Application of beta-elemene in relieving or preventing acute inflammatory diseases

Abstract

The invention discloses an application of (1S, 2S, 4R)-1-methyl-2, 4-bis (prop-1-ene-2-yl)-1-vinylcyclohexane (alias, beta-elemene) in preparation of a medicine, and the medicine is used for treating or preventing diseases related to acute inflammation, such as acute inflammation, acute inflammation, acute inflammation, acute inflammation and acute inflammation. Comprise acute lung injury related to sepsis caused by lipopolysaccharide (LPS), acute edema pancreatitis induced by ceratidine and severe necrotizing pancreatitis induced by L-arginine, but are not limited to the inducers, and specifically, the inducers can be used for inducing acute lung injury related to sepsis caused by lipopolysaccharide (LPS), acute edema pancreatitis induced by ceratidine and severe necrotizing pancreatitis induced by L-arginine. The medicine can inhibit or improve pathological injury and inflammatory response of lung tissue and pancreatic tissue of acute lung injury and acute pancreatitis.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to the use of a compound of formula (I) (alias, β-elemene) in the preparation of a drug for relieving or preventing acute inflammatory diseases.

[0002] Background Art

[0003] Acute Lung Injury (ALI) is a clinical syndrome characterized by extensive inflammation of the lungs and destruction of the alveolar-capillary barrier. In severe cases, it can progress to Acute Respiratory Distress Syndrome (ARDS), which is a respiratory disease with a relatively high mortality rate. The pathological features of ALI are that inflammatory mediators (such as cytokines and oxygen free radicals) cause damage to alveolar epithelial and pulmonary capillary endothelial cells, pulmonary edema, and infiltration of inflammatory cells.

[0004] Pancreatitis refers to the autodigestion of the pancreas and is a pancreatic inflammatory disease in which pancreatic enzymes damage pancreatic tissue and cause glandular as well as remote organ and system dysfunction, with a relatively high incidence and mortality rate, increasing the social and economic burden. Clinically, most patients present with mild acute pancreatitis (AP), which is usually self-limiting and patients recover quickly. AP patients usually complain of severe acute pain in the upper left abdomen and have a high risk of developing systemic inflammation or multiple organ dysfunction syndrome (MODS). The pathophysiological features of AP are pancreatic interstitial edema, acinar cell vacuolization, infiltration of pancreatic tissue by neutrophils and macrophages, and elevated serum markers. Due to the lack of a systematic and in-depth understanding of the inflammatory response during AP and severe AP, there is currently no specific drug treatment method for acute and chronic pancreatitis in clinical practice.

[0005] Based on a large number of investigations, the inventors of the present invention found that β-elemene is a sesquiterpene compound extracted from turmeric, which has a wide range of antitumor activities and low toxicity and is used to treat various cancers. The latest research shows that β-elemene has an anti-inflammatory effect. However, so far, there are few studies on the treatment of inflammatory diseases with β-elemene, and it is still unclear whether β-elemene has a therapeutic effect on acute lung injury and acute pancreatitis. Summary of the Invention

[0006] The object of the present invention is to provide a new use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-ethenylcyclohexane (the compound of formula (I), alias β-elemene).

[0007] Specifically, the present invention provides a new use of the compound of formula (I) (β-elemene) in the preparation of a medicament for alleviating or preventing acute inflammatory diseases (acute lung injury and acute pancreatitis).

[0008]

[0009] The present invention also provides a use of the compound of formula (I) (β-elemene) in a medicament for improving acute inflammation (acute lung injury and acute pancreatitis).

[0010]

[0011] Acute Lung Injury (ALI) is a clinical syndrome characterized by acute inflammation and pulmonary edema, which may progress to Acute Respiratory Distress Syndrome (ARDS). Sepsis is the main inducer of ALI / ARDS. Lipopolysaccharide (LPS) is the main component of the outer membrane of Gram-negative bacteria. By activating the Toll-like receptor 4 (TLR4) signaling pathway, it triggers an inflammatory cascade reaction, precisely mimicking the acute lung injury caused by clinical sepsis or bacterial infection. Intratracheal instillation of lipopolysaccharide (LPS) directly acts on the lungs and rapidly induces local inflammation. Low-dose LPS (1 - 5 mg / kg) can induce mild reversible injury, which is suitable for the study of repair mechanisms. High-dose LPS (10 - 20 mg / kg) causes severe pulmonary edema and inflammation, which is suitable for acute pathological research. Preferably, the acute inflammation (acute lung injury) targeted by the present invention is mainly sepsis-related lung injury caused by lipopolysaccharide (LPS).

[0012] The main cause of acute pancreatitis is cholelithiasis. When the common bile duct is blocked, bile-pancreatic reflux will cause pancreatic acinar cell death and tissue inflammation. Ceruletide is a cholecystokinin (CCK) analogue. Repeated intraperitoneal injection of ceruletide (simulating supra-physiological doses of cholecystokinin) causes abnormal activation of pancreatic acinar cell zymogens, triggering pancreatic autodigestion. The pathology simulated by the ceruletide model is highly similar to that of human acute edematous pancreatitis, which is suitable for the study of mild and early inflammation. High-dose L-arginine (L-Arginine) generates nitric oxide (NO) and reactive oxygen species (ROS) through metabolism, resulting in mitochondrial dysfunction, endoplasmic reticulum stress, and pancreatic acinar cell necrosis. The pancreatic necrosis, systemic inflammatory response, and organ failure induced by L-arginine are consistent with the clinical process of human severe pancreatitis and are ideal models for studying severe, necrotic mechanisms, and systemic complications. The combination of the two can cover the dynamic pathological process of acute pancreatitis from mild to severe. Preferably, the acute inflammation (acute pancreatitis) targeted by the present invention is mainly acute edematous pancreatitis induced by ceruletide and severe necrotizing pancreatitis induced by L-arginine (L-Arginine).

[0013] Preferably, in the use of the present invention, the main symptoms of acute lung injury are proteinaceous fluid exudation in the alveolar lumen and interstitium (increased ratio of wet lung weight to dry lung weight), neutrophil aggregation in the alveoli, macrophage activation (increased cell count in bronchoalveolar lavage fluid BALF), and alveolar epithelial damage; the main symptoms of acute pancreatitis are pancreatic interstitial edema, acinar cell vacuolization, neutrophil infiltration of the pancreatic tissue, significant elevation of amylase and lipase, and inflammatory infiltration in the lung tissue (such as pulmonary edema).

[0014] Preferably, in the use of the present invention, the high-dose use of the compound of formula (I) (β-elemene) alone does not cause damage to the lung and pancreatic tissues statistically.

[0015] The drug in the use of the present invention is the pure compound of the compound of formula (I) (β-elemene) (purchased from Bide Medicine), without any form of excipients, and the pharmacological activity of the compound of formula (I) (β-elemene) itself can be directly observed, avoiding the possible synergistic or antagonistic effects of excipients (such as solvents, stabilizers, fillers, etc.). Excipients may have non-specific effects on experimental models (such as cells, animals) (such as cytotoxicity, enzyme activity inhibition), and the pure compound can avoid such interference. After the study of the pure compound is completed, excipients play a key role in the preparation (such as improving stability, improving bioavailability, controlling release rate, etc.). If the study is directly aimed at the final dosage form (such as oral tablets), excipients need to be added for verification in the later stage, and such studies are not within the scope of the present invention.

[0016] For the convenience of understanding, the present invention cites publicly available documents, which are for a clearer description of the present invention, and the full text content thereof is incorporated herein for reference. The present invention will be described in detail below through specific examples and drawings. It should be particularly noted that these descriptions are only partially exemplary descriptions and do not constitute a limitation on the scope of the present invention. Based on the discussion in this specification, many changes and alterations of the present invention will be obvious to those skilled in the art. Brief Description of the Drawings

[0017] Figure 1 Effect of the compound β-elemene of formula (I) on lipopolysaccharide (LPS)-induced acute lung injury mice.

[0018] Figure 2 Improvement effect of the compound β-elemene of formula (I) on the pathological damage of the lung tissue of lipopolysaccharide (LPS)-induced acute lung injury mice.

[0019] Figure 3 Improvement effect of the compound β-elemene of formula (I) on the inflammation of lipopolysaccharide (LPS)-induced acute lung injury mice.

[0020] Figure 4 The improvement effect of the compound β-elemene of formula (I) on the inflammation of mice with ceruletide-induced acute edematous pancreatitis.

[0021] Figure 5 The improvement effect of the compound β-elemene of formula (I) on the inflammation of severe necrotizing pancreatitis induced by L-arginine. Detailed implementation manners

[0022] The present invention is further illustrated in the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0023] Example 1 The compound of the present invention alleviates the lung injury condition of mice with acute lung injury.

[0024] C57BL / 6 mice were randomly divided into 5 groups with 6 mice in each group, namely:

[0025] Blank control group (Con group): 8-week-old C57BL / 6 mice were intraperitoneally injected with 0.9% normal saline at 12-hour intervals, and after 3 intraperitoneal injections were completed within 36 hours, 0.9% normal saline was instilled into the trachea;

[0026] High-dose β-elemene group (Ele 60mg / kg group): 8-week-old C57BL / 6 mice were intraperitoneally injected with β-elemene 60mg / kg at 12-hour intervals, and after 3 intraperitoneal injections were completed within 36 hours, 0.9% normal saline was instilled into the trachea;

[0027] LPS model group (LPS 5mg / kg group): 8-week-old C57BL / 6 mice were intraperitoneally injected with 0.9% normal saline at 12-hour intervals, and after 3 injections were completed within 36 hours, LPS 5mg / kg was instilled into the trachea;

[0028] Compound low-dose treatment group (LPS 5mg / kg + Ele 30mg / kg group): 8-week-old C57BL / 6 mice were intraperitoneally injected with β-elemene 30mg / kg at 12-hour intervals, and after 3 injections were completed within 36 hours, LPS 5mg / kg was instilled into the trachea;

[0029] Compound high-dose treatment group (LPS 5mg / kg + Ele 60mg / kg group): 8-week-old C57BL / 6 mice were intraperitoneally injected with β-elemene 60mg / kg at 12-hour intervals, and after 3 injections were completed within 36 hours, LPS 5mg / kg was instilled into the trachea.

[0030] Six hours after intratracheal instillation of 5 mg / kg LPS, mice were anesthetized with 0.3% pentobarbital, and the administration volume was 0.1 mL / 10 g. The mice were weighed, the abdominal cavity of the mice was opened, one bronchus was clamped with a hemostat, and the other lung tissue was lavaged with pre-cooled phosphate buffer to obtain bronchoalveolar lavage fluid (BALF). Then the lung tissue was removed for subsequent experiments. The schematic diagram of the model establishment is as shown in Figure 1 Figure A. The destruction of the alveolar-capillary barrier will lead to the exudation of proteinaceous fluid in the alveolar cavity and interstitium (the ratio of wet lung weight to dry lung weight increases). Therefore, the ratio of wet lung weight to dry lung weight was used to evaluate the degree of pulmonary edema. The results are shown in Figure 1 Figure B, showing that after administration of the compound β-elemene of formula (I), it had an obvious alleviating effect on pulmonary tissue edema in LPS-induced acute lung injury. The destruction of the alveolar-capillary barrier will lead to the aggregation of neutrophils and the activation of macrophages in the alveoli. Therefore, the collected bronchoalveolar lavage fluid (BALF) was analyzed. As shown in Figure 1 Figure C, the number of cells in the bronchoalveolar lavage fluid BALF of the LPS model group increased, and the number of cells in the alveolar lavage fluid of the mice decreased significantly after administration of the compound β-elemene of formula (I). After homogenizing the lung tissue, an MPO kit was used to detect the changes in the levels of inflammatory factors. The results are shown in Figure 1 Figure D, showing that the inflammatory level in the lungs of the mice was improved after administration of the compound β-elemene of formula (I).

[0031] The above results indicate that the compound β-elemene of formula (I) has a mitigating effect on the injury phenotype of LPS-induced acute lung injury.

[0032] Example 2 The compounds of the present invention significantly improved the pathological damage of the lung tissue of mice with acute lung injury.

[0033] Grouped and tested according to Example 1. After administration three times, the mice in each group were sacrificed, the lung tissue was taken, fixed with 4% formalin solution, embedded in paraffin, sectioned at 5 μm, and then stained with hematoxylin & eosin (H&E) and examined under a microscope. The results are shown in Figure 2 Figures A - B, the lung tissue of the LPS model group showed pulmonary edema, leukocyte infiltration, and increased alveolar wall thickness. While simultaneously administering the compound β-elemene of formula (I), the damage and inflammatory cell infiltration of the lung tissue of the mice were significantly improved. This indicates that the compound β-elemene of formula (I) can improve the pathological damage of the lung tissue caused by LPS-induced acute lung injury.

[0034] Example 3 The compounds of the present invention significantly improved the elevated levels of inflammatory factors in mice with acute lung injury.

[0035] Grouped and tested according to Example 1. After administering the drug three times, the mice in each group were sacrificed, and the sera and bronchoalveolar lavage fluids (BALF) of the mice in each group were taken. The expression levels of inflammatory factors in the mice in each group were detected using an Elisa kit. The results were as follows: Figure 3 As shown in A - C, the serum inflammatory factor indexes IL - 6, IL - 1β, and TNF - α in the LPS - induced model group of mice were significantly increased. After administering the compound β - elemene of formula (I), the levels of inflammatory factors in the mice were significantly improved. As Figure 3 shown in D - F, the bronchoalveolar lavage fluid (BALF) was taken according to the method of Example 1, and the concentrations of inflammatory factors in the bronchoalveolar lavage fluid (BALF) of the mice in each group were detected using an Elisa kit. The results showed that the inflammatory factor indexes IL - 6, IL - 1β, and TNF - α in the bronchoalveolar lavage fluid of the LPS - induced model group of mice were significantly increased. After administering the compound β - elemene of formula (I), the levels of inflammatory factors in the mice were significantly improved. The above results indicate that the compound β - elemene of formula (I) can improve the levels of inflammatory factors in acute lung injury caused by LPS, thereby alleviating lung tissue damage.

[0036] Example 4 The compound of the present invention significantly improved the pathological damage of the pancreatic tissue of mice with ceruletide - induced acute edematous pancreatitis and alleviated inflammation.

[0037] C57BL / 6 mice were randomly divided into 5 groups, with 6 mice in each group, namely:

[0038] Blank control group (Con group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and simultaneously received intraperitoneal injection of 0.9% normal saline for treatment;

[0039] High - dose β - elemene group (Ele 100mg / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and intraperitoneally injected with 100mg / kg of the compound β - elemene of formula (I). The injection times and intervals were the same as those in the compound treatment group;

[0040] Ceruletide - induced model group (Cer 50μg / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and intraperitoneally injected with ceruletide 50μg / kg, with a total of 8 injections at 1 - hour intervals to induce pancreatitis;

[0041] Compound low - dose treatment group (Cer 50μg / kg + Ele 50mg / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and intraperitoneally injected with ceruletide 50μg / kg, with a total of 8 injections at 1 - hour intervals to induce pancreatitis. The mice received treatment with 50mg / kg of the compound β - elemene of formula (I) 1 hour before the first injection of ceruletide, 3 hours and 6 hours after the injection;

[0042] Compound high-dose treatment group (Cer 50 μg / kg + Ele 100 mg / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours, and then caerulein was intraperitoneally injected at a dose of 50 μg / kg, with a total of 8 injections at 1-hour intervals to induce pancreatitis. One hour before the first injection of caerulein, 3 hours and 6 hours after the first injection, the mice received compound β-elemene of formula (I) at a dose of 100 mg / kg for treatment.

[0043] All mice were anesthetized with 0.3% pentobarbital 21 hours after the first injection of caerulein, with a dosing volume of 0.1 mL / 10 g. Serum, pancreas, and lung specimens were collected. The schematic diagram of the model establishment is as shown in Figure 4 Figure A. Biochemical analysis was performed using specific biochemical index detection kits. Compared with the Cer mice, the pancreas-to-body weight ratio, serum amylase, lipase, and lactate dehydrogenase (LDH) levels of the mice treated with β-elemene were lower (the results are as shown in Figure 4 Figure C), and the levels of serum markers all decreased. By comparing the gross morphology of the pancreas in mice, it was found that the pancreatic tissue in the Cer group was significantly edematous, and the degree of pancreatic tissue edema was alleviated after treatment with β-elemene (the results are as shown in Figure 4 Figure B).

[0044] Each group of mice was sacrificed according to the grouping. Pancreas and lung tissues were taken, fixed with 4% formalin solution, embedded in paraffin, sectioned at 5 μm, and then stained with hematoxylin & eosin (H&E) and F4 / 80 immunohistochemistry and examined under a microscope. The results are as shown in Figure 4 Figures D and 4E: The pancreatic interstitium of the mice in the Cer group was significantly edematous, and pulmonary fibrosis increased. Compared with the pancreatic and lung tissues of the mice in the Cer group, the degree of damage to the pancreatic and lung tissues of the mice after treatment with β-elemene was alleviated (the results are as shown in Figure 4 Figure D). The infiltration of macrophages in pancreatic and lung sections was evaluated by F4 / 80 immunohistochemistry staining. The infiltration of macrophages in the Cer group of mice increased significantly. After treatment with β-elemene, smaller inflammatory infiltration areas in the lung and pancreas were observed, and the levels of inflammatory factors were alleviated (the results are as shown in Figure 4 Figure E). These results indicate that β-elemene administered at 50 mg / kg and 100 mg / kg has a relieving effect in the caerulein-induced pancreatitis mouse model, can improve macrophage infiltration, and β-elemene has a therapeutic effect on acute edematous pancreatitis.

[0045] Example 5 The compound of the present invention significantly improved the pathological damage of pancreatic tissue in mice with L-arginine-induced severe necrotizing pancreatitis and alleviated inflammation.

[0046] C57BL / 6 mice were randomly divided into 5 groups, with 6 mice in each group, respectively:

[0047] Blank control group (Con group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and simultaneously received intraperitoneal injection of 0.9% normal saline for treatment;

[0048] High-dose β-elemene group (Ele 100mg / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and intraperitoneally injected with 100mg / kg of the compound β-elemene of formula (I). The injection times and intervals were the same as those in the compound treatment group;

[0049] L-arginine-induced pancreatitis model group (L-Arg 4g / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and intraperitoneally injected with L-arginine 4g / kg twice at an interval of 1 hour to induce pancreatitis;

[0050] Low-dose compound treatment group ((L-Arg 4g / kgr+Ele 50mg / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and intraperitoneally injected with L-arginine 4g / kg twice at an interval of 1 hour to induce pancreatitis. They received treatment with 50mg / kg of the compound β-elemene of formula (I) 1 hour before the first injection of L-arginine, 6 hours, 30 hours, and 54 hours after the first injection;

[0051] High-dose compound treatment group ((L-Arg 4g / kg+Ele 100mg / kg group): Male C57BL / 6 mice at 8 weeks of age were fasted for 14 hours and intraperitoneally injected with L-arginine 4g / kg twice at an interval of 1 hour to induce pancreatitis. They received treatment with 100mg / kg of the compound β-elemene of formula (I) 1 hour before the first injection of L-arginine, 6 hours, 30 hours, and 54 hours after the first injection.

[0052] At 72 hours after the first injection, the mice were anesthetized with 0.3% pentobarbital, and the administration volume was 0.1 mL / 10 g. Serum, pancreatic, and lung tissue samples were collected for analysis. The schematic diagram of the model establishment is as shown in Figure 5 Figure A. Biochemical analysis was performed using a specific biochemical index detection kit. Compared with the L-Arg mice, the pancreatic weight ratio, serum amylase, lipase, and lactate dehydrogenase (LDH) levels in the mice treated with β-elemene were lower (the results are as shown in Figure 5C), the levels of serum markers all decreased. By comparing the gross morphology of the pancreas in mice, it was found that the pancreatic tissue in the L-Arg group had increased edema and necrosis, and the degree of pancreatic tissue edema and necrosis was alleviated after β-elemene treatment (the results are as shown in Figure 5 B).

[0053] The mice in each group were sacrificed according to the grouping, and the pancreatic and lung tissues were taken, fixed with 4% formalin solution, embedded in paraffin, sectioned at 5 μm, and then subjected to hematoxylin & eosin (H&E) staining, F4 / 80 immunohistochemical staining and microscopic examination. The results are as shown in Figure 5 D and 4E: The pancreatic interstitium of the mice in the L-Arg group showed obvious edema and increased pulmonary fibrosis. Compared with the pancreatic and lung tissues of the mice in the L-Arg group, the degree of injury to the pancreatic and lung tissues of the mice after β-elemene treatment was alleviated (the results are as shown in Figure 5 D). The F4 / 80 immunohistochemical staining method was used to evaluate the macrophage infiltration in pancreatic and lung sections. The macrophage infiltration in the mice in the L-Arg group increased significantly, and the inflammatory infiltration area and inflammatory factor levels in the lungs and pancreas were alleviated after β-elemene treatment (the results are as shown in Figure 5 E). These results indicate that β-elemene administered at 50 mg / kg and 100 mg / kg has a relieving effect in the mouse L-arginine pancreatitis model, can improve macrophage infiltration, and β-elemene has a therapeutic effect on severe necrotizing pancreatitis.

Claims

1. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane in the preparation of drugs, characterized in that, The described drug is used to relieve or prevent diseases related to acute inflammation; The structural formula of the described (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-ethenylcyclohexane is as follows: The diseases related to acute inflammation described include lung tissue inflammation and its related diseases, and pancreatic tissue inflammation and its related diseases.

2. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 1 in the preparation of a drug, characterized in that, The disease related to acute inflammation described is acute lung injury or acute pancreatitis.

3. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 2 in the preparation of a medicament, characterized in that, The disease related to acute inflammation described is acute lung injury caused by sepsis.

4. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 3 in the preparation of a drug, characterized in that, The acute lung injury described is acute lung injury caused by LPS-induced sepsis.

5. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to any one of claims 1 to 4 in the preparation of a drug, characterized in that, The described drug is used to improve lung tissue dysfunction and pathological damage.

6. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 5 in the preparation of a drug, characterized in that, The lung tissue dysfunction and pathological damage described include alveolar damage and pulmonary edema.

7. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 2 in the preparation of drugs, characterized in that, The disease related to acute inflammation described is acute edematous pancreatitis or severe necrotizing pancreatitis.

8. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 7 in the preparation of a drug, characterized in that, The described acute edematous pancreatitis is induced by cerulein; The described severe necrotizing pancreatitis is induced by arginine.

9. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 1, 2, 7 or 8 in the preparation of a medicament, characterized in that, The described drug is used to improve pancreatic dysfunction and pathological damage.

10. Use of (1S,2S,4R)-1-methyl-2,4-bis(prop-1-en-2-yl)-1-vinylcyclohexane according to claim 9 in the preparation of a medicament, characterized in that, The pancreatic dysfunction and pathological damage described include pancreatic tissue edema, necrosis, inflammatory cell infiltration, and elevated serum markers.

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