CN113827591A

CN113827591A - Application of biotin in preparing medicament for treating sepsis

Info

Publication number: CN113827591A
Application number: CN202111323606.5A
Authority: CN
Inventors: 刘海鹏; 郑梦歌; 曹亚娟
Original assignee: Shanghai Pulmonary Hospital
Current assignee: Shanghai Pulmonary Hospital
Priority date: 2021-11-09
Filing date: 2021-11-09
Publication date: 2021-12-24
Anticipated expiration: 2041-11-09
Also published as: CN113827591B

Abstract

The invention provides an application of Biotin (Biotin) in preparing a medicament for treating sepsis, wherein the main active ingredient of the medicament is Biotin or pharmaceutically acceptable salt thereof. The invention verifies that Biotin can inhibit the release of sepsis inflammatory factors IFN-beta, CXCL-10 and IL-6, and obviously prolongs the survival period of sepsis mice. Therefore, Biotin has potential sepsis prevention and treatment values, and can be used for improving the cure rate of sepsis, improving the prognosis of patients and reducing medical resource consumption.

Description

Application of biotin in preparing medicament for treating sepsis

Technical Field

The invention relates to the field of biological medicines, in particular to application of biotin in preparation of a medicine for treating sepsis.

Background

Infection is a ubiquitous health problem for people of all ages. Often, the body's response to infection is appropriate, so treatment is rarely required. However, sometimes the response to infection is inappropriate and may lead to organ dysfunction, which is sepsis (sepsis). Sepsis can be caused by bacteria, fungi or viruses, and is a systemic inflammatory response syndrome caused by invasion of pathogenic microorganisms such as bacteria into the body. Because of the fierce illness and high disease death rate, about 14,000 people die from the complications every day in the world, although the anti-infection treatment and organ function support technology makes great progress, the disease death rate of the sepsis still reaches 30-70 percent, and no specific treatment method exists at present.

The definition and recognition criteria for sepsis is a continuing process, reviewing the development of the concept of sepsis, from "systemic inflammatory response syndrome induced by infection" (sepsis-1) to "severe, potentially fatal organic dysfunction caused by insufficient or unregulated host response to infection" (sepsis-3), reflecting the growing knowledge of its mechanism and the success and failure of diagnostic and therapeutic interventions. Sepsis therapeutic strategies have focused primarily on control of infectious agents, antibiotic combination organ function support, etc. to control infection. For initial treatment of patients with sepsis: "time is life". Early administration of broad spectrum antibiotics and early intake of large amounts of fluid are the basis for effective treatment of septic shock. It is reported that the survival rate decreases by 7.6% for each hour of delay in the use of antibiotics. Early antibiotic treatment, distinguishing the source of infection, is imperative because it facilitates early antibiotic treatment and/or surgical control of the lesion. Since inappropriate antibiotic treatment is associated with increased mortality from sepsis, the choice of antibiotic is crucial to the prognosis of the patient. Rational use of antibiotics minimizes side effects, bacterial resistance, toxicity and risk of re-infection, and reduces treatment costs, while currently there is no specific treatment for sepsis. Therefore, aiming at the pathogenesis of sepsis, the key problem to be solved urgently is to search for effective sepsis treatment and prevention medicines with clinical transformation value.

Biotin (Biotin) is a water-soluble complex b vitamin, an essential cofactor for 5 carboxylases. Biotin-dependent carboxylases are involved in various cellular metabolic pathways such as gluconeogenesis, fatty acid synthesis, branched chain amino acid and odd chain fatty acid metabolism, and metabolic abnormalities caused by biotin deficiency play an important role in immune and inflammatory diseases. Previous studies reported that biotin deficiency and genetic defects in carboxylase holoenzyme synthase (HLCS) or biotinases induce skin inflammation and immune disorders. Review of previous studies shows that biotin plays an essential role in regulating the inflammatory response of the body, and whether biotin can achieve the effect of treating sepsis by regulating the inflammatory response has not been reported.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides the application of biotin in preparing a medicament for treating sepsis.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect the invention provides a medicament for the treatment of sepsis, which medicament comprises biotin or a pharmaceutically acceptable salt thereof.

In a second aspect the invention provides a medicament for inhibiting the inflammatory response to sepsis, which medicament comprises biotin or a pharmaceutically acceptable salt thereof.

Further, the medicine also comprises a pharmaceutically acceptable carrier or excipient.

In a third aspect, the invention provides the use of biotin in the manufacture of a medicament for the treatment of sepsis, the main active ingredient of the medicament being biotin or a pharmaceutically acceptable salt thereof.

Further, the above drugs, after administration, can exert the following effects:

(a) obviously inhibit the expression of inflammatory factors IFN-beta, CXCL-10 and IL-6; and

(b) prolonging the life span.

Further, the administration route of the above drugs is oral, transdermal, intramuscular, subcutaneous or intravenous injection.

Furthermore, the dosage form of the medicine can be tablets, capsules, oral liquid, buccal agents, granules, medicinal granules, pills, powder, paste, pellets, suspensions, powder, solutions, injections, creams, sprays, drops or patches.

The fourth aspect of the invention provides the use of biotin in the manufacture of a medicament for inhibiting the inflammatory response to sepsis, the main active ingredient of the medicament being biotin or a pharmaceutically acceptable salt thereof

(b) prolonging the life span.

By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:

the invention verifies that Biotin can inhibit the release of sepsis inflammatory factors IFN-beta, CXCL-10 and IL-6, and obviously prolongs the survival period of sepsis mice. Therefore, Biotin has potential sepsis prevention and treatment values, and can be used for improving the cure rate of sepsis, improving the prognosis of patients and reducing medical resource consumption.

Drawings

FIG. 1 shows that Biotin inhibits macrophage sepsis inflammatory response in the abdominal cavity of mice in one embodiment of the present invention; wherein, the graph A shows that Biotin remarkably inhibits the expression of inflammatory factors IFN-beta, CXCL-10 and IL-6 induced by LPS, and is dose-dependent; panel B shows that Biotin significantly inhibited poly i: c-induced expression of the inflammatory factors IFN-beta, CXCL-10 and IL-6, and is dose-dependent;

FIG. 2 shows that Biotin inhibits mouse sepsis and its induced systemic inflammatory response in one embodiment of the present invention; wherein, the graph A is a mouse sepsis model experiment flow chart induced by LPS, and the graph B shows the observation result of the survival rate of a sepsis mouse induced by LPS interfered by Biotin.

Detailed Description

Infection factors in sepsis activate the mononuclear macrophage system and other inflammatory reaction cells of the organism, a large amount of inflammatory mediators such as IL-6, IL-1 beta, TNF alpha, IFN-beta, CXCL-10 and the like are generated and released, so that the immune function is unbalanced, and under the sepsis state, the immunosuppression can further aggravate the systemic inflammatory reaction to cause the multiple organ failure of the organism until the death which cannot be reversed. The research of the invention proves that Biotin can obviously inhibit the inflammatory reaction of mouse sepsis and can obviously prolong the survival time of a sepsis mouse. The invention provides the application of Biotin in preparing a medicament for treating sepsis based on the above, and the main active ingredient of the medicament is Biotin or pharmaceutically acceptable salt thereof.

In a preferred embodiment of the present invention, the above-mentioned medicament further comprises a pharmaceutically acceptable carrier or excipient.

The term "pharmaceutically acceptable salt" refers to salts of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; such organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, 1, 5-naphthalenedisulfonic acid, sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids; by "pharmaceutically acceptable" is meant a material that is suitable for use in humans without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.

The term "carrier or excipient" includes one or more of binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavouring agents, wetting agents and the like.

The present invention will be described in detail and specifically with reference to the following examples and drawings so as to provide a better understanding of the invention, but the following examples do not limit the scope of the invention.

In the examples, the conventional methods were used unless otherwise specified, and reagents used were those conventionally commercially available or formulated according to the conventional methods without specifically specified.

Example 1

This example demonstrates that Biotin inhibits sepsis inflammatory responses at the in vitro cytological level, and the specific procedures and results are as follows:

1. mouse peritoneal macrophages were first pretreated with no concentration of biotin (0, 10, 100, 1000, 2000 μm) for half an hour. Then, Lipopolysaccharide (LPS), a component of the outer wall of the cell wall of gram-negative bacteria, is added to induce the abdominal macrophages to produce inflammatory response.

As can be seen from FIG. 1A, Biotin can significantly inhibit the expression of inflammatory factors IFN-beta, CXCL-10 and IL-6 induced by LPS, and the inhibition shows drug dose dependence.

2. Innate immunity is known to be the first line of defense of the body against infection by foreign pathogens, and excessive activation leads to sepsis, autoimmune diseases, and the like. To further confirm whether Biotin exerts an anti-inflammatory function by modulating Pattern Recognition Receptor (PRR) pathways, such as Toll-like receptor (TLRs) pathways. Therefore, we have used different stimuli poly i in addition to LPS for induction of Toll-like receptors to initiate inflammatory responses: c (Toll-like receptor TLR3 agonist, fig. 1B) activates innate immune target genes to initiate downstream inflammatory responses.

As can be seen from fig. 1B, Biotin vs poly i: the C-induced sepsis inflammatory reaction of the mice has a remarkable inhibiting effect.

In conclusion, Biotin has a good inflammation-inhibiting effect on the over-stimulated inflammatory reaction caused by bacterial infection, so that Biotin is a small molecular drug for effectively inhibiting the inflammatory reaction of sepsis on a cytological level.

Example 2

This example demonstrates that Biotin inhibits sepsis inflammatory responses at the in vivo animal level, and the specific procedures and results are as follows:

LPS induces an acute inflammatory response in the whole body, and D-galactosamine (D-gal) is often used in combination with LPS to rapidly amplify the LPS effect and exacerbate sepsis development. As shown in figure 2A, the method is highly controllable and has good repeatability, and the systemic acute inflammatory response of a host to sepsis can be observed by adopting large dose, combined use and single intraperitoneal injection of lethal dose of LPS and D-gal to induce a mouse sepsis model. Based on the weight conversion, we administered LPS 1. mu.g/mouse or 10. mu.g/mouse combined with D-gal 7.5 mg/mouse intraperitoneal injection to induce sepsis, and administered Biotin 10mg/kg or 100mg/kg dose to intervene intraperitoneally every 8 hours, and at the same time closely observed the survival period of the mouse.

As shown in FIG. 2B, Biotin significantly prolonged the survival rate of LPS-induced septic mice.

In conclusion, Biotin is also a small molecule drug that effectively inhibits sepsis inflammatory responses at the animal level in vivo.

The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. It will be appreciated by those skilled in the art that any equivalent modifications and substitutions are within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.

Claims

1. A medicament for the treatment of sepsis, comprising biotin or a pharmaceutically acceptable salt thereof.

2. A medicament for inhibiting an inflammatory response to sepsis, comprising biotin or a pharmaceutically acceptable salt thereof.

3. The medicament of claim 1 or 2, further comprising a pharmaceutically acceptable carrier or excipient.

4. The application of biotin in preparing a medicament for treating sepsis is characterized in that the main active ingredient of the medicament is biotin or pharmaceutically acceptable salt thereof.

5. The application of biotin in preparing a medicament for inhibiting sepsis inflammatory response is characterized in that the main active ingredient of the medicament is biotin or pharmaceutically acceptable salt thereof.

6. The use according to claim 4 or 5, wherein the medicament further comprises a pharmaceutically acceptable carrier or excipient.

7. The use according to claim 4 or 5, wherein the medicament, after administration, exerts the following effects:

(b) prolonging the life span.

8. Use according to claim 4 or 5, wherein the route of administration of the medicament is oral, transdermal, intramuscular, subcutaneous or intravenous injection.

9. The use according to claim 4 or 5, wherein the medicament is in the form of tablets, capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, creams, sprays, drops or patches.