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WO2008020651A1 - antagoniste de récepteur P2X4 - Google Patents

antagoniste de récepteur P2X4 Download PDF

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Publication number
WO2008020651A1
WO2008020651A1 PCT/JP2007/066323 JP2007066323W WO2008020651A1 WO 2008020651 A1 WO2008020651 A1 WO 2008020651A1 JP 2007066323 W JP2007066323 W JP 2007066323W WO 2008020651 A1 WO2008020651 A1 WO 2008020651A1
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WO
WIPO (PCT)
Prior art keywords
receptor
pain
antagonist
pharmaceutical composition
paroxetine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2007/066323
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English (en)
Japanese (ja)
Inventor
Kazuhide Inoue
Makoto Tsuda
Kenichiro Nagata
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Kyushu University NUC
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Kyushu University NUC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Priority to JP2008529899A priority Critical patent/JPWO2008020651A1/ja
Publication of WO2008020651A1 publication Critical patent/WO2008020651A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a P2X4 receptor antagonist. Specifically, the present invention relates to a P2X4 receptor antagonist, which is a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • Rat spinal cord L5 nerve ligation resulted in activation of spinal microglia and increased expression of ⁇ 2-4 receptor, and it was reported that non-selective ⁇ 2-4 receptor antagonist significantly suppressed hyperalgesia (Tsuda, ⁇ ⁇ , Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A "Kohsaka, S., Salter, MW & Inoue, K,” P2X4 receptors induced in spinal microglia gate tactile allodjnaia after nerve injury. ", Nature, vol. 424, p. 778-783 (2003)) This report suggests the potential of P2X4 receptor antagonists for the treatment of human neuropathic pain, but currently it is selected for P2X4 receptors. There is no intelligent and powerful antagonist.
  • the present inventor conducted intensive studies for the purpose of evaluating P2X4 receptor antagonism and searching for a therapeutic agent for neuropathic pain having a strong antagonism against P2X4 receptor. .
  • the present inventor found a selective and potent antagonist for the P2X4 receptor, and completed the present invention.
  • the present invention is as follows.
  • antagonists include a selective serotonin reuptake inhibitor (SSRI). Specific examples include Paroxetine, Fluoxetine, Fluvoxamine and Citalopram; (2) A pharmaceutical composition for treating neuropathic pain, comprising an antagonist for the P2X4 receptor.
  • SSRI selective serotonin reuptake inhibitor
  • the antagonist to the P2X4 receptor includes, for example, a selective serotonin reuptake inhibitor (SSRI), specifically, Paroxetine, Fluoxetine, Fluvoxamine, Citalopram, etc .;
  • SSRI selective serotonin reuptake inhibitor
  • neuropathic pain includes, for example, alodynia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, postherpetic neuralgia, strangulated neuropathy, sympathetic nerve dependence Sexual pain and afferent block pain.
  • a method for treating neuropathic pain comprising administering the pharmaceutical composition according to (2) above to a patient.
  • FIG. 1 is a diagram showing changes in intracellular Ca level in response to ATP stimulation.
  • FIG. 2 is a diagram showing the ATP-induced calcium response inhibitory effect of Paroxetine ( ⁇ ) treatment.
  • FIG. 3 is a graph showing the effect of suppressing ATP-induced calcium response by treatment with various SSRIs (Drug in the figure) (10 ⁇ ).
  • FIG. 4 shows the concentration dependence of the ATP-induced calcium response inhibitory effect of Paroxetine treatment.
  • FIG. 5 is a graph showing the concentration dependence of the ATP-induced calcium response inhibitory effect of Paroxetine treatment.
  • FIG. 7 is a graph showing the results of observing the oral dynea inhibitory effect over time when Paroxetine was intrathecally administered on the seventh day after nerve injury.
  • the present inventor has already clarified that the receptor is a key factor of neuropathic pain by conducting various studies on the P2X4 receptor. This time, the present inventor has found that an SSRI antidepressant has an antagonistic action with the P2X4 receptor and has shown that it can be a candidate compound for the treatment of neuropathic pain.
  • the present inventor used a cell line that expresses only the P2X4 receptor as an ATP receptor, and antagonized the SSRI antidepressant using the increase in intracellular Ca ion concentration by ATP stimulation as an index. Evaluated. As a result, for example, it was found that SSRI antidepressants such as Paroxetine and Fluoxetine have a selective and strong antagonistic action on the P2X4 receptor, and the action shows high dose dependency.
  • the present inventor administered a SSRI antidepressant intrathecally to a nerve injury model animal, and compared with the control group (non-administration group), the administration group had a significant anti-alodinia action (alodinia suppression action).
  • the administration group showed a significant anti-arodinian action compared to the control group, and that the action showed a high dose dependency.
  • Most of the common analgesics such as morphine are available for chronic pain caused by nerve injuries such as diabetes and infection, and pain caused by cancer progression (these are called neuropathic pain). It is known not to work.
  • the present inventors have already shown that the P2X4 receptor, a type of ATP receptor in spinal cord microglia cells, is involved in the transmission of neuropathic pain signals.
  • the P2X4 receptor is an ion channel that exists in the cell membrane.
  • the P2X4 receptor is opened by ATP molecules. Then, it is thought that a large amount of sodium ions, calcium, and ions flow into the cell through this open ion channel, and as a result, pain is amplified.
  • antidepressants are known to alleviate the symptoms of patients with neuropathic pain, and are widely used in the clinic as analgesics. However, its mechanism of action has not yet been clarified. If P2X4 receptor antagonism is confirmed in antidepressant drugs, it will lead to the elucidation of the mechanism of the antidepressant drug's inhibitory effect on the alodiure, and treatments targeting the P2X4 receptor may be rapidly introduced into the clinic. Expected.
  • SSRI selective serotonin reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • the present inventors have focused on SSRI among the antidepressants and have found the present invention by conducting various evaluations on the P2X4 receptor antagonism of SSRI.
  • antagonist against P2X4 receptor means a substance having an antagonistic action on P2X4 receptor.
  • Antagonism against the P2X4 receptor is described in a known manner, for example, Miller KJ, Michel AD, Chessell IP, Humphrey PP.Cibacron blue allosterically modulates the rat P2X4 receptor. Neuropharmacology. 1998 Dec; 37 (l2): i579-86. It can be confirmed by the method described.
  • the antagonist for P2X4 receptor used in the present invention is not particularly limited, and includes a selective serotonin reuptake inhibitor (SSRI) which is an antidepressant.
  • SSRIs preferably used in the present invention include Paroxetine, Fluoxetine, Fluvoxamine and Citalopram, and pharmaceutically acceptable salts thereof.
  • SSRIs that are particularly preferred are Paroxetine, Fluoxetine, Fluvoxamine, which may be used alone or in combination of two or more.
  • These SSRI as the antidepressant agents are known, Merck-in deck scan (The Merck Index, 13 th Edition (2001)), are described in the textbook ⁇ NEW pharmacology, and the like.
  • the SSRI can be synthesized by methods well known to those skilled in the art, but a commercially available product may be used.
  • a well-known synthesis method of SSRI for example, for Paroxetine, J. Buus Lassen, Eur. J. Pharmacol., Vol. 47, p. 351 (1978); E. Habert et al., Ibid. , vol. 118, p. 107 (1985) et al., Fluoxetine (Kotsure, Te (ma, DT Wong et al "Life Sci., vol. 15, p. 471 (1974); JF Nash et al., Clin. Chem., Vol. 28, p.
  • paroxetine paroxetine
  • paxil Daraxo
  • Prozac manufactured by Eli Lily
  • For Fluvoxamine Depuromeru (manufactured by Meiji Seika Kaisha, Ltd.)
  • Rubo' box Asuterasu (manufactured by former Fujisawa Pharmaceutical) Co., Ltd.), for Citalopram, like Celexa (Lundbeck, Ltd.).
  • the present invention relates to a pharmaceutical composition for treating neuropathic pain comprising a P2X4 receptor antagonist as an active ingredient, and to administer the pharmaceutical composition to a patient with neuropathic pain.
  • a method of treatment is provided.
  • the present invention may also provide an antagonist to P2X4 receptor for the treatment of neuropathic pain and the use of antagonist to P2X4 receptor for the manufacture of a medicament for the treatment of neuropathic pain. it can.
  • SSRI antidepressants such as SSRI antidepressants
  • treatment generally means improving the symptoms of humans and mammals other than humans.
  • Improvement means, for example, the case where the degree of pain is reduced or not worsened compared to the case where the pharmaceutical composition of the present invention is not administered, and also includes the meaning of prevention.
  • pharmaceutical composition means a composition containing an active ingredient (SSRI antidepressant) useful in the present invention and an additive such as a carrier used in the preparation of a medicine.
  • the term “containing P2X4 receptor antagonist as an active ingredient” refers to a known compound that can function as a P2X4 receptor antagonist and a pharmaceutically acceptable form of this compound (for example, It is used in the sense to include all uses in the form of salts, esters, amides, hydrated or solvated forms, racemic mixtures, optically pure forms, etc.
  • the compound as an active ingredient used in the present invention may be a free form or a pharmaceutically acceptable salt.
  • Such “salts” include acid addition salts with inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or aliphatic monostrength rubonic acid, dicarboxylic acid, hydroxyalkanoic acid, hydrogen
  • salts derived from non-toxic organic acids such as droxyalkanedioic acid and amino acid, and also aromatic acids, aliphatic and aromatic sulfonic acids.
  • acid addition salts are hydrochloride, hydrobromide, nitrate, sulfate, hydrogen sulfate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, tartrate Oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate Salt, lactate, malate, glycolate, trifluoroacetate, etc.
  • the pharmaceutical composition of the present invention is effective for the treatment of neuropathic pain.
  • neuropathic pain include, for example, alodynia, diabetic neuralgia, cancer pain, prolonged pain after surgery and trauma, hyperalgesia, postherpetic neuralgia, trigeminal neuralgia, multiple sclerosis Pain, paraplegia due to spinal cord disorder, non-sensory pain, neuropathic pain in phantom limb pain, strangulation neuropathy, sympathetic nerve-dependent pain and afferent blockage pain.
  • the pharmaceutical composition of the present invention is particularly effective for the treatment of arodinia.
  • the dosage form of the pharmaceutical composition of the present invention is not particularly limited, and can be orally or parenterally administered to humans and animals other than humans.
  • the P2X4 receptor antagonist that is an active ingredient may be incorporated alone, but is provided in the form of a preparation by incorporating a pharmaceutically acceptable carrier or additive for the preparation. You can also do it.
  • the P2X4 receptor antagonist as the active ingredient of the present invention can contain, for example, 0.1 to 99.9% by weight in the preparation.
  • Examples of pharmaceutically acceptable carriers or additives include excipients, disintegrants, disintegration aids, binders, lubricants, coating agents, dyes, diluents, solubilizers, solubilization aids, Tonicity agents, pH adjusters, stabilizers, etc. can be used.
  • Excipients include, for example, lactose, glucose, corn starch, sorbite, crystalline cellulose, sodium citrate, calcium carbonate, etc.
  • Disintegrants include, for example, starch, sodium alginate, gelatin powder, carbonic acid carbonate Calcium, calcium citrate, dextrin, and the like.
  • binders include dimethylcellulose, polyvinylenoreconole, polyvinylenole tenole, methinoresenorelose, ethinorece ⁇ / loose, arabian Examples thereof include rubber, gelatin, hydroxypropenoresenololose, and polyvinylpyrrolidone.
  • the lubricant include talc, magnesium stearate, polyethylene glycol, and hardened vegetable oil. Other carriers or additives can be appropriately selected by those skilled in the art.
  • preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, solutions or syrups.
  • various excipients such as crystalline cellulose, sodium citrate, calcium carbonate, disintegrants (starch, sodium alginate, etc.) and granulating binders (polyvinyl pyrrole) Dong, gelatin, arabic gum, etc.).
  • disintegrants starch, sodium alginate, etc.
  • granulating binders polyvinyl pyrrole
  • Magnesium stearate, Lubricants such as luc can also be used for tablet formation.
  • the active ingredient is used in combination with various sweeteners, flavors, colorants or dyes, and if necessary, an emulsifier and / or suspending agent is also used in combination with water, ethanol , Propylene glycol, glycerin, and the like, and combinations thereof.
  • preparations suitable for parenteral administration include injections such as intravenous injection and intramuscular injection, subcutaneous injections, suppositories, rectal administration agents, transdermal administration agents, intraspinal administration agents and the like.
  • the ability to dissolve the active ingredient of the present invention in either sesame oil or peanut oil, or a solution dissolved in an aqueous propylene dallicol solution can be used.
  • the aqueous solution should be buffered as necessary and the liquid diluent should be isotonic.
  • Such aqueous solutions are suitable for intravenous injection, and oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection.
  • the injection can be produced as a sterile solid composition by freeze-drying method or the like, dissolved in sterile distilled water for injection or other solvent before use, and used in a form prepared at the time of use. All these solutions can be easily prepared by standard pharmaceutical techniques well known to those skilled in the art.
  • the active ingredient of the present invention can also be administered locally such as on the skin.
  • topical administration in the form of creams, jellies, pastes, ointments is desirable according to standard pharmaceutical practice.
  • the dosage of the pharmaceutical composition of the present invention is not particularly limited, and an appropriate dosage according to various conditions such as the type of pain, the age and symptoms of the patient, the route of administration, the purpose of treatment, and the presence or absence of a concomitant drug. Can be selected.
  • the effective amount of the pharmaceutical composition of the present invention administered as a combination of the active ingredient SSRI, an appropriate diluent and a pharmacologically usable carrier is 0.1 g to 100 mg / body at a time. 1 to 50 g body, 1 to 20 ⁇ g / body, or 1 to: can be selected from the range of lO ⁇ ig / body, and is administered once a day to several times for 1 day or more.
  • Example 1 Example 1
  • Fura_2AM 5 ⁇ was added to 1321N1 human astrocytoma cells in which rat P2X4 receptor was forcibly expressed, followed by loading at room temperature for 45 minutes, followed by washing for 15 minutes after washing.
  • Cells extracellular fluid NaCl: 150mM, KCl: 5mM , CaCl 2: 1.8mM, MgCl 2: 1.2mM, HEPES: 25mM, D-Glucose: 10mM
  • Fura-2 to Karushiu beam inlet by ATP 30Myumyu stimulation We analyzed by calcium imaging method by fluorescence.
  • ATP (30 ⁇ ) was treated for 20 seconds to obtain a first response (Sl), followed by washing, followed by treatment with SSRI drugs (Paroxetine, Fluoxetine, Fluvoxamine, Citalopram) for 10 minutes.
  • SSRI drugs Pierisine, Fluoxetine, Fluvoxamine, Citalopram
  • ATP 30 ⁇ was treated for 20 seconds and the 2nd response (S2) was measured. After washing for 10 minutes, 3rd response (S3) was obtained and it was confirmed that the calcium response was recovered.
  • a transient intracellular Ca influx was observed after treatment with ATP at 30 ⁇ for 20 seconds. Comparing the intracellular Ca increase level using the ratio value change ( ⁇ ratio) as an index, the values were higher than 85% for the second ATP stimulation (S2) and 85% for the third ATP stimulation (S3). As shown (Fig. 1), the reproducibility of the response to at least three 30 ⁇ ATP stimuli was confirmed.
  • a ratio means the difference between the average value (Base ratio) and the peak value (Max ratio) of the ratio value (340/380) for about 15 seconds before ATP stimulation.
  • Pain behavior before drug administration was measured in rats 7 days after nerve injury. After injecting 10 ⁇ of drug into the catheter placed in the rat medullary cavity, another 10 ⁇ of PBS (-) was injected. Pain behavior was measured every 15 minutes for 2 hours after drug injection and every 30 minutes for the next 4 hours. Paroxetin was dissolved in 100% dim ethylsulfoxide (DMSO) and diluted with PBS (-) to prepare a final DMSO concentration of 5%.
  • an antagonist for the P2X4 receptor is provided. Since the activity of antagonist is strong and selective, the antagonist of the present invention is useful as a pharmaceutical composition for the treatment of neuropathic pain.

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  • Animal Behavior & Ethology (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention a pour objet un antagoniste d'un récepteur P2X4, par exemple un inhibiteur sélectif de recapture de la sérotonine (SSRI) tel que paroxétine, fluoxétine, fluvoxamine et citalopram.
PCT/JP2007/066323 2006-08-17 2007-08-16 antagoniste de récepteur P2X4 Ceased WO2008020651A1 (fr)

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JP2008529899A JPWO2008020651A1 (ja) 2006-08-17 2007-08-16 Ｐ２ｘ４受容体アンタゴニスト

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US83875906P 2006-08-17 2006-08-17
US60/838,759 2006-08-17

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WO2008020651A1 true WO2008020651A1 (fr) 2008-02-21

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Cited By (7)

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WO2012060397A1 (fr) 2010-11-05 2012-05-10 国立大学法人九州大学 Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
JPWO2012161301A1 (ja) * 2011-05-25 2014-07-31 国立大学法人九州大学 ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
WO2022030428A1 (fr) 2020-08-03 2022-02-10 日本ケミファ株式会社 Composition pharmaceutique pour la prévention, la suppression ou le traitement de symptômes associés à une réaction allergique
IT202100025124A1 (it) 2021-09-30 2023-03-30 Univ Degli Studi Di Firenze Medicamento per uso nel prevenire o trattare il dolore nocicettivo e/o viscerale
WO2023054578A1 (fr) 2021-09-30 2023-04-06 日本ケミファ株式会社 Agent prophylactique ou thérapeutique pour des maladies respiratoires
US11918589B2 (en) 2016-04-28 2024-03-05 Nippon Chemiphar Co., Ltd. Medicament for treatment of multiple sclerosis
US12090158B2 (en) 2018-09-03 2024-09-17 Nippon Chemiphar Co., Ltd. Medicine for diabetic peripheral neuropathy

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9561235B2 (en) 2010-11-05 2017-02-07 Kyushu University Preventive or therapeutic agent for pain associated with herpes zoster in acute phase
WO2012060397A1 (fr) 2010-11-05 2012-05-10 国立大学法人九州大学 Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
EP3132803A2 (fr) 2010-11-05 2017-02-22 Kyushu University Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
JP2017014224A (ja) * 2010-11-05 2017-01-19 国立大学法人九州大学 帯状疱疹関連痛の急性期疼痛の予防又は治療剤
JP2017119702A (ja) * 2011-05-25 2017-07-06 国立大学法人九州大学 ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
EP2716302A4 (fr) * 2011-05-25 2014-11-05 Univ Kyushu Agent prophylactique ou thérapeutique pour la douleur neuropathique associée au syndrome de guillain-barré
JPWO2012161301A1 (ja) * 2011-05-25 2014-07-31 国立大学法人九州大学 ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
US11918589B2 (en) 2016-04-28 2024-03-05 Nippon Chemiphar Co., Ltd. Medicament for treatment of multiple sclerosis
US12090158B2 (en) 2018-09-03 2024-09-17 Nippon Chemiphar Co., Ltd. Medicine for diabetic peripheral neuropathy
WO2022030428A1 (fr) 2020-08-03 2022-02-10 日本ケミファ株式会社 Composition pharmaceutique pour la prévention, la suppression ou le traitement de symptômes associés à une réaction allergique
IT202100025124A1 (it) 2021-09-30 2023-03-30 Univ Degli Studi Di Firenze Medicamento per uso nel prevenire o trattare il dolore nocicettivo e/o viscerale
WO2023054578A1 (fr) 2021-09-30 2023-04-06 日本ケミファ株式会社 Agent prophylactique ou thérapeutique pour des maladies respiratoires
WO2023052518A1 (fr) 2021-09-30 2023-04-06 Universita' Degli Studi Di Firenze Médicament comprenant un antagoniste du récepteur p2x4 pour la prévention ou le traitement de la douleur nociceptive et/ou de la douleur viscérale
KR20240130677A (ko) 2021-09-30 2024-08-29 닛뽕 케미파 가부시키가이샤 통각성 통증 및/또는 내장성 통증을 예방 또는 치료하기 위한 p2x4 수용체 길항제를 포함하는 약제

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