Application of coelenterazine in preparation of medicine for treating lung diseases

Abstract

The invention discloses application of coelenterazine or salt thereof in medicine preparation, the compound is used for treating or preventing acute lung injury, preferably lung diseases caused by serious infection, pneumonia and sepsis, but is not limited to the inducer, and specifically, the medicine can inhibit or improve various acute lung injuries.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to the use of a compound of formula (I) (codenamed CTZ) or a pharmaceutically acceptable salt thereof in the preparation of a method for treating or preventing lung diseases caused by acute diseases.

[0002] Background Art

[0003] Acute lung injury refers to diffuse pulmonary interstitial and alveolar edema caused by damage to pulmonary capillary endothelial cells and alveolar epithelial cells during non-cardiogenic diseases such as severe infection, shock, trauma and burns. When pathogens invade the host, they can trigger inflammatory responses in natural immune cells such as neutrophils and macrophages, which in turn produce abundant inflammatory cytokines such as IL-1β, IL-6, TNF-α, etc. Excessive production of cytokines can cause cytoskeleton contraction and increased microvascular permeability, thereby destroying the integrity of the alveolar endothelial cell barrier, leading to lung injury, hypoxemia, dyspnea, loss of alveolar capillary membrane integrity, pulmonary edema, inflammatory cell infiltration, etc., which seriously affect the patient's quality of life and even endanger his life.

[0004] Based on many years of research on pharmacology and pathological mechanisms, the inventors have discovered that coelenterazine can effectively treat acute diseases such as severe infection, pneumonia, sepsis, aspiration of gastric contents, severe post-traumatic hemorrhage, shock and burns, etc., which are induced by multiple factors. Lung-related pathological changes can be significantly improved. Summary of the invention

[0005] The object of the present invention is to provide a new use of coelenterazine (compound of formula (I), codenamed CTZ).

[0006] Specifically, the present invention provides the use of a compound of formula (I) (CTZ) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing acute lung injury.

[0007]

[0008] The active ingredient of the drug comprises coelenterazine or a pharmaceutically acceptable salt thereof.

[0009] Preferably, the use of the present invention is use in preparing a medicament for treating or preventing acute lung injury.

[0010] The present invention also provides use of the compound (CTZ) of formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for improving acute lung injury.

[0011]

[0012] Preferably, the use of the present invention is in the preparation of a medicament for improving acute lung injury.

[0013] There are many causes of lung diseases, including severe infection, pneumonia, sepsis, aspiration of gastric contents, severe post-traumatic hemorrhage, shock and burns. Different causes have different treatment methods. Among them, severe infection, pneumonia, and sepsis are common causes of inducing lung diseases, such as the most common acute lung injury (ALI), and its deterioration leading to acute respiratory distress syndrome (ARDS). Considering the mechanism of disease occurrence, the present invention is mainly aimed at lung diseases caused by severe infection, pneumonia, sepsis, etc., but is not limited to the above-mentioned pathogenic factors; most preferably, it is used to treat pathological changes in lung tissue under acute lung injury.

[0014] Preferably, in the use of the present invention, the main pathological features of the lung disease are pulmonary vascular damage, diffuse infiltration of inflammatory cells, alveolar wall thickening and pulmonary edema.

[0015] The functional changes in lung tissue include diffuse infiltration of inflammatory cells, thickening of alveolar walls and pulmonary edema.

[0016] The drug used in the present invention contains an effective dose of the compound of formula (I) (CTZ). The effective dose can be the content of the drug in a unit dosage form (such as a tablet, a needle, a pill or a dose), or it can be a unit dose (such as a unit body weight dose) of the patient to be treated / prevented. In the present invention, the effective dose (in terms of content) can be 10 μg-1g, preferably 0.1mg-500mg, and more preferably 1mg-100mg.

[0017] The drugs used in the present invention usually also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier used refers to a non-toxic filler, stabilizer, diluent, adjuvant or other formulation excipient. For example, diluents, excipients, such as water, physiological saline, etc.; fillers, such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginates, gelatin and / or polyvinyl pyrrolidone; wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate and / or sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants, such as hexadecanol; adsorption carriers, such as kaolin and / or soap clay; lubricants, such as talc, calcium / magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition of the present invention may further contain other excipients, such as flavoring agents, sweeteners, etc. According to the known technology in the art, the pharmaceutical composition can be prepared into various dosage forms according to the needs of the treatment purpose and the route of administration. Preferably, the composition is a unit dosage form, such as a lyophilized agent, a tablet, a capsule, a powder, an emulsion, an aqueous injection or a spray, and more preferably, the pharmaceutical composition is an injection form (such as a lyophilized powder injection) or an oral dosage form (such as a tablet, a capsule). The drug can be administered by conventional routes, particularly enteral, such as oral, such as in the form of a tablet or capsule, or parenteral, such as in the form of an injectable solution or suspension, topically, such as in the form of a lotion or gel, or in the form of a nasal agent or a test agent.

[0018] The present invention will be described in detail below through specific embodiments and drawings. It should be particularly pointed out that these descriptions are only partial exemplary descriptions and do not constitute a limitation on the scope of the present invention. According to the discussion of this specification, many changes and modifications of the present invention are obvious to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The compound (CTZ) of formula (I) has an alleviating effect on the structural disorder of lung tissue in mice with acute lung injury.

[0020] Figure 2 The compound (CTZ) of formula (I) has an alleviating effect on diffuse infiltration of inflammatory cells in lung tissue of mice with acute lung injury.

[0021] Figure 3 The compound (CTZ) of formula (I) has an alleviating effect on alveolar wall thickening and pulmonary edema in the lung tissue of mice with acute lung injury. DETAILED DESCRIPTION

[0022] The present invention is further described in the following examples. These examples are only for the purpose of illustrating the present invention, but are not intended to limit the scope of the present invention.

[0023] Example 1 The compounds of the present invention can significantly inhibit the lung structural disorder caused by lipopolysaccharide (inflammation).

[0024] C57BL / 6J mice were randomly divided into 4 groups (6 mice in each group), namely:

[0025] Control group: healthy C57BL / 6J mice;

[0026] Lipopolysaccharide (inflammation) group (HFD): LPS (5 mg / kg) was instilled into the trachea of ​​C57BL / 6J mice, and the mice were killed 6 h later;

[0027] Compound treatment group (LPS+CTZ 5 mg / kg or 10 mg / kg): Before the construction of lipopolysaccharide (inflammation) mice, the compound of formula (I) (CTZ) was intraperitoneally injected into the mice at a dose of 5 mg / kg or 10 mg / kg every 8 hours, 10% DMSO suspension (prepared in PBS buffer), for 3 consecutive times, and LPS (5 mg / kg) was instilled into the trachea 1 hour after the last administration.

[0028] 6 hours after modeling, the mice were killed, and the lung tissues were taken, fixed with 4% formalin, embedded in paraffin, and sliced ​​to 5 μm thickness for hematoxylin & eosin (H&E) staining and microscopic examination. The results of H&E staining showed that LPS caused structural disorder and pulmonary interstitial hyperplasia of the lung tissue, which was alleviated by CTZ administration ( Figure 1 ). (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0029] Example 2 The compounds of the present invention can significantly improve the diffuse infiltration of inflammatory cells in lung tissue caused by lipopolysaccharide (inflammation).

[0030] The samples were fixed with 4% formalin, embedded in paraffin, and sliced ​​to 5 μm thickness for immunohistochemical staining (Ly6G, F4 / 80) and microscopic examination. The results of immunohistochemical staining showed that lipopolysaccharide caused inflammatory cell infiltration in lung tissue, which was significantly alleviated by CTZ ( Figure 2 At the same time, we detected the expression of inflammatory cytokines in mouse serum and bronchoalveolar lavage fluid (BALF) ( Figure 2 b), the results showed that LPS caused a significant upregulation of inflammatory cytokines in mouse serum and bronchoalveolar lavage fluid, which was significantly alleviated by CTZ. At the same time, we detected the expression of inflammatory genes in lung tissue, and the results showed that LPS caused a significant upregulation of inflammatory genes in lung tissue, which was significantly alleviated by CTZ ( Figure 2 Middle c) (*p < 0.05, **p < 0.01 and ***p < 0.005 compared with the control group;# p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

[0031] Example 3 The compounds of the present invention can significantly alleviate the pathological changes of alveolar wall thickening and pulmonary edema caused by lipopolysaccharide.

[0032] 6 hours after modeling, the mice were killed, and the right upper lobe of the lung was taken. The wet weight and dry weight were weighed and the ratio was calculated. At the same time, after the blood was taken from the mice, the chest was opened, the cricoid cartilage was bluntly separated, the trachea was cut above the cricoid cartilage, and 200 μL PBS was injected from the cut to perform alveolar lavage. This was repeated 4 times, and the alveolar lavage fluid was collected. The results of the wet / dry ratio of lung tissue showed that the lesions of alveolar wall thickening and pulmonary edema caused by lipopolysaccharide were significantly alleviated by CTZ ( Figure 3 At the same time, we detected the expression of protein concentration and total cell number in bronchoalveolar lavage fluid. The results showed that lipopolysaccharide caused a significant increase in protein concentration and total cell number in bronchoalveolar lavage fluid, which was significantly alleviated by CTZ ( Figure 3 a). (*p<0.05, **p<0.01 and ***p<0.005 compared with the control group; # p<0.05, ## p<0.01 and ### p<0.005 compared with the model group).

Claims

1. Use of coelenterazine or its salt in the preparation of a drug, characterized in that: The drug is used to treat or prevent lung-related diseases; The structure of the coelenterazine is shown in formula (I): The active ingredient of the drug comprises coelenterazine or a pharmaceutically acceptable salt thereof.

2. The use of coelenterazine or its salt in drug preparation according to claim 1, characterized in that: The lung-related disease is acute lung injury.

3. The use of coelenterazine or its salt in drug preparation according to claim 1, characterized in that: The lung-related disease is acute lung injury caused by lipopolysaccharide.

4. Use of coelenterazine or a salt thereof in the preparation of a drug according to any one of claims 1 to 3, characterized in that: The lung-related diseases are changes in lung tissue function and pathological damage.

5. The use of coelenterazine or a salt thereof in the preparation of a drug according to claim 4, characterized in that: The functional changes and pathological damage of lung tissue include diffuse infiltration of inflammatory cells, thickening of alveolar walls and pulmonary edema.

6. The use of coelenterazine or a salt thereof in the preparation of a drug according to claim 4, characterized in that: The lung tissue functional changes and pathological damage include lung tissue structural disorder and pulmonary interstitial hyperplasia.

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