Application of D-(+)-phenyllactic acid in preparation of medicine for preventing or treating sepsis

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of D-(+)-phenyllactic acid in preparation of a medicine for preventing or treating sepsis. D-(+)-phenyllactic acid is used as a unique active component, so that the problem of treatment of sepsis and multi-organ injury caused by sepsis is solved, the multi-organ injury in a sepsis model is remarkably improved, the protection effect on lung, kidney and liver injury related to sepsis is realized, and a new application direction is provided for D-(+)-phenyllactic acid.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of D-(+)-phenyllactic acid in the preparation of drugs for the prevention or treatment of sepsis. Background Technology

[0002] D-(+)-Phenyllactic acid (3-PLA) is an aromatic amino acid metabolite, primarily derived from the phenylalanine metabolic pathway. It can be synthesized by various intestinal microorganisms, particularly lactic acid bacteria and some fungi, which produce it in large quantities during their metabolism. As a phenylalanine derivative, D-(+)-Phenyllactic acid not only plays a crucial role in maintaining intestinal microecological stability but also exhibits various biological activities, including antibacterial, anti-inflammatory, and immunomodulatory effects. Previous studies have shown that D-(+)-Phenyllactic acid can effectively inhibit the growth of both Gram-positive and Gram-negative bacteria and regulate host immune responses.

[0003] Sepsis is a systemic inflammatory response syndrome induced by infection, often accompanied by immune dysfunction and multiple organ dysfunction, and is one of the leading causes of death in intensive care units. Its pathological mechanisms are complex, involving multiple factors such as cytokine storms, oxidative stress, intestinal barrier disruption, and gut microbiota imbalance. In recent years, some studies have confirmed that the gut plays a role in the occurrence and progression of sepsis, with intestinal barrier dysfunction and gut microbiota imbalance considered important driving factors for sepsis exacerbation. Against this backdrop, the effectiveness of D-(+)-phenyllactic acid in preventing and treating multi-organ damage caused by sepsis remains uncertain. Summary of the Invention

[0004] The following is an overview of the topics described in detail in this article.

[0005] This invention aims to provide the application of D-(+)-phenyllactic acid in the preparation of drugs for the prevention or treatment of sepsis, thereby addressing the problems existing in the prior art. This invention discovers the clinical application value of D-(+)-phenyllactic acid in the preparation of drugs for the prevention or treatment of sepsis and its resulting multi-organ damage, proposing that D-(+)-phenyllactic acid has a good protective effect against sepsis and its resulting multi-organ damage, can improve pathological damage to the lungs / kidneys / liver, has significant anti-inflammatory effects, and few side effects.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: In one aspect, the present invention provides the use of D-(+)-phenyllactic acid or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention or treatment of sepsis.

[0007] According to some embodiments of the present invention, D-(+)-phenyllactic acid is the sole active ingredient of the drug.

[0008] According to some embodiments of the present invention, the drug prevents or treats at least one of sepsis-induced multi-organ damage, inflammatory response, and oxidative stress response.

[0009] According to some embodiments of the present invention, the multi-organ injury includes one or more functional impairments of the brain, lungs, liver, kidneys, spleen, heart, and skeletal muscles.

[0010] According to some embodiments of the present invention, the drug prevents or treats the multi-organ damage by inhibiting cytokine production or suppressing cytokine storms or reducing the release of damaging factors.

[0011] According to some embodiments of the present invention, the cytokines include at least one of TNF-α, IL-6, and IL-1β.

[0012] According to some embodiments of the present invention, the damage factor includes at least one of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), and myeloperoxidase (MPO).

[0013] According to some embodiments of the present invention, the drug reduces the mortality rate of sepsis and improves the survival rate of sepsis.

[0014] According to some embodiments of the present invention, the sepsis includes sepsis caused by at least one precipitating factor selected from LPS, lipoproteins, glycoproteins, lipopeptides, nucleic acids, trauma, and burns.

[0015] According to some embodiments of the present invention, the dosage form of the drug is selected from tablets, capsules, granules, powders, liquid preparations, ointments, injections, or sprays.

[0016] According to some embodiments of the present invention, the drug can be administered to patients requiring this treatment via oral or parenteral administration.

[0017] For example, when used for parenteral administration, it can be formulated as an injection. When formulating injections, conventional methods in the existing pharmaceutical field can be used, employing either aqueous or non-aqueous solvents. The most commonly used aqueous solvent is water for injection, but 0.9% sodium chloride solution or other suitable aqueous solutions can also be used. Commonly used non-aqueous solvents are vegetable oils, primarily soybean oil for injection, and other aqueous solutions of ethanol, propylene glycol, polyethylene glycol, etc. When formulating injections, excipients may be omitted or added according to the properties of the drug, such as osmotic pressure regulators, pH regulators, solubilizers, fillers, antioxidants, antibacterial agents, emulsifiers, and suspending agents. For oral administration, it can be formulated as conventional solid dosage forms, such as tablets, capsules, powders, pills, and granules; or as oral liquid dosage forms, such as oral solutions, oral suspensions, and syrups. When formulating oral dosage forms, suitable fillers, binders, disintegrants, and lubricants can be added.

[0018] According to some embodiments of the present invention, the medicament further includes pharmaceutically acceptable excipients.

[0019] The specific frequency of drug administration in this invention can be determined by those skilled in the art through known techniques and by observing results obtained under similar conditions. Preferably, the frequency of drug administration is once to three times daily, or once every 2 to 30 days; for example, it can be once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every eight days, once every nine days, once every ten days, once every fifteen days, once every twenty days, once every twenty-five days, or once every thirty days.

[0020] Based on mouse body weight, the effective dose of the D-(+)-phenyllactic acid or its pharmaceutically acceptable salt in mice is 20 mg / kg / d to 100 mg / kg / d, specifically about 50 mg / kg / d.

[0021] In this invention, the drug treatment targets mammals, including humans and mice. Those skilled in the art can estimate the human dose per unit body weight based on the equivalent dose conversion between humans and experimental animals. According to the dose-per-unit-body-weight conversion, the equivalent dose for mice is approximately nine times that for humans.

[0022] According to some embodiments of the present invention, a "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed by the compound of the present invention with an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0023] Compared with the prior art, some embodiments of the present invention have at least the following beneficial effects: This invention discovers that D-(+)-phenyllactic acid can significantly reduce the mortality rate of mice caused by sepsis, alleviate damage to the liver, kidneys, and lungs, and reduce the expression of inflammatory factors. The effects are significant and the treatment is safe. It has broad application prospects in the prevention and treatment of sepsis and can be used to prepare drugs for the prevention and treatment of sepsis and its multi-organ damage.

[0024] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0025] Figure 1 This is a graph showing the survival rate of mice in each group in Example 1; Figure 2 The graph shows the results of organ damage index detection in each group of mice in Example 2; Figure 3 This is a graph showing the results of cytokine concentration detection in each group of mice in Example 2; Figure 4 The images show the H&E staining results of liver, kidney, and lung pathological sections from mice in each group in Example 2. Detailed Implementation

[0026] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0027] Unless otherwise specified, in this invention, "about" means that the allowable error is within ±10%, and further, within ±5%.

[0028] When a numerical range is disclosed herein, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0029] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0030] Animals: Male C57BL / 6J mice aged 6-8 weeks, weighing 16-22 g, were selected for the experiment and purchased from Spiford (Beijing) Biotechnology Co., Ltd.

[0031] Reagents and instruments: D-(+)-phenyllactic acid (MedChemExpress); sodium pentobarbital (Sigma-Aldrich); sterile sutures (Ningbo Medical Suture Co., Ltd.); physiological saline (Shijiazhuang No.4 Pharmaceutical Co., Ltd.); 18G injection needles (Zhejiang Kangdelai Medical Instrument Co., Ltd.).

[0032] Example 1 This embodiment tests whether D-(+)-phenyllactic acid can significantly improve the survival rate of mice in the cecal ligation and perforation (CLP) model.

[0033] Six-week-old male C57BL / 6 mice were randomly divided into a CLP group and a 3-PLA+CLP group, with 15 mice in each group. The CLP group received an intraperitoneal injection of 200 μL PBS buffer, while the 3-PLA+CLP group received an intraperitoneal injection of 50 mg / kg of 3-PLA. Two hours after the injections, the mice underwent severe CLP surgery: anesthesia was administered via intraperitoneal injection of 3% sodium pentobarbital. After disinfection and preparation with 75% anhydrous ethanol, the cecum was removed from the mid-abdominal linea alba and ligated 1 cm from the blind end with 4-0 sutures. An 18G needle was used to puncture the cecum at 3 / 4 of its length, a small amount of contents was expelled, the cecum was reinserted, and the peritoneum was sutured in layers. Survival rates were observed, and Kaplan-Meier survival curves were plotted.

[0034] The results are as follows Figure 1 As shown, the survival rate of mice in the 3-PLA+CLP group was significantly higher than that in the CLP group. Therefore, D-(+)-phenyllactic acid has a protective effect on mice after CLP surgery.

[0035] Example 2 This embodiment tests the protective effect of D-(+)-phenyllactic acid against multi-organ damage in mice after CLP surgery.

[0036] Six-week-old male C57BL / 6 mice were randomly divided into a CLP group and a 3-PLA+CLP group. The CLP group received an intraperitoneal injection of 200 μL PBS buffer, while the 3-PLA+CLP group received an intraperitoneal injection of 50 mg / kg 3-PLA. Two hours after injection, the mice underwent severe CLP surgery, and 12 hours after model establishment, samples of peritoneal lavage fluid, blood, liver, kidney, lung, and intestine were collected and frozen at -80 °C for later use. Serum ALT, AST, Cr, and BUN levels, as well as MPO damage levels in lung tissue, were detected using commercially available kits from Nanjing Jiancheng Biological Research Institute. Liver, kidney, and lung tissues were fixed, dehydrated, embedded, and then stained with hematoxylin and eosin (HE) to detect pathological changes. Furthermore, serum TNF-α, IL-6, and IL-1β cytokine concentrations were measured using ELISA to assess the systemic inflammatory response levels in each group.

[0037] ALT and AST are biomarkers for assessing liver damage; BUN and Crea can indicate decreased glomerular filtration rate and renal failure, serving as biomarkers for assessing kidney damage; elevated MPO levels in lung tissue directly reflect neutrophil-mediated inflammatory responses and the degree of oxidative stress, and are important indicators for assessing sepsis-related lung injury. Figure 2 The results showed that the organ damage indicators in the 3-PLA+CLP group were significantly lower than those in the CLP group.

[0038] Sepsis is a systemic inflammatory response syndrome. Inflammatory cytokines such as IL-1β, IL-6, and TNF-α play important roles in the pathological process of sepsis. Elevated levels of these inflammatory cytokines lead to systemic inflammation and multiple organ dysfunction. Changes in inflammatory cytokine levels can reflect the anti-inflammatory effects of drugs and their intervention in the pathological process of sepsis. Figure 3 The results showed that the cytokine concentrations in the 3-PLA+CLP group were significantly lower than those in the CLP group.

[0039] Figure 4 The results of HE staining of liver, kidney, and lung pathological sections from each group of mice are shown. Figure 4 The results showed that the liver, lung, and kidney damage in mice in the 3-PLA+CLP group was significantly reduced compared to the CLP group.

[0040] In summary, D-(+)-phenyllactic acid can significantly reduce the level of multi-organ damage after CLP surgery in mice.

[0041] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. The use of D-(+)-phenyllactic acid or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention or treatment of sepsis.

2. The application according to claim 1, characterized in that, The drug is used to prevent or treat at least one of the following: multi-organ damage, inflammatory response, and oxidative stress caused by sepsis.

3. The application according to claim 2, characterized in that, The multi-organ injury includes one or more functional impairments in the brain, lungs, liver, kidneys, spleen, heart, and skeletal muscles.

4. The application according to claim 2, characterized in that, The drug prevents or treats the multi-organ damage by inhibiting cytokine production, suppressing cytokine storms, or reducing the release of damaging factors.

5. The application according to claim 4, characterized in that, The cytokines include at least one of TNF-α, IL-6, and IL-1β.

6. The application according to claim 4, characterized in that, The damage factors include at least one of alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, and myeloperoxidase.

7. The application according to claim 1, characterized in that, The drug reduces the mortality rate of sepsis.

8. The application according to claim 1, characterized in that, The sepsis includes sepsis caused by at least one of the following factors: LPS, lipoproteins, glycoproteins, lipopeptides, nucleic acids, trauma, and burns.

9. The application according to claim 1, characterized in that, The dosage form of the drug is selected from tablets, capsules, granules, powders, liquid preparations, ointments, injections, or sprays.

10. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable excipients.

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