Application of chlorpiramine hydrochloride in preparation of medicine for treating sepsis lung injury

Abstract

The invention provides an application of chlorpiramine hydrochloride in preparation of a medicine for treating sepsis lung injury, and belongs to the technical field of medicines. According to the present invention, the clopiramine hydrochloride is adopted to treat the sepsis lung injury, the new use of the clopiramine hydrochloride is found, the treatment effect of the clopiramine hydrochloride on the sepsis lung injury is detected, and the results prove that the treatment of the clopiramine hydrochloride can reduce the lung tissue pathological injury caused by the sepsis lung injury, reduce the inflammatory factor level, and improve the treatment effect of the clopiramine hydrochloride on the sepsis lung injury. The medicine is a novel medicine for effectively treating the sepsis lung injury, and the problem that the medicine for effectively preventing and treating the sepsis lung injury is lacked clinically is solved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to application of clopyramine hydrochloride in preparing a medicine for treating septic lung injury. Background Art

[0002] Sepsis-related lung injury is a common and serious complication in the course of sepsis. It is mainly caused by systemic inflammatory response, leading to damage to lung tissue and impaired function, with or without acute lung injury or respiratory failure. This complication may aggravate the symptoms of sepsis, such as high fever and chills, and further affect the patient's respiratory function and increase the risk of death.

[0003] With the deepening of medical research, people have found that septic lung injury involves complex biological processes, including inflammatory response, oxidative stress, apoptosis, etc., and its pathogenesis has not yet been fully elucidated. At present, the clinical treatment of septic lung injury mainly relies on antibiotics and supportive therapies, such as mechanical ventilation and hemodynamic support, but these methods cannot effectively control inflammatory response and tissue damage, and the effect is limited, resulting in high morbidity and mortality of septic lung injury, which brings great challenges to clinical treatment.

[0004] The study of septic lung injury is of great significance. First, in-depth research on its pathogenesis will help us better understand the disease process of septic lung injury and provide theoretical support for the development of more effective treatment strategies. Secondly, through research, we can find new therapeutic targets, develop new treatment methods and drugs, improve the treatment effect of septic lung injury, and reduce the mortality rate of patients. In addition, the study of septic lung injury will also help promote the development of related disciplines, such as inflammatory biology, immunology, etc., and further enrich the theoretical system of medical science. Finally, the research results will help improve the efficiency and quality of clinical treatment, reduce the suffering of patients, improve the quality of life and survival rate of patients, and have a positive role in promoting public health.

[0005] In general, septic lung injury is a complex disease involving the interaction of multiple cells and molecules. Understanding its mechanisms and finding effective treatment strategies are the focus of current research.

[0006] Clopyramine hydrochloride, molecular formula: C16H20ClN3 HCl, molecular weight: 326.26. Clopyramine hydrochloride is an ethylenediamine antihistamine, a histamine H1 receptor antagonist. It has a short duration of action and a weak sedative effect. It is used for various allergic diseases, with a fast onset and a short effect. It has a good antipruritic effect. At present, there is no example of using clopyramine hydrochloride to reduce septic lung injury.

[0007] Pharmacokinetics: Clopyramine hydrochloride is slowly absorbed, with a lag time of 0.4-1.26h, an absorption half-life of 0.35-0.04h, and an elimination half-life of 18.5-3.4h. Adverse reactions: drowsiness, dry mouth, dizziness, blurred vision, and urinary retention, etc., mainly related to its anticholinergic effect.

[0008] Precautions: ① Contraindications to parenteral or oral administration include benign prostatic hyperplasia, peptic ulcer, pyloric and duodenal stenosis, uncontrolled glaucoma, pregnancy and breastfeeding. ② Clopyramine hydrochloride can enhance the sedative effect of central nervous system depressants (such as alcohol, barbiturates and benzodiazepines), so caution should be used when using it. Summary of the invention

[0009] The object of the present invention is to provide an application of clopyramine hydrochloride in the preparation of a drug for treating septic lung injury, wherein clopyramine hydrochloride can reduce pathological damage to lung tissue caused by septic lung injury and reduce the level of inflammatory factors.

[0010] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions: The present invention provides an application of clopyramine hydrochloride in preparing a medicine for treating sepsis-induced lung injury.

[0011] Preferably, the clopyramine hydrochloride can reduce pathological damage to lung tissue caused by septic lung injury and reduce the level of inflammatory factors.

[0012] Preferably, the drug for treating sepsis may be added with a pharmaceutically acceptable carrier.

[0013] Preferably, the dosage form of the drug for treating septic lung injury is one or more of powder, injection, capsule, granule, tablet, emulsion, suspension, spray, powder, liposome, oral solution, and pill.

[0014] Preferably, the administration of clopyramine hydrochloride is one or more of intramuscular injection, subcutaneous injection, intravenous injection, oral administration, sublingual administration, intralesional or intracerebral or implanted delivery, and spray administration.

[0015] The beneficial effects of the present invention compared with the prior art are: The present invention utilizes clopyramine hydrochloride to treat septic lung injury, discovers a new use of clopyramine hydrochloride, and detects the therapeutic effect of clopyramine hydrochloride on septic lung injury. The results show that clopyramine hydrochloride treatment can reduce lung tissue pathological damage caused by septic lung injury and reduce the level of inflammatory factors. The present invention is a new type of effective therapeutic drug for septic lung injury, which improves the problem of lack of effective preventive and therapeutic drugs for septic lung injury in clinical practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0017] Figure 1 This is the mouse survival rate curve of Example 1 of the present invention; Figure 2 The inflammatory factor levels of the bronchoalveolar lavage fluid of mice in Example 1 of the present invention, wherein A is TNF-α and B is IL-6; Figure 3 This is HE pathological staining and scoring of lung injury in mice in Example 1 of the present invention. DETAILED DESCRIPTION

[0018] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0019] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0020] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0021] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.

[0022] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0023] Example 1 Example 1 of the present invention detects the therapeutic effect of clopyramine hydrochloride on septic lung injury, and the specific steps are as follows: (1) Establishment of sepsis lung injury model: Establishment of mouse CLP model: mice were anesthetized by isoflurane breathing. After the mice were anesthetized, they were fixed, the abdominal surgical area was shaved and the skin was prepared. The abdominal skin of the mice was disinfected with 75% alcohol. A 1-2 cm cut was made along the midline of the abdomen to separate the epidermis and muscle layer. The cecum was found and ligated with a 4-0 shell suture absorbable thread at 3 / 4 of the end of the cecum. After ligation, a 1.2*38TWLB needle was used to pierce a hole at the blind end of the cecum. The needle penetrated the cecum, squeezed out a small amount of intestinal contents from the needle hole, and returned the cecum. The intestinal contents were avoided from adhering to the surgical incision as much as possible. The muscle layer and skin were sutured layer by layer. After surgery, each mouse was subcutaneously injected with 1 mL of 37°C preheated saline for fluid resuscitation. 24 hours after surgery, vena cava blood, ileum, cecum, colon, liver, lung and kidney tissues were taken for examination.

[0024] Experimental groups: (2) Twenty-four 6-8 week old C57BL / 6J mice were randomly divided into four groups: Sham group, CLP group, Chloropyramine hydrochloride + CLP group, and Chloropyramine hydrochloride + Sham group. 1) Sham group: The sterile mice were subjected to routine abdominal midline incision and suture without CLP modeling; 2) CLP group: Solvent control was added to the drinking water of mice in advance, and the intestinal CLP model was established in mice 6 days later; 3) Chloropyramine hydrochloride + sepsis lung injury model group (Chloropyramine + CLP): 10 mg / kg was added to the drinking water of mice in advance -1 *d -1 of chlorpyrilamine hydrochloride solution, and 6 days later, the intestinal CLP model was established in mice; 4) Chloropyramine hydrochloride + sham group: 10 mg / kg was added to the drinking water of mice in advance. -1 *d -1 The mice were injected with chlorpyrilamine hydrochloride solution, and the conventional abdominal midline incision was sutured 6 days later without CLP modeling. All the operation steps for the other mice were consistent with those for CLP.

[0025] (3) Detection indicators and technical methods: 1) Observe and record the survival of mice for 7 days. Figure 1shown.

[0026] Figure 1 The results showed that after the mice were established with a sepsis model, the mortality rate was significantly reduced; and after treatment with chlorpyrilamine hydrochloride, the survival rate of septic mice was significantly increased, suggesting that chlorpyrilamine hydrochloride is a potentially effective therapeutic drug for the prevention and treatment of sepsis.

[0027] 2) Assessment of lung tissue damage: A. Sample extraction: 24 hours after injury, mice were euthanized by intraperitoneal injection of pentobarbital, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected for analysis. 1 mL of PBS was injected into the trachea, and lavage was repeated three times to collect BALF.

[0028] B. Assessment of lung tissue inflammation level: BALF supernatant was stored after ultracentrifugation and used for enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of TNF-α and IL-6; Figure 2 The results showed that after the mice established a sepsis model, the level of inflammatory factors in the alveolar lavage fluid increased significantly; after treatment with clopyramine hydrochloride, the level of inflammatory factors in the alveolar lavage fluid of septic mice decreased significantly, suggesting that clopyramine hydrochloride is a potentially effective therapeutic drug for the prevention and treatment of acute lung injury in sepsis.

[0029] C. Histological analysis: Part of the lung tissue was fixed with 4% paraformaldehyde (PFA), embedded in paraffin, and then stained with H&E. Areas (10-15 fields of view) were randomly selected from 5 μM sections using light microscopy. The severity of ALI was assessed by inflammatory cell infiltration and alveolar wall thickening by two members who were blinded to the experimental grouping. Another part of the lung tissue was frozen in liquid nitrogen for RNA and protein isolation. The results are shown in Figure 3 shown.

[0030] Figure 3 The results showed that after the mice were established with a sepsis model, the pathological damage and scores of the lung tissue increased significantly; after treatment with chlorpyrilamine hydrochloride, the pathological damage and scores of the lung tissue of the septic mice were significantly reduced, suggesting that chlorpyrilamine hydrochloride is a potentially effective therapeutic drug for the prevention and treatment of acute lung injury in sepsis.

[0031] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An application of clopyramine hydrochloride in the preparation of a drug for treating septic lung injury.

2. The use of clopyramine hydrochloride according to claim 1 in the preparation of a drug for treating septic lung injury, characterized in that: The clopyrilamine hydrochloride can reduce the pathological damage of lung tissue caused by septic lung injury and reduce the level of inflammatory factors.

3. The use of clopyramine hydrochloride in the preparation of a drug for treating septic lung injury according to claim 2, characterized in that: The drug for treating sepsis may be added with a pharmaceutically acceptable carrier.

4. The use of clopyramine hydrochloride in the preparation of a drug for treating septic lung injury according to claim 3, characterized in that: The dosage form of the drug for treating septic lung injury is one or more of powder, injection, capsule, granule, tablet, emulsion, suspension, spray, powder, liposome, oral solution and pill.

5. The use of clopyramine hydrochloride in the preparation of a drug for treating septic lung injury according to claim 3, characterized in that: The administration method of clopyrilamine hydrochloride is one or more of intramuscular injection, subcutaneous injection, intravenous injection, oral administration, sublingual administration, intralesional or intracerebral or implanted delivery, and spray administration.

Images