WO2022185742A1 - Composition prophylactique ou thérapeutique pour le syndrome de coagulation intravasculaire disséminée - Google Patents

Composition prophylactique ou thérapeutique pour le syndrome de coagulation intravasculaire disséminée Download PDF

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WO2022185742A1
WO2022185742A1 PCT/JP2022/001353 JP2022001353W WO2022185742A1 WO 2022185742 A1 WO2022185742 A1 WO 2022185742A1 JP 2022001353 W JP2022001353 W JP 2022001353W WO 2022185742 A1 WO2022185742 A1 WO 2022185742A1
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adenosine
cells
added
receptor
dopamine
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Japanese (ja)
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祥 松下
雅章 川野
美枝子 戸叶
理英 高木
繁文 前▲崎▼
憲人 樽本
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学校法人埼玉医科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a preventive or therapeutic composition for disseminated intravascular coagulation.
  • DIC Disseminated intravascular coagulation
  • DIC Disseminated intravascular coagulation
  • It is also referred to as consumption coagulopathy, as hemostatic factors such as platelets and clotting factors are often reduced as a result of microthrombosis.
  • This consumptive coagulopathy and subsequent activation of fibrinolysis cause bleeding symptoms, and frequent occurrence of microthrombi leads to disturbance of microcirculation, leading to various organ failures. Therefore, immediate treatment is required.
  • NETs neutrophil extracellular traps
  • LPS lipopolysaccharide
  • NETs are structures in which DNA and histones present in the nucleus of neutrophils themselves, and antibacterial proteins such as neutrophil elastase and myeloperoxidase present in the cytoplasm and neutrophil granules are bound.
  • pathogens such as viruses attach and trap pathogens.
  • pathogens are effectively killed by said antimicrobial protein.
  • NETs in sputum become longer when the inflammatory reaction is high, and that the length of NETs in sputum becomes shorter as the inflammatory reaction improves (Non-patent literature). 1).
  • NETs are an organism's infection defense mechanism, but excessive NETs production may exacerbate pathological conditions.
  • One example is disseminated intravascular coagulation. Disseminated intravascular coagulation occurs when the body's defense reaction, which locally coagulates and traps pathogens such as viruses that have entered the blood and prevents them from spreading further throughout the body, progresses excessively.
  • COVID-19 an infectious disease caused by a virus. Severe cases of COVID-19 co-occur with acute respiratory distress syndrome (ARDS), chronic inflammatory conditions, and even sepsis. Enhanced procoagulant activity, disseminated intravascular coagulation, and endothelial damage may also occur in such cases.
  • ARDS acute respiratory distress syndrome
  • Enhanced procoagulant activity, disseminated intravascular coagulation, and endothelial damage may also occur in such cases.
  • COVID-19 patients elevated neutrophil counts, elevated blood levels of C-reactive protein (CRP), LDH, fibrinogen, IL-1 ⁇ , IL-6, IL-8 and other inflammatory markers An increase is also observed (see Non-Patent Document 3).
  • CRP C-reactive protein
  • Non-Patent Document 4 COVID-19 patients tend to release NETs (see Non-Patent Document 4), increased NETs formation correlates with COVID-19-associated acute respiratory distress syndrome (ARDS), and COVID-19 with thrombus -19 patients are known to have significant increases in D-dimer, calprotectin, and cell-free DNA, which are indicators of enhanced fibrinolysis in thrombosis (Non-Patent Document 1 and 5).
  • disseminated intravascular coagulation For the treatment of disseminated intravascular coagulation, medication is administered according to the underlying disease that causes disseminated intravascular coagulation. Antibiotics are administered. However, many of the underlying diseases that cause disseminated intravascular coagulation are serious, and it is difficult to hope for early treatment of disseminated intravascular coagulation.
  • the object of the present invention is to solve the above-mentioned problems in the past and to achieve the following objects. That is, the present invention has an excellent neutrophil chemotactic factor and its inducer production inhibitory action, and prevents or treats disseminated intravascular coagulation caused by neutrophil extracellular traps (NETs). An object of the present invention is to provide a preventive or therapeutic composition for disseminated intravascular coagulation.
  • NETs neutrophil extracellular traps
  • the prevention or A therapeutic composition As a means for solving the above-mentioned problems, the prevention or A therapeutic composition.
  • the said problems in the former can be solved, the said objective can be achieved, it has the outstanding production inhibitory effect
  • FIG. 1A shows flow cytometry analysis results of co-staining cells cultured by 2-way MLR with fluorescein isothiocyanate (FITC)-rat anti-mouse CD4 antibody and phycoerythrin (PE)-rat anti-mouse IL-17A antibody. It is a figure which shows.
  • FIG. 1B shows the results of flow cytometry analysis in which cells cultured in the presence of adenosine by 2-way MLR were co-stained with FITC-rat anti-mouse CD4 antibody and PE-rat anti-mouse IL-17A antibody.
  • FIG. 1C is a graph showing the effect of adenosine on IL-17A in 2-way MLR.
  • FIG. 1D is a graph showing the effect of adenosine on IFN ⁇ in 2-way MLR. In the figure, “*” indicates “p ⁇ 0.05” for the group to which adenosine was added to the medium alone.
  • FIG. 1E is a graph showing the effect of adenosine on IL-5 in 2-way MLR. "**” in the figure indicates that the group to which adenosine was added to the medium alone is "p ⁇ 0.01".
  • FIG. 2A is a graph showing the effect of an adenosine A2a receptor antagonist (istradefylline) on IL-17A in a 2-way MLR.
  • "**" in the figure indicates that the group to which adenosine (100 ⁇ M) alone was added and the group to which the adenosine A2a receptor antagonist (istradefylline) was further added was "p ⁇ 0.01".
  • FIG. 2B is a graph showing the effect of an adenosine A2a receptor antagonist (istradefylline) on IFN ⁇ in the 2-way MLR.
  • FIG. 2C is a graph showing the effect of an adenosine A2a receptor antagonist (Istradefylline) on IL-5 in a 2-way MLR.
  • Figure 3A is a graph showing the effect of an adenosine A2a receptor agonist (PSB0777) on IL-17A in a 2-way MLR.
  • PBS0777 adenosine A2a receptor agonist
  • “*” in the figure indicates that the group to which the adenosine A2a receptor agonist (PSB0777) was added is "p ⁇ 0.05" with respect to the medium only
  • "**" in the figure indicates that the medium only , indicates that the group to which the adenosine A2a receptor agonist was added is “p ⁇ 0.01”.
  • FIG. 3B is a graph showing the effect of an adenosine A2a receptor agonist (PSB0777) on IFN ⁇ in 2-way MLR.
  • FIG. 3C is a graph showing the effect of an adenosine A2a receptor agonist (PSB0777) on IL-5 in the 2-way MLR.
  • N.D indicates non-detection.
  • FIG. 3D is a graph showing the effect of adenosine A1 receptor agonist (CCPA) on IL-17A in 2-way MLR.
  • Figure 3E is a graph showing the effect of an adenosine A2b receptor agonist (BAY 60-6583) on IL-17A in the 2-way MLR.
  • FIG. 3F is a graph showing the effect of adenosine A3 receptor agonist (HEMADO) on IL-17A in 2-way MLR.
  • FIG. 4A is a graph showing the effect of a CD39 inhibitor (ARL67156) on IL-17A in 2-way MLR. In the figure, “*” indicates “p ⁇ 0.05” for the group to which the CD39 inhibitor (ARL67156) was added to the medium alone.
  • FIG. 4B is a graph showing the effect of CD73 inhibitor (AMP-CP) on IL-17A in 2-way MLR. In the figure, “*” indicates “p ⁇ 0.05” for the group to which the CD73 inhibitor (AMP-CP) was added to the medium alone.
  • FIG. 4A is a graph showing the effect of a CD39 inhibitor (ARL67156) on IL-17A in 2-way MLR. In the figure, “*” indicates “p ⁇ 0.05” for the group to which the CD73 inhibitor (AMP-CP) was added to the medium alone.
  • AMP-CP CD
  • FIG. 4C is a graph showing the effect of an adenosine A2a receptor antagonist (istradefylline) on IL-17A in a 2-way MLR.
  • “*” in the figure indicates that the group to which the adenosine A2a receptor antagonist (istradefylline) was added to the medium alone is “p ⁇ 0.05”, and “**” in the figure indicates the medium only.
  • the group to which the adenosine A2a receptor antagonist (Istradefylline) was added shows "p ⁇ 0.01".
  • FIG. 5A is a graph showing the effect of a CD39 inhibitor (ARL67156) on adenosine in 2-way MLR.
  • FIG. 5B is a graph showing the effect of a CD39 inhibitor (ARL67156) on ATP in 2-way MLR.
  • FIG. 5C is a graph showing the effect of CD73 inhibitor (AMP-CP) on adenosine in 2-way MLR.
  • “**” indicates "p ⁇ 0.01" for the group to which the CD73 inhibitor (AMP-CP) was added to the medium alone.
  • FIG. 5D is a graph showing the effect of CD73 inhibitor (AMP-CP) on ATP in 2-way MLR.
  • FIG. 6A is a graph showing the effect of a CD39 inhibitor (ARL67156) on IL-17A in a co-culture system of DO11.10 mouse CD4 + T cells and bone marrow dendritic cells in the presence of LPS and OVA peptide.
  • “**" in the figure indicates that "p ⁇ 0.01" for the group to which the CD39 inhibitor (ARL67156) was further added to the group to which the LPS and OVA peptides were added.
  • FIG. 6B is a graph showing the effect of a CD73 inhibitor (AMP-CP) on IL-17A in a co-culture system of DO11.10 mouse CD4 + T cells and bone marrow dendritic cells in the presence of LPS and OVA peptide. be.
  • FIG. 1 CD39 inhibitor
  • FIG. 6C shows the IL-induced effects of a CD39 inhibitor (ARL67156) and a CD73 inhibitor (AMP-CP) in a co-culture system of DO11.10 mouse CD4 + T cells and bone marrow dendritic cells in the presence of LPS and OVA peptide.
  • 17A is a graph showing the effect on 17A.
  • "**" indicates that "p ⁇ 0.01" for the group to which the LPS and OVA peptides were added, and the group to which the CD39 inhibitor (ARL67156) and CD73 inhibitor (AMP-CP) were added. indicates FIG.
  • FIG. 6D shows the effect of an adenosine A2a receptor antagonist (Istradefylline) on IL-17A in a co-culture system of DO11.10 mouse CD4 + T cells and bone marrow dendritic cells in the presence of LPS and OVA peptide.
  • “*” indicates "p ⁇ 0.05" for the group to which the adenosine A2a receptor antagonist (istradefylline) was further added to the group to which the LPS and OVA peptides were added.
  • FIG. 7A is a graph showing the effect of adenosine concentration on IL-17A in a culture system of CD4 + T cells activated by CD3/CD28 stimulation.
  • FIG. 7B is a graph showing the effect of adenosine duration on IL-17A in a CD3/CD28-stimulated, activated CD4 + T cell culture system.
  • "**” indicates that "p ⁇ 0.01” for the group to which adenosine was added compared to the medium-only group.
  • “N.D.” in the figure indicates non-detection.
  • FIG. 7B is a graph showing the effect of adenosine duration on IL-17A in a CD3/CD28-stimulated, activated CD4 + T cell culture system.
  • “**” indicates that "p ⁇ 0.01” for the group to which adenosine was added compared to the medium-only group.
  • “N.D.” in the figure indicates non-detection.
  • FIG. 7C is a graph showing the effect of an adenosine A2a receptor agonist (PSB0777) on IL-17A in a CD3/CD28-stimulated, activated CD4 + T cell culture system.
  • PSB0777 an adenosine A2a receptor agonist
  • “*” indicates “p ⁇ 0.05” for the group to which the adenosine A2a receptor agonist (PSB0777) was added compared to the medium-only group.
  • N.D in the figure indicates non-detection.
  • FIG. 7D is a graph showing the effect of an adenosine A2a receptor antagonist (istradefylline) on IL-17A in a CD3/CD28-stimulated, activated CD4 + T cell culture system.
  • FIG. 7E is a graph showing the effect of a cAMP inhibitor (MDL-12330A) on IL-17A in a CD3/CD28-stimulated, activated CD4 + T cell culture system.
  • MDL-12330A cAMP inhibitor
  • FIG. 7F is a graph showing the effect of a protein kinase A inhibitor (H-89) on IL-17A in a CD3/CD28-stimulated, activated CD4 + T cell culture system.
  • H-89 protein kinase A inhibitor
  • ** in the figure indicates that "p ⁇ 0.01” for the group to which protein kinase A inhibitor (H-89) was further added to the group to which adenosine (600 ⁇ M) was added.
  • N.D. in the figure indicates non-detection.
  • FIG. 7G is a graph showing the effect of adenosine on IL-17A in CD4 + CD62L + T cell and CD4 + CD62L ⁇ T cell culture systems.
  • “*” indicates “p ⁇ 0.05” for the group to which adenosine was added compared to the medium-only group.
  • “N.D.” in the figure indicates non-detection.
  • FIG. 8 shows that ATP is produced upon antigen presentation in the narrow space of an immunological synapse formed between effector T cells (CD4 + T cells) and bone marrow dendritic cells, and the ATP is converted into membrane-type enzyme CD39.
  • FIG. 9 shows the results of evaluating the effect on IL-8 production by co-cultivating human peripheral blood mononuclear cells (PBMC) with a Candida antigen in the presence of a dopamine D2-like receptor agonist (pramipexole or ropinirole).
  • PBMC peripheral blood mononuclear cells
  • a dopamine D2-like receptor agonist pramipexole or ropinirole
  • Figure 10 shows a system in which human peripheral blood mononuclear cells (PBMC) are co-cultured with a Candida antigen, coexisting with a dopamine D2-like receptor agonist (talipexole, pramipexole, or ropinirole) or an adenosine A2a receptor antagonist (istradefylline).
  • PBMC peripheral blood mononuclear cells
  • talipexole, pramipexole, or ropinirole a dopamine D2-like receptor agonist
  • adenosine A2a receptor antagonist istradefylline
  • FIG. 11A shows L243 ( 1 is a graph showing the effect of anti-HLA-DRB1+B3+B4 IgG2a), HU-4 (anti-HLA-DRB1+B5 IgG2a), or 1a3 (anti-HLA-DQ IgG2a) on IL-8.
  • "**" indicates that "p ⁇ 0.01" in the antibody-added group compared to the antibody-free group.
  • FIG. 11B shows L243 ( 1 is a graph showing the effect of anti-HLA-DRB1+B3+B4 IgG2a), HU-4 (anti-HLA-DRB1+B5 IgG2a), or 1a3 (anti-HLA-DQ IgG2a) on IL-8.
  • "**" indicates that "p ⁇ 0.01" in the antibody-added group compared to the antibody-free group.
  • FIG. 11C shows L243 ( 1 is a graph showing the effect of anti-HLA-DRB1+B3+B4 IgG2a), HU-4 (anti-HLA-DRB1+B5 IgG2a), or 1a3 (anti-HLA-DQ IgG2a) on IL-8.
  • FIG. 12A is a system in which Japanese COVID-19 patient-derived peripheral blood mononuclear cells (PBMC) (patient number 4) are co-cultured with SARS-CoV-2 spike protein-derived peptide (SEQ ID NO: 6), dopamine D2
  • PBMC peripheral blood mononuclear cells
  • SEQ ID NO: 6 SARS-CoV-2 spike protein-derived peptide
  • Fig. 10 is a graph showing the results of evaluating the effect on IL-8 production in the coexistence of an adenosine-like receptor agonist (ropinirole) or an adenosine A2a receptor antagonist (istradefylline).
  • FIG. 12B is a system in which Japanese COVID-19 patient-derived peripheral blood mononuclear cells (PBMC) (patient number 11) are co-cultured with SARS-CoV-2 spike protein-derived peptide (SEQ ID NO: 6), dopamine D2 Fig.
  • PBMC peripheral blood mononuclear cells
  • FIG. 10 is a graph showing the results of evaluating the effect on IL-8 production in the coexistence of an adenosine-like receptor agonist (ropinirole) or an adenosine A2a receptor antagonist (istradefylline).
  • the number in parentheses for each drug in "Drug (x Cmax)" indicates how many times the final concentration is the Cmax of each drug.
  • the group to which the dopamine D2-like receptor agonist or the adenosine A2a receptor antagonist was added shows "p ⁇ 0.01".
  • PBMC peripheral blood mononuclear cells
  • SEQ ID NO: 1 SARS-CoV-2 spike protein-derived peptide
  • Fig. 10 is a graph showing the results of evaluating the effect on IL-8 production in the coexistence of an adenosine-like receptor agonist (ropinirole) or an adenosine A2a receptor antagonist (istradefylline).
  • the number in parentheses for each drug in "Drug (x Cmax)" indicates how many times the final concentration is the Cmax of each drug.
  • the group to which the dopamine D2-like receptor agonist or the adenosine A2a receptor antagonist was added shows "p ⁇ 0.01".
  • composition for prevention or treatment of disseminated intravascular coagulation contains at least one selected from an adenosine A2a receptor antagonist and a dopamine D2-like receptor agonist as an active ingredient. , and optionally other components.
  • IL-17 whose production is suppressed by the composition for preventing or treating disseminated intravascular coagulation is not particularly limited, but IL-17A and IL-17F are preferred, and IL-17A is more preferred.
  • cytokines Physiologically active proteins collectively called cytokines play an important role in the activation and function suppression of immune cells, and IL-17 and IL-8 are also types of cytokines.
  • One of the cytokine-producing cells is activated T-cells.
  • activated T cells are helper T cells differentiated by recognizing specific antigens via T cell receptors, and include so-called effector T cells and memory T cells.
  • helper T cells include Th1 cells, Th2 cells, Th17 cells and the like. These helper T cells can be distinguished by the production of specific cytokines.
  • the Th1 cell-specific cytokines include interferon (IFN) ⁇ , IL-2, IL-8 and the like.
  • the Th2 cell-specific cytokines include IL-4, IL-5, IL-13, and the like.
  • Specific cytokines for Th17 cells include IL-17 and IL-8.
  • dopamine D2-like receptor agonists act not only in inducing differentiation of T cells, but also on activated Th1 and Th17 cells, which are effector CD4 + T cells, and their IL -17 production and IL-8 production (Toshiyuki Matsuyama et al, Clin. Exp. Neuroimmunol, 2018, 9, p.251-257 and see Patent No. 6562332).
  • Th17 cells have been known as IL-17-producing cells in the past, but the present inventors have made intensive studies and discovered that IL-17 is also produced from adenosine-responsive effector CD4 + T cells. IL-17 production from CD4 + T cells is involved in signal transduction via the adenosine A2a receptor . It was newly found that it can be suppressed by
  • Target cells that inhibit at least one of IL-17 production and IL-8 production by the preventive or therapeutic composition for disseminated intravascular coagulation are preferably adenosine-responsive effector CD4 + T cells, and adenosine-responsive CD4 + T cells. More preferred are adenosine-responsive Th1 cells and adenosine-responsive Th17 cells.
  • At least one selected from adenosine A2a receptor antagonists and dopamine D2-like receptor agonists which the composition for preventing or treating disseminated intravascular coagulation contains as an active ingredient, activates It exerts its effect through a novel mechanism of suppressing the production of at least one of IL-17 and IL-8 from T cells.
  • the composition for preventing or treating disseminated intravascular coagulation can suppress the formation of microthrombi caused by NETs, and delay or prevent the onset of disseminated intravascular coagulation. or alleviate or alleviate the symptoms of disseminated intravascular coagulation.
  • the indicator for the suppression of NETs is not particularly limited and can be appropriately selected depending on the purpose. , IL-6, IL-8, peripheral blood platelets, TNF ⁇ , etc. (Karolina Janiuk et al., Cells, 2021, 10(1), 151 and Shigeto Hamaguchi, Kazunori Asano, Journal of Thrombosis and Hemostasis). , 2016, Vol. 27, No. 1, p.34-41). Also, as noted above, reduction of IL-17 can be used as an indicator of suppression of the NETs.
  • the indicator for the prevention or treatment of disseminated intravascular coagulation is not particularly limited and can be appropriately selected according to the purpose. - Dimer reduction, calprotectin reduction, cell-free DNA reduction, etc. (Shigeto Hamaguchi, Kazunori Asano, Journal of Thrombosis and Hemostasis, 2016, Vol. 27, No. 1, p. 34-41 and Yu Zuo et al., JCI Insight, 2020, Jun 4, 5 (11)).
  • ⁇ Adenosine A2a receptor antagonist suppresses IL-8 and/or IL-17 production from IL-17 and/or IL-8-producing cells, preferably adenosine-responsive effector CD4 + T cells. do. Therefore, it is advantageous for the prevention or treatment of disseminated intravascular coagulation caused by NETs.
  • suppression of production of at least one of IL-8 and IL-17 from cells producing L-17 and/or IL-8 includes IL-8 and/or Inhibiting production of at least one of IL-17 and inhibiting differentiation into said producing cells are included.
  • Adenosine one of the bases that make up DNA, is a purine metabolite produced by many cells in living organisms and is involved in various life phenomena. In the central nervous system, it functions as a neurotransmitter in the globus pallidum and striatum. Adenosine is produced intracellularly by the degradation of adenosine triphosphate (ATP), adenosine diphosphate (ADP), or adenosine monophosphate (AMP).
  • ATP adenosine triphosphate
  • ADP adenosine diphosphate
  • AMP adenosine monophosphate
  • extracellular ATP and ADP are released by the membrane-type enzymes CD39 (ectoATPDase; ectonucleoside triphosphate diphsphohydrolase 1) and CD73 (ecto-5'-nucleotidase).
  • CD39 ectoATPDase; ectonucleoside triphosphate diphsphohydrolase 1
  • CD73 ecto-5'-nucleotidase
  • Adenosine receptors are G protein-coupled receptor molecules for adenosine, and humans have four subtypes: adenosine A1 receptor, adenosine A2a receptor, adenosine A2b receptor, and adenosine A3 receptor. , each with different distributions and signaling pathways.
  • Adenosine A1 and adenosine A2a receptors have high affinity for adenosine
  • adenosine A2b and adenosine A3 receptors have low affinity for adenosine.
  • adenosine A2a receptor when stimulated on the cell surface, activates adenylyl cyclase in the cell, promotes cAMP production, and transmits a signal. This means that the adenosine A2a receptor is activated.
  • adenosine A2a receptor antagonist means a compound that binds to the adenosine A2a receptor and inhibits activation of the adenosine A2a receptor.
  • the adenosine A2a receptor antagonist as an active ingredient of the composition for preventing or treating disseminated intravascular coagulation is not particularly limited and can be appropriately selected depending on the intended purpose.
  • adenosine A2a receptor antagonists include istradefylline (a compound represented by the following structural formula 1), preladenant (a compound represented by the following structural formula 2), and vipadenant (a compound represented by the following structural formula 3).
  • the adenosine A2a receptor antagonists include, for example, xanthine derivatives exhibiting an antagonistic effect on adenosine A2a receptors disclosed in JP-A-6-211856 or JP-A-2016-003186; Special table 2013-523711, Special table 2012-505264, Special table 2011-513417, Special table 2011-500833, Special table 2011-500819, Special table 2010-523497, JP 2008-297312, JP 2009-508871, JP 2008-524330, JP 2007-521243, or JP 2005-506352, for the adenosine A2a receptor Pyrimidine derivatives that exhibit antagonistic activity; for example, amino-quinoxaline derivatives that exhibit antagonistic activity against adenosine A2a receptors disclosed in Japanese Patent Application Publication No. 2011-514350; anti-adenosine A2a receptor antibodies, etc.
  • the adenosine A2a receptor antagonist may be used singly or in combination of two or more. Among these, istradefylline and AB928 are preferred, and istradefylline is more preferred.
  • adenosine A2a receptor antagonist examples include pharmacologically acceptable salts, hydrates, and solvates as long as they bind to the adenosine A2a receptor and inhibit the activation of the adenosine A2a receptor. included.
  • the pharmacologically acceptable salt is not particularly limited and can be appropriately selected according to each structure of the adenosine A2a receptor antagonist.
  • Examples include acid addition salts, base addition salts, organic amine addition salts. , amino acid addition salts and the like.
  • Examples of the acid addition salt include hydrochloride, hydrobromide, sulfate, hydrogensulfate, nitrate, carbonate, hydrogencarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, and the like.
  • inorganic acid salts organic acid salts such as acetates, propionates, lactates, citrates and tartrates
  • base addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; zinc salts; aluminum salts; ammonium salts;
  • organic amine addition salts include addition salts of morpholine, piperidine and the like.
  • amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.
  • the hydrate or solvate is not particularly limited, and examples include those obtained by adding 0.1 to 10 molecules of water or a solvent to 1 molecule of the adenosine A2a receptor antagonist or salt thereof. .
  • adenosine A2a receptor antagonist as long as it binds to the adenosine A2a receptor and exhibits the effect of inhibiting the activation of the adenosine A2a receptor, tautomers, geometric isomers, and chiral carbon-based All isomers or mixtures of isomers such as optical isomers, stereoisomers are included.
  • the adenosine A2a receptor antagonist binds to the adenosine A2a receptor and exhibits an action of inhibiting the activation of the adenosine A2a receptor, and the adenosine A2a receptor antagonist can be oxidized, reduced, or oxidized in vivo.
  • the adenosine A2a receptor antagonist can be obtained by purchasing a commercial product, since many compounds have been developed and are commercially available. Moreover, even if they are not commercially available, they may be produced as appropriate, since many reports have been made on methods for producing these compounds.
  • the content of the adenosine A2a receptor antagonist in the composition for preventing or treating disseminated intravascular coagulation is not particularly limited as long as it can prevent, improve, or treat disseminated intravascular coagulation. , can be appropriately selected so as to obtain a desired dosage.
  • Dopamine D2-like receptor agonist suppresses IL-8 and/or IL-17 production from IL-17 and/or IL-8 producing cells, preferably effector CD4 + T cells.
  • IL-8 and/or IL-17 production from IL-17 and/or IL-8 producing cells, preferably effector CD4 + T cells.
  • Th2 Toshiyuki Matsuyama et al, Clin. Exp. Neuroimmunol, 2018, 9, p.251-257
  • it does not suppress the production of neutralizing antibodies. Therefore, it is advantageous for the prevention or treatment of disseminated intravascular coagulation caused by NETs.
  • dopamine D1 receptor There are five subtypes of dopamine receptors: dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor, dopamine D4 receptor, and dopamine D5 receptor. It is generally known to have the function of sending a signal. These are differentiated into dopamine D1-like receptors and dopamine D2-like receptors by the action of cAMP. Dopamine D1 and dopamine D5 receptors are collectively referred to as “dopamine D1-like receptors” and dopamine D2, dopamine D3 and dopamine D4 receptors are collectively referred to as "dopamine D2-like receptors”. It is called. Activation of the dopamine D2-like receptor promotes the degradation of intracellular cAMP and decreases the intracellular cAMP concentration.
  • Typical amino acid sequences of human-derived dopamine D2 receptors are disclosed in NCBI Reference Sequence: NP_000786.1, NCBI Reference Sequence: NP_057658.2, and the like.
  • a typical amino acid sequence of a human-derived dopamine D3 receptor is disclosed in NCBI Reference Sequence: NP_000787.2 and the like.
  • a typical amino acid sequence of a human-derived dopamine D4 receptor is disclosed in NCBI Reference Sequence: NP_000788.2 and the like.
  • dopamine D2-like receptor agonist means a compound that binds to a dopamine D2-like receptor and activates the dopamine D2-like receptor, thereby activating the signal transduction.
  • the dopamine D2-like receptor agonist as an active ingredient of the composition for preventing or treating disseminated intravascular coagulation is not particularly limited as long as it can activate the dopamine D2-like receptor. , can be appropriately selected depending on the purpose, and may be a known dopamine D2-like receptor agonist.
  • Examples of the known dopamine D2-like receptor agonists include cabergoline (cavasal, etc.) (compound represented by the following structural formula 23), pergolide (permax, etc.) (compound represented by the following structural formula 24), bromocriptine (parlodel etc.) (compound represented by the following structural formula 25) and other ergot-type dopamine agonists; ) (compound represented by the following structural formula 27), ropinirole (Requip (registered trademark), Harropi (registered trademark), etc.) (compound represented by the following structural formula 28), rotigotine (Neupro (registered trademark), etc.) (below compound represented by structural formula 29), apomorphine hydrochloride hydrate (such as apocaine) (compound represented by structural formula 30 below), and other non-ergot-type dopamine agonists.
  • cabergoline cavasal, etc.
  • pergolide permax, etc.
  • bromocriptine parlodel etc
  • dopamine D2-like receptor agonists include, for example, tannic acid, gallic acid, catechins and gallic acid esters thereof (e.g., catechin, epicatechin, gallocatechin, epigallocatechin, epicatechin gallate, gallocatechin gallate, epigallocatechin gallate, etc.).
  • the dopamine D2-like receptor agonists may be used singly or in combination of two or more.
  • cabergoline, pergolide, bromocriptine, talipexole, pramipexole, ropinirole, rotigotine, apomorphine hydrochloride hydrate are preferred, and ropinirole is recommended for severe cases where a patch (Harropi®) is present and under respiratory control. It is more preferable because it is easy for patients to use.
  • the dopamine D2-like receptor agonists also include pharmacologically acceptable salts, hydrates, and solvates as long as they have the effect of activating the dopamine D2-like receptors.
  • the pharmacologically acceptable salt include those described in the above ⁇ Adenosine A2a receptor antagonist>.
  • the hydrate or solvate is not particularly limited, and examples thereof include those obtained by adding 0.1 to 10 molecules of water or a solvent to 1 molecule of the dopamine D2-like receptor agonist or salt thereof. be done.
  • the dopamine D2-like receptor agonist includes tautomers, geometric isomers, optical isomers based on an asymmetric carbon, stereoisomers, etc., as long as they have the effect of activating the dopamine D2-like receptor. All isomers or isomeric mixtures are included.
  • the dopamine D2-like receptor agonist as long as the dopamine D2-like receptor agonist has an effect of activating the dopamine D2-like receptor, the dopamine D2-like receptor agonist can be oxidized, reduced, hydrolyzed, aminated, and deaminated in vivo. compounds undergoing metabolism such as conversion, hydroxylation, phosphorylation, dehydration-oxidation, alkylation, dealkylation, and conjugation; , phosphorylation, dehydration-oxidation, alkylation, dealkylation, conjugation, etc., to form said dopamine D2-like receptor agonist.
  • the dopamine D2-like receptor agonist can be obtained by purchasing a commercial product, since many compounds have been developed and are commercially available. Moreover, even if they are not commercially available, they may be produced as appropriate, since many reports have been made on methods for producing these compounds.
  • the content of the dopamine D2-like receptor agonist in the composition for preventing or treating disseminated intravascular coagulation is not particularly limited as long as it can prevent, improve, or treat disseminated intravascular coagulation. It can be appropriately selected so as to obtain a desired dosage.
  • compositions for preventing or treating disseminated intravascular coagulation are not particularly limited as long as they do not impair the effects of the present invention, and additives commonly used in pharmaceutical compositions can be used depending on the purpose.
  • excipients for example, excipients, disintegrants, lubricants, binders, flavoring agents, buffers, stabilizers, wetting agents, preservatives, coloring agents, surfactants, sweeteners , tonicity agent, local anesthetic, fragrance, flow agent, stabilizer, pH adjuster, coating agent, moisture-proof agent, preservative, thickener, thickener, emulsifier, antioxidant, acidulant, seasoning ingredients, oily components, ultraviolet absorbers, thickeners, alcohols, powder components, aqueous components, water, bases, and the like.
  • the composition for preventing or treating disseminated intravascular coagulation may also contain one or more other ingredients effective for preventing or treating disseminated intravascular coagulation.
  • excipient examples include mannitol, lactose (anhydrous or hydrate), sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, micro Crystalline cellulose, silicic acid, calcium silicate, talc, refined gelatin, hydroxypropyl starch, polyvinylpyrrolidone and the like.
  • disintegrant examples include corn starch, sodium starch glycolate, carmellose calcium, crospovidone, croscarmellose sodium, methylcellulose, sodium carboxymethylstarch, low-substituted hydroxypropylcellulose, carmellose, partially pregelatinized starch, dried Starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, lactose and the like.
  • lubricant examples include talc, magnesium stearate, calcium stearate, borax, polyethylene glycol, hydrogenated oil, bleached beeswax, carnauba wax, sodium stearyl malate, and stearic acid.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, hypromellose, Examples include partially saponified polyvinyl alcohol.
  • flavoring agent examples include sucrose, orange peel, citric acid, and tartaric acid.
  • buffering agent examples include sodium citrate.
  • Examples of the stabilizer include tragacanth, gum arabic, gelatin, sodium pyrosulfite, ethylenediaminetetraacetic acid (EDTA), thioglycolic acid, thiolactic acid and the like.
  • Examples of the base include liquid paraffin, white petrolatum, bleached beeswax, octyldodecyl alcohol, and paraffin.
  • Examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate.
  • Examples of the coloring agent include titanium oxide and iron oxide.
  • Examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
  • Examples of the tonicity agent include sodium chloride and glucose.
  • Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
  • the content of the other ingredients in the composition for preventing or treating disseminated intravascular coagulation is not particularly limited as long as it does not impair the effects of the present invention, and can be appropriately selected according to the purpose.
  • composition for the prevention or treatment of disseminated intravascular coagulation contains an excellent neutrophil chemoattractant and its inducer, in particular at least one of IL-17 and IL-8 from activated T cells. Since it has a production inhibitory effect and can prevent or treat disseminated intravascular coagulation, it can be suitably used for the prevention or treatment of disseminated intravascular coagulation caused by infectious diseases, particularly , SARS-CoV-2 can be suitably used for the prevention or treatment of disseminated intravascular coagulation caused by COVID-19.
  • the preventive or therapeutic composition for disseminated intravascular coagulation can be used as a composition for preventing aggravation of COVID-19 or a composition for treating severe COVID-19.
  • severe COVID-19 means COVID-19 forming NETs.
  • the preventive or therapeutic composition for disseminated intravascular coagulation can be suitably used, for example, as pharmaceuticals, quasi-drugs, food and drink, and the like.
  • the preventive or therapeutic composition for disseminated intravascular coagulation can also be used as a reagent for research purposes (for example, in vitro or in vivo experiments).
  • composition for preventing or treating disseminated intravascular coagulation in pharmaceuticals, quasi-drugs, food and drink, etc. is not particularly limited in terms of dosage, usage, and dosage form. , the degree of absorption of the active ingredient in the body, the rate of inactivity, the rate of excretion, the presence or absence of diseases other than menopausal symptoms, the presence or absence or type of drugs to be used in combination, and the like.
  • the usage is not particularly limited and can be appropriately selected according to the purpose. Examples include oral, parenteral, and external usage. Among these, oral use and external use are preferred.
  • the dosage form is not particularly limited and can be appropriately selected depending on the intended purpose.
  • Oral solid preparations or oral liquid preparations such as turbid solutions; Oral preparations such as gums, lozenges, sublingual tablets, buccal tablets, adhesion agents, oral sprays, oral semi-solid preparations, dentifrices, and gargles; , suspensions, injections such as solid formulations for dissolution for use; inhalants such as inhalants, inhalation solutions, and inhalation aerosols; nasal drops such as nasal powders and nasal solutions; rectal formulations such as solid formulations and enema; external preparations such as powders for external use, liniments, lotions, aerosols for external use, pump sprays, ointments, creams, patches and gels.
  • the solid oral preparation includes, for example, at least one selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist, an excipient, and if necessary, a binder, a disintegrant, and a lubricant.
  • Additives such as agents, coloring agents, and flavoring agents can be added, and can be produced by a conventional method.
  • Examples of methods of using at least one tablet selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist for patients who have difficulty swallowing tablets include: , a method of simply suspending a tablet and administering it to the stomach via a nasogastric tube (see “List of Possibility of Simple Suspension", published by Kure Medical Center).
  • a method of simply suspending a tablet and administering it to the stomach via a nasogastric tube see "List of Possibility of Simple Suspension", published by Kure Medical Center).
  • Noualist tablets Istradefylline
  • Bi-Siflor tablets Pieripexole
  • additives such as flavoring agents, buffering agents and stabilizers are added to at least one selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist.
  • additives such as flavoring agents, buffering agents and stabilizers are added to at least one selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist.
  • rectal preparation for example, known suppository preparations such as polyethylene glycol, lanolin, cacao butter, fatty acid triglycerides, etc., are added to at least one selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist. It can be produced by a conventional method after adding a carrier used in (1) and, if necessary, a surfactant such as TWEEN (registered trademark).
  • a surfactant such as TWEEN (registered trademark).
  • At least one selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist is blended with a known base, stabilizer, wetting agent, preservative, etc. It can be mixed and manufactured according to the method.
  • Examples of the patches include creams, gels, and pastes as ointments containing at least one selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist on a known support. etc. can be applied and manufactured by a conventional method.
  • Examples of the support include woven fabrics and nonwoven fabrics made of cotton, staple fiber, and chemical fibers, films of soft vinyl chloride, polyethylene, polyurethane, and the like, foam sheets, and the like.
  • the injection includes, for example, at least one selected from the adenosine A2a receptor antagonist and the dopamine D2-like receptor agonist, a pH adjuster, a buffer, a stabilizer, a tonicity agent, and a local anesthetic. etc. can be added, and injections for subcutaneous, intramuscular, intravenous use, etc. can be produced by a conventional method.
  • the formulation to be applied in the oral cavity can also be formulated by a known pharmaceutical method depending on its properties.
  • the food or drink When the composition for preventing or treating disseminated intravascular coagulation is used as a food or drink, the food or drink has little risk of harming human health and is ingested by oral or gastrointestinal administration in normal social life. It is not limited to administrative divisions such as foods, pharmaceuticals, and quasi-drugs. Therefore, the food and drink include orally ingested general food, health food (functional food and drink), food with health claims (food for specified health use, food with nutrient function claims, food with functional claims, food for sick people), food It means a wide range of foods and drinks that constitute additives, quasi-drugs, pharmaceuticals, etc.
  • the type of food and drink is not particularly limited and can be appropriately selected according to the purpose.
  • Examples include soups; Beverages such as jelly-like drinks and functional drinks; Frozen desserts such as ice cream, ice sherbet, and shaved ice; , chocolate, tablets, snacks, biscuits, jelly, jam, cream, baked goods, bread and other sweets; , scallops, abalone, sea urchin, salmon roe, tokobushi and other marine products or their processed foods; fish cakes, hams, sausages and other marine or livestock processed foods; fermented milk, fermented soy milk, processed milk, fermented milk, yogurt and other dairy products; salad oil , Tempura oil, margarine, mayonnaise, shortening, whipped cream, dressings and other oils and fats or processed foods; Miso, sauces, sauces and other seasonings; Retort pouch foods such as tendon, eel bowl, hayashi rice, oden, mapo doufu, beef
  • the production of the food and drink can be carried out by a production technique known in the technical field.
  • the food and drink may contain one or more ingredients effective against disseminated intravascular coagulation. Also, by combining with other ingredients effective against disseminated intravascular coagulation or with other functional foods, multifunctional foods and drinks may be prepared.
  • the preventive or therapeutic composition for disseminated intravascular coagulation is preferably applied to humans. Hamsters, dogs, cats, cows, pigs, monkeys, horses, goats, birds, etc.).
  • the dosage of the preventive or therapeutic composition for disseminated intravascular coagulation is not particularly limited as long as the effect is exhibited, and it is appropriate according to the type, age, body weight, sex, symptoms, etc. of the administration subject.
  • the amount of the adenosine A2a receptor antagonist, which is the active ingredient is selected within the range of 0.04 mg to 500 mg per day for an adult human, and the amount of the dopamine, which is the active ingredient, is preferably selected.
  • the amount of D2-like receptor agonist is selected within the range of 0.04 mg to 500 mg.
  • the administration frequency of the preventive or therapeutic composition for disseminated intravascular coagulation is not particularly limited and can be appropriately selected according to the purpose. It may be administered in one dose or may be administered in multiple doses. In addition, administration may be performed not every day but, for example, once to four times a week.
  • the preventive or therapeutic composition for disseminated intravascular coagulation may be used in combination with one or more other pharmaceutical compositions effective for the prevention or treatment of disseminated intravascular coagulation.
  • the product of the composition for the prevention or treatment of disseminated intravascular coagulation contains at least one of IL-17 and IL-8 It may be labeled as being used for suppressing the production of this and/or being used for the prevention or treatment of disseminated intravascular coagulation.
  • labeled on the product or instruction manual means that the label is attached to the main body, container, packaging, etc. of the product, or instruction manuals, attached documents, advertising materials, and other printed materials that disclose product information It means that the display is attached to etc.
  • Test Example 1-1 Effect of adenosine in two-way mixed lymphocyte culture reaction (2-way MLR) 1)
  • MLR mixed lymphocyte culture reaction
  • MLR mixed lymphocyte culture reaction
  • T cells that responded to allogeneic MHC class II molecules and peptide complexes divided. which is a proliferating reaction.
  • MLR mixed lymphocyte culture reaction
  • Mainly reacting antigen-presenting cells having MHC class II and allogeneic CD4 + T cells that recognize the MHC and peptides Kenneth M, Casey W. Janeway's Immunobiology. Ninth Edition. Garland Science (New York); 2016).
  • DMEM Gibco (registered trademark) Dulbecco's Modified Eagle Medium, manufactured by Thermo Fisher Scientific
  • 5 Spin to homogenize add an additional 5 mL of DMEM, and transfer a total of 10 mL of splenocytes to a 50 mL tube.
  • Ficoll (registered trademark)-Paque PREMIUM 1.084, manufactured by GE healthcare) was added to the lower end of the 50 mL tube containing the spleen cell solution using a pipette aid so as not to disturb the interface between the spleen cell solution and Ficoll. Add gently and centrifuge at 1,500 rpm (430 ⁇ g) for 30 minutes at room temperature (18° C.-24° C.).
  • PBMCs peripheral blood mononuclear cells
  • DMEM peripheral blood mononuclear cells
  • DMEM D10 medium
  • D10 medium was added to the prepared BALB/c mouse-derived mononuclear cells and SJL/J mouse-derived mononuclear cells to adjust each to 3 ⁇ 10 6 cells/mL. and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from BALB/c mice and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from SJL/J mice to induce 2-way MLR. were mixed in a 12-well plate to give 6 ⁇ 10 6 cells/2 mL/well.
  • adenosine manufactured by Sigma was added to a final concentration of 0 ⁇ M or 100 ⁇ M, and BALB/c mouse-derived mononuclear cells and SJL/J mouse-derived mononuclear cells were co-cultured at 37°C.
  • ⁇ Staining of intracellular IL-17A in CD4 + T cells After 7 days of culture, the cells were harvested and seeded in a round-bottomed 96-well plate at 2 ⁇ 10 6 cells/100 ⁇ L. After blocking Fc receptors with rat anti-mouse CD16/CD32 monoclonal antibody (Mouse BD Fc Block, BD Biosciences), the cells were reacted with FITC-rat anti-mouse CD4 antibody (BioLegend) at 4°C for 30 minutes. .
  • Test Example 1-2 Effect of adenosine in two-way mixed lymphocyte culture reaction (2-way MLR) 2
  • Mononuclear cells were isolated from splenocytes of BALB/c mice and SJL/J mice with different H-2 by the same method as described in Test Example 1-1, D10 medium was added, and 3 ⁇ 10 6 cells were added to each cell. Adjusted to cells/mL. and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from BALB/c mice and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from SJL/J mice to induce 2-way MLR. were mixed in a 12-well plate to give 6 ⁇ 10 6 cells/2 mL/well.
  • adenosine manufactured by Sigma was added to a final concentration of 0 ⁇ M to 600 ⁇ M, and BALB/c mouse-derived mononuclear cells and SJL/J mouse-derived mononuclear cells were co-cultured at 37°C.
  • the concentrations of IL-17A (Th17 cytokine), IFN ⁇ (Th1 cytokine), and IL-5 (Th2 cytokine) in the supernatant 7 days after the initiation of culture were quantified by ELISA.
  • the ELISA method was performed using a Duo Set kit (manufactured by R&D Systems) according to the attached manual. Unless otherwise specified, the ELISA method in the following test examples is the same.
  • FIG. 1C The results are shown in Figures 1C to 1E.
  • IL-17A production was induced in an adenosine concentration-dependent manner (see FIG. 1C). This was thought to be a phenomenon associated with antigen presentation by MHC class II. IFN ⁇ was also found to produce adenosine concentration-dependently (see FIG. 1D). IL-5 production tended to decrease in an adenosine concentration-dependent manner (see FIG. 1E).
  • Test Example 2 Effect of adenosine A2a receptor antagonist in 2-way MLR
  • Mononuclear cells were isolated from splenocytes of BALB/c mice and SJL/J mice with different H-2 by the same method as described in Test Example 1-1, D10 medium was added, and 3 ⁇ 10 6 cells were added to each cell. Adjusted to cells/mL. and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from BALB/c mice and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from SJL/J mice to induce 2-way MLR. were mixed in a 12-well plate to give 6 ⁇ 10 6 cells/2 mL/well.
  • adenosine manufactured by Sigma
  • adenosine A2a receptor antagonist trade name: NOURIAST, general name: Istradefylline, Kyowa Kirin Co., Ltd.
  • NOURIAST general name: Istradefylline, Kyowa Kirin Co., Ltd.
  • the concentrations of IL-17A, IFN ⁇ , and IL-5 in the supernatant 7 days after the initiation of culture were quantified by ELISA.
  • FIG. 2A A significant dose-dependent suppression of IL-17A production by the adenosine A2a receptor antagonist was observed (see FIG. 2A).
  • the production of IFN ⁇ was enhanced in an adenosine A2a receptor antagonist concentration-dependent manner (see FIG. 2B), and no significant change was observed in IL-5 (see FIG. 2C). From this result, cytokine suppression by the adenosine A2a receptor antagonist was IL-17A specific.
  • Test Example 3 Effect of adenosine A2a receptor agonist, adenosine A1 receptor agonist, adenosine A2b receptor agonist, or adenosine A3 receptor agonist in 2-way MLR
  • Mononuclear cells were isolated from splenocytes of BALB/c mice and SJL/J mice with different H-2 by the same method as described in Test Example 1-1, D10 medium was added, and 3 ⁇ 10 6 cells were added to each cell. Adjusted to cells/mL.
  • an adenosine A2a receptor agonist (PSB0777 ammonium salt, manufactured by TOCRIS BIOSCIENCE) was added to a final concentration of 0.01 ⁇ M to 10 ⁇ M, and mononuclear cells derived from BALB/c mice and mononuclear cells derived from SJL/J mice were added. Spheres were co-cultured at 37°C. The concentrations of IL-17A, IFN ⁇ , and IL-5 in the supernatant 7 days after the initiation of culture were quantified by ELISA.
  • adenosine A1 receptor agonist CCPA; 2-chloro-N 6 -cyclopentyladenosine, manufactured by TOCRIS BIOSCIENCE
  • adenosine A2b receptor agonist BAY 60-6583
  • BALB/c mouse-derived mononuclear cells and SJL/J mouse-derived mononuclear cells were co-cultured at 37°C with the addition of an adenosine A3 receptor agonist (HEMADO, TOCRIS BIOSCIENCE). .
  • HEMADO adenosine A3 receptor agonist
  • Test Example 4 Effect of CD39 inhibitor or CD73 inhibitor in 2-way MLR
  • Mononuclear cells were isolated from splenocytes of BALB/c mice and SJL/J mice with different H-2 by the same method as described in Test Example 1-1, D10 medium was added, and 3 ⁇ 10 6 cells were added to each cell. Adjusted to cells/mL. and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from BALB/c mice and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from SJL/J mice to induce 2-way MLR. were mixed in a 12-well plate to give 6 ⁇ 10 6 cells/2 mL/well.
  • a CD39 inhibitor (ARL67156 trisodium salt, manufactured by TOCRIS BIOSCIENCE) or a CD73 inhibitor (AMP-CP (adenosine 5′-( ⁇ , ⁇ -methylene) diphosphate) was added to a final concentration of 0.1 ⁇ M to 10 ⁇ M BALB/c mouse-derived mononuclear cells and SJL/J mouse-derived mononuclear cells were co-cultured at 37° C. After 7 days from the start of culture, the supernatant was The concentration of IL-17A was quantified by ELISA.
  • an adenosine A2a receptor antagonist (Istradefylline, manufactured by Kyowa Kirin Co., Ltd.) was added to a final concentration of 0.01 nM to 100 nM, and mononuclear cells derived from BALB/c mice and SJL/J cells were added. Mouse-derived mononuclear cells were co-cultured at 37°C. The concentration of IL-17A in the supernatant 7 days after the initiation of culture was quantified by ELISA.
  • Mononuclear cells were isolated from splenocytes of BALB/c mice and SJL/J mice with different H-2 by the same method as described in Test Example 1-1, D10 medium was added, and 3 ⁇ 10 6 cells were added to each cell. Adjusted to cells/mL. and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from BALB/c mice and 1 mL of mononuclear cells (3 ⁇ 10 6 cells/mL) from SJL/J mice to induce 2-way MLR. were mixed in a 12-well plate to give 6 ⁇ 10 6 cells/2 mL/well.
  • a CD39 inhibitor (ARL67156 trisodium salt, manufactured by TOCRIS BIOSCIENCE) or a CD73 inhibitor (AMP-CP (adenosine 5′-( ⁇ , ⁇ -methylene) diphosphate) was added to a final concentration of 0.1 ⁇ M to 10 ⁇ M BALB/c mouse-derived mononuclear cells and SJL/J mouse-derived mononuclear cells were co-cultured at 37° C. After 7 days from the start of culture, the supernatant was , the adenosine concentration and the ATP concentration were quantified using the Adeonsine Assay Kit (manufactured by BioVision).
  • the washing solution was added to the 15 mL tube to bring the total volume to 10 mL. Leaving the tissue fragments that immediately accumulated at the bottom of the 15 mL tube, the supernatant was transferred again to a new 15 mL tube and centrifuged at room temperature at 1,200 rpm (270 x g) for 5 minutes to obtain a pellet containing lymphocytes. rice field. The supernatant was removed and the pellet loosened. After that, 250 ⁇ L of NH 4 Cl-Tris solution was added and stirred to remove red blood cells.
  • CD4 + T cells were prepared by positive selection using magnetic beads (mouse CD4 (L3T4) MicroBeads, manufactured by Miltenyi Biotec) according to the manual.
  • BM-DCs bone-marrow-derived dendritic cells
  • OVA albumin-specific TCR transgenic DO11.10 mice (Jackson Institute, Bar The tissue containing the femur and tibia was removed from the bone (obtained from Harbor), the surrounding muscle tissue was removed with a knife, both ends of the femur and tibia were cut with scissors in a dish containing 5 mL of DMEM, and the bone marrow in the bone was removed.
  • Bone marrow cells (2 ⁇ 10 6 cells) were seeded in 10 mL of D10 medium containing 20 ng/mL of granulocyte-macrophage colony-stimulating factor (GM-CSF, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and placed in a 10 cm dish.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • BM-DCs bone marrow dendritic cells
  • LPS manufactured by Sigma
  • OVA peptide IA b / IA d OVA helper peptide, Igaku Co., Ltd.
  • MBL Biological Laboratories
  • CD39 inhibitor ARL67156 trisodium salt, manufactured by TOCRIS BIOSCIENCE
  • CD73 inhibitor AMP -CP, manufactured by TOCRIS BIOSCIENCE
  • adenosine A2a receptor antagonist Istradefylline, manufactured by Kyowa Kirin Co., Ltd.
  • DO11.10 mouse bone marrow dendritic cells were added to 500 ⁇ L of D10 medium so that the prepared DO11.10 mouse CD4 + T cells were 3 ⁇ 10 5 cells. ) was adjusted to 3 ⁇ 10 4 cells and added.
  • OVA peptide IA b /IA d OVA helper peptide, manufactured by MEDICAL & BIOLOGICAL LABORATORY CO., LTD. (MBL)
  • MBL BIOLOGICAL LABORATORY CO., LTD.
  • an immunological synapse Upon antigen presentation, a narrow space called an immunological synapse is formed (see Grakoui A et al., Science, 1999, 285, p.221-27).
  • a supramolecular activation complex SMAC
  • various proteins such as membrane-type enzymes and signaling molecules are regularly arranged concentrically (Monks CR et al., Nature, 1998). , 395, p.82-86).
  • Various other molecules are also involved, and functional adhesion surfaces such as T cells and antigen-presenting cells, cytotoxic T cells, natural killer cells and target cells are generally called immunological synapses.
  • bone marrow dendritic cells produce ATP upon antigen presentation reaction, and the ATP is converted to adenosine by the membrane-type enzymes CD39 and CD73 in the narrow space of the immunological synapse, resulting in the production of adenosine. was thought to act on CD4 + T cells to produce IL-17A (see FIG. 8).
  • the supernatant was transferred again to a new 15 mL tube and centrifuged at room temperature at 1,200 rpm (270 x g) for 5 minutes to obtain a pellet containing lymphocytes. rice field. The supernatant was removed and the pellet loosened. After that, 250 ⁇ L of NH 4 Cl-Tris solution was added and stirred to remove red blood cells. After that, 10 mL of DMEM was quickly added and centrifuged at 1,200 rpm (270 ⁇ g) for 5 minutes at room temperature to obtain a pellet containing lymphocytes. After removing the supernatant and loosening the pellet, 10 mL of DMEM was added again.
  • the medium containing the lymphocytes was transferred to a new 15 mL tube with a pipette while taking as little denatured red blood cells as possible, and centrifuged again at room temperature at 1,200 rpm (270 ⁇ g) for 5 minutes. After removing the supernatant, the pellet was loosened. It was suspended again in 10 mL of DMEM and centrifuged at room temperature at 1,200 rpm (270 xg) for 5 minutes. The supernatant was removed and finally suspended in 2 mL of D10 medium. Then, CD4 + T cells were prepared by positive selection using magnetic beads (mouse CD4 (L3T4) MicroBeads, manufactured by Miltenyi Biotec) according to the manual.
  • ⁇ Preparation of CD4 + CD62L + T cells> Except for using magnetic beads (mouse CD4 + CD62L + T cell MicroBeads, manufactured by Miltenyi Biotec) instead of magnetic beads (mouse CD4 (L3T4) MicroBeads, manufactured by Miltenyi Biotec) in ⁇ Preparation of CD4 + T cells> were separated into CD4 + CD62L + T cells and their Flow Through in the same manner as ⁇ Preparation of CD4 + T cells>.
  • Adenosine manufactured by Sigma was added to the prepared mouse CD4 + T cells to a final concentration of 100 ⁇ M to 1,000 ⁇ M, and an anti-mouse CD3 ⁇ agonist antibody (final concentration: 1 ⁇ g/mL, BioLegend (registered trademark), Clone: 145-2C11) and anti-mouse CD28 agonist antibody (final concentration: 0.5 ⁇ g/mL, BioLegend (registered trademark), Clone: 37.51) were added to 24 wells at 1 ⁇ 10 6 cells/500 ⁇ L. Plates were inoculated and cultured at 37°C. After 1 day, 3 days, 5 days, and 7 days from the initiation of culture, cell supernatants were collected. The concentration of IL-17A contained in the recovered cell supernatant was quantified by ELISA.
  • PSB0777 ammonium salt manufactured by TOCRIS BIOSCIENCE
  • TOCRIS BIOSCIENCE which is an adenosine A2a receptor agonist
  • adenosine A2a receptor antagonist on CD4 + T cells adenosine (manufactured by Sigma) was added to a final concentration of 600 ⁇ M, and the adenosine A2a receptor antagonist istradefylline (Kyowa Kirin Co., Ltd.) was added, and an anti-mouse CD3 ⁇ agonist antibody (final concentration: 1 ⁇ g/mL, BioLegend (registered trademark), Clone: 145-2C11) and an anti-mouse CD28 agonist antibody (final concentration: 0.5 ⁇ g/ mL, BioLegend (registered trademark), Clone: 37.51), seeded in a 24-well plate at 1 ⁇ 10 6 cells/500 ⁇ L, and cultured at 37°C. Cell supernatants were collected 7 days after the initiation of culture. The concentration of IL-17A contained in the recovered cell supernatant was quantified by ELISA.
  • CD4 + T cells activated by CD3/CD28 stimulation are induced to produce IL-17A by the addition of adenosine. 17A production was shown to be suppressed.
  • ⁇ Effect of adenosine on CD4 + CD62L + T cells To the prepared mouse CD4 + CD62L + T cells or their Flow Through (CD4 + CD62L ⁇ T cells), together with adenosine (manufactured by Sigma) added to a final concentration of 0 ⁇ M to 1,000 ⁇ M, an anti-mouse CD3 ⁇ agonist antibody ( Final concentration: 1 ⁇ g/mL, BioLegend (registered trademark), Clone: 145-2C11), and anti-mouse CD28 agonist antibody (final concentration: 0.5 ⁇ g/mL, BioLegend (registered trademark), Clone: 37.51) was added, seeded in a 24-well plate at 1 ⁇ 10 6 cells/500 ⁇ L, and cultured at 37°C. Cell supernatants were collected 7 days after the initiation of culture. The concentration of IL-17A contained in the recovered cell supernatant was quantified by ELISA.
  • IL-17A secretion was induced from CD4 + CD62L ⁇ T cells, but not from CD4 + CD62L + T cells. This suggested that effector CD4 + T cells were adenosine-stimulated to produce IL-17A.
  • adenosine is produced depending on the interaction between T cells and antigen-presenting cells during the acute phase of inflammation and cell damage, which is the early stage of adaptive immune response, and induces neutrophilic inflammation. By doing so, it was thought to play a role in the interface between innate immunity and acquired immunity. In contrast, it was suggested that adenosine A2a receptor antagonists can suppress the neutrophilic inflammation.
  • Test Example 8 Effect of dopamine D2-like receptor agonist on activated T cells
  • Stimulation of human peripheral blood mononuclear cells (PBMC) with Candida antigen results in the production of IFN ⁇ , IL-17, and IL-8 (Toshiyuki Matsuyama et al, Clin. Exp. Neuroimmunol, 2018, 9, p. 251-257).
  • PBMC peripheral blood mononuclear cells
  • Candida antigen results in the production of IFN ⁇ , IL-17, and IL-8 (Toshiyuki Matsuyama et al, Clin. Exp. Neuroimmunol, 2018, 9, p. 251-257).
  • PBMC peripheral blood mononuclear cells
  • heparinized venous blood collected from healthy subjects was centrifuged at 450 g for 10 minutes to separate blood cells and plasma.
  • RPMI1640 manufactured by Sigma-Aldrich
  • Ficoll registered trademark
  • Paque Plus manufactured by GE Healthcare
  • peripheral blood mononuclear cells were added to RPMI1640 containing 10% by volume human serum, 2 mM L-glutamine (manufactured by Sigma-Aldrich), and 0.1 mg/mL streptomycin and 100 U/mL penicillin (manufactured by Sigma-Aldrich). floated.
  • peripheral blood mononuclear cells were seeded at 1.5 ⁇ 10 5 cells/well, and in the presence of 5 ⁇ g/mL Candida antigen (allergen scratch extract “Torii”, manufactured by Torii Pharmaceutical Co., Ltd.).
  • Candida antigen allergen scratch extract “Torii”, manufactured by Torii Pharmaceutical Co., Ltd.
  • Dopamine D2-like receptor agonist pramipexole manufactured by Sigma-Aldrich
  • ropinirole ropinirole hydrochloride, manufactured by Sigma-Aldrich
  • peripheral blood mononuclear cells were cultured in the same manner as described above, except that the drug was not added.
  • a dopamine D2-like receptor antagonist, haloperidol manufactured by Sigma-Aldrich
  • haloperidol manufactured by Sigma-Aldrich
  • PBMC Peripheral blood mononuclear cells
  • Ficoll registered trademark
  • Paque Plus manufactured by GE Healthcare
  • the resulting peripheral blood mononuclear cells were added to RPMI1640 containing 10% by volume human serum, 2 mM L-glutamine (Sigma-Aldrich), and 0.1 mg/mL streptomycin and 100 U/mL penicillin (Sigma-Aldrich). floated.
  • the peripheral blood mononuclear cells were seeded at 1.5 ⁇ 10 5 cells/well, and in the presence of 5 ⁇ g/mL Candida antigen (allergen scratch extract “Torii”, manufactured by Torii Pharmaceutical Co., Ltd.).
  • Candida antigen allergen scratch extract “Torii”, manufactured by Torii Pharmaceutical Co., Ltd.
  • Any one of the following agents (1) to (4) was added at three concentrations, and cultured at 37°C under 5% CO 2 saturated water vapor pressure.
  • the concentration of each drug is based on the "pharmaceutical interview form" (published by the Japanese Association of Hospital Pharmacists) for each drug, and the final concentration per well is 100 times the Cmax of each drug, 10 times the concentration, or A 1 ⁇ concentration was added to each well.
  • peripheral blood mononuclear cells were cultured in the same manner as described above, except that the drug was not added. Seven days after the start of culture, the IL-17A concentration in each supernatant was quantified using an ELISA kit (Human IL-17A Duoset ELISA, DY317, manufactured by R&D Systems).
  • Dopamine D2-like receptor agonist talipexole (B-HT920 dihydrochloride talipexole, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Cmax 0.7 ng / mL (“Pharmaceutical Interview Form” Revised August 2019 9th edition reference))
  • Dopamine D2-like receptor agonist pramipexole (pramipexole dihydrochloride monohydrate, manufactured by Tokyo Chemical Industry Co., Ltd., Cmax 0.6 ng/ml (see “Pharmaceutical Interview Form”, revised 8th edition in June 2020) )
  • Dopamine D2-like receptor agonist ropinirole (ropinirole hydrochloride, manufactured by Sigma-Aldrich, Cmax 1.5 ng / ml ("Pharmaceutical Interview Form”, ropinirole sustained release tablet 2 mg "Sawai", revised August 2019 No.
  • Adenosine A2a receptor antagonist Istradefylline (Nouriast, manufactured by Kyowa Kirin Co., Ltd., Cmax 170 ng/mL (see “Pharmaceutical Interview Form”, 4th edition revised in July 2019))
  • the drug is selected as a selection criterion that it is a Parkinson's disease drug that can be used clinically in Japan, that it is water-soluble, and that the dopamine D2-like receptor agonist is selective for the dopamine D2-like receptor. did.
  • IL-17A production was inhibited by dopamine D2-like receptor agonists and adenosine A2a receptor antagonists.
  • ropinirole and istradefylline inhibited IL-17A production in a dose-dependent manner.
  • istradefylline was found to have a significant IL-17A production inhibitory effect even at a concentration of 1-fold the Cmax.
  • peripheral blood mononuclear cells were added to RPMI1640 containing 10% by volume human serum, 2 mM L-glutamine (Sigma-Aldrich), and 0.1 mg/mL streptomycin and 100 U/mL penicillin (Sigma-Aldrich). floated. Surplus PBMCs were cryopreserved and used in Test Examples 10-2 and 10-3.
  • SARS-CoV-2 spike protein-derived peptide is a study by Alba G et al. immune response against COVID-19", Cell Host Microbe 2021; 29: 1076-1092.
  • CD4 T cell epitopes when it binds to HLA allele products that are relatively frequently seen in the Japanese population
  • SEQ ID NOs: 1 to 9 shown in Table 1 below.
  • the synthesized peptides represented by SEQ ID NOS: 1 to 9 were analyzed with a mass spectrometer, and the novel coronavirus SARS-Cov-2 genome sequence
  • DDBJ DNA Data Bank of Japan
  • the public information http://getentry.ddbj.nig.ac.jp/getentry/na/BS000685-BS000694/
  • point mutation residues observed from alpha strain to delta strain No base was included.
  • ⁇ IL-8 response of peripheral blood mononuclear cells to SARS-CoV-2 spike protein-derived peptide> Prepared COVID-19 patient-derived peripheral blood mononuclear cells were seeded in a 96-well flat-bottom plate at 1.5 ⁇ 10 5 cells/well, and peptides represented by SEQ ID NOs: 1 to 9 were added to a final concentration of 5 ⁇ M. and cultured at 37° C. under 5% CO 2 saturated steam pressure. As a negative control, peripheral blood mononuclear cells were cultured in the same manner as described above, except that the peptide was not added. Seven days after the initiation of culture, the concentrations of IL-8, IFN ⁇ , IL-5 and IL-17A in each supernatant were quantified by ELISA.
  • the results are shown in Tables 2-1 and 2-2 below.
  • the results are obtained by subtracting the IL-8 production amount (concentration) by peripheral blood mononuclear cells alone, which is a negative control, from the IL-8 production amount (concentration) by peripheral blood mononuclear cells cultured with the addition of each peptide. -8 (ng/mL).
  • the amount (concentration) of IFN ⁇ , IL-5, or IL-17A produced by peripheral blood mononuclear cells cultured with the addition of each peptide was determined to be negative for each.
  • ⁇ IFN ⁇ ng/mL
  • ⁇ IL-5 ng/mL
  • ⁇ IL-17A ng/mL
  • concentration concentration of IFN ⁇ , IL-5, or IL-17A by control peripheral blood mononuclear cells alone ng/mL.
  • "-" indicates less than 0.1 ng/mL.
  • Test Example 10-2 HLA restriction in IL-8 response of peripheral blood mononuclear cells to SARS-CoV-2 spike protein-derived peptide
  • Test Example 10-1 using cryopreserved peripheral blood mononuclear cells of a patient who showed a strong peptide-specific IL-8 response, an experiment was conducted to suppress the peptide-specific response with an anti-HLA antibody.
  • Peripheral blood mononuclear cells of patient No. 4, patient No. 11, or patient No. 13 prepared in Test Example 10-1 were seeded in a 96-well flat-bottom plate at 1.5 ⁇ 10 5 cells/well, and anti-HLA antibody was added.
  • peripheral blood mononuclear cells were cultured in the same manner as described above, except that the anti-HLA antibody was not added. After 7 days from the start of culture, the IL-8 concentration in each supernatant was quantified by ELISA.
  • FIGS. 11A-11C The results are shown in FIGS. 11A-11C.
  • the IL-8 response was suppressed by anti-HLA-DR antibodies (L243 and HU-4) but not by anti-HLA-DQ antibody (1a3) (p ⁇ 0.01).
  • This result suggests presentation by a complex (heterodimer) of HLA-DRB1 and HLA-DRA. This strongly suggests that CD4 + T cells are responding.
  • Test Example 10-3 Effect of adenosine A2a receptor antagonist and dopamine D2-like receptor agonist on IL-8 of peripheral blood mononuclear cells for SARS-CoV-2 spike protein-derived peptide
  • Peripheral blood mononuclear cells of patient No. 4, patient No. 11, or patient No. 13 prepared in Test Example 10-1 were seeded at 1.5 ⁇ 10 5 cells/well in a 96-well flat-bottom plate, and the following (1 ) or (2) was added at two different concentrations, and cultured at 37° C. under 5% CO 2 saturated steam pressure for 30 minutes.
  • the peptide represented by SEQ ID NO: 6 or SEQ ID NO: 1 synthesized in Test Example 10-1 was added to a final concentration of 5 ⁇ M, and further added to 5% CO 2 saturated water vapor pressure. , and cultured at 37°C for 7 days.
  • the concentration of each drug is based on the "medicine interview form" (published by the Japanese Association of Hospital Pharmacists) for each drug, and the final concentration per well is 10 times the Cmax of each drug, or 1 time. was added to each well so that As a negative control, peripheral blood mononuclear cells were cultured in the same manner as described above, except that the drug was not added.
  • IL-8 concentration in each supernatant was quantified by ELISA.
  • Dopamine D2-like receptor agonist ropinirole (ropinirole hydrochloride, manufactured by Sigma-Aldrich, Cmax 1.5 ng / ml ("Pharmaceutical Interview Form”, ropinirole sustained release tablet 2 mg "Sawai", revised August 2019 No. 2 see version))
  • Adenosine A2a receptor antagonist Istradefylline (Nouriast, manufactured by Kyowa Kirin Co., Ltd., Cmax 170 ng/mL (see “Pharmaceutical Interview Form”, 4th edition revised in July 2019))
  • Embodiments of the present invention include, for example, the following.
  • a composition for preventing or treating disseminated intravascular coagulation comprising at least one selected from an adenosine A2a receptor antagonist and a dopamine D2-like receptor agonist as an active ingredient.
  • ⁇ 3> Any of ⁇ 1> to ⁇ 2> above, wherein the dopamine D2-like receptor agonist is at least one selected from cabergoline, pergolide, bromocriptine, talipexole, pramipexole, ropinirole, rotigotine, and apomorphine hydrochloride hydrate. It is a composition for prevention or treatment of disseminated intravascular coagulation according to 1.
  • ⁇ 4> The composition for preventing or treating disseminated intravascular coagulation according to any one of ⁇ 1> to ⁇ 3>, wherein the disseminated intravascular coagulation is caused by an infectious disease.
  • the adenosine A2a receptor antagonist is an oral suspension of istradefylline,
  • the composition for the prevention or treatment of disseminated intravascular coagulation contains an excellent neutrophil chemoattractant and its inducer, in particular at least one of IL-17A and IL-8 from activated T cells. Since it has a production inhibitory effect and can prevent or treat disseminated intravascular coagulation, it can be suitably used for the prevention or treatment of disseminated intravascular coagulation caused by infectious diseases, particularly , SARS-CoV-2 can be suitably used for the prevention or treatment of disseminated intravascular coagulation caused by COVID-19.

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Abstract

L'invention concerne une composition prophylactique ou thérapeutique pour le syndrome de coagulation intravasculaire disséminée, la composition comprenant, en tant que principe actif, au moins un élément choisi parmi des antagonistes du récepteur de l'adénosine A2a et des agonistes du récepteur de type dopamine D2.
PCT/JP2022/001353 2021-03-01 2022-01-17 Composition prophylactique ou thérapeutique pour le syndrome de coagulation intravasculaire disséminée WO2022185742A1 (fr)

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WO2014123186A1 (fr) * 2013-02-06 2014-08-14 公立大学法人横浜市立大学 Anticorps anti-sémaphorine 3a, et traitement de la maladie d'alzheimer ainsi que des maladies immunologiques et inflammatoires mettant en œuvre celui-ci
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