or F4/80 (Abcam) primary antibody were incubated overnight at 4 ℃. Other ZO-1 immunohistochemistry as above.
Experimental results: as can be seen from fig. 4 a-b, the number of colon leukocytes and macrophages was significantly increased in mice of the enteritis model group compared to the control group. Compared with enteritis model mice, the colon leukocyte number of the dextromethorphan treatment mice is significantly reduced, which indicates that dextromethorphan can significantly reduce the inflammation level of colonitis mice.
Example 5 dextromethorphan reduces modulation of Dextran Sodium Sulfate (DSS) ulcerative colitis mice intestinal flora
Mouse faeces were collected, genomic DNA was extracted from the faeces using a faecal DNA extraction kit (Omega Bio-Tek, USA), and the V3-V4 region of the extracted genomic DNA was subjected to specific PCR amplification, 16S rDNA sequencing, and the change in faecal flora was analyzed.
Experimental results: as can be seen from FIGS. 5 a-b, dextromethorphan treatment increased the phylum-to-bacteroides ratio over the enteritis model group. Dextromethorphan treatment can increase the abundance of Dunaliella (dubosiella) to a level comparable to the control group for the genus level, indicating that dextromethorphan treatment can improve intestinal dysbacteriosis in enteritis mice.
Although the present invention has been described with respect to specific examples, it will be appreciated by those skilled in the art that the present invention may be embodied in other specific forms within the scope of the invention as described herein.
Claims (5)
1. Use of dextromethorphan in the manufacture of a medicament for ameliorating an intestinal dysbacteriosis caused by ulcerative colitis, wherein ameliorating the intestinal dysbacteriosis is increasing the phylum-to-bacteroides ratio, and increasing the abundance of dupont (dubosiella) at the genus level.
2. The use according to claim 1, wherein the medicament is for use at a dose of about 10ng/kg dextromethorphan per day.
3. The use according to claim 1, wherein the medicament is any one of an oral formulation, an injectable formulation.
4. The use according to claim 3, wherein the oral formulation comprises any one of a tablet, capsule, powder or granule, and the injectable formulation comprises any one of intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection or intraluminal injection dosage forms.
5. The use according to claim 1, wherein the medicament further comprises pharmaceutically acceptable excipients.
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