Application of liver injury attenuating agent in preparation of medicine for preventing and / or treating drug-induced liver injury
By combining liver injury attenuators with antipsychotic drugs, the problem of drug-derived liver injury caused by AAPD treatment was solved, effective prevention and treatment of drug-derived liver injury was achieved, drug compliance was improved and disease recurrence was reduced.
Patent Information
- Application Number
- CN202510195824.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-21
- Publication Date
- 2025-05-27
AI Technical Summary
Existing antipsychotic drugs (AAPD) treatments are prone to drug-derived liver damage, especially when long-term use of olanzapine, patients often experience adverse reactions such as liver damage and lipid metabolism disorders, resulting in reduced drug compliance and recurrence of the disease.
A liver injury attenuator, free compounds with the structure of Formula 1 and their pharmaceutically acceptable salts, amides, and crystals are used to prepare a compound drug active ingredient that can prevent and treat drug-derived liver injury.
This liver injury attenuator can effectively alleviate drug-derived liver injury, adapt to the characteristics of antipsychotic liver injury pathways, significantly reduce liver damage caused by long-term administration, improve drug compliance, and reduce the risk of disease recurrence.
Smart Images
Figure CN120037241A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of drugs, and particularly relates to the field of drugs for drug-induced liver injury. Background Art
[0002] As the center of in-vivo drug metabolism, the liver is extremely vulnerable to drugs that cause liver damage, especially drugs that need to be used for a long time to control symptoms. Such adverse reactions are called drug-induced liver injury (DILI).
[0003] For example, the second-generation antipsychotics (atypical antipsychotic drugs, AAPD) used to treat schizophrenia are currently the main treatment methods for various mental disorders including schizophrenia and cannot be replaced. However, the adverse reactions caused by AAPD treatment need to receive great attention just like its unique therapeutic effects. The most common ones are abnormal liver metabolism and liver damage-related adverse reactions. Approximately 30% of the patients treated with AAPD have metabolic syndrome (MetS), and usually have elevated liver function indicators related to transaminases. Olanzapine is the most obvious. After using olanzapine, adverse reactions that affect medication compliance such as weight gain, liver function damage, and liver lipid metabolism disorder are likely to occur, and patients often stop taking the drug and the disease relapses.
[0004] Regarding the liver injury problem caused by AAPD treatment, the clinical measures mainly include stopping the drug, replacing it with a drug that has less impact on liver function such as aripiprazole, or combining it with liver-protecting drugs and lipid-lowering and hypoglycemic drugs to reduce its adverse reactions on the liver. However, for patients who have been using the same antipsychotic drug such as olanzapine for a long time, olanzapine has a good therapeutic effect on controlling the symptoms of specific individual patients, and the symptoms of the patients may relapse after stopping the drug or changing the drug. In addition, combining other drugs that improve glucose and lipid load such as metformin is likely to introduce new adverse reactions such as gastrointestinal adverse reactions.
[0005] Therefore, how to significantly reduce the liver injury caused by long-term administration of AAPD while avoiding stopping or changing the AAPD is a problem that needs to be properly solved clinically. Summary of the Invention
[0006] Aiming at the problem that the existing AAPD treatment is prone to drug-induced liver injury, the present invention provides an application of a liver injury attenuator in the preparation of drugs for preventing and / or treating drug-induced liver injury, aiming to effectively prevent and / or treat the liver injury caused by AAPD treatment.
[0007] The second object of the present invention is to provide a composite AAPD drug active ingredient and a pharmaceutical preparation that can prevent liver injury.
[0008] Use of a liver injury attenuator in the preparation of a medicament for preventing and / or treating drug-induced liver injury, wherein the liver injury attenuator is at least one of a free compound having the structure of Formula 1, its pharmaceutically acceptable salts, amides, and crystals;
[0009]
[0010] Studies in the present invention have shown that the component of Formula 1 can effectively alleviate drug-induced liver injury and can be used for the prevention and treatment of liver injury indications caused by drug treatment.
[0011] In the present invention, the drug-induced liver injury refers to liver injury caused by the administration of antipsychotic drugs. Studies in the present invention have shown that Formula 1 can efficiently adapt to the characteristics of the liver injury pathway caused by antipsychotic drug treatment and can be used for attenuating the liver injury caused by antipsychotic drugs, effectively preventing and treating liver injury indications caused by antipsychotic drug treatment.
[0012] In the present invention, the antipsychotic drugs include olanzapine.
[0013] For the application described in the present invention, the Formula 1 and pharmaceutically acceptable excipients are combined to prepare a pharmaceutically acceptable dosage form for preventing and / or treating drug-induced liver injury.
[0014] The present invention also provides a drug active ingredient for compound antipsychotics that can prevent liver injury, which contains the liver injury attenuator of Formula 1 and also contains an antipsychotic drug.
[0015] Studies in the present invention have shown that the compound of Formula 1 can adapt to the characteristics of liver injury caused by antipsychotic drugs. When combined with antipsychotic drugs, it can effectively prevent and alleviate the liver injury caused by their treatment while achieving good antipsychotic treatment.
[0016] For the drug active ingredient described in the present invention, the antipsychotic drugs include olanzapine.
[0017] For the drug active ingredient described in the present invention, the liver injury attenuator and the antipsychotic drug exist in the form of a mixture or exist independently of each other before administration.
[0018] The present invention also provides a compound antipsychotic drug that can prevent liver injury, which contains a pharmaceutically effective amount of the above-mentioned drug active ingredient.
[0019] The antipsychotic drug that can prevent liver injury described in the present invention further contains pharmaceutically acceptable excipients.
[0020] The antipsychotic drug that can prevent liver injury described in the present invention has a pharmaceutically acceptable dosage form.
[0021] Beneficial effects
[0022] The research of the present invention shows that the component of formula 1 can effectively alleviate drug-induced liver injury, especially can adapt to the characteristics of the liver injury pathway of antipsychotic drugs, and can be used for the prevention and treatment of liver injury indications caused by drug treatment. Brief Description of the Drawings
[0023] Figure 1 : Results of Oil Red O staining and HE staining of the model group and the control group; A. HE staining map of liver sections in the high-fat group; B. HE staining map of liver sections in the high-fat + olanzapine group; C. Oil Red O staining map of the high-fat group; D. Oil Red O staining map of the high-fat + olanzapine group;
[0024] Figure 2 : Comparison of serum biochemical results between the model group and the control group; ALT, alanine aminotransferase, AST, aspartate aminotransferase, TBIL, total bilirubin, ALP, serum alkaline phosphatase, TG, triglyceride, CHOL, cholesterol;
[0025] Figure 3 : Comparison of liver tissue and serum free fatty acid levels between the model group and the control group
[0026] Figure 4 : Expression of genes related to lipid metabolism and inflammatory factors in the model group and the control group; Fasn, fatty acid synthase, FAT, fatty acid translocase, FATP, fatty acid transport protein, CCL2, chemokine 2, ACC1, acetyl-CoA carboxylase 1;
[0027] Figure 5 : Oil Red O staining map of liver sections after intervention with "Formula One" and Comparative Formula A; A, model group; B, model group plus low-dose "Formula One"; C, model group plus high-dose "Formula One"; D, model group plus Comparative Formula A;
[0028] Figure 6 : HE staining map of liver sections after intervention with "Formula One" and Comparative Formula A; A, model group; B, model group plus low-dose "Formula One"; C, model group plus high-dose "Formula One"; D, model group plus Comparative Formula A;
[0029] Figure 7 : Serum biochemical levels of different-dose "Formula One" groups and Comparative Formula A group; ALT, alanine aminotransferase, AST, aspartate aminotransferase, TBIL, total bilirubin, ALP, serum alkaline phosphatase, TG, triglyceride, CHOL, cholesterol;
[0030] Figure 8 : Distribution of liver and serum free fatty acids in different-dose "Formula One" groups Detailed Embodiments
[0031] 1. Model establishment
[0032] Establishment of a Drug-induced Liver Injury Model in Rats by Olanzapine Combined with a High-fat Diet
[0033] Main reagents and consumables: Olanzapine (C10595950, Macklin, China; also known as OLZ)
[0034] Free Fatty Acid Assay Kit (AKFA008M, boxbio, China)
[0035] Experimental animal feed: High-fat diet (D12492, Research Diets, USA)
[0036] Experimental animals: 200g SPF-grade male SD rats were purchased from Hunan Slack Jingda Experimental Animal Co., Ltd. [License number: SCXK(Hunan)2019 - 0004]. The animals were housed in the Experimental Animal Center of the Second Xiangya Hospital of Central South University [License number: SYXK(Hunan)2022 - 0012]. This study was reviewed by the Experimental Animal Welfare and Ethics Committee of the Second Xiangya Hospital of Central South University, and all experimental operations complied with the "Regulations on the Administration of Experimental Animals". (Ethical acceptance number: 20240580)
[0037] Modeling process: A total of 16 male SD rats were randomly divided into a high-fat group (n = 8) and a high-fat combined with olanzapine group (n = 8) according to body weight using a randomized block design, and were adaptively fed in a barrier system for 7 days. Formal experiments began in the second week. Both groups were continuously fed a high-fat diet for 5 weeks, and the high-fat combined with olanzapine group was simultaneously intraperitoneally injected with 10 mg / kg olanzapine. During the experiment, the experimental rats had free access to water and food.
[0038] Pathological staining: Through liver section H&E staining and Oil Red O staining analysis, the liver pathological changes and lipid accumulation were compared between different groups. In the high-fat group, the boundaries of the hepatic lobules were relatively obvious, arranged relatively regularly, and there was a slight compression of the hepatic cords; the hepatocytes were irregular polygonal in shape, the overall cytoplasm was uniform, and there were individual fatty degenerations; in the high-fat combined with olanzapine group, the boundaries of the hepatic lobules were chaotic, obvious compression of the hepatic cords was observed, and the arrangement of hepatocytes was chaotic; extensive fatty degeneration of hepatocytes was visible in the tissue, small round vacuoles were visible, and individual lymphocyte infiltrations were observed (see Figure 1 ).
[0039] Serum biochemical indicators: Compared with the high-fat group, the levels of serum alanine aminotransferase, aspartate aminotransferase, blood lipid levels, and FFA levels in the high-fat combined with olanzapine group showed an upward trend and were significant. (See Figure 2 , Figure 3 )
[0040] qPCR: The mRNA expression levels of fatty acid synthesis-related gene Fasn, fatty acid transport genes, and inflammatory chemokines increased. (SeeFigure 4 )
[0041] 2. Treatment
[0042] Experimental procedure: A total of 40 male SD rats were randomly divided into groups according to body weight in a randomized block design. They were divided into a high-fat combined with olanzapine group (model group; also known as Group A) (n = 8), model group + low-dose "Formula 1" (n = 8; also known as Group B), model group + high-dose "Formula 1" (n = 8; also known as Group C), and model group + high-dose control Formula A group (n = 8; also known as Group D, with the same dosage of active ingredient as Group C). They were adaptively fed in a barrier system for 7 days. The formal experiment started in the second week. All 5 experimental groups were continuously fed with high-fat diet for 5 weeks and intraperitoneally injected with 10 mg / kg olanzapine. The model group was intragastrically administered with the same solvent as a blank. The other three groups were sequentially intragastrically administered with low-dose "Formula 1", high-dose "Formula 1", and control Formula A. During the experiment, the experimental rats had free access to water and food. The so-called Formula 1 is Formula 1.
[0043] Pathological staining: Analyzed by H&E staining and Oil Red O staining of liver sections. The liver tissues of the rats in the model group showed significant fatty degeneration of a large number of hepatocytes, with a large number of round vesicles in the cytoplasm, dilation or extrusion of hepatic cords and disordered arrangement. While in the liver tissues of the rats in the low-dose "Formula 1" group, high-dose "Formula 1" group, and control Formula A group, there was less fatty degeneration of hepatocytes, with a small amount of round microvesicles in the cytoplasm, hepatic cords arranged radially, without extrusion, and no obvious inflammatory cell infiltration (see Figure 5 , Figure 6 ).
[0044] Liver biochemical indexes: Compared with the model group, the levels of serum and liver alanine aminotransferase, aspartate aminotransferase, blood lipid levels, and FFA levels in the low-dose, high-dose "Formula 1" groups and control Formula A group showed a downward trend and were significant. Among them, the high-dose "Formula 1" group and control Formula A group had the best improvement in liver function of the model group (see Figure 7 , Figure 8 ).
Claims
1. Use of a liver injury attenuating agent in the preparation of a drug for preventing and / or treating drug-induced liver injury, characterized in that: The liver injury reducing agent is at least one of a free compound having a structure of Formula 1 and a pharmaceutically acceptable salt, amide, or crystal thereof; 2. The use according to claim 1, characterized in that The drug-induced liver injury refers to liver injury caused by the administration of atypical antipsychotic drugs.
3. The use according to claim 2, characterized in that The atypical antipsychotic drugs include olanzapine.
4. The use according to any one of claims 1 to 3, characterized in that: The formula 1 is combined with a pharmaceutically acceptable adjuvant to prepare a pharmaceutically acceptable dosage form for preventing and / or treating drug-induced liver injury.
5. A composite antipsychotic active ingredient capable of preventing liver damage, characterized in that: A liver injury attenuating agent according to formula 1 as claimed in any one of claims 1 to 4, further comprising an antipsychotic drug.
6. The active pharmaceutical ingredient according to claim 5, characterized in that The antipsychotic drugs include olanzapine.
7. The active pharmaceutical ingredient according to claim 5 or 6, characterized in that The liver injury reducing agent and antipsychotic drug are present in the form of a mixture, or exist independently of each other before administration.
8. A composite antipsychotic drug capable of preventing liver damage, characterized in that: A pharmaceutical composition comprising a pharmaceutically effective amount of the active ingredient according to any one of claims 5 to 7.
9. The composite antipsychotic drug capable of preventing liver damage according to claim 8, characterized in that: Also contains pharmaceutically acceptable excipients.
10. The composite antipsychotic drug capable of preventing liver damage according to claim 8 or 9, characterized in that: It has a pharmaceutically acceptable dosage form.