CN117138047A - Application of TLR4 inhibitor in preparation of medicine for relieving gastrointestinal toxicity caused by sorafenib - Google Patents
Application of TLR4 inhibitor in preparation of medicine for relieving gastrointestinal toxicity caused by sorafenib Download PDFInfo
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- CN117138047A CN117138047A CN202311200215.3A CN202311200215A CN117138047A CN 117138047 A CN117138047 A CN 117138047A CN 202311200215 A CN202311200215 A CN 202311200215A CN 117138047 A CN117138047 A CN 117138047A
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Classifications
-
- 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
-
- 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
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of a TLR4 inhibitor in preparation of a drug for relieving gastrointestinal toxicity caused by sorafenib, and relates to the field of biological medicine. The TLR4 inhibitor has a relieving effect on sorafenib-induced gastrointestinal toxicity, can be used for adjusting the weight of mice caused by sorafenib to be slow, relieving the damage of intestinal mucosa of the mice caused by sorafenib and relieving the intestinal oxidative stress caused by sorafenib.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of a TLR4 inhibitor in preparation of a medicine for relieving gastrointestinal toxicity caused by sorafenib.
Background
Sorafenib (Sorafenib) is the earliest molecular targeting drug for liver cancer treatment. A plurality of clinical researches show that sorafenib has good curative effects on advanced liver cancer patients in different national regions and with different liver disease backgrounds. However, sorafenib often accompanies numerous adverse reactions during use, where gastrointestinal toxicity is a very common adverse reaction of sorafenib, mainly manifested as diarrhea, nausea and vomiting, etc., with a incidence of up to 40% or more, and some patients even develop gastrointestinal perforation. These adverse reactions often reduce the quality of life of the patient, and the tolerance to sorafenib is reduced, resulting in reduced clinical medication and even withdrawal, which greatly affects the clinical efficacy.
Therefore, how to alleviate the gastrointestinal side effects caused by sorafenib is a problem that needs to be solved clinically at present.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides application of a TLR4 inhibitor in preparing medicines for relieving gastrointestinal toxicity caused by sorafenib.
Use of a TLR4 inhibitor according to an embodiment of the first aspect of the invention in the manufacture of a medicament for preventing and/or alleviating sorafenib-induced gastrointestinal toxicity.
The application according to the embodiment of the invention has at least the following beneficial effects:
the invention proves that the TLR4 inhibitor has a relieving effect on the gastrointestinal toxicity induced by sorafenib, can regulate the weight of mice caused by sorafenib to be slow, relieve the damage of intestinal mucosa of the mice caused by sorafenib, and relieve the intestinal oxidative stress caused by sorafenib. The application of sorafenib in clinical treatment is widened, evidence and foundation are provided for research and development of medicines for inhibiting sorafenib gastrointestinal toxicity, and the sorafenib has clinical practicability. The invention also expands the indication of TAK-242, and the safety of people is ensured to show the potential application in the future.
According to some embodiments of the invention, the drug may call back to slow weight gain in sorafenib-induced mice.
According to some embodiments of the invention, the medicament may prevent and/or alleviate sorafenib-induced damage to the intestinal mucosa of mice.
According to some embodiments of the invention, the preventing and/or alleviating sorafenib-induced damage to the mouse intestinal mucosa comprises at least one of A1) to A5);
a1 Increasing colon length;
a2 Increasing the small intestine length;
a3 Increasing the villus length of the ileum;
a4 Increasing the ratio of the fluff length to the recess depth;
a5 Improving at least one of ileal villus atrophy, loose structure, and defective symptoms.
According to some embodiments of the invention, the medicament may alleviate oxidative stress in the intestinal tract caused by sorafenib.
According to some embodiments of the invention, the reducing the sorafenib-induced intestinal oxidative stress comprises at least one of B1) to B4);
b1 Reducing intestinal MDA content;
b2 Increasing CAT activity;
b3 Increasing SOD activity;
b4 Improving the total antioxidant capacity.
According to some embodiments of the invention, the TLR4 inhibitor may be a small molecule, a peptide, a protein, an antibody or antigen binding fragment thereof, an antibody mimetic, an aptamer, or a nucleic acid molecule.
According to some embodiments of the invention, the TLR4 inhibitor comprises at least one of TAK-242, E5531, E5564, (+) Naloxone (Naloxone), (-) Naloxone, (+) Naltrexone (Naltrexone), (-) Naltrexone, T5342126, TP6034019, IAANS, auranofin (aurofin), JTT705, curcumin, antrodic acid a, berberine.
According to some embodiments of the invention, the active ingredients of the medicament include TLR4 inhibitors and other ingredients useful for preventing and/or alleviating sorafenib-induced gastrointestinal toxicity. The ingredients preferably do not affect the efficacy of the TLR4 inhibitor. Such ingredients include, but are not limited to loperamide hydrochloride, montmorillonite powder, metoclopramide (metoclopramide), dexamethasone, diphenhydramine, chlorpromazine, ondansetron, or lidamidine.
According to some embodiments of the invention, the medicament further comprises a pharmaceutically acceptable carrier or excipient.
According to some embodiments of the invention, the pharmaceutical is in the form of a granule, hard capsule, soft capsule, tablet, emulsion or suspension.
In the present invention, the subject to be treated with the drug is a mammal, including human, mouse, etc. The person skilled in the art can use the dose of the human body to calculate the unit weight dose of the animal according to the equivalent dose conversion relation between the human body and the experimental animal. The equivalent dose in mice was about 0.75 times that in humans, in terms of unit body weight dose.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a technical route diagram of the relief effect of the TLR4 inhibitors of the present invention on sorafenib-induced gastrointestinal toxicity;
FIG. 2 shows the results of weight change in mice of each treatment group;
FIG. 3 shows the results of colon (A) and small intestine (B) length measurements for each treatment group of mice;
FIG. 4 shows ileal histopathological changes in mice of each treatment group;
FIG. 5 shows the changes in ileal villus length (A), crypt depth (B) and V/C values (C) for each treated group of mice;
FIG. 6 shows the results of the detection of T-AOC (A), CAT (B), SOD activity (C) and MDA content (D) in intestinal tissues of mice of each treatment group.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The apparatus used did not identify the manufacturer and was a conventional product available for commercial purchase.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values for the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
In the embodiment of the invention, C57BL/6J mice are purchased from Vetolihua laboratory animal technology Co., ltd and are bred in SPF-class barrier environment of laboratory animal center of Shenzhen drug inspection institute;
the mouse feed is provided by the experimental animal center of Shenzhen drug inspection institute;
sorafenib was purchased from MedChemExpress (MCE) under the designation HY-10201;
TLR4 inhibitor (TAK-242) was purchased from MedChemExpress (MCE) under the trade designation HY-11109;
sodium carboxymethyl cellulose (CMC) was purchased from Macklin under the trade designation C804625;
dimethyl sulfoxide (DMSO) was purchased from Solarbio under the trade designation D8370;
sterile saline was purchased from Guangzhou cloud source biotechnology limited under the GY-128 designation;
phosphate buffered saline (PBS, phosphate buffer saline) was purchased from the biotechnology company, servicebio, marmor, trade name G4202;
the general tissue fixative was purchased from the biological technology company of Sieve (Servicebio) under the product number G1101;
catalase (CAT) activity assay kit was purchased from Solarbio under the accession number BC0205;
total antioxidant capacity (T-AOC) detection kit was purchased from Solarbio under the accession number BC1315;
malondialdehyde (MDA) content detection kit was purchased from Solarbio under the accession number BC0025;
a superoxide dismutase (SOD) activity detection kit is purchased from Solarbio under the product number BC0175.
Alleviation of sorafenib-induced gastrointestinal toxicity by TLR4 inhibitors
After 30C 57BL/6J mice (20 g±2g, male, five weeks old) were adaptively bred for one week, they were randomly divided into 4 groups, which were respectively a normal Control group (Control, n=7), a Sorafenib group (Sorafenib, n=7), a TLR4 inhibitor group (TAK-242-C, n=8), and a sorafenib+tlr 4 inhibitor combination group (TAK-242-S, n=8); the treatment with dosing was carried out for 21 days and the body weight of the mice was recorded daily. Mice were sacrificed 24h after the last dose, intestinal tissue of mice was collected, and colon length and small intestine length were recorded; simultaneously, cutting off the terminal tissue of the ileum with the length of 1-1.5 cm, washing the terminal tissue with PBS solution pre-cooled in advance at the temperature of 4 ℃, then placing the terminal tissue in general tissue fixing solution for fixing for 24 hours, and delivering the terminal tissue to the Wohan Sieve biotechnology limited company for Hematoxylin-eosin (H & E) staining to perform histopathological analysis (image acquisition by an Aperio GT 450 automatic large-capacity digital pathological slide scanner and histopathological evaluation), randomly selecting 3 samples from each group of samples, and measuring the length of the ileum villus and the depth of the crypt by using Aperio ImageScope pathological slide inspection software; the remaining intestinal tissue was snap frozen in liquid nitrogen and stored in an ultra-low temperature refrigerator for subsequent analysis of biochemical indicators (CAT activity, T-AOC, MDA content, SOD activity) (n=6, 6 samples randomly selected from each group of samples), steps were performed according to the instructions of the corresponding kit.
The experimental technical scheme is shown in fig. 1. The dosing of each group of mice was as follows:
normal Control group (Control): oral gastric lavage cosolvent 0.5% sodium carboxymethylcellulose solution with dosage of 0.1mL/kg once daily;
sorafenib group (Sorafenib): oral gavage of the suspension solution of the sorafenib at a dose of 120mg/kg, the dosage of the suspension solution of the sorafenib is 0.1mL/kg, and the suspension solution is used once a day;
TLR4 inhibitor group (TAK-242-C): TAK-242 solution is injected intraperitoneally at a dose of 3mg/kg, the dosage is 0.1mL/kg, once every 2 days;
sorafenib+tlr 4 inhibitor combination (TAK-242-S): oral gavage of the suspension solution of the sorafenib at a dose of 120mg/kg, the dosage of the suspension solution of the sorafenib is 0.1mL/kg, and the suspension solution is used once a day; TAK-242 solution was injected intraperitoneally at a dose of 3mg/kg, in an amount of 0.1mL/kg, once every 2 days.
The preparation method of the sorafenib suspension solution comprises the following steps: accurately weighing 0.5g of sodium carboxymethylcellulose, and taking 100mL of distilled water into a glass beaker; placing the beaker on a heating magnetic stirrer, scattering the weighed sodium carboxymethylcellulose (CMC) on the water surface for a plurality of times in a small amount, and stirring while adding until the solution is clear and transparent to obtain 0.5% sodium carboxymethylcellulose solution (for preparation at present); and adding sorafenib into 0.5% sodium carboxymethyl cellulose solution for ultrasonic dissolution to obtain sorafenib suspension solution.
The preparation method of the TAK-242 solution comprises the following steps: TAK-242 was dissolved in DMSO and then diluted in sterile saline to a final DMSO concentration of 1% (as-is).
Statistical analysis was performed using GraphPad Prism 8. All values are expressed as Mean ± standard deviation (Mean ± SEM), unless otherwise indicated. Differences between groups were analyzed using One-way ANOVA (One-way ANOVA) or Two-way ANOVA (Two-way ANOVA). In all cases, p <0.05 is considered statistically significant, where x represents a significant difference (p < 0.05), x represents a significant difference (p < 0.01), and x represents a significant difference (p < 0.001).
The results are shown in fig. 2 to 6.
During the experiment, the body weight of the normal control group mice keeps steadily increasing. The sorafenib mice showed a significant decrease in body weight in the early experimental period, and the latter experimental period began to recover slowly, but still showed a tendency to gain slowly after dosing, compared to the normal control group. Whereas mice with sorafenib were able to return to a slow weight gain after TAK-242. As shown in fig. 2.
The length of each segment of the intestine is one of the important parameters for assessing intestinal inflammation. The colon and small intestine lengths of sorafenib mice were significantly shorter than those of the normal control group, while the combination of TAK-242 reversed the reduction in colon and small intestine lengths of sorafenib mice. As shown in fig. 3.
The ileum villus and crypt of the normal control group mice are arranged regularly and in complete form, and the ileum villus of the sorafenib group mice is atrophic, loose in structure and even has symptoms such as defect. And after TAK-242 is combined, ileum villus is atrophic, the structure is loose, and even defects and other symptoms are light. As shown in fig. 4.
Villus length (Villi length), crypt depth (Crypt depth), and the ratio of villus length to Crypt depth (V/C) are common indicators for assessing intestinal morphology and structure, which can be used to characterize the health of the intestinal tract; shortening of villi and deeper crypts reduce nutrient absorption at the surface area of the intestinal tract, and a decrease in the V/C ratio indicates a damaged mucosa and a decrease in digestion and absorption capacity. Compared with the normal control group, the sorafenib group mice have obviously reduced villus length of ileum, little change of crypt depth and obviously reduced V/C value; the villi length of the ileum was significantly increased and the V/C values were significantly increased in the mice of the sorafenib + TLR4 inhibitor combination group compared to the sorafenib group. As shown in fig. 5.
MDA levels and antioxidant enzyme activity can be used to assess the oxidative stress status of intestinal tissue. Compared with the normal control group, the total antioxidant capacity of the intestinal tissues of the sorafenib group mice is reduced, CAT activity and SOD activity are obviously reduced, and MDA content is increased (indicating that the organism is in a lipid peroxidation state); while the combination of TAK-242 can significantly alleviate the decrease of CAT activity and SOD activity of intestinal tissues and the increase of MDA content caused by sorafenib.
In conclusion, TAK-242 can be used for adjusting the weight gain of mice caused by sorafenib slowly, relieving the damage of intestinal mucosa of the mice caused by sorafenib and relieving the oxidative stress of intestinal tracts caused by sorafenib.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present invention.
Claims (10)
- Use of a tlr4 inhibitor for the preparation of a medicament for preventing and/or alleviating gastrointestinal toxicity caused by sorafenib.
- 2. The use according to claim 1, wherein the medicament is capable of recalling that weight gain in sorafenib-induced mice is slow.
- 3. The use according to claim 1, wherein the medicament is for preventing and/or alleviating sorafenib-induced damage to the intestinal mucosa of mice.
- 4. The use according to claim 3, wherein said preventing and/or alleviating sorafenib-induced damage to the intestinal mucosa of a mouse comprises at least one of A1) to A5);a1 Increasing colon length;a2 Increasing the small intestine length;a3 Increasing the villus length of the ileum;a4 Increasing the ratio of the fluff length to the recess depth;a5 Improving at least one of ileal villus atrophy, loose structure, and defective symptoms.
- 5. The use according to claim 1, wherein the medicament is for alleviating oxidative stress in the intestine caused by sorafenib.
- 6. The use according to claim 5, wherein said alleviation of sorafenib-induced intestinal oxidative stress comprises at least one of B1) to B4);b1 Reducing intestinal MDA content;b2 Increasing CAT activity;b3 Increasing SOD activity;b4 Improving the total antioxidant capacity.
- 7. The use according to claim 1, wherein the TLR4 inhibitor comprises at least one of TAK-242, E5531, E5564, (+) naloxone, (-) naloxone, (+) naltrexone, (-) naltrexone, T5342126, TP6034019, IAANS, auranofin, JTT705, curcumin, antrodia camphorate, berberine.
- 8. The use according to claim 1, wherein the active ingredients of the medicament comprise TLR4 inhibitors and other ingredients useful for preventing and/or alleviating sorafenib-induced gastrointestinal toxicity.
- 9. The use according to claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier or excipient.
- 10. The use according to claim 1, wherein the medicament is in the form of granules, hard capsules, soft capsules, tablets, emulsions or suspensions.
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