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JP2008019221A - Drugs for preventing and / or treating aneurysms - Google Patents

Drugs for preventing and / or treating aneurysms Download PDF

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Publication number
JP2008019221A
JP2008019221A JP2006193689A JP2006193689A JP2008019221A JP 2008019221 A JP2008019221 A JP 2008019221A JP 2006193689 A JP2006193689 A JP 2006193689A JP 2006193689 A JP2006193689 A JP 2006193689A JP 2008019221 A JP2008019221 A JP 2008019221A
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aneurysm
aneurysms
tranilast
mediator release
therapeutic agent
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Toshihiro Tsuruta
敏博 鶴田
Kazuo Kitamura
和雄 北村
Takeshi Kato
丈司 加藤
Kinta Hatakeyama
金太 畠山
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Kissei Pharmaceutical Co Ltd
University of Miyazaki NUC
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University of Miyazaki NUC
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Priority to PCT/JP2007/063703 priority patent/WO2008007654A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/14Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

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Abstract

【課題】 動脈瘤の予防及び/又は治療薬を提供する。
【解決手段】 ケミカルメディエーター遊離抑制薬を有効成分とする動脈瘤の予防及び/又は治療薬。
トラニラスト、フマル酸ケトチフェン、クロモグリク酸ナトリウム、レピリナスト、ペミロラストカリウム、イブジラスト及びアシタザノラスト水和物等のケミカルメディエーター遊離抑制薬は、動脈瘤の発生や進展を抑制するため、動脈瘤の予防及び/又は治療薬として用いることができる。
【選択図】図1
PROBLEM TO BE SOLVED: To provide a preventive and / or therapeutic agent for aneurysm.
An agent for preventing and / or treating an aneurysm comprising a chemical mediator release inhibitor as an active ingredient.
Chemical mediator release inhibitors such as tranilast, ketotifen fumarate, sodium cromoglycate, repirinast, pemirolast potassium, ibudilast and acitazanolast hydrate suppress the occurrence and progression of aneurysms and prevent aneurysms It can be used as a therapeutic agent.
[Selection] Figure 1

Description

本発明は、動脈瘤の予防及び/又は治療薬に関するものである。さらに詳しく述べれば、ケミカルメディエーター遊離抑制薬を有効成分とする動脈瘤の予防及び/又は治療薬に関するものである。   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.

動脈瘤は、一般に、動脈硬化、嚢胞性中膜壊死、梅毒性又は真菌性感染症、大動脈炎及び外傷等が原因となる血管壁の局所的脆弱化によって発生すると考えられている血管、特に大動脈又は末梢動脈の限局性の拡張である。大動脈瘤の3/4は腹部大動脈に、1/4は胸部大動脈に発生し、いずれも先行する症状がないまま、動脈瘤が大きくなり破裂することも多い(非特許文献1参照)。動脈瘤は、60歳以上の男性に多く、厳密な血圧コントロールの下、定期的に超音波やCT検査により瘤径を測定し、増大傾向にある場合、動脈瘤の破裂を防ぐため手術適応となる。しかしながら、患者の年齢が高く、また他の疾患を有する場合が多いことから、術後合併症や術後のQOL低下を考慮しなければならない。現在、動脈瘤を内科的に根治治療する方法はない。   Aneurysms are generally considered to be caused by local weakening of the vascular wall caused by arteriosclerosis, cystic medial necrosis, syphilis or fungal infection, aortitis and trauma, especially the aorta Or a localized dilation of the peripheral artery. 3/4 of the aortic aneurysm occurs in the abdominal aorta, and 1/4 occurs in the thoracic aorta, and the aneurysm is often enlarged and ruptured without any preceding symptoms (see Non-Patent Document 1). Aneurysms are common among men over 60 years old, and under strict blood pressure control, the diameter of the aneurysm is regularly measured by ultrasound and CT examination. Become. However, since patients are older and often have other diseases, postoperative complications and postoperative QOL reduction must be considered. Currently, there is no way to cure aneurysm medically.

動脈瘤の発生原因となる動脈硬化や破裂の原因となる高血圧では、血管周囲の線維芽細胞や肥満細胞等が活性化し、これらが血管リモデリングの進行に関与している(非特許文献2参照)。肥満細胞は、血管では主に外膜に存在し、動脈硬化との関連性が示唆されている(非特許文献3参照)が、その病態生理学的な役割については不明な点が多く、ヒスタミン等の化学伝達物質や酵素、脂質メディエーター等のケミカルメディエーターを産生、放出する一種の「内分泌器官」であると考えられている。   In hypertension that causes arteriosclerosis and rupture that causes aneurysms, fibroblasts and mast cells around blood vessels are activated, and these are involved in the progression of vascular remodeling (see Non-Patent Document 2). ). Mast cells are mainly present in the outer membrane of blood vessels and have been suggested to be associated with arteriosclerosis (see Non-Patent Document 3), but there are many unclear points regarding their pathophysiological roles, such as histamine It is thought to be a kind of “endocrine organ” that produces and releases chemical mediators such as chemical mediators, enzymes, and lipid mediators.

最近、動脈瘤における血管壁の局所的脆弱化を抑制し得る薬物療法として、マトリックスメタロプロテアーゼ(MMP)阻害剤やJNK阻害剤を用いる方法が提案された(特許文献1〜3参照)。MMPは、細胞外マトリックスを分解する酵素であり、関節炎、肺気腫、動脈瘤、動脈硬化等の炎症性疾患の発生や進展に関わりがあると考えられている。JNKは、c−Junのアミノ酸末端をリン酸化する酵素であり、IL−1、TNF−α等のサイトカインや、紫外線、熱ショック、高浸透圧等の物理化学的なストレス刺激で活性化され、MMP活性を亢進させる機能を有する。しかしながら、MMP阻害剤及びJNK阻害剤ともに実用化されたものはない。   Recently, a method using a matrix metalloproteinase (MMP) inhibitor or a JNK inhibitor has been proposed as a pharmacotherapy that can suppress local weakening of the blood vessel wall in an aneurysm (see Patent Documents 1 to 3). MMP is an enzyme that degrades the extracellular matrix, and is thought to be involved in the development and progression of inflammatory diseases such as arthritis, emphysema, aneurysm, and arteriosclerosis. JNK is an enzyme that phosphorylates the amino acid terminal of c-Jun, and is activated by cytokines such as IL-1 and TNF-α, and physicochemical stress stimulation such as ultraviolet light, heat shock, and high osmotic pressure, It has a function of enhancing MMP activity. However, neither MMP inhibitor nor JNK inhibitor has been put to practical use.

ケミカルメディエーター遊離抑制薬は、主として、気管支喘息やアレルギー性鼻炎等の治療及び/又は予防に用いられており、動脈瘤との関係については知られていない。また、ケミカルメディエーター遊離抑制に加えてコラーゲン合成阻害作用を有するトラニラストが、PTCA後の再狭窄等の血管内膜細胞過剰増殖疾患、心肥大、粥状動脈硬化症、血管新生阻害、心臓移植後の心血管肥厚、高血圧性細動脈障害及び心不全の治療効果を有することは知られている(特許文献4〜11参照)。しかしながら、トラニラストの血管外膜における作用、及びトラニラストと動脈瘤との関係は知られておらず、それを示唆するものもない。   Chemical mediator release inhibitors are mainly used for the treatment and / or prevention of bronchial asthma, allergic rhinitis and the like, and the relationship with aneurysms is not known. In addition to the suppression of chemical mediator release, tranilast, which has an action of inhibiting collagen synthesis, may cause an intimal cell hyperproliferative disease such as restenosis after PTCA, cardiac hypertrophy, atherosclerosis, angiogenesis inhibition, after heart transplantation It is known to have a therapeutic effect on cardiovascular thickening, 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.

メルクマニュアル 診断と治療 第17版Merck Manual Diagnosis and Treatment 17th Edition Tsuruda, Biophys. Biochem. Res. Commun. 2004;325:80Tsuruda, Biophys. Biochem. Res. Commun. 2004; 325: 80 Atkison JB, et al. Hum. Pathol. 1994;25;154Atkison JB, et al. Hum. Pathol. 1994; 25; 154 特表平11−509870号公報Japanese National Patent Publication No. 11-509870 特開2000−143625号公報JP 2000-143625 A 特開2006−89455号公報JP 2006-89455 A 特開平5−163222号公報JP-A-5-163222 特開平6−135829号公報Japanese Patent Laid-Open No. 6-135829 特開平7−277966号公報JP-A-7-277966 特開平9−227371号公報JP-A-9-227371 WO97/29744パンフレットWO97 / 29744 pamphlet WO01/05394パンフレットWO01 / 05394 brochure WO01/13911パンフレットWO01 / 13911 brochure WO01/13952パンフレットWO01 / 13952 pamphlet

本発明は、動脈瘤の予防及び/又は治療薬を提供することを課題とする。   An object of the present invention is to provide a prophylactic and / or therapeutic agent for aneurysms.

本発明者らは、動脈瘤の内科的治療の研究において、ヒト腹部大動脈瘤の血管壁では正常血管に比べ肥満細胞数が顕著に増加しており、異常なコラーゲン沈着を認めることを発見した。これは、肥満細胞が線維化に関与する種々の生理活性物質を産生することで、血管壁における細胞外基質の代謝異常を誘導し、血管壁の脆弱、すなわち動脈瘤形成を引き起こすことを示唆するものである。したがって、肥満細胞からの生理活性物質の放出を抑制すれば、動脈瘤の形成を阻止することができる可能性がある。   In the study of medical treatment of aneurysms, the present inventors have found that the number of mast cells is markedly increased in the blood vessel wall of human abdominal aortic aneurysm compared to normal blood vessels, and abnormal collagen deposition is observed. This suggests that mast cells produce various physiologically active substances involved in fibrosis, leading to abnormal metabolism of extracellular matrix in the vascular wall and causing vascular wall weakness, ie, aneurysm formation Is. Therefore, if the release of the physiologically active substance from mast cells is suppressed, the formation of an aneurysm may be prevented.

本発明者は、以上の知見をもとに、肥満細胞と動脈瘤形成との関係について鋭意研究した結果、肥満細胞の生理活性物質放出を抑制するケミカルメディエーター遊離抑制薬が動脈瘤の形成を阻止し得ることを見出し、本発明を完成させた。   Based on the above findings, the present inventor has conducted intensive research on the relationship between mast cells and aneurysm formation. As a result, chemical mediator release inhibitors that inhibit the release of physiologically active substances from mast cells prevent aneurysm formation. The present invention has been completed.

すなわち、本発明の要旨は、ケミカルメディエーター遊離抑制薬を有効成分とする動脈瘤の予防及び/又は治療薬に存する。   That is, 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.

ケミカルメディエーター遊離抑制薬は、動脈瘤の形成を抑制するため、動脈瘤の予防及び/又は治療薬として用いることができる。   The chemical mediator release inhibitor can be used as a prophylactic and / or therapeutic agent for aneurysms because it suppresses the formation of aneurysms.

本明細書において、動脈瘤としては、例えば、腹部大動脈瘤及び胸部大動脈瘤等の大動脈瘤;膝窩動脈瘤、腸骨動脈瘤及び大腿動脈瘤等の末梢動脈瘤などが挙げられる。   In this specification, 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.

ケミカルメディエーター遊離抑制薬は、肥満細胞からのケミカルメディエーターの遊離を抑制するものであれば任意であり、例えば、ヒスタミン等の化学伝達物質の遊離を抑制するトラニラスト、フマル酸ケトチフェン、クロモグリク酸ナトリウム、レピリナスト、ペミロラストカリウム、イブジラスト及びアシタザノラスト水和物等が挙げられる。これらのうち、コラーゲン合成阻害作用を有するトラニラストが最も好ましい。これらのケミカルメディエーター遊離抑制薬は、いずれも公知の化合物であり、それぞれ公知の方法により製造することができる。また、市販されている製品を用いることもできる。   The chemical mediator release inhibitor is arbitrary as long as it suppresses the release of chemical mediators from mast cells. For example, tranilast, ketotifen fumarate, sodium cromoglycate, repirinast, , Pemirolast potassium, ibudilast, and acitazanolast hydrate. Of these, tranilast having a collagen synthesis inhibitory effect is most preferred. These chemical mediator release inhibitors are all known compounds and can be produced by known methods, respectively. Commercially available products can also be used.

本発明に係る動脈瘤の予防及び/又は治療薬は、ケミカルメディエーター遊離抑制薬と、慣用されている製剤担体とを混合することにより製造することができる。   The aneurysm preventive and / or therapeutic agent according to the present invention can be produced by mixing a chemical mediator release inhibitor and a commonly used pharmaceutical carrier.

製剤担体は、投与形態に応じて、適宜、組み合わせて用いればよく、例えば、乳糖等の賦形剤;ステアリン酸マグネシウム等の滑沢剤;カルボキシメチルセルロース等の崩壊剤;ヒドロキシプロピルメチルセルロース等の結合剤;マクロゴール等の界面活性剤;炭酸水素ナトリウム等の発泡剤;シクロデキストリン等の溶解補助剤;クエン酸等の酸味剤;エデト酸ナトリウム等の安定化剤;リン酸塩等のpH調整剤などが挙げられる。   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; binders such as hydroxypropylmethylcellulose Surfactants such as macrogol; foaming agents such as sodium bicarbonate; solubilizers such as cyclodextrin; sour agents such as citric acid; stabilizers such as sodium edetate; pH adjusters such as phosphate Is mentioned.

本発明に係る動脈瘤の予防及び/又は治療薬の投与形態としては、例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤及びカプセル剤等の経口投与剤;注射剤、軟膏剤、トローチ剤及び貼付剤等の非経口投与剤などが挙げられる。   Examples of the administration form of the 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, ointments, troches And parenteral agents such as patches and patches.

上記製剤中に含まれるケミカルメディエーター遊離抑制薬は、それぞれの薬剤において適宜定めて調製すればよい。例えば、トラニラストの場合、経口投与では成人1日当たり100mg〜1000mg、非経口投与では成人1日当たり30mg〜300mgの範囲である。   The chemical mediator release inhibitor contained in the preparation may be appropriately determined and prepared for each drug. For example, in the case of tranilast, oral administration ranges from 100 mg to 1000 mg per day for adults, and parenteral administration ranges from 30 mg to 300 mg per day for adults.

以下に本発明を実験例に基づいて、さらに詳細に説明するが、本発明はその内容に限定されるものではない。   Hereinafter, the present invention will be described in more detail based on experimental examples, but the present invention is not limited to the contents.

[実施例1]
12週齢の雄性ラット(Slc: WsRC-+/+;日本エスエルシー株式会社)を麻酔下で開腹し、血管周囲の結合組織を剥離して腹部大動脈を単離した。腎動脈分岐下部の腹部大動脈壁に滅菌綿棒を用いて0.4mol/L塩化カルシウム溶液を15分間塗布し(Basalyga DM, et al. Circulation 110:3480-3487,2004)、滅菌生理食塩水で腹腔内を洗浄後、閉腹した。トラニラスト投与群(10匹)には1%炭酸水素ナトリウム2mLに溶解したトラニラスト400mg/kg/dayを1日2回、対照群(10匹)には1%炭酸水素ナトリウム溶液2mLを1日2回、モデル作成1週間前より開始し、動脈瘤モデル作成後14日間引き続き胃管チューブを用いて経口投与した。モデル作成14日後、開腹して動脈径(瘤径)を測定した。結果を図1に示す。
[Example 1]
A 12-week-old male rat (Slc: WsRC-+ / +; Nippon SLC Co., Ltd.) was laparotomized under anesthesia, and the connective tissue around the blood vessel was peeled to isolate the abdominal aorta. Apply 0.4 mol / L calcium chloride solution to the abdominal aortic wall under the renal artery bifurcation using a sterile cotton swab for 15 minutes (Basalyga DM, et al. Circulation 110: 3480-3487, 2004) and peritoneal cavity with sterile physiological saline After washing the inside, the abdomen was closed. 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 bicarbonate solution twice a day. The test was started one week before the model was created, and was orally administered using a gastric tube for 14 days after the aneurysm model was created. After 14 days of model creation, the abdomen was opened and the artery diameter (aneurysm diameter) was measured. The results are shown in FIG.

トラニラストは、動脈瘤の発生や進展を抑制するので、動脈瘤の治療及び/又は予防薬として用いることができる。   Tranilast can be used as a therapeutic and / or prophylactic agent for aneurysms because it suppresses the occurrence and progression of aneurysms.

図1は、動脈径の拡大を示す図である。左は対照群、右はトラニラスト投与群であり、縦軸は動脈瘤モデル作成前(塩化カルシウム塗布前)の動脈径に対する拡大%を表し、**はスチューデントT検定によるP<0.01の有意差を表す。FIG. 1 is a diagram showing the enlargement of the artery diameter. The left is the control group, the right is the tranilast administration group, the vertical axis represents the percentage of enlargement relative to the artery diameter before aneurysm model creation (before calcium chloride application), and ** is significant with P <0.01 by Student T test Represents the difference.

Claims (4)

ケミカルメディエーター遊離抑制薬を有効成分とする動脈瘤の予防及び/又は治療薬。 An aneurysm prophylactic and / or therapeutic agent comprising a chemical mediator release inhibitor as an active ingredient. 動脈瘤が、腹部大動脈瘤であることを特徴とする請求項1の動脈瘤の予防及び/又は治療薬。 The prophylactic and / or therapeutic agent for an aneurysm according to claim 1, wherein the aneurysm is an abdominal aortic aneurysm. ケミカルメディエーター遊離抑制薬が、トラニラストであることを特徴とする請求項1又は2記載の動脈瘤の予防及び/又は治療薬。 The agent for preventing and / or treating aneurysms according to claim 1 or 2, wherein the chemical mediator release inhibitor is tranilast. トラニラストを有効成分とする腹部大動脈の予防及び/又は治療薬。 A prophylactic and / or therapeutic drug for abdominal aorta containing tranilast as an active ingredient.
JP2006193689A 2006-07-14 2006-07-14 Drugs for preventing and / or treating aneurysms Pending JP2008019221A (en)

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WO2014175287A1 (en) 2013-04-26 2014-10-30 国立大学法人 京都大学 Medicinal composition for inhibiting formation and/or enlargement of cerebral aneurysm or shrinking same

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CA2696041A1 (en) * 2007-08-15 2009-02-19 Kyorin Pharmaceutical Co., Ltd. Preventive, inhibitor or remedy for cerebral aneurysm comprising ibudilast as an active ingredient
US20220395476A1 (en) * 2019-09-30 2022-12-15 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Drug for treating artery-related diseases, and use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014175287A1 (en) 2013-04-26 2014-10-30 国立大学法人 京都大学 Medicinal composition for inhibiting formation and/or enlargement of cerebral aneurysm or shrinking same
US9629834B2 (en) 2013-04-26 2017-04-25 Kyoto University Medicinal composition for inhibiting formation and/or enlargement of cerebral aneurysm or shrinking same

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