Application of vericiguat in treating acute lung injury

Abstract

The invention discloses an application of vericiguat in treating acute lung injury, and belongs to the technical field of medicines. The invention finds that the Velciguat has a very remarkable effect on preventing and treating the acute lung injury, can improve the elastic characteristic and respiratory function of lung tissues, can reduce the mRNA expression level of IL-6, IL-1beta and TNF-alpha in the acute lung injury, and can be used for preparing the medicine for treating the acute lung injury. The invention has important clinical guiding significance for treating acute lung injury, provides a new treatment approach for clinical treatment of acute lung injury, and has a relatively wide application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to the use of vericipiracil in the treatment of acute lung injury. Background Art

[0002] Acute lung injury (ALI) is an immune-inflammatory disease of the lung characterized by increased alveolar capillary permeability, triggered by multiple factors. It is a clinical problem caused by acute, excessive lung inflammation, with a mortality rate as high as 25% to 45% due to multiple complications. Despite significant advances in modern critical care medicine, ALI still results in high morbidity and mortality, necessitating the urgent need for effective ALI treatments and therapies.

[0003] Vericiguat, molecular formula: C 19 H 16 F2N8O2, molecular weight: 426.38. Developed by Bayer, it was approved for marketing by the U.S. FDA in 2021, becoming the first drug approved specifically for the treatment of heart failure that year. It can be used to treat patients with symptomatic chronic heart failure and an ejection fraction less than 45% who have experienced a worsening heart failure event, to reduce the risk of hospitalization for heart failure or the need for emergency intravenous diuretic treatment. Vericigum is a soluble guanylate cyclase (sGC) stimulator that directly stimulates sGC, increasing intracellular cGMP levels, thereby relaxing smooth muscle and dilating blood vessels. Unlike previous heart failure drugs that mainly act on the activation of neuro-hormonal mechanisms and metabolic inflammatory mechanism disorders, Vericipaguat targets cell-signaling pathway disorders, does not rely on endogenous nitric oxide (NO), and directly stimulates guanylate cyclase (sGC) to increase cGMP production; at the same time, it has a synergistic effect with endogenous NO, which can increase the sensitivity of sGC to NO, repair the damaged NO-sGC-cGMP pathway, improve vascular endothelial function, and thereby improve the function of target organs such as the heart and kidneys.

[0004] However, to date, no studies on the application of vericipiracil in the treatment of acute lung injury have been reported. Summary of the Invention

[0005] In view of this, the object of the present invention is to provide use of Vericiguat in the treatment of acute lung injury.

[0006] The object of the present invention is to achieve the following goals:

[0007] The present invention provides use of vericipiraguat in preparing a medicament for preventing or treating acute lung injury.

[0008] Based on the above technical solution, further, the drug includes an effective amount of vericiguat and pharmaceutically acceptable excipients.

[0009] Based on the above technical solution, further, the pharmaceutically acceptable excipients include fillers, diluents, binders, disintegrants, emulsifiers and drug carriers without toxic side effects.

[0010] Based on the above technical solution, further, the drug uses Vericiguat as the only active ingredient.

[0011] Based on the above technical solution, further, the drug is prepared into a pharmaceutically acceptable dosage form.

[0012] Based on the above technical solution, further, the dosage forms include tablets, drops, injection preparations and capsule preparations.

[0013] Based on the above technical solution, further, the drug is prepared in the form of a single-dose drug.

[0014] Based on the above technical solution, further, the single-dose drug contains 1-1000 mg of vericipiraguat.

[0015] Based on the above technical solution, further, the drug can improve the elasticity characteristics of lung tissue and respiratory function.

[0016] Based on the above technical solution, further, the drug can reduce the mRNA expression levels of IL-6, IL-1β and TNF-α in acute lung injury.

[0017] The present invention has the following beneficial effects compared to the prior art:

[0018] In response to the current lack of therapeutic drugs and methods for acute lung injury, the present invention discovered for the first time that Vericipiguat has a very significant effect in preventing and treating acute lung injury. Experimental results showed that compared with the blank group, the model group had significant inflammation and tissue swelling, and the situation was significantly reversed after administration of Vericipiguat. Vericipiguat can be used to prepare drugs for treating acute lung injury, providing an important theoretical basis for exploring new ideas for low-toxic and high-efficiency prevention and treatment of acute lung injury. It has important clinical guidance significance for the treatment of acute lung injury and provides a new therapeutic approach for the clinical treatment of acute lung injury. The present invention provides a foundation for new uses of old drugs and innovative therapies. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention, the drawings related to the embodiments are briefly introduced below.

[0020] Figure 1 These are the HE staining results of acute lung injury in mice in different experimental groups, among which A is the CON group, B is the CLP group, C is the CLP+Vericiguat (L) group, D is the CLP+Vericiguat (H) group, and E is the Vericiguat group.

[0021] Figure 2 Figure 2 is the lung function test results of mice in different experimental groups, where A is the Cdyn value, B is the FVC100 value, C is the IC value, and D is the FVC value.

[0022] Figure 3 The results of bacterial colony-forming units (CFUs) detection in the blood (A), lung tissue (B), and peritoneal lavage fluid (C) of mice in different experimental groups.

[0023] Figure 4 The following are the qRT-PCR test results for the expression of lung inflammation-related factors in mice in different experimental groups, where A is the expression of IL-1β, B is the expression of TNF-α, and C is the expression of IL-6.

[0024] Figure 5 These are the results of the expression of inflammatory factor TNF-α in the serum of mice in different experimental groups. DETAILED DESCRIPTION

[0025] The present invention is described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto. Obviously, the embodiments described below are only some embodiments of the present invention. For those skilled in the art, other similar embodiments obtained without creative work all fall within the scope of protection of the present invention.

[0026] Example 1

[0027] This example investigates the effect of Vericipiracil on acute lung injury induced by cecal ligation and puncture (CLP).

[0028] CLP surgery involves anesthetizing mice with a gas anesthesia machine, making an abdominal incision, and then removing the cecum for double perforation using a 21g needle. The peritoneum and skin are sutured after surgery, and the mice are rewarmed and cultured normally for 24 hours before sampling and testing.

[0029] Thirty-five male 8-week-old C57BL / 6 mice were randomly divided into five groups: (1) blank control group (CON): 7 mice, free access to water and diet; (2) model (CLP) group: 7 mice, CLP model was established on the 8th day; (3) CLP+Vericiguat (H) group: 7 mice, Vericiguat (5 mg / kg / day) was administered by gavage before model establishment for 7 consecutive days, and CLP model was established on the 8th day; (4) CLP+Vericiguat (L) group: 7 mice, Vericiguat (2.5 mg / kg / day) was administered by gavage before model establishment for 7 consecutive days, and CLP model was established on the 8th day; (5) single drug administration group (Vericiguat): 7 mice, Vericiguat (5 mg / kg) was administered by gavage for 7 consecutive days at the same time as the drug administration group; the mice were killed after 9 days.

[0030] The lung tissues of the mice sacrificed in the above experimental groups were fixed with paraformaldehyde, embedded in paraffin blocks and then stained with HE.

[0031] The results are as follows Figure 1 As shown, compared with the CON group, the lung tissue of the CLP group showed a large number of inflammatory cell infiltration and tissue swelling ( Figure 1 B), Inflammatory cell infiltration and tissue edema in the lung tissues of mice in the CLP+Vericiguat(L) and CLP+Vericiguat(H) groups were significantly reduced ( Figure 1 C, Figure 1 D). In order to verify the effect of Vericiguat itself on the mouse body, this example conducted a single-drug group. The results showed that Vericiguat had no obvious damage to the tissues ( Figure 1 E).

[0032] The ventilation status of mice in each group after tracheotomy was tested using a mouse lung function tester. The results were as follows: Figure 2 As shown in the figure, compared with the control group, the Cdyn, FVC100, IC and FVC values of the mice in the drug-treated group were significantly decreased (p<0.05), indicating that the lung function of the mice given Vericiguat was improved, reflecting the recovery of lung tissue elasticity and respiratory function.

[0033] 20ul of blood, 20ul of peritoneal lavage fluid, and 20ul of PBS-diluted suspension of 0.04g lung tissue from each group of mice were respectively taken and coated on agarose culture medium for colony counting.

[0034] The results are as follows Figure 3 As shown, compared with the CON group, a large number of colonies were found in the blood, peritoneal lavage fluid, and lung tissue of the CLP group, and the drug-treated groups showed a partial reversal. Single-dose administration had no harmful effect on mice.

[0035] Real-time fluorescence quantitative qRT-PCR was used to determine the mRNA expression levels of inflammatory indicators such as IL-6, IL-1β, and TNF-α in the lung tissues of the mice sacrificed in the above experimental groups. The specific steps were as follows: appropriate amount of lung tissue was taken for RNA extraction and then cDNA was synthesized and stored at 4°C. Real-time PCR reaction was performed, with pre-denaturation at 95°C for 30s, reaction at the same temperature for 5s, and 60°C for 30s, for 39 cycles. GAPDH was used as an internal reference, and three replicates were measured at the same time, using 2 ﹣ΔΔCt , calculate the relative expression level of the target gene.

[0036] The results are as follows Figure 4 As shown in the figure, the expression levels of lung inflammation-related factors (TNF-α, IL-6, and IL-1β) in mice in the CLP group were significantly higher than those in the CON group, indicating that the CLP-induced sepsis model successfully triggered a lung inflammatory response;

[0037] The inflammatory factors in the CLP+Vericiguat(L) group and the CLP+Vericiguat(H) group were significantly lower than those in the modeling group, indicating that Vericiguat has a significant anti-inflammatory effect and that Vericiguat alone has no significant effect on normal mice.

[0038] The expression of inflammatory factor TNF-α in the serum of mice in different experimental groups was detected. The specific operation steps were as follows: the serum of mice in different experimental groups was centrifuged at about 1500g for 20 minutes at 4°C, and the yellow or light yellow supernatant was taken. The number of samples was determined, and two parallel replicates were performed for each concentration. The ELISA kit was purchased from CUSABIO and measured according to the manufacturer's protocol. The sample, standard, and sample diluent were added to the corresponding wells at 100μL / well as the standard test group, standard group, and blank group. After adding the corresponding reagents according to the steps and mixing, A was immediately measured. 450 Calculate the average absorbance of each set of repeated standards and samples. The number of repetitions should be within 20% of the average value. Draw a standard curve for TNF-α standard. With the concentration of the standard as the horizontal axis, A 450 The values are the vertical coordinates, and the coordinate points of each standard are connected by smooth lines. The corresponding concentration of the sample is calculated based on the absorbance value of the sample and the standard curve.

[0039] The results are as follows Figure 5 As shown, CLP surgery alone increased TNF-α secretion, while vericiguat administration inhibited TNF-α expression. Vericiguat administration alone had no effect on mice.

[0040] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of Vericiguat in the preparation of a medicament for preventing or treating acute lung injury.

2. The use according to claim 1, characterized in that The drug comprises an effective amount of vericipiguat and pharmaceutically acceptable excipients.

3. The use according to claim 2, characterized in that The pharmaceutically acceptable excipients include fillers, diluents, binders, disintegrants, emulsifiers and drug carriers with no toxic or side effects.

4. The use according to any one of claims 1 to 3, characterized in that The medicine is prepared into a pharmaceutically acceptable dosage form.

5. The use according to claim 4, characterized in that The dosage forms include tablets, drops, injection preparations and capsule preparations.

6. The use according to claim 1, characterized in that The medicine is prepared in the form of a single-dose medicine.

7. The use according to claim 6, characterized in that The single-dose medicine contains 1-1000 mg of vericipiguat.

8. The use according to claim 1, characterized in that The drug can improve the elasticity of lung tissue and respiratory function.

9. The use according to claim 1, characterized in that The drug can reduce the mRNA expression levels of IL-6, IL-1β and TNF-α in acute lung injury.

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