WO2004032915A1 - Agent du virus anti-influenza - Google Patents

Agent du virus anti-influenza Download PDF

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Publication number
WO2004032915A1
WO2004032915A1 PCT/JP2003/013049 JP0313049W WO2004032915A1 WO 2004032915 A1 WO2004032915 A1 WO 2004032915A1 JP 0313049 W JP0313049 W JP 0313049W WO 2004032915 A1 WO2004032915 A1 WO 2004032915A1
Authority
WO
WIPO (PCT)
Prior art keywords
influenza virus
type
tranexamic acid
crude drug
salt
Prior art date
Application number
PCT/JP2003/013049
Other languages
English (en)
Japanese (ja)
Inventor
Kenji Tsunoda
Original Assignee
Daiichi Pharmaceutical Co., Ltd.
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
Application filed by Daiichi Pharmaceutical Co., Ltd. filed Critical Daiichi Pharmaceutical Co., Ltd.
Priority to JP2004542873A priority Critical patent/JP4600882B2/ja
Priority to AU2003272974A priority patent/AU2003272974A1/en
Publication of WO2004032915A1 publication Critical patent/WO2004032915A1/fr

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to anti-influenza virus agents
  • the present invention relates to a prophylactic and / or therapeutic agent.
  • Tranexamic acid or a salt thereof is a highly safe drug known for its antiplasmin, antiallergic, and antiinflammatory effects, and its efficacy is based on bleeding tendency (leukemia) considered to be related to systemic fibrinolysis. , Aplastic anemia, purpura, etc. and during surgery ⁇ abnormal bleeding after surgery); abnormal bleeding thought to involve local hyperlysis (pulmonary bleeding, epistaxis, genital bleeding, renal bleeding, prostate surgery ⁇ during surgery) Abnormal bleeding later); eczema and similar diseases, juniper, drug eruption, erythema in poisoning rash, swelling, pruritus; sore throat, sore throat in pharyngolaryngitis, redness, redness, swelling, etc.
  • tranexamic acid or a salt thereof can be used as a therapeutic agent for pigmentation disease in addition to the above-mentioned actions and effects (Japanese Patent Application Laid-Open No. 243825/1991).
  • tranexamic acid or its salts are not known to have anti-influenza virus activity.
  • ama ntadine hy drochloride force S known force Is also used as an antiparkinsonian and must be administered with caution. Amantadine hydrochloride has no effect other than influenza A virus infection. Disclosure of the invention
  • An object of the present invention is to provide a new anti-influenza virus agent and a prophylactic and / or therapeutic agent for influenza virus infection.
  • tranexamic acid or a salt thereof has an anti-influenza virus activity, and completed the present invention.
  • the present invention provides an anti-influenza virus agent containing tranexamic acid or a salt thereof, as well as a prophylactic and / or therapeutic agent for influenza virus infection.
  • the present invention also provides a pharmaceutical composition for preventing and / or treating influenza virus infection, comprising tranexamic acid or a salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a method for treating influenza virus infection, which comprises administering an effective amount of tranexamic acid or a salt thereof. Furthermore, the present invention provides the use of tranexamic acid or a salt thereof for the prevention of influenza virus infection and the production of a therapeutic agent or Z.
  • Tranexamic acid or a salt thereof has an anti-influenza virus effect, and is useful as an anti-influenza virus agent, and a preventive and / or therapeutic agent for influenza virils infection.
  • tranexamic acid or a salt thereof has an effect not only on influenza A virus but also on influenza B virus, and is extremely useful.
  • FIG. 1 shows the effect of tranexamic acid on the growth of influenza virus A / WSN / 33 (H1N1).
  • FIG. 2 shows the effect of tranexamic acid on the survival rate of cells infected with influenza virus A / WSN / 33 (H1N1).
  • FIG. 3 shows the effect of tranexamic acid on the growth of influenza virus A / Guizhou / 54/89 (H 3 N 2).
  • FIG. 4 is a graph showing the effect of tranexamic acid on the survival rate of cells infected with influenza virus A / Guizhou / 54/89 (H 3 N 2).
  • FIG. 5 shows the effect of tranexamic acid on the proliferation of influenza virus BZ Ibaraki Z 2/85.
  • FIG. 6 shows the effect of tranexamic acid on the survival rate of cells infected with influenza virus BZ Ibaraki / 2Z85.
  • FIG. 7 shows the effect of tranexamic acid on the survival rate of influenza virus AZPR / 834 lower respiratory tract infected mice.
  • FIG. 8 is a graph showing the effect of amantadine hydrochloride on the survival rate of Influenzae A / PR / 8Z34 lower respiratory tract infected mice.
  • tranexamic acid trans-41-aminomethylcyclohexanecarboxylic acid
  • a salt thereof is a known compound, and a commercially available product may be used. It is also possible to manufacture based on this.
  • tranexamic acid salts include mineral salts such as hydrochloride, nitrate, and sulfate; organic acid salts such as methanesulfonic acid; alkali metals such as sodium, potassium, calcium, and magnesium; and alkaline earths. Metal salts and the like can be mentioned.
  • tranexamic acid or a salt thereof is preferably tranexamic acid.
  • the anti-influenza virus agent, the prophylactic and / or therapeutic agent for influenza virus infection of the present invention is a patient infected with an influenza virus or infected.
  • infected patients show symptoms such as sneezing, runny nose, stuffy nose, cough, sputum, chills, fever, headache, sore throat, and so on. It may be administered (in combination). In addition to being used in combination, it can be mixed with the anti-influenza virus agent of the present invention to form a mixture (composition).
  • symptomatic drug which can be administered in addition to the anti-influenza virus agent of the present invention, aspirin, aspirin aluminum, sazapyrine, ethenzamide, salicylamide, ibuprofen, acetoaminophen, and isopropylantipyrine Nervous stimulants such as caffeine, anhydrous caffeine, sodium caffeine benzoate, etc .; sedatives such as bromperyl urea, arylisopropyl acetyl urea; chlorpheniramine maleate, diphenhydramine, etc.
  • Antihistamines such as diphenhydramine salitinoleate, clemastine fumanolate, carbinoxamine maleate, mequitazine, arimemidine tartrate, diphenyl viraline hydrochloride, triprolidine hydrochloride; salted lysozyme, bromela Anti-inflammatory drugs such as sulphate, therapase, semi-alkali proteinase, glycyrrhizinate, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, sodium azulene sulphonate; dihydrocodine phosphate, codine phosphate, nospin hydrochloride, Nospin, dextromethorphan hydrobromide, dextromethorphan phenol phthalate salt, dimemorphine phosphate, tipidine hibenzate, tipidine quinate, epradinone hydrochloride
  • vitamin B 2 vitamin B 6 Vitamin B 1 2
  • vitamin C calcium Asukorubin acid
  • vitamin D vitamin E
  • vitamin agents such as co-Haq acid tocopheryl Hue roll calcium
  • pantothenate, Panteno Le sodium pantothenate, calcium pantothenate, pantethine, nicotinic acid, nicotinic acid Metabolism of amide, glucuronic acid, dalchronolactone, aminoethylsulfonate, biotin, ⁇ -oryzanol, etc.
  • the symptomatic drug may be a single component, or a combination or combination of two or more.
  • the anti-influenza antiviral agent of the present invention can be administered orally or parenterally.
  • the preparation for oral administration include tablets, capsules, powders, fine granules, liquids, troches, and jellies.
  • Formulations for parenteral administration include injections, plasters, alcoholic beverages, extracts, suppositories, suspensions, tinctures, ointments, cataplasms, nasal drops, inhalants, and liniments. , Lotion agents, and azole agents.
  • the anti-influenza virus agent of the present invention may be blended in a mouthwash, a throat spray, a mouthwash and the like.
  • oral Administration preparations are preferable, and solid preparations such as tablets, capsules, powders, fine granules, troches, and gels are particularly preferable.
  • preparations can be manufactured by a conventional preparation method known to those skilled in the art, and in order to prepare pharmaceutical preparations of such various dosage forms, other pharmaceutically acceptable carriers are added as required. It is possible.
  • the carrier include an excipient, a binder, a disintegrant, a fluidizing agent, an emulsifier, a stabilizer and the like.
  • Influenza virus is roughly classified into three types: type A, type B, and type C. In the present invention, it is preferable to target influenza A and B viruses.
  • the dosage of the anti-influenza virus agent of the present invention to a patient varies depending on the patient's sex, age, symptoms, administration method, administration frequency, administration timing, and the like.
  • tranexamic acid or The salt is preferably administered at 10 to 300 Omg, more preferably at 400 to 75 Omg.
  • the concentration of tranexamic acid or a salt thereof in the preparation is 0.1 to 5.Ow / w%, preferably 1.0 to 3.OwZw.
  • the preparation is prepared with the concentration of tranexamic acid or a salt thereof in the preparation being 0.05 to 5.0 Ow / w%, preferably 0.5 to 2.0.
  • Anti-influenza virus test (invitro) 3013049 cultured M adi n-Da rbycanineki dn ey (MD CK) influenza virus A / WSN / 3 3 was grown in cells embryonated chicken eggs (h1n
  • influenza virus A / Gu izhou / 54/89 (H3N2), influenza virus B / Ibaraki Z 2/85 were infected with protease absence at 37 ° C 5% C0 2 conditions, cytopathic effect ( The cells were cultured until cytopathic effect was observed (3-4 days). Collect culture supernatant and after centrifugation
  • influenza virus suspension was measured for the infectivity of MDCK cells in the presence of trypsin, and propagated in MDCK cells in the presence and absence of trypsin until an influenza virus with a difference in infectivity was obtained. Was repeated.
  • influenza virus obtained in the previous section was infected to MDCK cells in the presence of trypsin (3 ⁇ g / m1, Sigma), and tranexamic acid was added (final concentration 0.39-100 ⁇ / ⁇ 1). .
  • the cells were cultured for 3 to 4 days, the amount of influenza virus in the culture supernatant was measured by sialidase activity, and the cell viability was measured by the MTT method. Complete TM mini (Roche Diagnostics) was used as a positive control.
  • Figures 1 to 6 show the results for each influenza virus.
  • '' Figures 1 and 2 show the results for influenza virus A / WSN / 33 (H1N1)
  • Figures 3 and 4 show the results for influenza virus A / Guizhou / 54/89 (H3N1).
  • mice One hour before, one day, two days, three days, four days, and five days after virus inoculation, the stomach of mice was administered using an oral sonde so that the dose of tranexamic acid was 1 OmgZkg or 10 Omg / kg. Was administered by gavage. Similarly, water was administered instead of tranexamic acid as a control, and amantadine hydrochloride was administered as a positive control group so that the dose was 1 OmgZkg or 10 OmgZkg.
  • mice receiving 10 OmgZkg of amantadine hydrochloride had a 6% survival rate from day 11 to day 16. 7%, and 56% of the mice survived even on the 21st day, indicating that the survival rate was increased and the survival days were prolonged as compared with the control group (FIGS. 7 and 8 ).
  • the average survival time in each group was 12.9 days for the control group, 14.9 days for the tranexamic acid 1 Omg / kg group, and 16.5 days for the tranexamic acid 10 Omg / kg group.
  • the period was 15.3 days
  • in the group administered with amantadine hydrochloride at 10 Omg / kg was 16.5 days.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Oncology (AREA)
  • Pulmonology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un agent de virus anti-influenza contenant un acide tranexamique et son sel et un préventif et/ou un remède contre l'infection dérivée de virus de l'influenza.
PCT/JP2003/013049 2002-10-11 2003-10-10 Agent du virus anti-influenza WO2004032915A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2004542873A JP4600882B2 (ja) 2002-10-11 2003-10-10 抗インフルエンザウイルス剤
AU2003272974A AU2003272974A1 (en) 2002-10-11 2003-10-10 Anti-influenza virus agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002298501 2002-10-11
JP2002-298501 2002-10-11

Publications (1)

Publication Number Publication Date
WO2004032915A1 true WO2004032915A1 (fr) 2004-04-22

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PCT/JP2003/013049 WO2004032915A1 (fr) 2002-10-11 2003-10-10 Agent du virus anti-influenza

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JP (1) JP4600882B2 (fr)
AU (1) AU2003272974A1 (fr)
WO (1) WO2004032915A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007277222A (ja) * 2006-03-17 2007-10-25 Daiichi Sankyo Healthcare Co Ltd 抗炎症用医薬組成物
JP2007291067A (ja) * 2006-03-29 2007-11-08 Daiichi Sankyo Healthcare Co Ltd 医薬組成物
JP2007291072A (ja) * 2006-03-27 2007-11-08 Daiichi Sankyo Healthcare Co Ltd 医薬組成物
JP2008115168A (ja) * 2006-10-12 2008-05-22 Daiichi Sankyo Healthcare Co Ltd 抗アデノウイルス剤
JP2013237666A (ja) * 2012-04-16 2013-11-28 Daiichi Sankyo Healthcare Co Ltd 過労又は慢性疲労に伴う疾患の治療及び／又は予防剤
JP2015091884A (ja) * 2010-04-26 2015-05-14 第一三共ヘルスケア株式会社 抗潰瘍剤組成物
WO2019045989A1 (fr) * 2017-08-27 2019-03-07 Anti-Plasmin Technologies, Llc Méthodes et compositions pour l'utilisation antivirale d'analogues et de mimétiques synthétiques de lysine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06172199A (ja) * 1992-12-07 1994-06-21 Tsumura & Co ペプチド類経鼻投与用組成物
WO1995033474A1 (fr) * 1994-06-03 1995-12-14 Tsumura & Co. Composition medicinale
WO1997012582A2 (fr) * 1995-10-06 1997-04-10 Agrimmune, Inc. Procede de prevention et de traitement de la coccidiose
JP2000095675A (ja) * 1998-09-22 2000-04-04 Rohto Pharmaceut Co Ltd 口中溶解型又は咀嚼型鼻炎治療用固形内服医薬組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06172199A (ja) * 1992-12-07 1994-06-21 Tsumura & Co ペプチド類経鼻投与用組成物
WO1995033474A1 (fr) * 1994-06-03 1995-12-14 Tsumura & Co. Composition medicinale
WO1997012582A2 (fr) * 1995-10-06 1997-04-10 Agrimmune, Inc. Procede de prevention et de traitement de la coccidiose
JP2000095675A (ja) * 1998-09-22 2000-04-04 Rohto Pharmaceut Co Ltd 口中溶解型又は咀嚼型鼻炎治療用固形内服医薬組成物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NAKATANI AKIRA: "Kaze shokogun ni taisuru tranexamic-san iri kazegusuri K-CW no shiyo keiken", BASIC PHARMACOLOGY & THERAPEUTICS, vol. 18, no. 2, 1990, pages 799 - 808, XP002977473 *
TOBA TSUYOSHI: "Shoni no kaze shokogun ni taisuru tranexamic-san ganyu kazegusuri K-CW no rinsho koka no kento", BASIC PHARMACOLOGY & THERAPEUTICS, vol. 18, no. 2, 1990, pages 821 - 830, XP002977472 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007277222A (ja) * 2006-03-17 2007-10-25 Daiichi Sankyo Healthcare Co Ltd 抗炎症用医薬組成物
JP2007291072A (ja) * 2006-03-27 2007-11-08 Daiichi Sankyo Healthcare Co Ltd 医薬組成物
JP2007291067A (ja) * 2006-03-29 2007-11-08 Daiichi Sankyo Healthcare Co Ltd 医薬組成物
JP2008115168A (ja) * 2006-10-12 2008-05-22 Daiichi Sankyo Healthcare Co Ltd 抗アデノウイルス剤
JP2015091884A (ja) * 2010-04-26 2015-05-14 第一三共ヘルスケア株式会社 抗潰瘍剤組成物
JP2013237666A (ja) * 2012-04-16 2013-11-28 Daiichi Sankyo Healthcare Co Ltd 過労又は慢性疲労に伴う疾患の治療及び／又は予防剤
WO2019045989A1 (fr) * 2017-08-27 2019-03-07 Anti-Plasmin Technologies, Llc Méthodes et compositions pour l'utilisation antivirale d'analogues et de mimétiques synthétiques de lysine
JP2020531586A (ja) * 2017-08-27 2020-11-05 アンタイ−ヴァイラル テクノロジーズ， エルエルシー 合成リジンアナログ及び模倣物の抗ウイルス用途のための方法及び組成物
US11413279B2 (en) 2017-08-27 2022-08-16 Anti-Viral Technologies, Llc Methods and compositions for the antiviral use of synthetic lysine analogs and mimetics
US20220288050A1 (en) * 2017-08-27 2022-09-15 Anti-Viral Technologies, Llc Methods and compositions for the antiviral use of synthetic lysine analogs and mimetics

Also Published As

Publication number Publication date
JP4600882B2 (ja) 2010-12-22
AU2003272974A1 (en) 2004-05-04
JPWO2004032915A1 (ja) 2006-02-02

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