CN114831974A - Application of nitisinone in preparing medicine for preventing and treating endotoxic shock diseases - Google Patents
Application of nitisinone in preparing medicine for preventing and treating endotoxic shock diseases Download PDFInfo
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- CN114831974A CN114831974A CN202210716732.5A CN202210716732A CN114831974A CN 114831974 A CN114831974 A CN 114831974A CN 202210716732 A CN202210716732 A CN 202210716732A CN 114831974 A CN114831974 A CN 114831974A
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The invention discloses an application of nitisinone in preparing a medicine for preventing and treating endotoxic shock diseases, belonging to the field of biological medicines. Animal experiments prove that the survival rate of mice with endotoxin shock can be improved by inhibiting the secretion of inflammatory cytokines IL-1b, IL-6, TNF-alpha, chemotactic factor MCP-1 and the like caused by LPS exposure by the nitrexicillin, so that the nitrexicillin has the potential value of being developed into a new generation of new generation medicaments for preventing and treating the endotoxin shock, and provides a new way for preventing and treating the endotoxin shock.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of nitisinone in preparing a medicine for preventing and treating endotoxic shock diseases.
Background
Ninxiong, english name: nitisinone, chemical name: 2- (2-nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione, also known as english: 2- [2-nitro-4- (trifluoromethylmethyl) benzoyl]cyclohexenone-1, 3-dione, 2- (2-nitro-4-trifluoromethylbenzoyl) -1, 3-cyclohexenone, NTBC, etc.; the molecular formula is as follows: c 14 H 10 F 3 NO 5 (ii) a Molecular weight: 329.23, the chemical formula is as follows:
nitisinone is a reversible inhibitor of 4-hydroxyphenylpyruvate oxidase (dioxygenase), is mainly used for treating hereditary tyrosinemia type 1 at present, and can prevent accumulation of toxic substances, namely Maleylacetoacetate (Maleylacetoacetate), Fumarylacetoacetate (Fumarylacetoacetate) and the like in a tyrosine metabolic process.
Septicemia, endotoxemia and shock caused by bacterial infection are the common causes of death of patients infected clinically, and bacterial endotoxin/Lipopolysaccharide (LPS) is the main pathogenic substance of the diseases. LPS is one of the main components of the cell wall of gram-negative bacteria and has a strong inflammatory action. In bacterial infection, LPS enters blood circulation to activate various inflammatory cells to release inflammatory mediators, so that inflammatory reaction is caused, and multiple organ failure can be caused in severe cases. Therefore, it is of great interest to research effective endotoxin antagonizing drugs.
The pathogenesis of endotoxemia/shock is complex. From the current basic research, it is known that the onset of endotoxemia/shock is not only inflammatory defensive reaction caused by invasion of pathogenic microorganisms into human bodies, but also relates to a series of systemic reactions. At present, comprehensive measures are mainly adopted for treating endotoxemia/shock, and no specific medicine is available. Therefore, the search for novel safe endotoxemia/shock prevention and treatment drugs can save more patients, and has extremely important clinical significance.
Disclosure of Invention
The invention aims to provide application of nitisinone in preparing a medicament for preventing and treating endotoxic shock diseases.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides an application of nitisinone in preparing a medicament for preventing and treating endotoxic shock diseases.
Preferably, the medicament comprises nitisinone or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable adjuvant.
Preferably, the dosage of the nitisinone is 0.02 mg/kg.
Preferably, the medicament is in the form of tablets, capsules, oral liquid, buccal agents, granules, pills, powder, paste, suspensions, powder or injections.
Preferably, the route of administration of the drug is oral, transdermal, intramuscular, subcutaneous or intravenous injection.
Animal experiments prove that the nitrendipine can improve the survival rate of mice with endotoxin shock by inhibiting the secretion of inflammatory cytokines IL-1b, IL-6, TNF-a, chemotactic factor MCP-1 and the like caused by LPS exposure, so that the nitrendipine can be further used for preparing a medicament for treating and preventing the endotoxin shock, widens the application range of the nitrendipine, and provides a new way for preventing and treating the endotoxin shock.
Drawings
FIG. 1 is a graph of the effect of nitisinone on survival of endotoxin shock mice;
FIG. 2 is a graph of the effect of nitisinone on the peripheral blood MCP-1 levels in endotoxic shock mice;
FIG. 3 is a graph of the effect of nitisinone on the peripheral blood IL-1 β levels in endotoxic shock mice;
FIG. 4 is a graph of the effect of nitisinone on the peripheral blood IL-6 levels in endotoxic shock mice;
FIG. 5 is a graph of the effect of nitisinone on peripheral blood TNF- α levels in endotoxic shock mice.
Detailed Description
The present invention will be further described in detail below with reference to the drawings and specific examples to better understand the present invention, but the following examples do not limit the scope of the present 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.
(I) test materials
Preparing Nitisinone (Nitisinone): 10mg of Nitisinone was dissolved in 30.37uL of DMSO, molar concentration 1M, and mass to volume ratio was 329.23 mg/mL. Adding 999uL double distilled water into 1uL of the solution, diluting 1000 times, wherein the molar concentration is 1mM, and the mass-to-volume ratio is 329.23 ug/mL. 15uL of the Nitisinone solution is added with 2.485mL of double distilled water, and the solution is diluted by 164.6 times to prepare 2ug/mL of Nitisinone solution.
Endotoxin (LPS) preparation: after 20mL of autoclaved PBS (pH7.4) was added to 100mg of LPS, the mixture was mixed until complete dissolution of LPS to a concentration of 5mg/mL, and 2.56mL of 5mg/mL of LPS was diluted to 4mg/mL with 0.64mL of PBS. Administered by intraperitoneal injection at a dose of 50mg/kg body weight.
Experimental animals: 6-8 week old C57BL/6 male mice, weighing 20 + -2 g, SPF grade, offered by Xuzhou university of medical laboratory animal center, laboratory animal production license: SCXK (threo) 2020-.
(II) animal model and Experimental Process
1. Effect of Nitisinone on survival of endotoxic shock mice
One week after adaptive feeding of male mice, the mice were randomly divided into 2 groups of 5 mice, each group consisting of: LPS group and LPS + Nitisinone group. Two groups of mice were administered with LPS at a dose of 50mg/kg, and two hours before LPS injection, the LPS + Nitisinone group was administered with Nitisinone (0.02mg/kg) at a dose of 0.0 p.i..
2. Effects of Nitisinone on the levels of inflammatory factors in endotoxic shock mice
One week after adaptive feeding of male mice, the mice were randomly divided into 3 groups of 10 mice each, with the groups: control group (control), LPS group and LPS + Nitisinone group. LPS is injected into the abdominal cavity of mice in an LPS group and an LPS + Nitisinone group according to the dose of 50mg/kg, Nitisinone (0.02mg/kg) is injected into the abdominal cavity of the LPS + Nitisinone group before the LPS is injected, a corresponding control solvent is injected into a control group, 3 groups of mice are killed by dissection after 4 hours of LPS injection, peripheral blood is taken out of an EP (Eppendorf) tube, serum is collected, and inflammatory factors in the peripheral blood of the mice are detected.
1) Serum collection
a) The non-anticoagulated peripheral blood is placed in an EP tube, marked, placed at 37 ℃ for 30 minutes, and blood is coagulated.
b) The liquid fraction was collected by pipette into a new EP tube, and was placed into a centrifuge for balancing and centrifugation at 12000rpm at 4 ℃ for 10 minutes.
c) Collecting the upper layer light yellow liquid, namely serum, and detecting the content of each cytokine.
2) IL-1 beta detection
a) The detection sample is the peripheral serum stock solution collected in the step 1).
b) The murine IL-1. beta. detection kit from BioLegend was used: and (3) performing quantitative detection on the IL-1 beta in the serum to be detected by ELISA MAXTX Deluxe Set Mouse IL-1 beta, and performing related operations according to a kit instruction.
3) TNF-alpha, IL6, MCP-1 and the like
a) The test sample is the peripheral serum collected in step 1).
b) And (3) using the serum sample stock solution to be detected for detecting TNF-alpha.
c) The serum sample to be detected is diluted by 100 times by PBS for detecting IL-6 and MCP-1.
d) Quantitative detection is carried out on TNF-alpha, IL6, MCP-1 and the like in a serum sample diluent to be detected by adopting a flow-type cytokine microsphere multi-factor detection technology, and related operations are carried out according to a BD company kit-BD TM Cytomeric Bead Array (CBA).
3. Statistical analysis
All data in the experiment are expressed by mean +/-standard deviation, GraphPad Prism 5.0 statistical software is adopted, Mantel-Cox is adopted for survival rate comparison, one-way ANOVA (one-way ANOVA) is adopted for comparison among three groups, and P <0.05 has statistical significance for difference.
4. Analysis of results
The effect of nitisinone on endotoxin shock mouse survival is shown in figure 1. In FIG. 1, nitisinone 0.02mg/kg body weight significantly reduced mortality in mice induced by intraperitoneal LPS injection.
The effect of nitisinone on the expression of chemokine MCP-1 in peripheral blood of endotoxic shock mice is shown in figure 2. In FIG. 2, nitisinone has a significant inhibitory effect on the expression of inflammatory factor MCP-1 in LPS-induced peripheral blood at a weight of 0.02 mg/kg; performing t test on the LPS group and the LPS + Nitisinone group; denotes 0.01< P < 0.05.
A graph of the effect of nitisinone on the expression of the inflammatory factor IL-1 β in peripheral blood of endotoxic shock mice is shown in FIG. 3. In FIG. 3, nitisinone has a significant inhibitory effect on the expression of inflammatory factor IL-1 β in LPS-induced peripheral blood at 0.02mg/kg body weight; performing t test on the LPS group and the LPS + Nitisinone group; denotes P < 0.01.
A graph of the effect of nitisinone on the expression of the inflammatory factor IL-6 in the peripheral blood of endotoxic shock mice is shown in FIG. 4. In FIG. 4, nitisinone has a significant inhibitory effect on the expression of inflammatory factor IL-6 in LPS-induced peripheral blood at 0.02mg/kg body weight; performing t test on the LPS group and the LPS + Nitisinone group; denotes P < 0.01.
A graph of the effect of nitisinone on the expression of the inflammatory factor TNF- α in peripheral blood of endotoxic shock mice is shown in FIG. 5. In FIG. 5, nitisinone has a significant inhibitory effect on the expression of inflammatory factor IL-6 in LPS-induced peripheral blood at 0.02mg/kg body weight; performing t test on the LPS group and the LPS + Nitisinone group; denotes P < 0.01.
The above results show that: the nitisinone can reduce the level of endotoxemia inflammatory factors and remarkably reduce death risk caused by endotoxin shock, and the nitisinone can be used for preparing a medicine for treating or preventing the endotoxin shock and related symptoms.
The above description is only for the purpose of illustrating the present invention and the appended claims are not to be construed as limiting the scope of the invention, which is intended to cover all modifications, equivalents and improvements that are within the spirit and scope of the invention as defined by the appended claims.
Claims (5)
1. Application of nitisinone in preparing medicine for preventing and treating endotoxic shock.
2. The use according to claim 1, wherein the medicament comprises nitisinone or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.
3. The use according to claim 2, wherein the nitisinone is administered in an amount of 0.02 mg/kg.
4. The use according to claim 1 or 2, wherein the medicament is in the form of tablets, capsules, oral liquids, buccal agents, granules, pills, powders, ointments, suspensions, powders or injections.
5. Use according to claim 1 or 2, wherein the route of administration of the medicament is oral, transdermal, intramuscular, subcutaneous or intravenous injection.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210716732.5A CN114831974A (en) | 2022-06-23 | 2022-06-23 | Application of nitisinone in preparing medicine for preventing and treating endotoxic shock diseases |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210716732.5A CN114831974A (en) | 2022-06-23 | 2022-06-23 | Application of nitisinone in preparing medicine for preventing and treating endotoxic shock diseases |
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| CN114831974A true CN114831974A (en) | 2022-08-02 |
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| CN202210716732.5A Pending CN114831974A (en) | 2022-06-23 | 2022-06-23 | Application of nitisinone in preparing medicine for preventing and treating endotoxic shock diseases |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100227936A1 (en) * | 2009-03-09 | 2010-09-09 | Moran Graham R | Treatment of microbial infections with compounds that inhibit 4-hydroxyphenylpyruvate dioxygenase |
| CN103747781A (en) * | 2011-06-23 | 2014-04-23 | 瑞典奥芬拜欧沃特姆国际公司 | Liquid pharmaceutical composition comprising nitisinone |
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2022
- 2022-06-23 CN CN202210716732.5A patent/CN114831974A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100227936A1 (en) * | 2009-03-09 | 2010-09-09 | Moran Graham R | Treatment of microbial infections with compounds that inhibit 4-hydroxyphenylpyruvate dioxygenase |
| CN103747781A (en) * | 2011-06-23 | 2014-04-23 | 瑞典奥芬拜欧沃特姆国际公司 | Liquid pharmaceutical composition comprising nitisinone |
Non-Patent Citations (1)
| Title |
|---|
| 孙利平;常彦祥;: "尼替西农对酪氨酸血症Ⅰ型所致肝损伤的保护作用" * |
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