CN111249266B - Application of peramivir in preparation of medicine for treating inflammatory storm caused by infectious diseases - Google Patents
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/12—Antivirals
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Abstract
The invention discloses an application of peramivir in preparing a medicament for treating an inflammatory storm caused by infectious diseases, wherein the infectious diseases are infections caused by viruses, chlamydia, mycoplasma, bacteria or parasites, the inflammatory storm is a phenomenon that a plurality of cell factors in an organism are rapidly and massively produced due to the infectious diseases, and the plurality of cell factors in the organism are TNF alpha, IL-6, IL-1 beta, IL-12, IFN alpha and IFN-gamma. The invention proves that the peramivir has the effect of treating inflammatory storm caused by infectious diseases for the first time, can be used for preparing medicaments for treating the inflammatory storm caused by the infectious diseases, and provides a new anti-inflammatory scheme for clinical treatment.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of peramivir in preparation of a medicine for treating inflammatory storm caused by infectious diseases.
Background
Infectious diseases are diseases in which a patient is infected with various pathogens such as viruses, chlamydia, mycoplasma, bacteria, or parasites. With the continuous aggravation of infection, the immune system produces a large amount of cytokines, and the proinflammatory cytokines can chemotact more immune cells to form a positive feedback cycle to cause an 'inflammation storm', do not attack enemy and my ground, and cause damage to the immune system of a human body and important organs such as liver, kidney, heart and the like. "inflammatory storm", also known as Cytokine Storm Syndrome (CSS), refers to the phenomenon of rapid and massive production of various cytokines such as TNF alpha, IL-1 beta, IL-6 and MCP-1 in body fluids after the body is infected with microbes, and is an important cause of acute respiratory distress syndrome and multiple organ failure [ Anji Red infection and cytokine storm, J.laboratory and clinical infections, 2013,7(6):925 and 926 ]. For example, this global outbreak of new coronavirus pneumonia ("Novel coronavirus pneumonia", abbreviated as "NCP") is a serious epidemic caused by infection with a new strain of coronavirus (COVID-19) that has never been found in humans before. The 'inflammatory storm' phenomenon in the body of a new coronary pneumonia patient is an important node for the conversion from mild disease to severe disease and critical disease, and is also an important reason for death of the patient. Therefore, inhibition of the massive secretion of inflammatory factors is an important strategy for clinical treatment of infectious diseases.
In innate immune cell responses, the pattern recognition signaling receptor, Toll-like receptors (TLRs), recognize pathogen-associated molecular patterns (PAMPs). According to different expression sites, the expression of the NF-kB mediated inflammatory cytokines can be divided into TLRs (such as TLR4, which can recognize bacterial lipopolysaccharide) expressed in a cell membrane and TLRs (such as TLR3, TLR7, TLR8 and TLR9, which can recognize virus nucleic acid) expressed in an endosome and a phagosome membrane, and viruses and bacteria can recognize different TLRs but are dependent on common signal transduction pathways (dependent on MyD88 and dependent on TRIF). Inflammatory storms are characterized by a massive release of systemic and local tissue cytokines, of which TNF α is produced mainly by mononuclear macrophages and can be involved in the development of fever and inflammation. Therefore, the drug screening by using the TNF alpha as an anti-inflammatory activity index and using a model that Lipopolysaccharide (LPS) serving as a bacterial endotoxin component stimulates macrophages in mouse abdominal cavity is a strategy for safely and rapidly discovering and effectively inhibiting 'inflammatory storm' of infectious disease patients. Firstly, an anti-infective old drug library (comprising 525 listed drugs such as antiviral drugs and antibacterial drugs and clinical research drugs) is constructed, and anti-inflammatory drug screening is carried out by applying a strategy of 'new use of old drugs and multiple use of one drug'.
Peramivir (Peramivir) is a novel cyclopentane-type anti-influenza virus drug, belongs to neuraminidase inhibitor, and is effective for influenza A and B, and 2009 the United states Food and Drug Administration (FDA) approves injection liquid for treating certain known or suspected hospitalized patients with influenza A H1N 1. In 2013, the national food and drug administration approved the sodium chloride injection. At present, the clinical application of peramivir as a medicament for inhibiting inflammatory storm caused by infectious diseases is not clearly reported.
Disclosure of Invention
The invention aims to provide application of peramivir in preparation of a medicine for treating inflammatory storm caused by infectious diseases.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides an application of peramivir in preparing a medicament for treating inflammatory storm caused by infectious diseases.
The infectious diseases are infections caused by various pathogens such as viruses, chlamydia, mycoplasma, bacteria or parasites.
The inflammatory storm is a phenomenon that a plurality of cytokines in an organism are rapidly and massively generated due to infectious diseases, and is a phenomenon that a plurality of cytokines in the organism such as TNF alpha, IL-6, IL-1 beta, IL-12, IFN alpha, IFN-gamma and the like are rapidly and massively generated when a patient with the infectious diseases is converted from mild diseases to severe diseases and critical diseases.
The peramivir can be in the form of a raw material drug, a solvate and a salt.
The structural formula of the peramivir [ Babu, Y.S., Chand, P., Bantia, S.A., Kotian, P.A., Dehghani, A.A., El-Kattan, Y.A., Lin, T.H., Hutchison, T.L., Elliott, A.J., Parker, C.D., Anth, S.L., Horn, L.L., Laver, G.W., Montgomery, J.A. (2000). BCX-1812 (RWJ-270201)' discovery of a novel point, highlyry point, orallyactive, and selective in-fluent in-near-coupled restriction of strain 3486), formula 3443:
the dose of the peramivir for inhibiting the TNF alpha at a cellular level is 0.3125-40 mu mol/L.
The single application dose of the peramivir for inhibiting various cytokines at the animal level is 60 mg/kg.
The peramivir can be prepared into a pharmaceutical preparation with a pharmaceutically conventional pharmaceutical excipient, and the pharmaceutical preparation can be administered through gastrointestinal tract or parenteral.
The pharmaceutical preparation is an oral preparation, an injection preparation or a powder injection.
Due to the adoption of the technical scheme, the invention has the following advantages and beneficial effects:
the experimental result of the invention shows that in an LPS (low-pressure lipoprotein lipase) stimulation mouse abdominal cavity macrophage model, the peramivir can inhibit the secretion of a cell factor TNF alpha in a dose-dependent manner, and does not show cytotoxicity in an effective dose; in a mouse model with CSS induced by LPS, peramivir has obvious inhibition effect on characteristic cytokines (TNF alpha, IL6 and the like) of inflammatory storm caused by infectious diseases; the peramivir can be used as a medicine for treating inflammatory storm caused by infectious diseases.
The dose of the peramivir for inhibiting TNF alpha at a cellular level is 0.3125-40 mu mol/L, and the peramivir provided by the invention shows that secretion of various cytokines is obviously reduced and obvious cytotoxicity is not generated; the invention proves that the peramivir has the effect of inhibiting inflammatory storm caused by infectious diseases for the first time, can be used for preparing medicaments for treating the inflammatory storm caused by the infectious diseases, and provides a new anti-inflammatory scheme for clinical treatment.
Drawings
FIG. 1 is a schematic diagram showing the inhibition effect of peramivir on the secretion of the cytokine TNF alpha in an LPS-stimulated mouse abdominal cavity macrophage model.
FIG. 2 is a graph showing the effect of peramivir on cell viability at the same dose in a model in which LPS stimulates mouse peritoneal macrophages.
FIG. 3 is a schematic diagram showing the inhibition effect of peramivir on the cytokines TNF alpha, IL-6, IL-1 beta, IL-12, IFN alpha and IFN-gamma in plasma in a mouse model with CSS induced by LPS.
FIG. 4 is a graph showing the inhibition of TNF α and IL6 in alveolar lavage fluid by peramivir in a CSS mouse model induced by LPS.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Peramivir (Peramivir) used in the following examples was all of the structure shown in formula 1, with a purity of > 98%.
The peramivir used in the examples of the present invention was purchased from Shanghai ceramic Biotechnology, Inc.
Example 1
Establishing an LPS (lipopolysaccharide) stimulated mouse abdominal cavity macrophage model:
1.1 materials
The C57BL/6 strain mouse, male, weighing 18-22g, was purchased from Kyowa Kavens laboratory animals Co., Ltd, and was given a production license number of SCXK (threo) 2016-; LPS was derived from E.coli 0111: B4 and purchased from Sigma-Aldrich; RPMI-1640 medium, fetal bovine serum and double antibody are products of Gibco company; CCK8 was purchased from the college chemical institute; the TNF α Elisa test kit was purchased from Invitrogen (cat. No.: BMS607-3 TEN); the microplate reader is of the BioTek brand.
1.2 isolated culture of mouse peritoneal macrophages
C57BL/6 mice were injected intraperitoneally with 3ml of broth medium containing 3% mercaptosulfate (purchased from BD), and after 3 days cervical dislocation was sacrificed and soaked in 75% alcohol 2 times for 1 minute each. Then will beThe mice were placed on a sterile operating table and the skin of the abdomen of the mice was gently cut along the midline of the abdomen, taking care not to destroy the integrity of the peritoneum. The syringe was slowly filled with 5ml of RPMI-1640 medium, the abdomen was repeatedly massaged to disperse the cells in the medium, and then the liquid was slowly withdrawn, filtered through a 40 μm cell mesh into a 50ml centrifuge tube, and lavage was repeated 3 times. After filtration, the cells were centrifuged at 1500rpm for 3 minutes, the cell pellet was resuspended in RPMI-1640 medium, and the cells plated in 96-well plates at a density of 5X 10 cells per well 5 And (4) one cell. 4 hours after cell attachment, cells were washed 2 times with PBS and replaced with RPMI-1640 medium containing 10% serum and 1% double antibody (whole medium). Cells were cultured overnight and then given subsequent treatments.
1.3 cell model preparation and detection
(1) The whole medium containing 100ng/ml LPS was prepared, and cells were treated with peramivir by setting 8 concentration gradients (40, 20, 10, 5, 2.5, 1.25, 0.625, 0.3125. mu.M, respectively) for 4 hours.
(2) And (3) adding a whole culture medium containing 10% of CCK8 into the cells, continuously incubating for 30 minutes, measuring absorbance under the excitation of a 450nm wavelength by using an enzyme labeling instrument, converting the absorbance corresponding to different drug concentrations into relative cell activity by taking the absorbance of the LPS control group cells as 1, and judging the cytotoxicity of the peramivir.
(3) The cell supernatant was diluted 10-fold and an Elisa experiment was performed according to the procedure of the kit.
As shown in FIG. 1, FIG. 1 is a schematic diagram showing the inhibitory effect of peramivir on the secretion of the cytokine TNF alpha in an LPS-stimulated mouse abdominal cavity macrophage model. In figure 1, the abscissa is the Log value of concentration, the ordinate is the TNF alpha inhibition rate, and it can be seen from the figure that in a model in which LPS stimulates mouse abdominal cavity macrophages, the peramivir has an obvious dose-effect relationship on the inhibition effect of TNF alpha secretion in the dosage range of 0.3125-40 mu mol/L, and the half inhibition concentration IC 50 It was 4.319. mu. mol/L.
As shown in fig. 2, fig. 2 is a graph illustrating the effect of peramivir on cell survival at the same dose in a model in which LPS stimulates mouse peritoneal macrophages. In FIG. 2, the abscissa represents the concentration, and the ordinate represents the viability of the cells relative to the control cells without drug treatment, and it can be seen from the figure that in the model in which LPS stimulates the mouse peritoneal macrophages, the peramivir has no cytotoxicity to the mouse peritoneal macrophages in the dose range of 0.3125-40. mu. mol/L, and the relative viability of the cells is not affected in the dose range of 0.3125-40. mu. mol/L.
Example 2
Establishment of LPS-evoked CSS mouse model:
1.1 materials
The C57BL/6 strain mouse, male, weighing 18-22g, was purchased from Kyowa Kavens laboratory animals Co., Ltd, and was given a production license number of SCXK (threo) 2016-; LPS was derived from E.coli 0111: B4 from Sigma-Aldrich; the multi-factor assay kit was purchased from BioLegend (Mouse Anti-Virus Panel, Cat No: 740622; Mouse Inflammation Panel, Cat No: 740446); CytoFlex flow cytometers are the american beckmann coulter brand.
1.2 animal models
The LPS is selected from mice injected intraperitoneally with a dose of 15mg/kg to induce CSS.
1.3 plasma separation
After 4 hours after LPS injection, blood is collected from the orbit to an anticoagulant tube containing EDTA, the anticoagulant tube is stood for 30 minutes, the rotation speed of 4000rpm is rotated, the anticoagulant tube is centrifuged for 15 minutes at 4 ℃, and supernatant, namely blood plasma, is collected to an EP tube for standby.
1.4 Collection of mouse alveolar lavage fluid (BALF)
After LPS injection for 8 hours, mice are killed by dislocation of cervical vertebrae, neck skin is slowly cut along a median line, soft tissues around a trachea are slowly separated, the trachea is cut at a thyroid gland position after tissues are exposed, the tip of a syringe needle is cut and blunt and then inserted into the trachea, a 4-number surgical line is used for ligating the trachea to fix the needle, 0.3ml of PBS solution is slowly injected into the lung by a 1ml syringe, the lung is gently massaged, the liquid is slowly pumped back after 1 minute, the pumped back liquid is placed into a 1.5ml EP tube, and lavage is repeated for 3 times, and the total amount of lavage liquid is 0.9 ml. The lavage solution was then centrifuged at 500g for 5 minutes and the supernatant transferred to a new EP tube for use.
1.5 flow cytometry detection of multiple cytokines: the used analytical reagents and buffers come from a flow cytometer detection multi-cytokine detection kit, and the experimental operation is performed according to the steps provided by the kit, specifically as follows:
(1) corresponding amount of 1.5ml centrifuge tubes are taken according to the number of samples and labeled, and another 8 1.5ml centrifuge tubes are labeled as C1-C8 respectively.
(2) Add 25. mu.L of assay buffer to the sample tube and 25. mu.l of matrix A to each of the 8 standard tubes.
(3) Vortex the bead mixing vial for 30 seconds, add 25. mu.l of the mixed beads to each centrifuge tube, and then add 25. mu.l of each sample or standard to the corresponding centrifuge tube.
(4) Shaking at 500rpm for 2 hours at room temperature.
(5) Add 500. mu.L of 1 XWash buffer to each centrifuge tube and centrifuge at 2000rpm for 10 min. The wash buffer was aspirated as much as possible, leaving the precipitated beads.
(6) Add 25 μ L of detection antibody to each centrifuge tube.
(7) After vortexing, the vortexes were vortexed at 500rpm for 1 hour at room temperature.
(8) 25 μ L of SA-PE was added directly to each 1.5mL centrifuge tube. Shaking at 500rpm for 30 minutes at room temperature.
(9) And repeating the operation of the step 5.
(10) Add 200. mu.L of 1 Xwash buffer to each centrifuge tube and vortex for 1 min.
(11) Samples were read on a flow cytometer and the generated FCS file should be analyzed using legend plex v8.0 data analysis software from BioLegend.
1.6 animal Experimental procedures
(1) C57BL/6 was randomly divided into a model control group (given the same volume of physiological saline) and a peramivir treatment group (single administration, dose 60mg/kg), and intraperitoneal injection was performed 30 minutes before molding.
(2) The LPS is selected from a 15mg/kg dose of an intraperitoneal injection mouse to induce CSS.
(3) Plasma was taken 4 hours after molding or BALF was taken 8 hours after molding.
(4) The flow cytometer measures the multiple cytokines in plasma and BALF, respectively.
As shown in FIG. 3, FIG. 3 is a graph showing the inhibition of the plasma cytokines TNF α, IL-6, IL-1 β, IL-12, IFN α and IFN- γ by peramivir in a mouse model with CSS induced by LPS. In FIG. 3 are blank controls and peramivir, the values of cytokine concentration in plasma (in pg/ml) are plotted on the ordinate. As shown in FIG. 4, FIG. 4 is a graph showing the inhibition of the cytokines TNF α and IL6 in alveolar lavage fluid by peramivir in the LPS-induced CSS mouse model. In FIG. 4 are blank controls and peramivir, plotted on the ordinate as the concentration of cytokine in alveolar lavage fluid in pg/ml. As can be seen from fig. 3 and 4, peramivir had a significant inhibitory effect on multiple cytokines in mouse plasma (fig. 3) and alveolar lavage fluid (fig. 4) at a dose of 60mg/kg in the LPS-induced CSS mouse model.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (6)
1. An application of peramivir in preparing a medicament for treating inflammatory storm caused by infectious diseases is characterized in that,
the infectious disease is an infection caused by bacteria;
the inflammatory storm is a phenomenon that a plurality of cytokines in an organism are rapidly and massively produced due to infectious diseases;
the multiple cytokines in the organism are TNF alpha, IL-6, IL-1 beta, IL-12, IFN alpha and IFN-gamma;
the dose of the peramivir for inhibiting the TNF alpha at a cellular level is 0.3125-40 mu mol/L.
2. The use of peramivir as claimed in claim 1 in the preparation of a medicament for treating inflammatory storm caused by infectious diseases, wherein the peramivir is a raw material drug or salt thereof.
3. The use of peramivir according to claim 1 in the preparation of a medicament for treating inflammatory storm caused by infectious disease, wherein the structural formula of peramivir is as shown in formula 1:
4. the use of peramivir in the preparation of a medicament for treating inflammatory storm caused by infectious diseases according to claim 1, wherein the single use dose of peramivir inhibiting multiple cytokines at animal level is 60 mg/kg.
5. The use of peramivir according to claim 1 in the preparation of a medicament for treating inflammatory storm caused by infectious diseases, wherein the peramivir and pharmaceutically acceptable conventional pharmaceutical excipients are formulated into a pharmaceutical formulation.
6. The use of peramivir in the preparation of a medicament for treating inflammatory storm caused by infectious disease according to claim 5, wherein the pharmaceutical preparation is an oral dosage form, an injection dosage form or a powder injection.
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| WO2019041239A1 (en) * | 2017-08-31 | 2019-03-07 | 汉义生物科技（北京）有限公司 | Uses of cannabidiol in preparation of drugs for resisting against influenza |
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| CN102036658A (en) * | 2008-05-23 | 2011-04-27 | 香港大学 | Combination therapy for the treatment of influenza |
| JP2017160168A (en) * | 2016-03-11 | 2017-09-14 | 国立大学法人 岡山大学 | Influenza therapeutic agent |
| WO2019041239A1 (en) * | 2017-08-31 | 2019-03-07 | 汉义生物科技（北京）有限公司 | Uses of cannabidiol in preparation of drugs for resisting against influenza |
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