New applications of daptomycin

Abstract

The present invention belongs to the field of biological medicine technology, and relates to a new application of daptomycin, specifically the application of daptomycin in the preparation of drugs for treating or preventing chronic pancreatitis. Daptomycin can inhibit macrophage M2 polarization, reduce pancreatic fibrosis caused by chronic pancreatitis, and reduce pancreatic tissue changes caused by chronic pancreatitis. The present invention may provide an effective prodrug for the prevention and treatment of chronic pancreatitis.

Description

Technical Field

[0001] The invention belongs to the technical field of biological medicines, and in particular relates to a new application of daptomycin. Background Art

[0002] Chronic pancreatitis (CP) is a chronic inflammatory disease caused by genetic, environmental and other factors, accompanied by irreversible damage to pancreatic tissue and function. Pancreatic fibrosis is a characteristic pathological change of CP, which is mainly caused by the extracellular matrix secreted by activated pancreatic stellate cells (PSCs), which promotes the occurrence and development of fibrosis. At present, the medical community has not yet clarified the pathogenesis of CP. The main methods for clinical treatment of CP include screening and treatment of complications, and there is a lack of specific therapies to delay or reverse the progression of CP.

[0003] Improving fibrosis in CP will be the key and difficulty in treating CP, which has good academic value and clinical significance. Studies have reported that macrophage polarization plays an important role in the process of pancreatic fibrosis. Deepening the research on macrophage polarization in CP may alleviate the development of pancreatic fibrosis.

[0004] Daptomycin is a calcium-dependent, membrane-bound lipopeptide antibiotic, which is a cyclic peptide composed of 13 amino acids and a decanoyl fatty acid chain. It was approved by the FDA in 2003 for the treatment of complicated skin and skin structure infections or bacteremia associated with right-sided infective endocarditis. Currently, there are no studies on daptomycin in chronic pancreatitis. Summary of the invention

[0005] The purpose of the present invention is to study the new application of daptomycin, especially the improvement effect of daptomycin on pancreatic damage caused by chronic pancreatitis, and to provide an experimental basis for the effective drug treatment of chronic pancreatitis.

[0006] The present invention provides an application of daptomycin in preparing a medicine for treating or preventing chronic pancreatitis.

[0007] The structural formula of daptomycin is as follows:

[0008]

[0009] In the above technical solution, further, the application is to reduce pancreatic fibrosis caused by chronic pancreatitis.

[0010] In the above technical solution, further, the application is to reduce the changes in pancreatic tissue caused by chronic pancreatitis.

[0011] In the above technical solution, further, the application is to inhibit macrophage M2 polarization.

[0012] The present invention also provides a pharmaceutical composition for preventing or treating chronic pancreatitis, wherein the pharmaceutical composition uses daptomycin as an active ingredient.

[0013] In the above technical solution, further, the drug is an oral preparation or an injectable preparation.

[0014] Compared with the prior art, the present invention has the following beneficial effects: the present invention provides the use of daptomycin in drugs for treating or preventing chronic pancreatitis. Through experiments in mice, it was found that daptomycin can reduce pancreatic tissue damage, fibrosis and infiltration of M2 macrophages in the pancreas caused by chronic pancreatitis. The present invention may provide an effective prodrug for the prevention and treatment of chronic pancreatitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 HE staining was used to observe the pathological changes of the heart, liver, spleen, lung, kidney, brain, small intestine and pancreas of mice (400×). Dap, daptomycin.

[0016] Figure 2 Flow cytometry was used to detect the effect of daptomycin on the content of M2 macrophages in the spleen of mice with CP. Dap, daptomycin.

[0017] Figure 3 F4-80 + -CD206 + Double immunofluorescence staining was used to detect the effect of daptomycin on M2 macrophages in the pancreas of mice with CP. Dap, daptomycin.

[0018] Figure 4 HE staining was used to observe the effect of daptomycin on pancreatic pathological damage in mice with CP. Dap, daptomycin.

[0019] Figure 5 Masson staining was used to observe the effect of daptomycin on pancreatic fibrosis in mice with CP. Dap, daptomycin. DETAILED DESCRIPTION

[0020] The present invention is further described below in conjunction with specific embodiments, but the present invention is not limited in any way.

[0021] Example 1

[0022] 1. Experimental plan:

[0023] 1) In vivo toxicity experiment: After one week of acclimatization, 16 C57BL / 6 mice were randomly divided into two groups, 8 mice in each group: Ctrl group and daptomycin group. The Ctrl group and daptomycin group (Dap group) were intraperitoneally injected with equal amounts of saline and daptomycin (50 mg / kg / day), respectively. After 4 weeks, the mice were anesthetized with isoflurane and blood was collected from the abdominal aorta to be killed. The hearts, livers, spleens, lungs, kidneys, brains, intestines and pancreas of the mice were collected for HE staining to evaluate the toxicity of daptomycin in mice.

[0024] 2) In vivo efficacy experiment: After one week of adaptation, 24 C57BL / 6 mice were randomly divided into 3 groups, 8 mice in each group: Ctrl group, CP group and CP+daptomycin group (CP+Dap group) for in vivo pharmacodynamic evaluation. CP was modeled with caerulein, and caerulein (50μg / kg) was injected intraperitoneally on Mondays, Wednesdays and Fridays, with an interval of 1h / time, 6 times a day, for 8 weeks; daptomycin was injected intraperitoneally starting from the 4th week after the start of CP modeling (50mg / kg / day, for 4 weeks); the Ctrl group mice were injected intraperitoneally with an equal amount of normal saline at the same frequency of administration. After 8 weeks, the mice were anesthetized with isoflurane and bled from the abdominal aorta. The spleen tissue of the mice was ground to obtain single cells, and the content of M2 macrophages in the spleen was detected by flow cytometry to evaluate the effect of daptomycin on the polarization of M2 macrophages. The pancreas was subjected to fluorescent staining, HE and Masson staining of M2 macrophages to evaluate the effect of daptomycin on CP-induced pancreatic injury and fibrosis.

[0025] 2. Experimental results:

[0026] 1) Evaluation of daptomycin toxicity in vivo

[0027] like Figure 1 As shown, daptomycin (50 mg / kg / day) was administered for 4 weeks, and the results of HE staining showed that the tissue morphology of the heart, liver, spleen, lung, kidney, brain, intestine, and pancreas of the Dap group mice was normal, and there was no obvious pathological damage compared with the Ctrl group. This shows that daptomycin (50 mg / kg / day) has no obvious toxic side effects on normal mice.

[0028] 2) Daptomycin improves pancreatic injury and fibrotic lesions in CP mice by reducing M2 polarization of macrophages

[0029] like Figure 2 As shown in the figure, the content of M2 macrophages in the spleen was detected by flow cytometry, and it was found that compared with the CP group, the number of M2 macrophages (F4-80 + -CD206 + In addition, the number of F4-80 + -CD206+ The results of double immunofluorescence showed that compared with the Ctrl group, the expression of F4-80 (red fluorescence area) and CD206 (green fluorescence area) in the pancreatic tissue of CP mice was significantly upregulated, that is, the amount of M2 macrophages infiltrating in the pancreas increased significantly during CP, while the expression of F4-80 and CD206 in the pancreas of the CP+Dap group was reduced ( Figure 3 ). Therefore, we can conclude that daptomycin can reduce the M2 polarization of macrophages.

[0030] HE staining was used to further evaluate the effect of daptomycin in CP. Figure 4 As shown in the figure, compared with the Ctrl group, the pancreatic tissue of the mice in the CP group was atrophic, whitened, and had obvious nodules, while the pancreatic tissue damage of the mice in the CP+Dap group was significantly alleviated. At the same time, Masson staining showed that the pancreatic fibrosis area of ​​the mice in the CP group was significantly increased (blue area), but the pancreatic fibrosis area of ​​the mice in the CP+Dap group was significantly reduced ( Figure 5 ). The above results indicate that daptomycin can reduce the M2 polarization of infiltrating macrophages in the pancreas, tissue damage and fibrosis caused by CP.

[0031] The above results show that daptomycin can reduce CP-induced pancreatic macrophage infiltration and M2 transformation, thereby alleviating pancreatic damage and fibrosis in CP mice, and is expected to become a candidate drug for the clinical prevention and treatment of CP in the future.

Claims

1. Use of daptomycin in the preparation of drugs for treating or preventing chronic pancreatitis.

2. Use of a pharmaceutical composition in the preparation of a drug for preventing or treating chronic pancreatitis, wherein the pharmaceutical composition contains daptomycin as an active ingredient.

3. The use according to claim 2, characterized in that: The medicine is an oral preparation or an injection preparation.

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