Application of salbutamol in preparation of medicine for preventing and treating sepsis renal injury

Abstract

The invention belongs to the technical field of biology, and particularly relates to application of salbutamol in preparation of a medicine for preventing and treating sepsis renal injury. The salbutamol is a salbutamol oral solution; the salbutamol can effectively relieve the sepsis renal injury and inflammation level and obviously prolong the survival time of model animals. The salbutamol is used for preventing and treating sepsis renal injury, the effect is remarkable, and sepsis renal injury indexes can be effectively improved by oral administration before operation; the side effect is small, the excitement effect on the heart is very small, and no central effect exists; the medicine is a clinical common medicine, can be atomized and inhaled in the perioperative period, and takes effect quickly; the traditional Chinese medicine composition is a common asthma treatment medicine, and can improve ventilation of patients and improve prognosis.

Description

Technical Field

[0001] The invention belongs to the field of biotechnology, and particularly relates to application of salbutamol in preparing medicine for preventing and treating sepsis-induced kidney injury. Background Art

[0002] Sepsis is a systemic inflammatory response syndrome caused by the invasion of bacteria and other pathogenic microorganisms into the body, with a high incidence and mortality rate. The kidney is one of the organs most commonly affected by organ dysfunction in sepsis, and acute kidney injury has been confirmed to be an independent risk factor for increased mortality in patients with sepsis. Therefore, prevention and treatment of sepsis-induced kidney injury is of great significance for improving patient prognosis. Among them, patient factors, anesthesia factors and surgery-related factors can all cause sepsis-induced kidney injury to varying degrees.

[0003] The pathogenesis of septic renal injury is very complex and has not yet been fully elucidated. In the past, it was believed that the main mechanism of septic renal injury was related to renal ischemia-reperfusion injury, but some septic renal injury can occur under normal or increased whole-renal blood flow. Other studies have found that septic renal injury involves damage and dysfunction of multiple cell types, including neutrophils, macrophages, vascular endothelial cells, and renal tubular epithelial cells, as well as their interactions and associations. These studies have demonstrated that the pathogenesis of septic renal injury is multifactorial and complex, involving interactions between inflammation, microcirculatory dysfunction, and metabolic reprogramming. Therefore, effective prevention and treatment strategies and drugs need to be further explored; currently, there is a lack of effective biomarkers for septic renal injury in clinical practice.

[0004] In patients with sepsis, inflammation and hypoperfusion in the intestine are important pathophysiological mechanisms for the aggravation of damage. Impaired intestinal barrier function caused by intestinal damage allows bacteria and toxins to transfer from the intestinal cavity to the mesenteric lymph and systemic circulation, leading to systemic inflammatory response and even multiple organ failure and collective death. The dysregulation of the interaction between the intestinal epithelium, the immune system, the body's endogenous microbiota and the kidneys may lead to the deterioration of systemic inflammation and aggravate sepsis renal injury. Therefore, these studies suggest that sepsis renal injury is closely related to the destruction of the intestinal barrier and the translocation of intestinal flora. However, the regulatory mechanism of salbutamol in improving sepsis renal injury and intestinal flora has not been reported.

[0005] In general, septic renal 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. Summary of the invention

[0006] The purpose of the present invention is to provide a use of salbutamol in the preparation of a medicament for preventing and treating sepsis-induced kidney injury, so as to effectively improve sepsis-induced kidney injury indicators and enhance prognosis.

[0007] The objective of the present invention is achieved through the following technical solutions: The invention provides an application of salbutamol in preparing a medicine for preventing and treating sepsis-induced kidney injury.

[0008] Furthermore, the salbutamol prevents and treats sepsis-induced kidney injury by reducing small intestinal pathological damage and systemic inflammatory response indicators.

[0009] Furthermore, the dosage forms of the drug include tablets, capsules, oral preparations and injections.

[0010] Furthermore, the tablet comprises a coated tablet.

[0011] Furthermore, the oral preparation includes oral solution, oral granules and oral powder.

[0012] Furthermore, the injection includes freeze-dried powder injection and injection emulsion.

[0013] Furthermore, in the drug, salbutamol is the only active ingredient.

[0014] Furthermore, the drug also includes a pharmaceutically acceptable carrier. Beneficial Effects

[0015] The present invention has been verified by preliminary animal experiments and clinical samples, and the salbutamol oral solution can effectively improve sepsis-induced renal injury in mice and patients. Compared with existing therapies, its advantages are: 1. The effect is significant. Oral administration before surgery can effectively improve the indicators of kidney injury in sepsis; 2. Small side effects, little excitatory effect on the heart, and no central nervous system effect; 3. It is easy to use and is a commonly used drug in clinical practice. It can be aerosolized and inhaled during the perioperative period and has a rapid onset of effect. 4. It has diverse therapeutic effects. It is a common asthma treatment drug that can improve patients’ ventilation and prognosis. 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 work.

[0017] Figure 1 This is a validation diagram of salbutamol alleviating acute kidney injury in sepsis, where A is the survival rate of different treatment groups, and B is the BUN level in plasma of different treatment groups.

[0018] Figure 2This is a verification chart of salbutamol reducing the level of inflammatory factors in sepsis, where A is IL-6 and B is TNF-α. DETAILED DESCRIPTION

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0024] The test methods used in the following implementations, unless otherwise specified, are all commonly used experimental methods in this field; Unless otherwise specified, the experimental materials used in the following examples are all commonly used experimental materials in this field.

[0025] The specific product information of the salbutamol oral solution used in the present invention is as follows: Product Name: Salbutamol Oral Solution Molecular formula: (C 13 H 21 NO 3 )2 ·H 2 SO 4 Molecular weight: 576.71 Pharmacokinetics: After oral administration of 10 mL of albuterol sulfate syrup (oral solution) (4 mg albuterol) in normal volunteers, albuterol is rapidly absorbed. The maximum plasma concentration of albuterol reaches approximately 18 ng / mL within 2 hours, after which the drug is metabolized with a half-life of approximately 5 hours.

[0026] In other studies, analysis of urine samples from patients who took 8 mg of salbutamol orally showed that 76% of the dose was excreted within three days, with most of the dose excreted within the first 24 hours. Sixty percent of the radioactivity was shown to be metabolites. Feces collected during this period accounted for 4% of the administered dose.

[0027] Adverse Reactions: The most common adverse reactions are: taste changes (bad, unpleasant and unusual taste), mouth and throat irritation, tremor (usually in the hands), nausea, sweating, agitation, headache and dizziness. These adverse effects may subside with continued treatment.

[0028] Precautions: ① Like all sympathomimetic amines, salbutamol sulfate syrup (oral solution) should be used with caution in patients with cardiovascular disease, especially coronary artery insufficiency, arrhythmia and hypertension. ② Salbutamol sulfate syrup (oral solution) can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, salbutamol sulfate syrup (oral solution) should be discontinued immediately and alternative therapy should be adopted. ③ Hypersensitivity reactions may occur immediately after taking salbutamol, as confirmed by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema. Like other beta-adrenergic agonists, salbutamol can produce significant cardiovascular effects in some patients through changes in pulse rate, blood pressure, symptoms and / or electrocardiogram.

[0029] This product, salbutamol oral solution, was purchased from Dongguan Kaifa Biotechnology Co., Ltd., and the company is responsible for the specific production process.

[0030] Example 1 In vivo validation of salbutamol oral solution to reduce sepsis-induced renal injury 1. 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, the epidermis and muscle layer were separated, and the cecum was found. The cecum was ligated with a 4-0 shell suture absorbable thread at 3 / 4 of the distance from the end. After ligation, a 1.2*38TWLB needle was used to pierce the blind end of the cecum horizontally, and the needle was used to penetrate the cecum. A small amount of intestinal contents were squeezed out from the needle hole, and the cecum was returned, and 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℃ preheated normal saline for fluid resuscitation. 24 hours after surgery, the inferior vena cava blood, ileum, cecum, colon and kidney tissues were removed for examination. The sham group (sham) was operated in the same way as the CLP group except that the needle did not penetrate the cecum.

[0031] 2. Experimental groups: Sixteen C57BL / 6J mice aged 6-8 weeks were randomly divided into sham operation group (Sham), cecal ligation and puncture group (CLP), salbutamol oral solution + cecal ligation and puncture group (SalbutamolOS + CLP), and salbutamol oral solution + sham operation group (SalbutamolOS + Sham).

[0032] (1) Sham group: except for not inserting the needle through the cecum, all other operation steps for mice were consistent with CLP; (2) CLP group: CLP model was established in mice; (3) Salbutamol oral solution + cecal ligation and puncture group (SalbutamolOS + CLP): The CLP model was established by gavage of 1 mg / kg salbutamol oral solution every day for 4 consecutive days; (4) Salbutamol OS + Sham group: The mice were gavaged with 1 mg / kg of salbutamol OS every day for 4 consecutive days. Except for not piercing the cecum with a needle, all other operation steps for the mice were consistent with CLP.

[0033] 3. Testing indicators and technical methods: (1) Observe and record the survival status of mice for 7 days.

[0034] (2) Assessment of renal tissue damage: a. H&E pathological scoring: The small intestinal segments were stained with hematoxylin and eosin (H&E), and photographed using an optical microscope. Two members who were unaware of the experimental groups independently assessed the degree of renal tissue damage. At least 5 microscopic fields were randomly selected for scoring for each mouse, and the average value was taken as the renal injury score of the mouse. b. Detection of urea nitrogen levels in plasma: Detection was performed according to the steps provided in the kit instructions.

[0035] (3) Detection of plasma inflammatory factor levels: Detection was performed according to the steps provided in the kit instructions.

[0036] In summary, in this example, different concentrations of salbutamol oral solution were given for pretreatment at the animal level, and a cecum ligation and puncture (CLP) model was established using C57BL / 6J mice. The 7-day survival rate of mice, plasma IL-6 and TNF-α levels, renal HE pathological damage, and urea nitrogen levels were detected. It was found that salbutamol can reduce the level of systemic inflammatory factors IL-6-TNF-α, effectively reduce sepsis-induced renal damage, and significantly increase the survival time of model animals. The specific results are as follows: Figure 1-2 As shown, after the sepsis model was established in mice, the survival rate was significantly decreased, and the BUN level and the levels of inflammatory factors IL-6 and TNF-α in plasma were significantly increased; after treatment with salbutamol, the survival rate of septic mice was significantly increased, and the BUN level and the levels of inflammatory factors IL-6 and TNF-α in plasma were significantly decreased, indicating that salbutamol is a potentially effective therapeutic drug for the prevention and treatment of acute kidney injury in sepsis, confirming that salbutamol oral solution can reduce sepsis-induced kidney injury.

[0037] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. The application of salbutamol in the preparation of drugs for preventing and treating septic renal injury.

2. The use according to claim 1, characterized in that The salbutamol prevents and treats sepsis-induced kidney injury by reducing systemic inflammatory response indicators.

3. The use according to claim 1, characterized in that The dosage forms of the drug include tablets, capsules, oral preparations and injections.

4. The use according to claim 3, characterized in that: The tablets include coated tablets.

5. The use according to claim 3, characterized in that: The oral preparation includes oral solution, oral granules and oral powder.

6. The use according to claim 3, characterized in that: The injection includes freeze-dried powder injection and injection emulsion.

7. The use according to claim 1, characterized in that: In the drug, salbutamol is the only active ingredient.

8. The use according to claim 1, characterized in that The medicament further includes a pharmaceutically acceptable carrier.

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