Application of D-glucaric acid-1, 4-lactone in preparation of medicine for relieving intestinal injury caused by sorafenib

Abstract

The invention belongs to the technical field of medicines, discloses application of D-glucaric acid-1, 4-lactone in preparation of a medicine for relieving intestinal injury caused by sorafenib, and particularly discloses application of D-glucaric acid-1, 4-lactone or pharmaceutically acceptable salt thereof in preparation of a medicine for treating and / or preventing intestinal injury. The invention discloses the application potential of the D-glucaric acid-1, 4-lactone in preparation of medicines for relieving the intestinal injury (especially the intestinal injury caused by molecular targeting medicine sorafenib) for the first time. In the treatment process of sorafenib, patients often need to pause or stop medication due to adverse reactions of gastrointestinal tracts, and the treatment effect of sorafenib is remarkably restricted. Experiments prove that the D-glucaric acid-1, 4-lactone can effectively relieve intestinal injury caused by sorafenib, can relieve mouse intestinal mucosa injury caused by sorafenib, and can relieve intestinal oxidative stress and inflammatory response caused by sorafenib.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to application of D-glucaroyl-1,4-lactone in preparing a drug for alleviating intestinal damage caused by sorafenib. Background Art

[0002] Sorafenib, an oral multi-tyrosine kinase inhibitor, has been approved in more than 80 countries and is mainly used as a first-line treatment for advanced renal cell carcinoma and / or hepatocellular carcinoma. However, sorafenib often causes adverse gastrointestinal reactions, such as diarrhea and vomiting, with an incidence rate of over 40%, and even intestinal perforation in a small number of patients, which seriously affects the quality of life and tolerance, leading to reduction or discontinuation of medication and reduced efficacy. Therefore, reducing its gastrointestinal side effects has become a clinical problem that needs to be urgently solved.

[0003] Sorafenib can be glucuronidated by UDP-glucuronosyltransferase 1A9 (UGT1A9) in the liver, and its pharmacokinetic characteristics have significant individual differences. After oral administration of sorafenib, absorption is slow and delayed, and some patients have obvious secondary peaks, indicating the presence of enterohepatic circulation characteristics, and enterohepatic circulation will increase the exposure of sorafenib in the human body by more than 50%, resulting in a large accumulation of sorafenib in the intestine and causing intestinal damage. At present, there is still a lack of effective intervention measures for intestinal damage caused by sorafenib in clinical practice.

[0004] D-saccharic acid 1,4-lactone (DSL) is a derivative of D-glucuronic acid with a molecular formula of C6H 10 O8, CAS number 61278-30-6, is widely found in many dietary plants such as cruciferous vegetables, citrus fruits, apples, etc. Among the derivatives of D-glucuronic acid, DSL is the most pharmacologically active lactone, with biological activities such as detoxification and anti-cancer. At present, there is no report on whether DSL plays a protective role in intestinal damage caused by sorafenib. Summary of the invention

[0005] The purpose of the first aspect of the present invention is to provide the use of D-glucaroyl-1,4-lactone or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing intestinal damage.

[0006] The second aspect of the present invention aims to provide a medicine.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention provides the use of D-glucaroyl-1,4-lactone or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing intestinal damage.

[0009] In some embodiments of the present invention, the intestinal injury includes intestinal injury induced by sorafenib.

[0010] In some embodiments of the present invention, the intestinal injury includes colon, small intestine and / or ileum injury.

[0011] In some embodiments of the present invention, the drug can treat and / or prevent intestinal mucosal damage caused by sorafenib.

[0012] In some embodiments of the present invention, the treatment and / or prevention of intestinal mucosal damage caused by sorafenib includes at least one of A1) to A5);

[0013] A1) Increase colon length;

[0014] A2) Increase the length of the small intestine;

[0015] A3) Increase the length of villi in the ileum;

[0016] A4) Increase the ratio of villus length to crypt depth in the ileum;

[0017] A4) Improve ileal villi atrophy, loose structure and / or defects.

[0018] In some embodiments of the present invention, the drug can reduce intestinal oxidative stress caused by sorafenib.

[0019] In some embodiments of the present invention, the reducing intestinal oxidative stress caused by sorafenib comprises at least one of B1) to B3);

[0020] B1) Reduce the level of malondialdehyde in the intestine;

[0021] B2) Increased catalase activity;

[0022] B3) Increase superoxide dismutase activity.

[0023] In some embodiments of the present invention, the drug can reduce the inflammatory response caused by sorafenib.

[0024] In some embodiments of the present invention, the reducing the inflammatory response caused by sorafenib comprises reducing the expression levels of inflammatory factors TNF-α and IL-6.

[0025] In some embodiments of the present invention, the pharmaceutically acceptable salt includes at least one of a metal salt, an ammonium salt, a salt formed with an inorganic acid, a salt formed with an organic base, a salt formed with an organic acid, a salt formed with a basic amino acid, and a salt formed with an acidic amino acid.

[0026] In some embodiments of the present invention, the metal salt includes an alkali metal salt or an alkaline earth metal salt.

[0027] In some embodiments of the present invention, the alkali metal salt includes at least one of a sodium salt and a potassium salt.

[0028] In some embodiments of the present invention, the alkaline earth metal salt includes at least one of calcium salt, magnesium salt, barium salt and aluminum salt.

[0029] In some embodiments of the present invention, the salt formed with the organic base includes a salt formed with the following organic bases: at least one of trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine.

[0030] In some embodiments of the present invention, the salt formed with an inorganic acid includes a salt formed with the following inorganic acids: at least one of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.

[0031] In some embodiments of the present invention, the salt formed with the organic acid includes a salt formed with the following organic acids: at least one of 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, and p-toluenesulfonic acid.

[0032] In some embodiments of the present invention, the salt formed with a basic amino acid includes a salt formed with the following basic amino acids: at least one of arginine, lysine, and ornithine.

[0033] In some embodiments of the present invention, the salt formed with the acidic amino acid includes a salt formed with the following acidic amino acids: at least one of aspartic acid and glutamic acid.

[0034] In some embodiments of the present invention, the drug further comprises a pharmaceutically acceptable excipient, and / or any one or more other active ingredients capable of treating or preventing sorafenib-induced gastrointestinal damage.

[0035] In some embodiments of the present invention, the pharmaceutically acceptable excipients include at least one of solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, and carriers.

[0036] In some embodiments of the present invention, the effective dose of D-glucaroside-1,4-lactone or a pharmaceutically acceptable salt thereof in the drug is 100 to 300 mg / kg body weight; further 150 to 200 mg / kg body weight.

[0037] The second aspect of the present invention provides a drug comprising D-glucaroyl-1,4-lactone or a pharmaceutically acceptable salt thereof and sorafenib.

[0038] In some embodiments of the present invention, the drug further comprises a pharmaceutically acceptable excipient.

[0039] In some embodiments of the present invention, the pharmaceutically acceptable excipients include at least one of solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, and carriers.

[0040] In some embodiments of the present invention, in order to facilitate medication, the active ingredient D-glucaric acid-1,4-lactone or its pharmaceutically acceptable salt can be processed into a specific dosage form with any one or more pharmaceutically acceptable excipients. These excipients can be diluents (such as starch, pregelatinized starch, dextrin, sucrose, lactose, mannitol and microcrystalline cellulose, etc.), absorbents (such as calcium sulfate, calcium hydrogen phosphate, light magnesium oxide and calcium carbonate, etc.), wetting agents (such as water and ethanol, etc.), binders (such as hydroxypropyl methylcellulose, povidone, starch slurry and syrup, etc.), disintegrants (such as dry starch, sodium hydroxymethyl starch, low-substituted hydroxypropyl cellulose, effervescent disintegrants and cross-linked polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol and micropowder silica gel, etc.), colorants (such as titanium dioxide, sunset yellow, methylene blue and medicinal iron oxide, etc.), coating materials (such as acrylic resin, hydroxypropyl methylcellulose and povidone, etc.), solvents (such as water for injection, ethanol, propylene glycol and glycerol, etc.), acid-base regulators (such as hydrochloric acid, lactic acid, sodium hydroxide, tartaric acid and sodium tartrate, etc.), antioxidants (such as sodium sulfite, sodium pyrosulfite and sodium thiosulfate, etc.), antibacterial agents (such as phenol, benzyl alcohol and thimerosal, etc.), and isotonic regulators (such as sodium chloride and glucose, etc.).

[0041] In some embodiments of the present invention, the dosage form of the drug includes a dosage form for gastrointestinal administration.

[0042] In some embodiments of the present invention, the dosage form for administration via the gastrointestinal tract includes at least one of powders, tablets, granules, capsules, sustained-release agents, solutions, dry suspensions, effervescent tablets, emulsions, suspensions, syrups, drops, and chewable tablets.

[0043] In some embodiments of the present invention, the dosage forms for administration through the gastrointestinal tract include but are not limited to enteric-coated tablets, coated tablets, film-coated tablets, sugar-coated tablets, dispersible tablets, sucking tablets, chewable tablets, effervescent tablets, scratched tablets, sustained-release and controlled-release dosage forms such as sustained-release tablets, sustained-release coated tablets, controlled-release tablets, orally disintegrating tablets, lozenges, etc.

[0044] In some embodiments of the present invention, the subject of the drug treatment is a mammal, including humans, mice, etc. Those skilled in the art can convert the human dose into the animal's unit body weight dose based on the equivalent dose conversion relationship between humans and experimental animals, and vice versa.

[0045] In some embodiments of the present invention, the drug may also include other ingredients that can be used to prevent and / or treat intestinal damage caused by sorafenib. The ingredients should preferably not affect the effect of D-glucaric acid-1,4-lactone. The ingredients include but are not limited to loperamide hydrochloride, montmorillonite powder, metoclopramide (metoclopramide), dexamethasone, diphenhydramine, chlorpromazine, ondansetron or lidamidine, etc.

[0046] The beneficial effects of the present invention are:

[0047] The present invention reveals for the first time the application potential of DSL in the preparation of drugs that alleviate intestinal damage (especially intestinal damage caused by the molecular targeted drug sorafenib). During the treatment with sorafenib, patients often need to suspend or terminate medication due to adverse gastrointestinal reactions, which significantly restricts its therapeutic effect. The present invention confirms through experiments that DSL can effectively alleviate intestinal damage caused by sorafenib, can alleviate intestinal mucosal damage caused by sorafenib in mice, and alleviate intestinal oxidative stress and inflammatory response caused by sorafenib. This discovery not only broadens the clinical application scope of sorafenib, but also provides a scientific basis and practical foundation for the development of drugs to alleviate the gastrointestinal toxicity of sorafenib, showing good clinical application value. In addition, the present invention further expands the scope of indications of DSL, and its verified safety indicates that it has broad application prospects in the future. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Schematic diagram of the experimental process in Example 1.

[0049] Figure 2 The average colon length (A) and the average small intestine length (B) of mice in each group, n=8.

[0050] Figure 3 Representative images of H&E staining of ileum tissues of mice in each group (scale bar = 200 μm).

[0051] Figure 4 The average intestinal villus length (A), average intestinal crypt depth (B) and average villus length / crypt depth ratio (C) of mice in each group, n=5.

[0052] Figure 5 are inflammatory factors in mouse serum; wherein, A is the expression level of inflammatory factor IL-6 in mouse serum, B is the expression level of inflammatory factor TNF-α in mouse serum, n=5.

[0053] Figure 6 are indicators related to oxidative stress in mouse intestinal tissue; wherein, A is the result of catalase (CAT) activity detection, B is the result of superoxide dismutase (SOD) activity detection, C is the malondialdehyde (MDA) content, and n=6. DETAILED DESCRIPTION

[0054] The present invention is further described in detail below through specific examples.

[0055] It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0056] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0057] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0058] Example

[0059] 1. Experimental Materials

[0060] C57BL / 6J mice were purchased from Weitong Lihua Company and raised in the SPF barrier environment of Shenzhen Institute for Drug Control.

[0061] Sorafenib: purchased from MedChemExpress (MCE), product number HY-10201.

[0062] D-Glucarboxylic acid-1,4-lactone: purchased from Shanghai Yuanye Biotechnology Co., Ltd., product number S49005.

[0063] Catalase (CAT) activity, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity detection kits were purchased from Solarbio with catalog numbers BC0205, BC0025, and BC0175, respectively.

[0064] Mouse interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) ELISA kits: purchased from Jiangsu Jingmei Biotechnology Co., Ltd., with catalog numbers JM-02446M1 and JM-02415M1, respectively.

[0065] 2. Experimental Methods

[0066] 1) Solution preparation

[0067] Preparation of Sorafenib suspension solution: Accurately weigh 250 mg of sodium carboxymethylcellulose (CMC), then take 50 mL of distilled water and place it in a glass beaker, and place the beaker on a heated magnetic stirring device. Next, gradually and in small amounts, sprinkle the weighed CMC evenly on the water surface, while continuously stirring until the solution becomes clear and transparent, thereby preparing a CMC solution with a concentration of 0.5%, which is used as a cosolvent, and this solution should be ready for use. Afterwards, sorafenib is added to this cosolvent, and its dissolution is promoted by ultrasonic treatment to form a sorafenib suspension solution. The dosage of the suspension solution is 120 mg / kg body weight.

[0068] Preparation of D-glucarboxylic acid-1,4-lactone solution: Weigh an appropriate amount of D-glucarboxylic acid-1,4-lactone and dissolve it in double distilled water. Prepare and use it immediately. The dose of D-glucarboxylic acid-1,4-lactone solution is 200 mg / kg body weight.

[0069] 2) Animal experiments

[0070] Grouping: Thirty-two five-week-old male C57BL / 6J mice (20 g ± 2 g) were adaptively fed for one week and then randomly divided into four groups (n = 8 mice in each group), namely, normal control group (Control), sorafenib group (Sorafenib), D-glucaric acid-1,4-lactone group (DSL-C), and sorafenib + D-glucaric acid-1,4-lactone combination group (DSL-S).

[0071] Processing process: The technical roadmap of the entire experiment is as follows Figure 1 As shown. The mice in the control group and DSL group were orally gavaged with 0.5% sodium carboxymethyl cellulose solution as a solubilizing agent at a dosage of 10 mL / kg once a day. The mice in the Sorafenib group and DSL-S group were orally gavaged with sorafenib suspension at a dose of 120 mg / kg at a dosage of 10 mL / kg once a day. In addition, the mice in the DSL-C group and DSL-S group were orally gavaged with DSL solution at a dose of 200 mg / kg at a dosage of 10 mL / kg once a day. The entire experimental process lasted for 21 days. The mice were killed 24 hours after the last administration, and the intestinal tissues of the mice were collected and the colon length and small intestine length were recorded. At the same time, 1 to 1.5 cm long terminal ileum tissue samples were cut, rinsed with 4°C pre-cooled PBS solution, and fixed in tissue fixative for 24 hours for histopathological analysis. The remaining intestinal tissue was quickly frozen in liquid nitrogen and then transferred to an ultra-low temperature refrigerator for storage for subsequent biochemical index detection.

[0072] 3) Pathological testing

[0073] Hematoxylin-eosin staining (H&E) staining: Mouse intestinal tissue fixed in tissue fluid was sent to Wuhan Saiweier Biotechnology Co., Ltd. for H&E staining experiments according to conventional methods. The conventional experimental process is dehydration, paraffin embedding, sectioning, dewaxing, hematoxylin staining, eosin staining, and dehydration and sealing. Finally, the slices were imaged and histopathologically evaluated using the Aperio GT 450 automatic large-capacity digital pathology slide scanner. The length of ileal villi and the depth of the crypts were measured using the Aperio ImageScope pathology slide viewing software.

[0074] Biochemical detection: After the mouse blood samples collected at the end of the experiment were allowed to stand for 30 minutes, they were centrifuged at 4000 rpm and 4°C for 20 minutes to obtain serum. Serum IL-6 and TNF-α were quantified according to the instructions of the kit. The concentrations of IL-6 and TNF-α were measured by using a multifunctional microplate reader at a wavelength of 450 nm and calculated using ELISA Calc software. In addition, an appropriate amount of intestinal tissue samples were cut and weighed. According to the instructions of the kit, the extract in the kit was used to grind the intestinal tissue mass (g): extract volume (mL) at a ratio of 1:10 to prepare tissue homogenate, and then centrifuged at 10000 rpm and 4°C for 10 minutes. The supernatant was placed on ice to test oxidative stress-related indicators, including catalase (CAT) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content.

[0075] Data processing: Statistical analysis was performed using GraphPad Prism 8. Unless otherwise stated, all values ​​are expressed as mean ± SEM. One-way ANOVA was used to analyze the differences between groups. In all cases, p < 0.05 was considered statistically significant (ns), where * represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, and **** represents p < 0.0001.

[0076] 3. Experimental results

[0077] 1) DSL can alleviate sorafenib-induced intestinal mucosal damage in mice

[0078] The length of each intestinal segment is a key indicator of the degree of intestinal inflammation. Figure 2 As shown in the figure, the length of the colon and small intestine of mice treated with sorafenib was significantly shortened compared with the normal control group. However, when sorafenib was used in combination with D-glucaroside-1,4-lactone, this shortening of the colon and small intestine length caused by sorafenib in mice was reversed. Figure 3 The pathological changes in the ileum tissue of each group of mice were shown. In the normal control group, the villi and crypts of the mouse ileum were arranged neatly, and the morphology remained intact. In contrast, the ileum of the mice in the sorafenib group showed pathological characteristics such as villous atrophy, loose structure, and even defects. However, in the group where sorafenib was used in combination with DSL, these pathological symptoms were relatively mild. Villus length, crypt depth and their ratio (V / C) are key parameters for measuring the morphological structure of the intestine, which can reflect the health of the intestine. Specifically, a shortening of the villus length and an increase in the crypt depth will lead to a decrease in the intestinal surface area, thereby affecting the absorption of nutrients. A decrease in the V / C ratio means that the mucosa is damaged, thereby reducing the digestion and absorption capacity. Figure 4As shown in the figure, when comparing the normal control group mice with the sorafenib group mice, it can be found that the intestinal villus length of the sorafenib group mice was significantly reduced, while the crypt depth did not change significantly, and the V / C ratio was also significantly reduced. However, when sorafenib was used in combination with DSL, the intestinal villus length of the mice increased significantly compared with the group using only sorafenib, and the V / C ratio also increased. These results strongly prove that DSL can effectively alleviate the intestinal mucosal damage of mice caused by sorafenib.

[0079] 2) DSL can reduce the inflammatory response of mice induced by sorafenib

[0080] IL-6 and TNF-α are key inflammatory factors that play a core role in inflammatory responses. TNF-α can activate immune cells, increase vascular permeability, and promote the release of other cytokines. IL-6 participates in immune responses and promotes the activation and proliferation of B cells and T cells. TNF-α and IL-6 play an important role in both immune regulation and inflammatory responses. Their abnormal expression and effects are closely related to the development of many diseases. Figure 5 As shown, the results of inflammatory factor detection showed that sorafenib caused a significant increase in the levels of TNF-α and IL-6 in the serum of mice, while DSL intervention significantly alleviated the sorafenib-induced inflammatory response.

[0081] 3) DSL can alleviate sorafenib-induced intestinal oxidative stress in mice

[0082] Under normal physiological conditions, the production and elimination of free radicals in the intestine are in a dynamic equilibrium. Excessive free radicals can easily attack intestinal cells and cause intestinal oxidative stress. In addition, excessive reactive oxygen species (ROS) and reactive nitrogen species (RNS) and changes in the antioxidant system may lead to oxidative stress. These mechanisms lead to the occurrence and development of diarrhea, intestinal mucosal infections, ulcerative colitis, Crohn's disease, and colon cancer. The human gastrointestinal organs mainly exert their antioxidant effects through antioxidant enzymes, scavenging free radicals, preventing oxidative damage, and preventing the occurrence and development of diseases. Therefore, the oxidative stress state is evaluated by detecting the level of oxidative stress products in intestinal tissue and the activity of antioxidant enzymes. Oxidative stress-related indicators in mouse intestinal tissue can be seen. Figure 6 Compared with the normal control group, the activities of catalase (CAT) and superoxide dismutase (SOD) in the intestinal tissue of mice treated with sorafenib were significantly decreased. However, DSL pretreatment can effectively alleviate the decrease in the activities of these two enzymes caused by sorafenib. Malondialdehyde (MDA) is the final product of lipid peroxidation, and its increased level means that the body is in a state of lipid peroxidation. Figure 6 As shown in the results, DSL could also significantly alleviate the increase of MDA level in intestinal tissue induced by sorafenib.

[0083] The embodiments of the present invention are described in detail above in conjunction with the accompanying drawings, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. Use of D-glucaroyl-1,4-lactone or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing intestinal damage.

2. The use according to claim 1, characterized in that: The intestinal damage includes intestinal damage induced by sorafenib.

3. The use according to claim 2, characterized in that: The intestinal injury includes damage to the colon, small intestine and / or ileum.

4. The use according to claim 1, characterized in that: The drug can treat and / or prevent intestinal mucosal damage caused by sorafenib.

5. The use according to claim 4, characterized in that: The treatment and / or prevention of intestinal mucosal damage caused by sorafenib includes at least one of A1) to A5); A1) Increase colon length; A2) Increase the length of the small intestine; A3) Increase the length of villi in the ileum; A4) Increase the ratio of villus length to crypt depth in the ileum; A5) Improve ileal villous atrophy, loose structure and / or defects.

6. The use according to any one of claims 2 to 5, characterized in that: The drug can reduce intestinal oxidative stress caused by sorafenib; and / or, the drug can reduce the inflammatory response caused by sorafenib.

7. The use according to claim 6, characterized in that: The method for reducing intestinal oxidative stress caused by sorafenib includes at least one of B1) to B3); B1) Reduce the level of malondialdehyde in the intestine; B2) Increased catalase activity; B3) Increase superoxide dismutase activity.

8. The use according to any one of claims 1 to 5, characterized in that: The pharmaceutically acceptable salt includes at least one of a metal salt, an ammonium salt, a salt formed with an inorganic acid, a salt formed with an organic base, a salt formed with an organic acid, a salt formed with a basic amino acid, and a salt formed with an acidic amino acid.

9. A medicament comprising D-glucaroyl-1,4-lactone or a pharmaceutically acceptable salt thereof and sorafenib.

10. The drug according to claim 9, characterized in that The drug also includes pharmaceutically acceptable excipients.

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