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WO2025070375A1 - Procédé de suppression d'immunoréaction - Google Patents

Procédé de suppression d'immunoréaction Download PDF

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Publication number
WO2025070375A1
WO2025070375A1 PCT/JP2024/033898 JP2024033898W WO2025070375A1 WO 2025070375 A1 WO2025070375 A1 WO 2025070375A1 JP 2024033898 W JP2024033898 W JP 2024033898W WO 2025070375 A1 WO2025070375 A1 WO 2025070375A1
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Prior art keywords
cells
composition
calcium ion
drug
agent
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English (en)
Japanese (ja)
Inventor
芳樹 久保田
清史 東
和之 北澤
葉子 山口
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Nanoegg Research Laboratories Inc
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Nanoegg Research Laboratories Inc
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a method and a pharmaceutical composition for suppressing an excessive immune response.
  • the immune system protects the body by recognizing and eliminating non-self substances, such as pathogens that invade from outside the body and abnormal cells and molecules produced within the body.
  • the immune system is precisely regulated so that it attacks non-self substances, such as pathogens and abnormal cells, while not attacking normal self substances.
  • this control mechanism breaks down, it can cause a variety of intractable diseases caused by excessive immune responses, such as autoimmune diseases such as psoriasis vulgaris and rheumatoid arthritis, and allergic diseases such as atopic dermatitis.
  • steroids are frequently prescribed as a treatment to reduce immune responses, but long-term use is not recommended due to safety concerns.
  • many molecules such as IL-4, IL-13, IL-31, Janus kinase, and phosphodiesterase, are widely and intricately involved in the immune response in atopic dermatitis, and drugs that suppress the function of these molecules have been developed.
  • drugs that suppress the function of these molecules have been developed.
  • satisfaction with the treatment is by no means high.
  • the objective of this disclosure is to provide a method for suppressing immune responses in subjects with excessively enhanced immune responses, such as patients with psoriasis vulgaris or atopic dermatitis.
  • the present inventors have found that the immune response of a subject can be suppressed by administering a therapeutically effective amount of a drug that reduces intracellular calcium ion concentration. Based on this finding, the present inventors have conducted further research and completed the invention of the present disclosure. That is, the present invention encompasses the following aspects.
  • (Item 1) A composition for suppressing an immune response in a subject, the composition comprising an agent that reduces intracellular free calcium ion concentration.
  • the drug is an agent capable of forming a complex with calcium ions or an agent capable of inhibiting or blocking the influx of calcium ions into the cell.
  • the immune cells are at least one selected from the group consisting of T lymphocytes, B lymphocytes, dendritic cells, macrophages, Langerhans cells, eosinophils, basophils, neutrophils and mast cells.
  • the immune cell is a T lymphocyte.
  • composition according to any of the preceding items, wherein the agent is a compound of formula (1) or a pharma- ceutically acceptable salt thereof.
  • R 1 to R 6 each independently represent a hydrogen atom or an alkyl group having 3 or less carbon atoms.
  • composition according to any of the preceding items, wherein the agent is selected from pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutically acceptable salt thereof.
  • the agent is selected from pyoktanin blue or a pharma- ceutically acceptable salt thereof.
  • compositions for treating or preventing an allergic disease in a subject comprising an agent that reduces intracellular calcium ion concentration.
  • the allergic disease is at least one selected from the group consisting of atopic dermatitis, asthma, seasonal allergic rhinitis and food allergy.
  • the allergic disease is atopic dermatitis.
  • compositions for treating or preventing an autoimmune disease in a subject comprising an agent that reduces intracellular calcium ion concentration.
  • composition according to any of the preceding items, wherein the autoimmune disease is at least one selected from the group consisting of psoriasis vulgaris, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease and ulcerative colitis.
  • the autoimmune disease is psoriasis vulgaris.
  • a calcium ion exporter comprising an agent capable of exporting calcium ions from within a cell and reducing the intracellular calcium ion concentration, the agent being a compound represented by formula (1) or a pharma- ceutical acceptable salt thereof.
  • a calcium ion exporter comprising an agent capable of exporting calcium ions from within a cell and reducing the intracellular calcium ion concentration, the agent being selected from pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutical acceptable salt thereof.
  • the calcium ion exporter according to any one of the preceding items, wherein the calcium ion exporter is for the treatment or prevention of ischemic heart disease, hypertension, epilepsy, headache, or pruritus.
  • the calcium ion exporter is for the treatment or prevention of ischemic heart disease, hypertension, epilepsy, headache, or pruritus.
  • the calcium ion exporter is for the treatment or prevention of ischemic heart disease, hypertension, epilepsy, headache, or pruritus.
  • the calcium ion exporter is for the treatment or prevention of ischemic heart disease, hypertension, epilepsy, headache, or pruritus.
  • the drug is an agent capable of forming a complex with calcium ions or an agent capable of inhibiting or blocking the influx of calcium ions into the cell.
  • the immune cells are at least one selected from the group consisting of T lymphocytes, B lymphocytes, dendritic cells, macrophages, Langerhans cells, eosinophils, basophils, neutrophils and mast cells.
  • the immune cells are T lymphocytes.
  • (Item 7A) The method according to any of the preceding items, wherein the agent is a compound of formula (1) or a pharma- ceutically acceptable salt thereof.
  • R 1 to R 6 each independently represent a hydrogen atom or an alkyl group having 3 or less carbon atoms.
  • (Item 8A) The method according to any of the preceding items, wherein the agent is selected from pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutically acceptable salt thereof.
  • (Item 9A) The method according to any of the preceding items, wherein the agent is selected from pyoktanin blue or a pharma- ceutically acceptable salt thereof.
  • (Item 10A) A method for treating or preventing an allergic disease in a subject, comprising administering to the subject an agent that decreases intracellular calcium ion concentration.
  • (Item 11A) The method according to any of the above items, wherein the allergic disease is at least one selected from the group consisting of atopic dermatitis, asthma, seasonal allergic rhinitis and food allergy.
  • (Item 12A) The method according to any of the above items, wherein the allergic disease is atopic dermatitis.
  • (Item 13A) 1. A method for treating or preventing an autoimmune disease in a subject, comprising administering to the subject an agent that decreases intracellular calcium ion concentration.
  • autoimmune disease is at least one selected from the group consisting of psoriasis vulgaris, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease and ulcerative colitis.
  • the autoimmune disease is psoriasis vulgaris.
  • the medicament is administered by topical administration, oral administration, intravenous administration, inhalation, intranasal administration, subcutaneous administration, intramuscular administration, sublingual administration, or ophthalmic administration.
  • (Item 17A) A method for decreasing a calcium ion concentration in a cell by excreting calcium ions from within the cell, the method comprising contacting the cell with an agent capable of excreting calcium ions from the cell and decreasing the calcium ion concentration in the cell, the agent being a compound represented by formula (1) or a pharma- ceutically acceptable salt thereof.
  • (Item 18A) A method for decreasing a calcium ion concentration in a cell by excreting calcium ions from within the cell, the method comprising contacting the cell with an agent capable of excreting calcium ions from the cell and decreasing the calcium ion concentration in the cell, the agent being selected from pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutically acceptable salt thereof.
  • the agent being selected from pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutically acceptable salt thereof.
  • an agent that reduces intracellular free calcium ion concentration in the manufacture of a medicament for suppressing an immune response in a subject is an agent capable of forming a complex with calcium ions or an agent capable of inhibiting or blocking the influx of calcium ions into the cell.
  • the agent is capable of excreting calcium ions from within the cells to reduce the calcium ion concentration within the cells.
  • the cell is an immune cell.
  • (Item 5B) The use according to any of the preceding items, wherein the immune cells are at least one selected from the group consisting of T lymphocytes, B lymphocytes, dendritic cells, macrophages, Langerhans cells, eosinophils, basophils, neutrophils and mast cells.
  • the immune cells are T lymphocytes.
  • the agent is a compound of formula (1) or a pharma- ceutically acceptable salt thereof.
  • R 1 to R 6 each independently represent a hydrogen atom or an alkyl group having 3 or less carbon atoms.
  • the agent is selected from pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutically acceptable salt thereof.
  • the agent is selected from pyoktanin blue or a pharma- ceutically acceptable salt thereof.
  • Item 10B 23. Use of an agent that reduces intracellular calcium ion concentration in the manufacture of a medicament for treating or preventing an allergic disease in a subject.
  • (Item 11B) The use according to any of the above items, wherein the allergic disease is at least one selected from the group consisting of atopic dermatitis, asthma, seasonal allergic rhinitis and food allergy.
  • (Item 12B) The use according to any of the above items, wherein the allergic disease is atopic dermatitis.
  • autoimmune disease is at least one selected from the group consisting of psoriasis vulgaris, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease and ulcerative colitis.
  • the autoimmune disease is psoriasis vulgaris.
  • the medicament is administered by topical administration, oral administration, intravenous administration, inhalation, nasal administration, subcutaneous administration, intramuscular administration, sublingual administration, or ophthalmic administration.
  • (Item 17B) Use of a drug capable of decreasing intracellular calcium ion concentration by excreting intracellular calcium ions in the manufacture of a calcium ion excretion agent, wherein the drug is a compound represented by formula (1) or a pharma- ceutical acceptable salt thereof.
  • (Item 18B) Use of a drug capable of releasing intracellular calcium ions and decreasing intracellular calcium ion concentration in the manufacture of a calcium ion exporter, wherein the drug is selected from pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutical acceptable salt thereof.
  • (Item 19B) The use according to any of the above items, wherein the calcium ion exporter is for the treatment or prevention of ischemic heart disease, hypertension, epilepsy, headache, or pruritus.
  • (Item 1C) An agent that reduces intracellular free calcium ion concentration to suppress an immune response in a subject.
  • (Item 2C) The agent described in the above item, wherein the agent is capable of forming a complex with calcium ions or capable of inhibiting or blocking the influx of calcium ions into the cell.
  • (Item 3C) The drug described in any of the above items, which is capable of expelling calcium ions from the cells to reduce the calcium ion concentration in the cells.
  • (Item 4C) The agent according to any of the preceding items, wherein the cell is an immune cell.
  • the immune cells are at least one type selected from the group consisting of T lymphocytes, B lymphocytes, dendritic cells, macrophages, Langerhans cells, eosinophils, basophils, neutrophils and mast cells.
  • the immune cells are T lymphocytes.
  • the agent is a compound of formula (1) or a pharma- ceutically acceptable salt thereof.
  • R 1 to R 6 each independently represent a hydrogen atom or an alkyl group having 3 or less carbon atoms.
  • R 1 to R 6 each independently represent a hydrogen atom or an alkyl group having 3 or less carbon atoms.
  • Item 9C The agent according to any of the preceding items, wherein the agent is selected from pyoktanin blue or a pharma- ceutically acceptable salt thereof.
  • the drug according to any of the above items, wherein the allergic disease is at least one selected from the group consisting of atopic dermatitis, asthma, seasonal allergic rhinitis and food allergy.
  • the drug according to any of the above items, wherein the allergic disease is atopic dermatitis.
  • the drug according to any of the above items, wherein the autoimmune disease is at least one selected from the group consisting of psoriasis vulgaris, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease and ulcerative colitis.
  • (Item 15C) The drug according to any of the above items, wherein the autoimmune disease is psoriasis vulgaris.
  • (Item 16C) The drug according to any one of the preceding items, characterized in that the drug is administered by topical administration, oral administration, intravenous administration, inhalation, nasal administration, subcutaneous administration, intramuscular administration, sublingual administration, or ophthalmic administration.
  • (Item 17C) A compound represented by the formula (1) or a pharma- ceutical acceptable salt thereof for decreasing intracellular calcium ion concentration by excreting intracellular calcium ions.
  • (Item 18C) Pyoktanin blue, methylene blue, or an analogue thereof, or a pharma- ceutically acceptable salt thereof, for expelling intracellular calcium ions to reduce the intracellular calcium ion concentration.
  • (Item 19C) The drug according to any of the above items, wherein the drug is for the treatment or prevention of ischemic heart disease, hypertension, epilepsy, headache, or pruritus.
  • symptoms can be improved in subjects with excessively enhanced immune responses by effectively suppressing the immune responses.
  • FIG. 1 shows an example of the measurement results of intracellular calcium ion concentration measured in Examples 1 and 2.
  • This is a graph showing relative fluorescence intensity over time, with the fluorescence intensity immediately before the addition of A23187 being 0% and the fluorescence intensity 15 minutes after the addition of A23187 being 100%.
  • the inhibition rate (%) of drug (1) was calculated from the relative fluorescence intensity of cells to which DMSO was added and cells to which drug (1) was added.
  • the vertical axis shows relative fluorescence intensity (%), and the horizontal axis shows time (minutes).
  • FIG. 1 shows an example of the measurement results of intracellular calcium ion concentration measured in Example 3.
  • the figure shows the relative fluorescence intensity over time, with the fluorescence intensity immediately before the addition of anti-CD3 antibody being 0% and the fluorescence intensity 3 minutes after the addition of anti-CD3 antibody being 100%.
  • the inhibition rate (%) of drug (1) was calculated from the relative fluorescence intensity of cells to which DMSO was added and cells to which drug (1) was added.
  • the vertical axis shows the relative fluorescence intensity (%), and the horizontal axis shows the time (minutes). This shows the number of viable mouse spleen cells measured in Example 5 using the OD450 value as an index. Groups with different alphabets indicate that there is a statistically significant difference (5% or less).
  • the vertical axis shows the OD450 value.
  • immune response refers to a response that recognizes and removes non-self substances, such as pathogens that invade from outside the body or abnormal cells or molecules produced within the body, and is carried out by immune cells such as T lymphocytes, B lymphocytes, dendritic cells, macrophages, Langerhans cells, eosinophils, basophils, neutrophils, and mast cells.
  • suppression of immune response means that the composition, agent, or method of the present disclosure reduces the immune response compared to before use of the composition, agent, or method of the present disclosure.
  • the reduction in immune response can be measured as a reduction in the number of immune cells, a reduction in cytokine and/or chemokine concentrations (e.g., a reduction in IL-2 concentration, a reduction in IL-17 concentration), and a reduction in IgE concentration.
  • Stimulants is a general term for substances that induce biological reactions such as immune responses, but in this specification, “stimulants” refers to substances that increase intracellular calcium ion concentrations.
  • Calcium ions are the main second messengers in intracellular signal transduction and play an important role in the physiological functions of various immune cells. Cytoplasmic calcium ion concentrations are strictly controlled and are usually maintained at low concentrations.
  • Known stimulants include calcium ionophores such as A23187 that nonspecifically increase intracellular calcium concentrations, and agonists such as antibodies (e.g., anti-CD3 antibodies) and low molecular weight compounds (e.g., acetylcholine) that specifically bind to cell surface molecules such as CD3 and CD28 to increase intracellular calcium concentrations.
  • allergic disease refers to a disease in which the immune response that would normally eliminate foreign substances from the outside occurs excessively in response to a specific foreign substance, and examples of such diseases include atopic dermatitis, asthma, seasonal allergic rhinitis, and food allergies.
  • autoimmune disease refers to a disease in which immune cells that normally do not react to the body's own tissues recognize the body's own tissues as foreign bodies and target and attack specific tissues and cells, causing inflammation and tissue damage.
  • diseases include psoriasis vulgaris, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, and ulcerative colitis.
  • a drug that reduces the intracellular free calcium ion concentration refers to a drug that reduces the intracellular free calcium ion concentration compared to before use of the drug.
  • a reduction in the intracellular free calcium ion concentration can be achieved by inhibiting or blocking the influx of calcium ions into the cell through calcium ion channels (e.g., calcium ion channel blockers, antagonists to calcium ion channels), forming a complex with calcium ions (e.g., chelating agents), or expelling intracellular calcium ions to the outside of the cell.
  • Chelating agents can be hydrophilic or hydrophobic.
  • Hydrophilic chelating agents include EDTA, EGTA, etc.
  • hydrophobic chelating agents include BAPTA-AM.
  • Hydrophilic chelating agents cannot penetrate into cells, so they can form complexes with calcium ions outside the cells, thereby reducing the free calcium ion concentration outside the cells and thereby reducing the amount of free calcium ions flowing into the cells.
  • Hydrophobic chelating agents penetrate into cells and form complexes with calcium ions inside the cells, reducing the free calcium ion concentration inside the cells.
  • a decrease in the intracellular free calcium ion concentration refers to a decrease in the intracellular free calcium ion concentration by a chelating agent forming a complex with calcium ions within the cells.
  • a chelating agent is BAPTA-AM (O,O'-bis(2-aminophenyl)ethylene glycol-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester).
  • BAPTA-AM is hydrophobic, so it can penetrate into cells, and when it is hydrolyzed by esterase within the cells, it is able to form a complex with calcium ions.
  • excretion of intracellular calcium ions refers to the excretion of intracellular calcium ions to the outside of the cells.
  • the excretion of intracellular calcium ions can be measured by the whole-cell clamp method or the patch clamp method.
  • Drugs that can excrete intracellular calcium ions and reduce the intracellular calcium ion concentration can be, for example, pyoktanin blue (gentian violet, crystal violet, methylrosalinin chloride), methylene blue (3,7-bis(dimethylamino)phenothiazinium chloride trihydrate), or analogs thereof, or pharma- ceutical acceptable salts thereof.
  • Such drugs are also called "calcium ion excreting agents.”
  • cellular homeostasis is maintained by decreasing the intracellular calcium ion concentration using molecules that release calcium ions into the extracellular space or into the endoplasmic reticulum.
  • Molecules that release calcium ions include Na + /Ca 2+ exchangers, Ca 2+ pumps (Ca 2+ -ATPases), and voltage-dependent Ca 2+ channels. Drugs that act directly or indirectly on these calcium ion release molecules can reduce elevated intracellular calcium ion concentrations.
  • alkyl group refers to a straight-chain or branched-chain hydrocarbon group formed by removing one hydrogen atom from an aliphatic saturated hydrocarbon.
  • analog refers to a compound whose core structure is the same or similar to that of the parent compound, but has chemical or physical modifications, such as different or additional functional groups.
  • the core structure of pyoktanin is the portion excluding the amino and ammonium groups (i.e., the triphenylmethane portion)
  • an analog of pyoktanin is a compound that has a functional group different from the amino or ammonium groups, or a functional group modified from the amino or ammonium groups.
  • the core structure of methylene blue is the portion excluding the amino group (i.e., the phenothiazine), and an analog of methylene blue is a compound that has a functional group different from the amino group, or a functional group modified from the amino group.
  • An analog has the same or similar biological activity as the parent compound.
  • the present disclosure relates to a method for suppressing an immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that reduces intracellular free calcium ion concentration, thereby suppressing the immune response in the subject.
  • the disclosure relates to a composition for suppressing an immune response in a subject, the composition comprising an agent that reduces intracellular free calcium ion concentration.
  • the subject is an organism to which the disclosed method, agent, or composition is applied, and the organism species is not particularly limited.
  • organism species include various mammals such as humans, monkeys, mice, rats, dogs, cats, and rabbits, and preferably humans. In the case of humans, there are no particular limitations as long as the subject has an enhanced immune response.
  • Examples include psoriasis vulgaris, psoriatic arthritis, atopic dermatitis, asthma, seasonal allergic rhinitis, allergic conjunctivitis, food allergies, systemic lupus erythematosus, contact dermatitis, urticaria, drug rash, prurigo, thrombocytopenia, granulocytopenia, neonatal hemolytic jaundice, hypersensitivity pneumonitis, lupus nephritis, Hashimoto's disease, Behcet's disease, graft-versus-host disease, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, Graves' disease, type I diabetes, vasculitis, Addison's disease, polymyositis, Sjogren's syndrome, systemic sclerosis, and glomerulonephritis.
  • the type of cells is not particularly limited as long as the intracellular calcium ion concentration can be measured, and examples include immune cells such as T lymphocytes, B lymphocytes, dendritic cells, macrophages, Langerhans cells, eosinophils, basophils, neutrophils, and mast cells (including immortalized cell lines of each immune cell), primary cells such as skin cells, muscle cells, nerve cells, adipocytes, and lung cells, and their immortalized cell lines, as well as various cancer cell lines, with immune cells being preferred.
  • Cell groups such as spleen cells, lymph node cells, and peripheral blood mononuclear cells, which contain different types of immune cells such as T lymphocytes and B lymphocytes, can also be used.
  • Methods for measuring intracellular calcium ion concentrations include the fluorescent dye method using calcium indicators and the patch clamp method, the former of which is particularly popular due to its simplicity and high sensitivity.
  • Calcium indicators include Fluo4, Fura2, Rhod2, Indo1, and Quin2, and it is preferable to use their acetoxymethyl (AM) derivatives to increase their permeability into cells.
  • AM acetoxymethyl
  • fluorescent measurement devices When measuring intracellular calcium ion concentrations using the fluorescent dye method, fluorescent measurement devices include fluorescent plate readers and fluorescent microscopes. Fluorescent plate readers are preferred because they are easy to operate and can evaluate many drugs at once, and because changes in intracellular calcium ion concentrations often occur immediately after the addition of stimuli, fluorescent plate readers equipped with an injector function are even more preferred.
  • a drug that reduces the intracellular free calcium ion concentration can be selected, for example, by the following method.
  • Mouse spleen cells fluorescently labeled with Fluo4-AM are seeded in a 96-well plate, the plate is placed in a fluorescent plate reader, and the fluorescence intensity is measured for 5 to 30 minutes so that the fluorescence intensity is at a steady value. Then, a stimulant is added and the fluorescence intensity is measured for 5 seconds to 30 minutes. If the fluorescence intensity decreases after the addition of the drug, the drug can be selected as a drug that reduces the calcium ion concentration after the intracellular calcium ion concentration is increased by the stimulant.
  • the intracellular free calcium ion concentration can be reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30, at least 40%, or at least 50% after application of the method, agent, or composition of the present disclosure compared to before application of the method, agent, or composition of the present disclosure.
  • the intracellular free calcium ion concentration can be reduced by at least 30% after application of the method, agent, or composition of the present disclosure compared to before application of the method, agent, or composition.
  • the agent that reduces the intracellular free calcium ion concentration may be an agent that can form a complex with calcium ions, an agent that can inhibit or block the influx of calcium ions into the cell, or an agent that can expel calcium ions from the cell to reduce the intracellular calcium ion concentration.
  • an agent that can expel calcium ions from the cell to reduce the intracellular calcium ion concentration may be advantageously used in the present disclosure.
  • Agents capable of forming complexes with calcium ions include, but are not limited to, chelating agents.
  • Chelating agents may be hydrophilic or hydrophobic.
  • the chelating agent may be any chelating agent capable of forming complexes with calcium ions.
  • hydrophilic chelating agents include, but are not limited to, EDTA, EGTA, etc.
  • hydrophobic chelating agents include, but are not limited to, BAPTA-AM.
  • Drugs that can suppress or block the influx of calcium ions into cells include, but are not limited to, calcium ion channel blockers and calcium ion channel antagonists.
  • calcium ion channel blockers or antagonists to calcium ion channels include, but are not limited to, isosorbide dinitrate, perampamil hydrochloride, diltiazem hydrochloride, nifedipine, amlodipine besylate, ethosuximide, lomerizine, crotamiton, and diphenhydramine hydrochloride.
  • the drug is a compound of formula (1)
  • R 1 to R 6 each independently represent a hydrogen atom or an alkyl group having 3 or less carbon atoms.
  • the compound of formula (1) has a basic structure of pyoktanin blue and can exhibit activity equivalent to that of pyoktanin blue (e.g., a decrease in intracellular calcium ion concentration).
  • the agent is selected from pyoktanine blue, methylene blue, or analogs thereof, or pharma- ceutically acceptable salts thereof.
  • the analog of pyoktanine blue can be the compound shown in FIG. 2 or a pharma- ceutically acceptable salt thereof.
  • Examples of analogs of methylene blue include, but are not limited to, cresyl violet acetate, neutral red, nile red, toluidine blue O, and safranin O.
  • the method for calculating the therapeutically effective amount of a drug that suppresses the immune response of a subject can be easily evaluated by administering various concentrations of a drug to a human or non-human animal with an enhanced immune response and measuring the quantitative changes in molecules produced by immune cells or the number of immune cells.
  • examples of such an animal include the diseases mentioned above.
  • examples of such an animal include model animals for human diseases with enhanced immune responses, such as mice administered imiquimod transdermally, which are model animals for psoriasis vulgaris, and mice administered ovalbumin transdermally, which are model animals for atopic dermatitis.
  • Molecules produced by immune cells include cytokines such as chemokines, hematopoietic colony-stimulating factors, interleukins (IL-2, IL-17, etc.), interferons, and transforming growth factors, as well as their receptors, chemical mediators such as histamine and serotonin, as well as their receptors, lipid mediators such as prostaglandins and leukotrienes, as well as their receptors, and immunoglobulins such as IgG and IgE.
  • cytokines such as chemokines, hematopoietic colony-stimulating factors, interleukins (IL-2, IL-17, etc.), interferons, and transforming growth factors, as well as their receptors
  • chemical mediators such as histamine and serotonin, as well as their receptors
  • lipid mediators such as prostaglandins and leukotrienes, as well as their receptors
  • immunoglobulins such as IgG and
  • molecules produced by immune cells are contained in body fluids such as blood, cerebrospinal fluid, urine, body secretions, saliva, tears, and sputum, tissues such as the spleen, lymph nodes, and skin, bronchoalveolar lavage fluid, sputum, etc., so that the concentration of molecules produced by immune cells can be quantified by collecting biological samples from these organisms.
  • body fluids such as blood, cerebrospinal fluid, urine, body secretions, saliva, tears, and sputum
  • tissues such as the spleen, lymph nodes, and skin, bronchoalveolar lavage fluid, sputum, etc.
  • a drug that suppresses immune responses using cultured immune cells.
  • a drug is added to mouse spleen cells or human T cell line Jurkat cells to which A23187 (and 12-O-tetradecanoylphorbol 13-acetate (TPA) is added as necessary), anti-CD3 antibodies, or anti-CD28 antibodies have been added, and the cells are cultured for about 30 minutes to 3 days.
  • the therapeutically effective dose of the drug can be roughly calculated by comparing the concentration of molecules produced by immune cells, such as interleukin-2 in the culture supernatant, and the number of immune cells with those without the addition of the drug.
  • the present disclosure also includes a pharmaceutical composition containing as an active ingredient an agent that reduces intracellular calcium ion concentration.
  • the pharmaceutical composition is a composition in which an agent that reduces intracellular calcium ion concentration is mixed with a pharma- ceutical acceptable carrier, excipient, and/or pharmaceutical additive, food additive, or cosmetic additive, and has the ability to suppress immune responses. This ability is important for normalizing immune responses by suppressing excessive immune responses.
  • the pharmaceutical composition can be used to treat diseases caused by excessively enhanced immune responses, including allergic diseases such as atopic dermatitis, and autoimmune diseases such as psoriasis vulgaris and rheumatoid arthritis.
  • allergic diseases such as atopic dermatitis
  • autoimmune diseases such as psoriasis vulgaris and rheumatoid arthritis.
  • the pharma- ceutically acceptable carriers, excipients, and/or pharmaceutical additives can be appropriately selected depending on the specific use of the composition.
  • the composition can also be in various solid, liquid, and other forms depending on the specific use. Examples include oral preparations such as powders, fine granules, granules, tablets, syrups, capsules, suspensions, emulsions, extracts, and pills, injections, external liquids, transdermal preparations such as ointments, suppositories, and topicals.
  • the dosage varies depending on the age, sex, weight, severity of the disease, and method of administration of the subject, but typically, for adult humans, the daily dosage is about 1 mg to about 2 g of active ingredient, preferably about 5 mg to about 1 g of active ingredient.
  • the daily dosage can be administered once or in divided doses.
  • the present disclosure provides a calcium ion exporter comprising an agent capable of exporting intracellular calcium ions to reduce the intracellular calcium ion concentration.
  • the agent contained in the calcium ion exporter may be a compound represented by the above formula (1) or a pharma- ceutical acceptable salt thereof, and may be pyoktanine blue, methylene blue, or an analog thereof, or a pharma- ceutical acceptable salt thereof.
  • Such calcium ion exporters can be used for the treatment or prevention of diseases or conditions that benefit from the export of intracellular calcium ions, such as ischemic heart disease, high blood pressure, epilepsy, headaches, or pruritus. Since ischemic heart disease, high blood pressure, epilepsy, headaches, and pruritus are known diseases for which calcium ion channel blockers and calcium ion channel antagonists are applicable, it is expected that the agents disclosed herein that reduce intracellular free calcium ion concentrations will also be effective in the prevention or treatment of these diseases or conditions.
  • Example 1 Analysis of the correlation between the effect of decreasing intracellular calcium ion concentration in a human T cell line after the calcium ion concentration has increased and the effect of suppressing immune responses (hereinafter, both effects are abbreviated as "both effects").
  • the fluorescently labeled cells were centrifuged (11,000xg, 30 seconds) to remove the supernatant, washed twice with PBS(-), suspended in 100 ⁇ L of Recording Medium from Calcium Kit-Fluo 4, and the same number of cells were seeded in each well of a 96-well plate and left to stand at room temperature for 30 minutes. The plate was then centrifuged (1,000 rpm, 5 minutes) to allow the cells to contact the bottom of the plate.
  • the plate was placed in a BioTek Synergy H1 Multimode Reader (Agilent) and the fluorescence intensity (excitation wavelength 488 nm, detection wavelength 528 nm, measured at 15 second intervals) was measured until it stabilized.
  • calcium ionophore A23187 (Sigma, catalog number: C7522) was added at a final concentration of 1 ⁇ M and the fluorescence intensity was measured for 15 minutes, after which 10 ⁇ M of the drug was added and the fluorescence intensity was measured for another 15 minutes.
  • the drug and A23187 were dissolved in DMSO and added, and the DMSO concentration in the Recording Medium was kept constant between wells.
  • the relative fluorescence intensity was calculated by setting the fluorescence intensity immediately before the addition of A23187 to 0% and the fluorescence intensity 15 minutes after the addition of A23187 to 100%.
  • the drug inhibition rate for the increase in intracellular calcium concentration due to A23187 stimulation was calculated according to the following formula, and the highest value 15 minutes after the addition of the drug was taken as the drug inhibition rate.
  • Inhibition rate (%) (1 - (relative fluorescence intensity drug /relative fluorescence intensity DMSO )) x 100
  • Relative fluorescence intensity DMSO relative fluorescence intensity of wells to which DMSO was added
  • Relative fluorescence intensity drug relative fluorescence intensity of wells to which drug was added
  • the inhibitory rates of the drugs against the increase in intracellular calcium concentration caused by A23187 stimulation are shown in Table 1.
  • the chemical structures of the drugs are shown in Figure 2.
  • the 96-well plate was centrifuged at 1000rpm for 5 minutes to collect the culture supernatant, and the IL-2 concentration in the culture supernatant was quantified using a human IL-2 ELISA kit (Diaclone, catalog number: 950.010.096).
  • the inhibitory rate of the drug against the enhancement of immune response (IL-2 concentration as an index) induced by A23187 and TPA stimulation was calculated according to the following formula.
  • Inhibition rate (%) ((IL-2 concentration DMSO + A23187 + TPA - IL-2 concentration drug + A23187 + TPA ) / (IL-2 concentration DMSO + A23187 + TPA - IL-2 concentration DMSO )) x100 IL-2 concentration DMSO + A23187 + TPA : IL-2 concentration in the culture supernatant of cells to which DMSO, A23187 and TPA were added IL-2 concentration drug + A23187 + TPA : IL-2 concentration in the culture supernatant of cells to which drug, A23187 and TPA were added IL-2 concentration DMSO : IL-2 concentration in the culture supernatant of cells to which DMSO only was added
  • the calculated inhibition rates are shown in Table 1.
  • Example 2 Correlation analysis of both actions in mouse spleen cells
  • Spleens were collected from 7-week-old male BALB/c mice (CLEA Japan) after cervical dislocation and minced in cold Hank's balanced salt solution (Fujifilm Wako, catalog number: 084-08965). The spleen pieces were transferred to a 70 ⁇ m cell strainer (pluriSelect Life Science, catalog number: 43-50070-03) and crushed with the plunger of a 2.5 mL disposable syringe. After washing with cold PBS(-), the spleen cell suspension was centrifuged at 4°C and 1000 rpm for 5 minutes to collect the pellet.
  • cold red blood cell lysis buffer (155 mM NH 4 Cl, 10 mM KHCO 3 , 0.1 mM EDTA) was added to the pellet and left to stand on ice for 5 minutes, followed by centrifugation. The pellet was washed with PBS(-) and then suspended in RPMI-1640 containing 10% fetal bovine serum to prepare mouse spleen cells.
  • Example 1 Mouse spleen cells were fluorescently labeled according to the method described in (a), and 100 ⁇ L of Recording Medium was added to suspend the cells, and the same number of cells were seeded in each well of a 96-well plate and allowed to stand at room temperature for 30 minutes. The plate was then centrifuged (1,000 rpm, 5 minutes) to allow the cells to contact the bottom of the plate. The plate was placed in a BioTek Synergy H1 Multimode Reader, and after the fluorescence intensity stabilized, 1 ⁇ M final concentration of A23187 was added and the fluorescence intensity was measured for 5 minutes. Next, 10 ⁇ M of drug or DMSO was added, and the fluorescence intensity was measured for another 5 minutes.
  • the relative fluorescence intensity was calculated by taking the fluorescence intensity immediately before the addition of A23187 as 0% and the fluorescence intensity 5 minutes after the addition of A23187 as 100%.
  • the inhibition rate of the drug was calculated according to the formula described in Example 1. (a), and the highest value 5 minutes after the addition of the drug was taken as the inhibition rate of the drug.
  • the inhibition rate of the drug against the increase in intracellular calcium concentration due to A23187 stimulation is shown in Table 2.
  • the viable cell count of mouse spleen cells was measured using Cell Counting Kit-8 (Dojindo, catalog number: 341-07761).
  • the reagents contained in the kit were added to a culture solution containing mouse spleen cells, and after culturing at 37°C and 5% CO2 for 1 hour, the absorbance at 450 nm (OD450) was measured.
  • the inhibitory rate of the drug against the enhancement of immune response (cell count as an index) by A23187 and TPA stimulation was calculated according to the following formula.
  • Inhibition rate (%) ((OD450 DMSO + A23187 + TPA - OD450 drug + A23187 + TPA ) /(OD450 DMSO+A23187+TPA -OD450 DMSO ))x100 OD450 DMSO + A23187 + TPA : absorbance at 450 nm of cells to which DMSO, A23187 and TPA were added OD450 drug + A23187 + TPA : absorbance at 450 nm of cells to which drug, A23187 and TPA were added OD450 DMSO : absorbance at 450 nm of cells to which only DMSO was added The calculated inhibition rates are shown in Table 2.
  • IL-2 concentration in culture supernatant was quantified using a mouse IL-2 ELISA kit (Diaclone, catalog number: 860.000.096).
  • the inhibitory rate of the drug against the enhancement of immune response (IL-2 concentration as an index) by A23187 and TPA stimulation was calculated according to the following formula.
  • Inhibition rate (%) ((IL-2 concentration DMSO + A23187 + TPA - IL-2 concentration drug + A23187 + TPA ) / (IL-2 concentration DMSO + A23187 + TPA - IL-2 concentration DMSO )) x100 IL-2 concentration DMSO + A23187 + TPA : IL-2 concentration in the culture supernatant of cells to which DMSO, A23187 and TPA were added IL-2 concentration drug + A23187 + TPA : IL-2 concentration in the culture supernatant of cells to which drug, A23187 and TPA were added IL-2 concentration DMSO : IL-2 concentration in the culture supernatant of cells to which DMSO only was added
  • the calculated inhibition rates are shown in Table 2.
  • Example 3 Effect of drug (1) on mouse spleen cells stimulated with anti-CD3 antibody (a) Measurement of intracellular calcium ion concentration
  • Example 1. 5 ⁇ g/mL anti-CD3 antibody (BioLegend, catalog number: 100302) was added to mouse spleen cells fluorescently labeled according to the method described in (a) above, and the cells were left to stand on ice for 30 minutes. After washing with PBS(-), Recording Medium was added and the cells were suspended and the same number of cells were seeded in each well of a 96-well plate and left to stand at room temperature for 30 minutes. The plate was then centrifuged (1,000 rpm, 5 minutes) to allow the cells to contact the bottom of the plate.
  • the plate was placed in a BioTek Synergy H1 Multimode Reader, and after the fluorescence intensity stabilized, a goat anti-hamster IgG antibody (Jackson ImmunoResearch, catalog number: 564-74561, hereinafter abbreviated as secondary antibody) was added at a final concentration of 20 ⁇ g/mL, and the fluorescence intensity was measured for 3 minutes. Next, 0.5 to 3 ⁇ M drug (1) or DMSO was added, and the fluorescence intensity was measured for another 5 minutes.
  • secondary antibody goat anti-hamster IgG antibody
  • the relative fluorescence intensity was calculated by taking the fluorescence intensity immediately before the addition of the secondary antibody as 0% and the fluorescence intensity 3 minutes after the addition of the secondary antibody as 100%.
  • the inhibition rate of the drug was calculated according to the formula described in Example 1. (a), and the highest value 5 minutes after the addition of the drug was taken as the inhibition rate of the drug.
  • the inhibition rate of drug (1) against the increase in intracellular calcium concentration due to stimulation with anti-CD3 antibody is shown in Table 3.
  • Suppression rate (%) ((OD450 anti-CD3 antibody + DMSO - OD450 anti-CD3 antibody + drug (1) ) / (OD450 anti-CD3 antibody + DMSO - OD450 PBS(-) + DMSO )) x100 OD450 anti-CD3 antibody + DMSO : OD450 of cells coated with anti-CD3 antibody and treated with DMSO OD450 anti-CD3 antibody + drug (1) : OD450 of cells coated with anti-CD3 antibody and treated with drug (1) OD450 PBS(-) + DMSO : OD450 of cells coated with PBS(-) and added with DMSO The calculated inhibition rates are shown in Table 4.
  • Suppression rate (%) ((IL-2 concentration anti-CD3 antibody + DMSO - IL-2 concentration anti-CD3 antibody + drug (1) ) /(IL-2 concentration anti-CD3 antibody + DMSO - IL-2 concentration PBS(-) + DMSO )) x100 IL-2 concentration: anti-CD3 antibody + DMSO : IL-2 concentration in the culture supernatant of cells coated with anti-CD3 antibody and added with DMSO IL-2 concentration: anti-CD3 antibody + drug (1) : IL-2 concentration in the culture supernatant of cells coated with anti-CD3 and added with drug (1) IL-2 concentration: PBS(-) + DMSO : IL-2 concentration in the culture supernatant of cells coated with PBS(-) and added with DMSO The calculated inhibition rates are shown in Table 4.
  • IL-17 concentration in culture supernatant was quantified using a mouse IL-17 Quantikine ELISA kit (R&D SYSTEMS, catalog number: M1700).
  • the inhibition rate of each concentration of drug (1) against the enhancement of immune response (IL-17 concentration as an index) induced by anti-CD3 antibody stimulation was calculated according to the following formula.
  • Suppression rate (%) ((IL-17 concentration anti-CD3 antibody + DMSO - IL-17 concentration anti-CD3 antibody + drug (1) ) /(IL-17 concentration anti-CD3 antibody + DMSO - IL-17 concentration PBS(-) + DMSO )) x100 IL-17 concentration: anti-CD3 antibody + DMSO : IL-17 concentration in the culture supernatant of cells coated with anti-CD3 antibody and added with DMSO. IL-17 concentration: anti-CD3 antibody + drug (1) : IL-17 concentration in the culture supernatant of cells coated with anti-CD3 and added with drug (1).
  • Example 4 Inhibitory effect of drug (1) on immune response in autoimmune disease model animals
  • Imiquimod an agonist of toll-like receptor 7 (TLR7)
  • TLR7 toll-like receptor 7
  • mice administered imiquimod percutaneously have clinical symptoms similar to those of human psoriasis vulgaris patients, and are therefore widely used as model animals for psoriasis vulgaris.
  • IL-17 secreted by activated T cells promotes the proliferation of epidermal cells, resulting in thickening of the epidermis.
  • mice Male, 8 weeks old obtained from CLEA Japan were anesthetized with isoflurane and had their backs shaved.
  • 100 ⁇ L of 0.02% or 0.1% (solvent: distilled water) drug (1) was then applied to the backs once a day for a total of six times.
  • 100 mg of 0.1% tacrolimus ointment manufactured by Sun Pharma, product name: Tacrolimus Ointment 0.1% "PP" was applied to the backs once a day for a total of six times.
  • BAPTA-AM O'-bis(2-aminophenyl)ethylene glycol-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester
  • AM acetoxymethyl ester
  • Mouse spleen cells prepared by the method described in Example 2(a) were seeded in a 96 -well plate at 5x105 cells per well. Then, DMSO or 5 ⁇ M BAPTA-AM, 1 ⁇ M drug (1), or 5 ⁇ g/mL imiquimod was added and cultured at 37°C under 5% CO2 for 3 days (medium volume was 200 ⁇ L). After culture, the 96-well plate was centrifuged at 1000rpm for 5 minutes to collect mouse spleen cells (containing 100 ⁇ L of culture medium) and 100 ⁇ L of culture supernatant. The OD450 of mouse spleen cells (containing 100 ⁇ L of culture medium) was measured according to the method described in Example 2(c)(1), and the measured values are shown in FIG. 4.
  • Calcium ion channel blockers or antagonists are also capable of inhibiting the influx of free calcium ions into cells, suggesting that they similarly inhibit immune responses. Since an increase in calcium ion concentration plays an important role in activating immune cells, it is believed that a decrease in calcium ion concentration has an inhibitory effect on immune responses. For example, in T cells and B cells, an increase in calcium ion concentration leads to cell proliferation and activation, and in mast cells, an increase in calcium ion concentration leads to degranulation. Also, in dendritic cells, an increase in calcium ion concentration promotes migration, which is one indicator of activation.
  • the present disclosure can provide a method for effectively suppressing immune responses in subjects with excessively enhanced immune responses, and can be used in the pharmaceutical and cosmetics industries.

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Abstract

La présente divulgation concerne un procédé de suppression d'une immunoréaction excessivement renforcée chez un individu. Dans un aspect, la présente divulgation concerne une méthode de suppression d'une immunoréaction excessivement renforcée chez un individu, la méthode consistant à administrer à l'individu une quantité thérapeutiquement efficace d'un médicament qui réduit la concentration intracellulaire de calcium. Dans un mode de réalisation, le médicament peut être un médicament apte de réduire la concentration intracellulaire d'ions calcium libres, un médicament apte à supprimer ou bloquer l'afflux d'ions calcium dans les cellules ou un médicament apte à décharger des ions calcium à partir de cellules pour réduire la concentration intracellulaire d'ions calcium.
PCT/JP2024/033898 2023-09-25 2024-09-24 Procédé de suppression d'immunoréaction Pending WO2025070375A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005509601A (ja) * 2001-09-12 2005-04-14 イースタン ヴァージニア メディカル スクール カルシウム流入阻害因子およびその単離方法
JP2005162680A (ja) * 2003-12-03 2005-06-23 Sagami Chem Res Center ３−（デカヒドロ−１Ｈ−ベンゾ［ｆ］クロメン−７−イル）メチル−２−メトキシ−５，６−ジメチルピラン−４−オン誘導体の製造方法、ならびにその製造中間体
WO2009081581A1 (fr) * 2007-12-25 2009-07-02 Nanoegg Research Laboratories, Inc. Composition pour le traitement ou la prévention d'une dermatite atopique
JP2013151528A (ja) * 2003-08-29 2013-08-08 Ono Pharmaceut Co Ltd Ｓ１ｐ受容体結合能を有する化合物およびその医薬用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005509601A (ja) * 2001-09-12 2005-04-14 イースタン ヴァージニア メディカル スクール カルシウム流入阻害因子およびその単離方法
JP2013151528A (ja) * 2003-08-29 2013-08-08 Ono Pharmaceut Co Ltd Ｓ１ｐ受容体結合能を有する化合物およびその医薬用途
JP2005162680A (ja) * 2003-12-03 2005-06-23 Sagami Chem Res Center ３−（デカヒドロ−１Ｈ−ベンゾ［ｆ］クロメン−７−イル）メチル−２−メトキシ−５，６−ジメチルピラン−４−オン誘導体の製造方法、ならびにその製造中間体
WO2009081581A1 (fr) * 2007-12-25 2009-07-02 Nanoegg Research Laboratories, Inc. Composition pour le traitement ou la prévention d'une dermatite atopique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BROWN D. M., DONALDSON K., BORM P. J., SCHINS R. P., DEHNHARDT M., GILMOUR P., JIMENEZ L. A., STONE V.: "Calcium and ROS-mediated activation of transcription factors and TNF-α cytokine gene expression in macrophages exposed to ultrafine particles", AMERICAN JOURNAL OF PHYSIOLOGY - LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 286, no. 2, 1 February 2004 (2004-02-01), US , pages L344 - L353, XP093298990, ISSN: 1040-0605, DOI: 10.1152/ajplung.00139.2003 *
KUBOTA, YOSHIKI ET AL.: "P1-16 Pyoktanin Blue suppresses the immune system and exhibits therapeutic effects on Psoriasis by regulating intracellular calcium density", THE JAPANESE JOURNAL OF DERMATOLOGY, vol. 134, no. 5, Spec. Iss., 15 May 2024 (2024-05-15) - 9 June 2024 (2024-06-09), JP , pages 1505, XP009562700, ISSN: 0021-499X, DOI: 10.14924/dermatol.134.1504 *
SAXENA, H.M. ; DIKSHIT, M.: "Abrogation of DTH response and mitogenic lectin- and alloantigen-induced activation of lymphocytes by calcium inhibitors TMB-8 and BAPTA-AM", IMMUNOLOGY LETTERS, vol. 101, no. 1, 15 October 2005 (2005-10-15), NL , pages 60 - 64, XP027672287, ISSN: 0165-2478 *

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