Application of flufenidone in preparation of medicine for treating pancreatic diseases

Abstract

The invention belongs to the field of biological medicines, and discloses application of flufenidone in preparation of a medicine for treating pancreatic diseases. Researches find that the flufenidone can improve serum amylase and lipase levels of an acute pancreatitis model mouse, and can improve pancreatic tissue edema, necrosis and inflammatory cell infiltration of the acute pancreatitis model mouse; the traditional Chinese medicine composition can improve acute pancreatitis model mouse lung tissue alveolar interval thickening and inflammatory cell infiltration, and provides guarantee for application of the traditional Chinese medicine composition in preparation of drugs for treating pancreatic diseases.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of biological medicine, and particularly relates to application of Furosemide in preparation of a drug for treating pancreatic diseases. BACKGROUND

[0002] Acute pancreatitis (AP) is a sudden inflammatory reaction and self-digestive disease of pancreatic tissue caused by various causes (such as cholelithiasis, alcohol abuse, hyperlipidemia, etc.), and its pathological characteristics are shown as damage of acinar cells, abnormal activation of pancreatic enzymes, local necrosis and systemic inflammatory response syndrome. The main clinical manifestations of mild patients are mainly pancreatic edema, sudden severe abdominal pain, nausea and vomiting, and elevated serum amylase / lipase; about 20% of patients can progress to severe acute pancreatitis (SAP), accompanied by extensive necrosis of the pancreas, multiple organ failure, and a mortality rate of up to 30%.

[0003] The condition of acute pancreatitis changes rapidly, and the current clinical treatment is mainly supportive therapy, including fluid resuscitation, pain management, enteral nutrition and complication prevention. For severe patients, antibiotics can be used to prevent infection or necrotic tissue debridement, but there is no specific drug that can effectively block the progressive damage of pancreatic parenchyma or inhibit the systemic inflammatory factor storm. Therefore, it is an urgent medical need to find an alternative therapy for acute pancreatitis.

[0004] Furosemide (1-(3-fluorophenyl)-5-methyl-2(1H) pyridinone) is a new pyridinone small molecule compound with anti-inflammatory and anti-fibrosis effects, which has been approved by the State Drug Administration for the 2-phase drug clinical trial of anti-liver fibrosis. Previous preclinical studies have found that furosemide can play a role in anti-liver, lung and kidney fibrosis. There is no research on the efficacy of furosemide on pancreatic diseases. SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the deficiencies and defects mentioned in the above background art, and to provide a furosemide for preparing a drug for treating pancreatic diseases.

[0006] To solve the above technical problems, the technical solution provided by the present application is: Application of furosemide in preparation of a drug for treating pancreatic diseases.

[0007] The application described above, preferably, the pancreatic disease includes acute pancreatitis.

[0008] The application described above, preferably, the drug for treating pancreatic diseases further comprises at least one of a pharmaceutically acceptable solid excipient or a liquid excipient or an adjuvant.

[0009] Compared with the prior art, the application has the beneficial effects of: (1) The application finds that flufarinenone can improve the serum amylase and lipase levels of an acute pancreatitis model mouse, can improve the edema, necrosis and inflammatory cell infiltration of the pancreas tissue of the acute pancreatitis model mouse, and can improve the alveolar septum thickening and inflammatory cell infiltration of the lung tissue of the acute pancreatitis model mouse, thereby providing a guarantee for the application of flufarinenone in the preparation of a drug for treating pancreas diseases.

[0010] (2) The application provides a new medical use of flufarinenone and a new clinical treatment method for acute pancreatitis. BRIEF DESCRIPTION OF DRAWINGS

[0011] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced as follows. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without any creative effort on the basis of these drawings.

[0012] Figure 1 The dosing regimen of flufarinenone for treating the acute pancreatitis model mouse induced by cerulein in the embodiments.

[0013] Figure 2 The detection results of the serum biochemical indicators of the mice in each group in the embodiments are shown in the following figures: figure A is the serum amylase level, and figure B is the serum lipase level.

[0014] Figure 3 The HE staining (200x) effects of the pancreas of the mice in each group in the embodiments are compared.

[0015] Figure 4 The HE staining (200x) effects of the lung of the mice in each group in the embodiments are compared. DETAILED DESCRIPTION

[0016] In order to facilitate the understanding of the present application, the present application will be described more fully below in conjunction with the accompanying drawings and preferred embodiments, but the scope of protection of the present application is not limited to the following specific embodiments.

[0017] Unless otherwise defined, all the professional terms used in the following description have the same meanings as understood by those skilled in the art. The professional terms used in the present application are only for the purpose of describing the specific embodiments and are not intended to limit the scope of protection of the present application.

[0018] Unless otherwise specified, the various raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or can be prepared by the existing methods.

[0019] All statistical analyses in this article were performed using SPSS Statistics 27.0 statistical analysis software. All quantitative data were expressed as —X ± S, and single factor variance (ANOVA) analysis was used for comparison among multiple groups. Bilateral P <0.05 was considered statistically significant.

[0020] Example 1: Use of a Furosemide in the preparation of a medicament for treating pancreatic disease.

[0021] To demonstrate the effect of furosemide in the preparation of a medicament for treating pancreatic disease, the following animal experiments are provided in this embodiment, and the animal experiment process is as follows: 1. Preparation and grouping of experimental animals Animals: SPF C57BL / 6 mice.

[0022] Specification: 6-8 weeks old, male, body weight 18-22 g.

[0023] Adaptive feeding: All mice were adaptively fed for 1 week before the experiment.

[0024] Grouping: After the adaptive feeding was completed, the mice were randomly divided into 5 groups, 6 in each group: Sham group: only received surgical simulation operation and solvent control treatment; acute pancreatitis model group (IRI24h): acute pancreatitis model was established, and only solvent control treatment was received; furosemide treatment group (125 mg / kg): furosemide treatment was given before the establishment of the acute pancreatitis model; Furosemide treatment group (250 mg / kg): furosemide treatment was given before the establishment of the acute pancreatitis model; furosemide treatment group (500 mg / kg): furosemide treatment was given before the establishment of the acute pancreatitis model.

[0025] 2. Drug preparation and pretreatment Furosemide preparation: Furosemide was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) aqueous solution.

[0026] Treatment group administration: 12 hours before starting to establish the acute pancreatitis model, the three furosemide treatment groups of mice were given gavage administration, with doses of 125 mg / kg, 250 mg / kg, and 500 mg / kg (drug dissolved in 0.5% CMC-Na).

[0027] Control group administration: Sham group (Sham) mice were given gavage administration of the corresponding volume of 0.5% CMC-Na solution. Acute pancreatitis model group (IRI24h) mice were given gavage administration of the corresponding volume of 0.5% CMC-Na solution.

[0028] 3. Model of acute pancreatitis (AP) was established Principle of modeling method: Celulerin is a cholecystokinin analogue that can mimic the pathological process of biliary and alcoholic acute pancreatitis by continuously activating cholecystokinin receptors, disrupting pancreatic enzyme secretion homeostasis, and pancreatic autodigestion. LPS was combined at the last injection to enhance the inflammatory response.

[0029] Modeling operation: Mice in the model group (IRI24h) and the furosemide treatment group began to receive celulerin injections (mice in the sham operation group did not undergo this operation).

[0030] Intraperitoneal injection of celulerin: The dose was 50 μg / kg.

[0031] Injection frequency: Injected once an hour.

[0032] Number of injections: Injected 7 times in a row.

[0033] Combined LPS injection: At the same time as the 7th injection of celulerin, lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 5 mg / kg.

[0034] The dosing regimen of furosemide in treating mice with celulerin-induced acute pancreatitis is shown in Figure 1 .

[0035] Post-modeling observation: Timing began from the first celulerin injection.

[0036] 4. Sample collection Time of sacrifice: All mice were euthanized 12 hours after the last injection (celulerin + LPS) was completed (i.e., 12 hours after modeling). Mouse serum, pancreas, and lung tissue were collected and stored at -80°C for subsequent experiments.

[0037] 5. Detection of serum biochemical indicators in mice The serum amylase and lipase levels in mice in each group were detected according to the kit instructions, and the results are shown in Figure 2 . According to Figure 2 , compared with the control group, the serum amylase and lipase levels in mice with acute pancreatitis were significantly increased. Compared with the model group, furosemide treatment can reduce the serum amylase and lipase levels in model mice, and the 500 mg / kg furosemide group has the best effect.

[0038] Therefore, furosemide can improve pancreatic injury in mice with acute pancreatitis.

[0039] 6. HE staining of pancreas and pancreatic injury score in mice in each group The pancreatic injury score was used to semi-quantitatively analyze the pancreatic tissue injury by Schmidt pathological score. Ten fields were randomly selected under 200x microscope for each pancreas, and the scores were given for acinar cell injury, inflammatory infiltration, necrosis, hemorrhage and fat necrosis, etc. The final severity score (0-16) was given. The specific scoring criteria are shown in Table 1.

[0040] Table 1 Scoring criteria

[0041] The results of acinar cell injury, inflammatory infiltration, necrosis, hemorrhage and fat necrosis under 200x microscope are shown in Table 2. Figure 3 As shown in Table 2, compared with the control group, the acinar cells of the acute pancreatitis model group of mice appeared edema, part of which was accompanied by necrosis, accompanied by a large number of inflammatory cell infiltration. Compared with the model group, fluorenine treatment can improve the edema of acinar cells and inflammatory cell infiltration in the pancreas of acute pancreatitis model mice, among which the pathological improvement of the 500mg / kg fluorenine group is the most obvious.

[0042] 7. Lung tissue HE staining and lung tissue injury score of mice in each group The lung injury score was given by HE staining of paraffin sections of the left lung of mice. Ten fields were randomly selected under 200x microscope, and a semi-quantitative score of 0-3 was given according to the degree of inflammatory cell infiltration, alveolar hemorrhage, alveolar structure and alveolar septum thickening, and the average value was taken as the lung injury score. The specific details are as follows: 0 points, normal alveolar structure; 1 point, mild lung injury, the injury area accounts for <20% of the total lung area; 2 points, moderate lung injury, the injury area accounts for 20%-50% of the total lung area; 3 points, severe lung injury, the injury area accounts for >50% of the total lung area.

[0043] The results are shown in Table 3. Figure 4 As shown in Table 3, compared with the control group, the lung tissue of the acute pancreatitis model group of mice was severely damaged, the alveolar structure was disordered, the alveolar septum was obviously thickened, and a large number of inflammatory cells were infiltrated. Compared with the model group, fluorenine treatment can improve the thickening of alveolar septum and inflammatory cell infiltration in the lung tissue of acute pancreatitis model mice, among which the pathological improvement of the 500mg / kg fluorenine group is the most obvious.

[0044] Therefore, fluorenine can improve the serum amylase and lipase levels of acute pancreatitis model mice, can improve the edema, necrosis and inflammatory cell infiltration of the pancreatic tissue of acute pancreatitis model mice, and can improve the thickening of alveolar septum and inflammatory cell infiltration in the lung tissue of acute pancreatitis model mice. Therefore, the verification results of fluorenine in animal experiments provide a basic basis for its application in the preparation of drugs for treating pancreatic diseases, and it is expected to be used in clinical experiments in the future.

Claims

1. Use of flufenidone in the preparation of a medicament for treating pancreatic diseases.

2. The use according to claim 1, characterized in that The pancreatic diseases include acute pancreatitis.

3. The use according to claim 1, characterized in that The drug for treating pancreatic diseases further comprises at least one of a pharmaceutically acceptable solid excipient, a liquid excipient or an adjuvant.

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