WO2008007654A1 - Agent prophylactique et/ou thérapeutique pour anévrisme - Google Patents

Agent prophylactique et/ou thérapeutique pour anévrisme Download PDF

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Publication number
WO2008007654A1
WO2008007654A1 PCT/JP2007/063703 JP2007063703W WO2008007654A1 WO 2008007654 A1 WO2008007654 A1 WO 2008007654A1 JP 2007063703 W JP2007063703 W JP 2007063703W WO 2008007654 A1 WO2008007654 A1 WO 2008007654A1
Authority
WO
WIPO (PCT)
Prior art keywords
aneurysm
prophylactic
therapeutic agent
aneurysms
tranilast
Prior art date
Application number
PCT/JP2007/063703
Other languages
English (en)
Japanese (ja)
Inventor
Toshihiro Tsuruda
Kazuo Kitamura
Johji Kato
Kinta Hatakeyama
Original Assignee
Kissei Pharmaceutical Co., Ltd.
University Of Miyazaki
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 Kissei Pharmaceutical Co., Ltd., University Of Miyazaki filed Critical Kissei Pharmaceutical Co., Ltd.
Publication of WO2008007654A1 publication Critical patent/WO2008007654A1/fr

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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
    • A61K31/185—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
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to a prophylactic and / or therapeutic agent for aneurysms. More specifically, the present invention relates to a prophylactic and / or therapeutic agent for aneurysms comprising a chemical mediator release inhibitor as an active ingredient.
  • Aneurysms are generally considered to be caused by local weakening of the blood vessel wall caused by arteriosclerosis, cystic medial necrosis, syphilis or fungal infection, macroarthritis and trauma. Is a localized dilation of blood vessels, especially the aorta or peripheral arteries. 3/4 of the aortic aneurysm occurs in the abdominal aorta, and 1/4 occurs in the thoracic aorta, both of which often grow and rupture without any preceding symptoms (see Non-Patent Document 1). For aneurysms, the diameter of the aneurysm is regularly measured by ultrasonic and CT examinations under strict blood pressure control, which is common among men over 60 years old. It becomes adaptation. However, since patients are often older and often have other diseases, postoperative complications and postoperative QOL decline must be considered. At present, there is no way to cure aneurysm medically.
  • MMP matrix meta-oral protease
  • JNK a pharmacotherapy capable of suppressing local weakening of the blood vessel wall in an aneurysm
  • MMP is an enzyme that breaks down the extracellular matrix, arthritis, It is thought to be involved in the development and development of inflammatory diseases such as emphysema, aneurysm and arteriosclerosis.
  • JNK is an enzyme that phosphorylates the amino acid terminus of c-Jun, and is activated by site force-in such as IL-1 and TNF-a, and physicochemical stress stimulation such as ultraviolet light, heat shock, and high osmotic pressure. And has a function of enhancing MMP activity.
  • neither MMP inhibitor nor JNK inhibitor has been put to practical use.
  • tranilast which has an inhibitory action on collagen synthesis, may cause intimal cell hyperproliferative diseases such as restenosis after PTCA, cardiac hypertrophy, atherosclerosis, angiogenesis inhibition, after heart transplantation. It is known to have therapeutic effects on cardiovascular hyperplasia, hypertensive arteriopathy and heart failure! (See Patent Documents 4 to 11). However, the action of tranilast on the adventitia and the relationship between tranilast and aneurysm are not known or suggested.
  • Non-Patent Document 1 Merck Manual Diagnosis and Treatment 17th Edition
  • Non-patent document 2 Tsuruda IV, et al., Biophys. Biochem. Res. Commun. 2004; 325: 80
  • Non-patent document 3 Atkinson J.B., et al., Hum. Pathol. 1994; 25; 154
  • Patent Document 1 Japanese Patent Publication No. 1 1 509870
  • Patent Document 2 JP 2000-143625 A
  • Patent Document 3 Japanese Patent Laid-Open No. 2006-89455
  • Patent Document 4 Japanese Patent Laid-Open No. 5-163222
  • Patent Document 5 Japanese Patent Laid-Open No. 6-135829
  • Patent Document 6 Japanese Patent Laid-Open No. 7-277966
  • Patent Document 7 JP-A-9 227371
  • Patent Document 10 WO01 / 1391 1 Pamphlet Disclosure of Invention Problems to be solved by the invention
  • An object of the present invention is to provide a prophylactic and / or therapeutic agent for aneurysms.
  • mast cells are significantly increased in the blood vessel wall of human abdominal aortic aneurysm compared to normal blood vessels, and abnormal collagen deposition is recognized. I discovered that. This suggests that mast cells produce various physiologically active substances involved in fibrosis, leading to abnormal metabolism of extracellular matrix in the vascular wall, leading to fragility of the vascular wall, that is, aneurysm formation Is. Therefore, if the release of a physiologically active substance from mast cells is suppressed, it may be possible to prevent the formation of an aneurysm.
  • the present inventor has intensively studied the relationship between mast cells and aneurysm formation, and as a result, a chemical mediator release inhibitor that suppresses the release of physiologically active substances from mast cells is an aneurysm.
  • the present invention has been completed.
  • the gist of the present invention resides in a prophylactic and / or therapeutic agent for aneurysms comprising a chemical mediator release inhibitor as an active ingredient.
  • the chemical mediator release inhibitor can be used as a prophylactic and / or therapeutic agent for aneurysms in order to suppress the formation of aneurysms.
  • FIG. 1 is a diagram showing an enlargement of an artery diameter.
  • the left is the control group, the right is the tranilast administration group, and the vertical axis is the enlargement of the artery diameter before aneurysm model creation (before calcium chloride application)
  • ** represents a significant difference of ⁇ ⁇ 0 ⁇ 01 by Student's T test.
  • examples of the aneurysm include an aortic aneurysm such as an abdominal aortic aneurysm and a thoracic aortic aneurysm; a peripheral aneurysm such as a popliteal aneurysm, an iliac aneurysm, and a femoral aneurysm.
  • an aortic aneurysm such as an abdominal aortic aneurysm and a thoracic aortic aneurysm
  • a peripheral aneurysm such as a popliteal aneurysm, an iliac aneurysm, and a femoral aneurysm.
  • the chemical mediator release inhibitor is a chemical mediator migration from mast cells. It is optional as long as it suppresses release, such as tranilast, ketotifen fumarate, sodium cromoglycate, levirinast, potassium pemirolast, ibudilast and isitazanolast hydrate, which suppresses the release of chemical mediators such as histamine. Can be mentioned. Of these, tranilast having an action of inhibiting collagen synthesis is most preferred. All of these chemorenomediator release inhibitors are known compounds, and can be produced by known methods. Commercially available products can also be used.
  • the preventive and / or therapeutic agent for aneurysms according to the present invention can be produced by mixing a chemical mediator release inhibitor and a commonly used pharmaceutical carrier.
  • the pharmaceutical carrier may be used in appropriate combination depending on the dosage form, for example, excipients such as lactose; lubricants such as magnesium stearate; disintegrants such as carboxymethylcellulose; hydroxypropylmethylcellulose and the like Binders such as macrogol; foaming agents such as sodium bicarbonate; solubilizing agents such as cyclodextrin; sour agents such as citrate; stabilizers such as sodium edetate; pH such as phosphates Examples include regulators
  • Examples of the administration form of a prophylactic and / or therapeutic agent for aneurysms according to the present invention include oral administration agents such as powders, granules, fine granules, dry syrups, tablets and capsules; injections and ointments And parenteral administration agents such as an agent, a troche and a patch.
  • the chemical mediator release inhibitor contained in the preparation may be appropriately determined and prepared for each drug.
  • oral administration is in the range of lOOmg to 1 mg per adult; 1000 mg, non-P administration is in the range of 30 mg to 300 mg per adult.
  • a 12-week-old male rat (Sic: WsRC-+ / +; Nippon SLC Co., Ltd.) was laparotomized under anesthesia, and the connective tissue surrounding the blood vessel was detached to isolate the abdominal aorta.
  • the tranilast administration group (10 animals) received tranilast 400 mg / kg / day dissolved in 2 mL of 1% sodium bicarbonate twice a day, and the control group (10 animals) received 2 mL of 1% sodium hydrogen carbonate solution 2 times a day.
  • the model was started 1 week before the model was created, and was administered orally using a gavage tube for 14 days after the aneurysm model was created. 14 days after model creation, the abdomen was opened and the artery diameter (aneurysm diameter) was measured. The results are shown in Figure 1.
  • tranilast suppresses the development and progression of aneurysms, it can be used as a therapeutic and / or prophylactic agent for aneurysms.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un agent prophylactique et/ou thérapeutique pour anévrisme qui contient un inhibiteur de libération de médiateur chimique comme ingrédient actif. Un inhibiteur de libération de médiateur chimique tel que le tranilast, le fumarate de kétotifène, le cromoglicate de sodium, le repirinast, le potassium de pemirolast, l'ibudilast et l'hydrate d'acitazanolast peut inhiber l'apparition ou le développement d'anévrisme et peut par conséquent être utilisé comme agent prophylactique et/ou thérapeutique pour l'anévrisme.
PCT/JP2007/063703 2006-07-14 2007-07-10 Agent prophylactique et/ou thérapeutique pour anévrisme WO2008007654A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006-193689 2006-07-14
JP2006193689A JP2008019221A (ja) 2006-07-14 2006-07-14 動脈瘤の予防及び／又は治療薬

Publications (1)

Publication Number Publication Date
WO2008007654A1 true WO2008007654A1 (fr) 2008-01-17

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JP (1) JP2008019221A (fr)
WO (1) WO2008007654A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009022740A1 (fr) * 2007-08-15 2009-02-19 Kyorin Pharmaceutical Co., Ltd. Agent préventif, inhibiteur ou remède pour l'anévrisme cérébral comportant de l'ibudilast en tant qu'ingrédient actif
CN112569219A (zh) * 2019-09-30 2021-03-30 中国科学院上海药物研究所 用于治疗动脉相关疾病的药物及其用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9629834B2 (en) 2013-04-26 2017-04-25 Kyoto University Medicinal composition for inhibiting formation and/or enlargement of cerebral aneurysm or shrinking same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006506336A (ja) * 2002-07-30 2006-02-23 ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス 動静脈の移植不全の予防及び／または処置のためのキマーゼ阻害剤の使用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006506336A (ja) * 2002-07-30 2006-02-23 ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス 動静脈の移植不全の予防及び／または処置のためのキマーゼ阻害剤の使用

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
FURUBAYASHI K. ET AL.: "Chymase Sogaiyaku no Domyakuryu Yokusei Koka ni Tsuite", JOURNAL OF BLOOD PRESSURE, vol. 12, no. 3, 2005, pages 70 - 74, XP003020592 *
MIKOSHIBA I.: "Inu Keidomyaku Balloon Shogai Model o Mochiita Tranilast ni yor Uchimaku Hiko Yokusei Koka no Kento to Chymase Izonsho Angiotensin II no Yakuwari no Kaiseki", JOURNAL OF THE OSAKA MEDICAL COLLEGE, vol. 56, no. 3, 1997, pages 62 - 74, XP003020596 *
TAIKAI S.: "Chymase no Byotai Seiri to Chymase Sogaiyaku no Kanosei", THE JOURNAL OF OSAKA MEDICAL COLLEGE, KENKYU KIKO SYMPOSIUM KOENSHU, vol. 64, no. 3, 2005, pages 82 - 86, XP003020594 *
TAKAI S. ET AL.: "Daidomyakuryu Shinten ni Okeru Chymase no Byotai Seirigakuteki Yakuwari (Pathophysiological role of chymase in progression of aortic aneurysm)", RECENT ADVANCES IN CLINICAL PHARMACOLOGY, no. 26, 2005, pages 145 - 150, XP003020593 *
TAKAMURO M. ET AL.: "Kawasakibyo Kandomyakuryu ni Taisuru 5-HT2 Juyotai Kikkozai ni Shiyo Keiken", DAI 38 KAI JAPANESE SOCIETY OF PEDIATRIC CARDIOLOGY AND CARDIAC SURGERY SOKAI.GAKUJUTSU SHUKAI SHOROKUSHU, 1 April 2002 (2002-04-01), pages 235 + ABSTR. NO. P-I-56, XP003020591 *
TOMITA Y. ET AL.: "Gamma Globulin Fuorei no Chiryo ni Tsuite Gamma Globulin Ikkai Chotairyo Ryoho ni Okeru Tsuika Toyo no Genjo", PROG. MED., vol. 17, no. 7, 1997, pages 1834 - 1842, XP003020590 *
TSUNEMI K. TE AL.: "Daidomyakuryuheki no Kaku Maku Betsu ni Mita Kyokusho Angiotensin II Sansei no Kento (Distribution of Angiotensin II, Angiotensin Converting Enzyme and Chymase, in Human Abdominal Aortic Aneurysms)", THE JOURNAL OF JAPANESE COLLEGE OF ANGIOLOGY, vol. 42, no. 10, 2002, pages 827 - 834, XP003020595 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009022740A1 (fr) * 2007-08-15 2009-02-19 Kyorin Pharmaceutical Co., Ltd. Agent préventif, inhibiteur ou remède pour l'anévrisme cérébral comportant de l'ibudilast en tant qu'ingrédient actif
CN112569219A (zh) * 2019-09-30 2021-03-30 中国科学院上海药物研究所 用于治疗动脉相关疾病的药物及其用途
CN112569219B (zh) * 2019-09-30 2023-05-02 中国科学院上海药物研究所 用于治疗动脉相关疾病的药物及其用途

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