CN116785278A - Application of notopterol in preparation of medicines for treating ulcerative colitis - Google Patents
Application of notopterol in preparation of medicines for treating ulcerative colitis Download PDFInfo
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Abstract
The invention discloses an application of notopterygol in preparing a medicament for treating ulcerative colitis. Experiments prove that the notopterygol can obviously improve colon inflammation of mice induced by dextran sodium sulfate, and is shown to obviously reduce the activity index of the mice diseases and obviously improve the colon length shortening of the mice caused by modeling; obviously reducing the MPO content in serum; significantly reducing the pathological changes of colon tissue of mice, including reducing inflammatory cell infiltration, restoring tissue structure and intestinal gland number; the content of the pro-inflammatory factor IL-1 beta in colon tissues is obviously reduced, the inflammatory reaction of colon parts is lightened, the activity of resisting ulcerative colitis is obvious, and the preparation method has good application prospect in preparing the medicament for treating the ulcerative colitis.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of notopterol in preparation of a medicine for treating ulcerative colitis.
Background
Ulcerative colitis is also known as chronic nonspecific ulcerative colitis, and lesions are localized in the rectum and sigmoid colon, and can spread to the descending colon, even the entire colon. The whole clinical symptoms are diarrhea, bloody pus, abdominal pain and tenesmus. Modern medicine considers that autoimmune abnormality leads to destruction of mucous membrane, or brain cortical dysfunction, autonomic nerve dysfunction and intestinal hyperkinesia, intestinal vascular smooth muscle spasm contraction, tissue ischemia, capillary permeability increase, thereby forming inflammation, erosion and ulcer of intestinal mucous membrane. The medicine for treating ulcerative colitis comprises broad-spectrum anti-inflammatory medicines such as sulfasalazine, adrenocortical hormone and the like, immunosuppression, immunomodulators and the like. At present, the application of notopterol in treating ulcerative colitis has not been reported.
Disclosure of Invention
The invention aims to provide an application of notopterygol in preparing a medicine for treating ulcerative colitis.
The invention aims at realizing the application of the notopterol serving as the main active substance or one of the active substances in preparing the medicine for treating the ulcerative colitis, wherein the dosage of the notopterol is 1-2 times per day, and 50-150 mg each time.
The beneficial effects of the invention are as follows: experiments prove that the notopterygol can obviously improve colon inflammation of mice induced by dextran sodium sulfate, and is shown to obviously reduce the activity index of the mice diseases and obviously improve the colon length shortening of the mice caused by modeling; obviously reducing the MPO content in serum; significantly reducing the pathological changes of colon tissue of mice, including reducing inflammatory cell infiltration, restoring tissue structure and intestinal gland number; the content of the pro-inflammatory factor IL-1 beta in colon tissues is obviously reduced, the inflammatory reaction of colon parts is lightened, the activity of resisting ulcerative colitis is obvious, and the preparation method has good application prospect in preparing the medicament for treating the ulcerative colitis.
Drawings
FIG. 1 is a graph showing the effect of notopterol on DSS-induced changes in colon histopathology in mice model UC according to the present invention (200X).
Detailed Description
The invention is further described below without limiting it in any way, and any modifications based on the invention fall within the scope of protection of the invention.
The invention provides application of notopterol serving as a main active substance or one of active substances in preparing a medicament for treating ulcerative colitis, wherein the administration dosage of the notopterol is 1-2 times per day, and 50-150 mg each time.
The dose of notopterol was 2 times daily, 100 mg a times.
The invention also provides the pharmaceutical composition comprising notopterygium alcohol and a pharmaceutically acceptable carrier or excipient.
The pharmaceutical composition is in the form of pills, capsules, tablets, powder, granules, injection, compound preparation or other oral dosage forms.
Example 1
Mixing the above with starch and dextrin, granulating with ethanol as wetting agent, adding magnesium stearate, and making into tablet.
Experimental example 1 Effect of Notopterygii rhizoma alcohol on treating ulcerative colitis caused by dextran sodium sulfate
1. Experimental materials
1.1 Main instrument
HHS-11-1 constant temperature water bath, medical equipment factory of Shanghai Boqing Utility company; 5424R small high-speed refrigerated centrifuge, ai Bende, china Co., ltd; one ten thousandth of electronic balance, BT 124S beijing certolis instruments systems limited; vortex oscillator, LAB-BLOGEN double-speed technology VTX-E; a water purifier (Milli-Q Academic A10 ultra-pure water system), millipore company, U.S.A.; ultralow temperature (-80 ℃) refrigerator, zemoer feishier technology (china) limited; an enzyme-labeled analyzer (Molecular Devices), molecular instruments, U.S.A.; ultrasonic cleaner, ningbo Xinzhi biotechnology Co., ltd.
1.2 Main medicine and kit
Notopterygium alcohol (Lemeitian medicine technologies Co., ltd., lot number: DSTDQ 004302); sulfasalazine enteric coated tablet (0.25. 0.25 g, shanghai Yi balance pharmaceutical Co., ltd., lot: 09210601); mouse Interleukin (IL) -1 beta ELISA kit (Hangzhou Union Biotechnology Co., ltd., lot number: A201B 21121), myeloperoxidase (MPO) detection kit (Hangzhou Union Biotechnology Co., ltd., lot number: A213320952). Dextran sodium sulfate (Dextran sulfate sodium salt, DSS; MW:36000-50000;MP Biomedicals company, lot number: S5648). Other chemical reagents were purchased from Yunnan Luodebao Biotech Co.
1.3 Experimental animal
C57BL/6 mice, male, 22±2 g, purchased from beijing Bei Fu biotechnology limited, license number: SCXK (Beijing) 2019-0010. Experimental mouse feed and pads, purchased from beijing Bei Fu biotechnology limited, license number: SCXK (Beijing) 2019-0010. After the experimental animals entered the animal feeding house, the experimental animals were fed adaptively under laboratory conditions for 1 week. The experimental method and the conditions are inspected to be qualified by the ethical committee of animal experiment centers of the university of Chinese medicine in Yunnan, and the number of animal ethical inspection files is as follows: r-062021LH115.
1.4 Preparation of main reagents
3% DSS solution, weighing DSS 30 g, adding distilled water 1000 mL, mixing well, dissolving thoroughly, and replacing every 2 days.
Sulfasalazine suspension: taking 1 tablet of sulfasalazine enteric coated tablet (0.25 g), scraping off enteric coating with a blade, fully grinding in a mortar, adding 0.5% sodium carboxymethyl cellulose solution, uniformly suspending to a final volume of 8.33 mL, and obtaining sulfasalazine suspension (0.03 g/mL) for later use. The stomach filling volume is 0.1 mL/10 g, and the administration dosage is 0.3 g/kg.
Preparing notopterygium alcohol suspension:
high dose group medicine liquid of notopterygium alcohol: taking a proper amount of pure notopterol, and preparing a solution of 5 mg/mL by using 0.5% sodium carboxymethyl cellulose. The stomach filling volume is 0.1 mL/10 g, and the administration dosage is 50 mg/kg.
Notopterygium alcohol low dose group medicine liquid: taking a proper amount of finished notopterygium alcohol product, and preparing a solution of 2.5 mg/mL by using 0.5% sodium carboxymethyl cellulose. The stomach filling volume is 0.1 mL/10 g, and the administration dosage is 25 mg/kg.
2. Experimental method
2.1 Grouping, modeling and administration of animals
Animals were randomized into the normal, model, high notopterol (50 mg/kg), low notopterol (25 mg/kg), and sulfasalazine (0.3 g/kg) groups for a total of 5 groups of 8 animals each. The start of the experiment was when the day was marked as day 0. Both the normal group and the model group were given equal volumes of 0.5% sodium carboxymethylcellulose solution for intragastric administration, and the other groups were given corresponding drugs for intragastric administration. Except for the normal group, the 3% DSS solution was freely drunk from day 0 of the start of the experiment, and when the mice began to develop significant hematochezia (about 5-6 days), the DSS solution was replaced with pure water, and then recovered for 3 days. The materials are taken for 12 hours before the day, and no water is forbidden during fasted food. The materials are obtained after 2 hours after the stomach is irrigated on the same day.
2.2 Mouse Disease Activity Index (DAI) score
DAI scores were performed on each group of mice based on the weight loss, stool characteristics, and occult blood conditions of the mice. The body weight scoring criteria were as follows: (weight of the previous day-weight of the current day)/weight of the previous day (negative score 0, 1% -5% drop rated as 1 score, 5% -10% drop rated as 2 score, 10% -15% drop rated as 3 score, and percent drop greater than 15% rated as 4 score), stool characteristics (normal 0, rare stool 2 score, watery stool 4 score), and stool bleeding (normal 0 score, occult blood positive 2 score, dominant bleeding 4 score). And taking the average value of the three scores to obtain the disease activity index (Disease activity index, DAI) of the mice.
2.3 Sample collection
On the 9 th day of the experiment, the mice are fasted without water control for 12 hours, on the 10 th day, after the end of the administration, eyes are picked up for blood taking, standing for 2 hours at room temperature, centrifuging at 4 ℃ for 15 minutes at 3000 rpm, collecting the supernatant, and storing in a refrigerator at-80 ℃ for standby. After blood collection, the mice are killed by cervical vertebra removal, the mice are dissected, the whole section of colon is cut, the mesentery is cleaned up, and then the mice are placed on filter paper in order, and the colon length is measured and recorded. Colonic tissue of 1 cm was cut at the same location in each section of colon and fixed in 4% paraformaldehyde solution. The rest colon tissue is rinsed with ice physiological saline and stored in a refrigerator at-80 ℃ for standby.
2.4 Colonography examination
After 24 h fixation with 4% paraformaldehyde, conventional dehydration, embedding, sectioning, staining. The degree of inflammation, crypt damage, depth of inflammation, area of inflammatory infiltrate and depth of lesions of colon tissue were observed under a microscope and scored at random for double blindness according to literature methods.
2.5 detection of MPO content in serum
All reagents, serum samples were removed to room temperature and equilibrated for 30 min. Working solution, standard solution and sample diluent are respectively prepared according to the instruction of the kit, and the determination is carried out. According to the standard curve, the content of the corresponding cytokine in each sample is calculated.
2.6 detection of the content of inflammatory factors IL-1 beta in the colon
The colon tissue preserved by 40 mg is cut, 360 mu LPBS is added, the mixture is fully homogenized by a low-temperature homogenizer, and the mixture is centrifuged at 4 ℃ and 12000 rpm for 15 min, and the supernatant is taken for later use. All reagents were removed to room temperature and equilibrated for 30 min. Working solution, standard solution and sample diluent are respectively prepared according to the instruction of the kit, and the determination is carried out. According to the standard curve, the content of the corresponding cytokine in each sample is calculated.
2.7 Statistical analysis of data
Experimental data were analyzed using SPSS 21.0, expressed as mean ± standard deviation (' X ± SD), using one-way analysis of variance (ANOVA). Data were analyzed for variance alignment, with Homogeneity of Variances, LSD and Tamhane's T2, with variance alignment.
3. Experimental results
3.1 Effect of notopterol on the Disease Activity Index (DAI) of mice
Since day 0 of the experiment, each group of mice was free to drink 3% DSS solution, except for the normal group. Mice develop physical signs of reduced activity, reduced food intake, and weight loss. Beginning on day 5 of the experiment, some mice developed diarrhea, a small amount of macroscopic hematochezia, and most mice developed diarrhea and hematochezia on day 6 of the experiment. On day 6 the 3% DSS solution of each modeling group was replaced with potable water. Model group mice developed the most severe degree of hematochezia and diarrhea by day 6; the mice in the model group have the effect of relieving the hematochezia and diarrhea from the 8 th day to the 10 th day of the experiment.
Table 1 effect of notopterol on DSS-induced UC model mouse DAI (n=8)
Note that: in comparison with the normal group, ## :p<0.01; in comparison with the set of models, * :p<0.05, ** :p<0.01
as can be seen from Table 1, the high and low dosage group of notopterol and the positive medicine sulfasalazine can obviously reduce DAI score of UC model mice from day 6 to day 9 of molding.
3.2 Effects on changes in colon length in mice
Table 2 effect of notopterol on DSS-induced changes in colon length in mice model UC (n=8)
Note that: in comparison with the normal group, ## :p<0.01; in comparison with the set of models, ** :p<0.01
as can be seen from Table 2, the colon length of the model mice is obviously shortened compared with that of the normal mice, and the high-dose group and the low-dose group of the notopterol can obviously improve the colon shortening condition of the mice, wherein the improvement effect of the low-dose group of the notopterol is equivalent to that of the sulfasalazine.
3.3 Effect of notopterol on weight change in mice
Table 3 effect of notopterol on DSS-induced changes in body weight in mice in UC model (n=8)
Note that: in comparison with the normal group, ## :p<0.01; in comparison with the set of models, * :p<0.05, ** :p<0.01
as can be seen from Table 3, the notopterygium alcohol high and low dose groups improved the weight loss of UC mice from day 7, and the low dose groups had significant trends on days 9 and 10.
3.4 Effect of notopterol on colon histopathological changes in mice
From fig. 1 and table 4, the normal group has complete tissue structure, and the intestinal gland is abundant, and no obvious abnormality is seen. The model group had a large number of intestinal glands disappeared, replaced by proliferated connective tissue, with more inflammatory cell infiltration. Compared with a model group, the low-dose group of the notopterygium alcohol can obviously reduce the score of colon pathological tissue slices, the high-dose group of the notopterygium alcohol has a reduced tendency, the slices show that the tissue structure is complete, the intestinal gland number is increased, and the method has an improvement effect on UC colon pathological tissue lesions.
Table 4 effect of notopterol on DSS-induced UC model mice colon histopathological scoring (n=6)
Note that: in comparison with the normal group, ## :p<0.01; in comparison with the set of models, ** :p<0.01, * :p<0.05
3.5 Influence of Notopterygium alcohol on MPO content in mouse serum
Table 5 effect of notopterol on MPO content in mouse serum (n=8)
Note that: in comparison with the normal group, ## :p<0.01; in comparison with the set of models, ** :p<0.01
as can be seen from Table 5, the serum MPO content of the model mice is significantly higher than that of the normal mice, and the high and low dosage groups of notopterol and the positive medicine sulfasalazine can significantly improve the phenomenon.
3.6 Effects on the inflammatory factor content of the colon tissue of mice
As can be seen from Table 6, the inflammatory factor IL-1. Beta. Content in colon tissue of mice in the model group was significantly increased as compared with that of mice in the normal group. The high dosage of notopterol and the positive medicine sulfasalazine can obviously reduce the content of IL-1 beta in colon tissues of mice, and the low dosage of notopterol has a reduction trend on IL-1 beta. The result shows that the notopterygol can obviously reduce the inflammatory response of the colon part of the UC model mouse.
TABLE 6 effect of notopterygol on IL-1 beta content in colon tissue of mice (n=8)
Note that: in comparison with the normal group, # :p<0.05; in comparison with the set of models, * :p<0.05
in conclusion, the notopterygol has remarkable activity of treating inflammatory bowel disease and has good application prospect in preparing the medicines for treating ulcerative colitis.
In the mouse test according to the invention, the doses of notopterol were 50 mg/kg, 25 mg/kg. The doses were 300 mg and 100 mg in terms of human (calculated as adult weight 60 kg). In view of the variety of body weights of humans, and various other pathological conditions, recommended doses are 1-2 times daily, 50-150 mg each time. The most common dose is 2 times daily, 100 mg a time.
Claims (4)
1. The use of notopterol as the main active substance or one of the active substances for the preparation of a medicament for the treatment of ulcerative colitis, characterized in that the notopterol is administered in a dose of from 1 to 2 times per day, each time of from 50 to 150 mg.
2. The use according to claim 1, characterized in that said notopterol is administered in a dose of 100 mg a/d 2 times per day.
3. A pharmaceutical composition for treating ulcerative colitis, comprising notopterygol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
4. The pharmaceutical composition of claim 3, wherein the drug is in the form of a pill, capsule, tablet, powder, granule, injection, compound preparation or other oral dosage forms.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN202310040130.7A CN116785278A (en) | 2023-01-13 | 2023-01-13 | Application of notopterol in preparation of medicines for treating ulcerative colitis |
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