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WO2011007565A1 - PRÉVENTION ET TRAITEMENT D'UN ANÉVRISME À L'AIDE D'INHIBITEUR DE PPARγ - Google Patents

PRÉVENTION ET TRAITEMENT D'UN ANÉVRISME À L'AIDE D'INHIBITEUR DE PPARγ Download PDF

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Publication number
WO2011007565A1
WO2011007565A1 PCT/JP2010/004570 JP2010004570W WO2011007565A1 WO 2011007565 A1 WO2011007565 A1 WO 2011007565A1 JP 2010004570 W JP2010004570 W JP 2010004570W WO 2011007565 A1 WO2011007565 A1 WO 2011007565A1
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WIPO (PCT)
Prior art keywords
aneurysm
pparγ
prevention
aortic
aortic aneurysm
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PCT/JP2010/004570
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English (en)
Japanese (ja)
Inventor
瀬藤光利
財満信宏
海野直樹
田中宏樹
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国立大学法人浜松医科大学
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Priority to JP2011522734A priority Critical patent/JPWO2011007565A1/ja
Publication of WO2011007565A1 publication Critical patent/WO2011007565A1/fr

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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
    • 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

Definitions

  • the present invention relates to the prevention and / or treatment of aneurysms.
  • An aortic aneurysm is a state in which a part of the aorta is abnormally expanded like an aneurysm, and abdominal aortic aneurysm (AAA) is a disease that is seen in 5-10% of men over 65 years old.
  • AAA abdominal aortic aneurysm
  • An aortic aneurysm is almost asymptomatic unless it ruptures, and does not interfere with daily life. However, if it is left unattended, it gradually expands and becomes more easily ruptured as it expands. Once the aneurysm ruptures, there is a risk of life, and the lifesaving rate is 30-50%.
  • an aneurysm Since an aneurysm is almost asymptomatic until it ruptures, an effective treatment for an aneurysm can be said to prevent this rupture and improve the prognosis of life.
  • the risk of rupture increases as the diameter of the aneurysm increases. Therefore, for small diameter aneurysms with little possibility of rupture of aneurysm, it is considered that a drug having an “expansion prevention” effect that does not expand further has a therapeutic effect.
  • An object of the present invention is to provide a method for preventing and / or treating an aneurysm using a drug effective for the prevention and treatment of an aneurysm. More specifically, the present invention relates to the overall treatment of an aneurysm that has occurred, and an object thereof is to provide a drug for preventing and / or treating an aneurysm that can prevent the progression of the aneurysm pharmacologically.
  • the present inventors have discovered that fibroblasts at the aneurysm site express PPAR ⁇ and differentiate into adipocytes, and substances having PPAR ⁇ inhibitory activity are effective as aneurysm prevention and / or treatment agents As a result, the present invention has been completed.
  • the present invention provides an agent for preventing and / or treating aneurysm progression comprising a substance having PPAR ⁇ inhibitory activity as an active ingredient.
  • the aneurysm is preferably an aortic aneurysm including a true aortic aneurysm and a dissecting aortic aneurysm.
  • the aneurysm is an aortic aneurysm comprising an abdominal aortic aneurysm and a thoracic aortic aneurysm.
  • the aneurysm preventive and / or therapeutic agent of the present invention is formulated for oral administration or formulated for injection.
  • the present invention provides a method for selecting a candidate substance for an aneurysm progression prevention and / or treatment agent.
  • This method involves contacting a test substance with a cell that expresses PPAR ⁇ , measuring the expression of PPAR ⁇ , and in the presence of the test substance, when the expression of PPAR ⁇ is lower than in the absence, the test
  • Each step of selecting a substance as a candidate substance for an aneurysm progression prevention and / or treatment agent is included.
  • the present invention prevents and / or treats aneurysm progression by administering a compound having PPAR ⁇ inhibitory activity to a mammal in need of prevention and / or treatment of aneurysm progression.
  • a method Provides a method.
  • the present invention provides a compound having PPAR ⁇ inhibitory activity for use in the prevention and / or treatment of aneurysm progression.
  • administration of a PPAR ⁇ inhibitor can prevent the onset and expansion of an aneurysm and prevent rupture, thereby improving the life prognosis of an aneurysm patient.
  • FIG. 1 shows a CT image of the abdominal aorta to be removed, and the distribution of cholesterol ester (CE), triglyceride (TG) and phosphatidylcholine (PC) in the removed aortic wall tissue.
  • Figure 2 shows the total cholesterol (TC) content and triglycerides (TG) in the intima & media and adventitia of the subrenal artery (infrarenal aortic neck) and aneurysm sac of the aortic wall ) Indicates the amount.
  • FIG. 1 shows a CT image of the abdominal aorta to be removed, and the distribution of cholesterol ester (CE), triglyceride (TG) and phosphatidylcholine (PC) in the removed aortic wall tissue.
  • Figure 2 shows the total cholesterol (TC) content and triglycerides (TG) in the intima & media and adventitia of the subrenal artery (infrarenal aortic neck)
  • FIG. 3 shows an Elastica-Wangieson-stained and Picrosirius red-stained image of the sub-renal artery (neck) and aneurysm (sac) outer skin tissue, and the localization of fibroblast markers and PPAR ⁇ 2.
  • FIG. 4 shows the HemB value, the vasa vasorum tissue section staining diagram, and the patency rate at the subrenal artery (neck) and aneurysmization site (sac).
  • FIG. 5 shows the amount of TG and the number of adipocytes (adipocytes) in the blood vessel wall of a model animal with vascular wall circulation disorder.
  • FIG. 1 shows an Elastica-Wangieson-stained and Picrosirius red-stained image of the sub-renal artery (neck) and aneurysm (sac) outer skin tissue, and the localization of fibroblast markers and PPAR ⁇ 2.
  • FIG. 4 shows the HemB value, the vasa vasorum
  • FIG. 6 shows the TG / PC, the amount of TG, and the number of adipocytes when a PPAR ⁇ inhibitor was administered to a vascular wall circulation disorder model animal.
  • FIG. 7 shows the amount of TG when a PPAR ⁇ inhibitor is administered to a vascular wall circulation disorder model animal.
  • the inventors of the present invention have repeatedly conducted observations applying mass microscopy to human abdominal aortic aneurysms and basic studies using rat animal experimental models, with the aim of developing effective aneurysm prevention and treatment drugs. As a result, we found PPAR ⁇ expressed in fibroblasts in the outer arterial membrane as a key factor for weakening the arterial wall.
  • PPAR peroxisome proliferator-activated receptor
  • PPAR ⁇ 2 which has a subtype and is involved in the present invention, enhances the insulin sensitivity of tissues and has become one of the targets for the treatment of diabetes, and has been pointed out to be involved in the immune process.
  • metabolic syndrome As the importance of metabolic syndrome in recent years spreads, it is one of the molecules expected as a target for improvement of lifestyle-related diseases in modern society.
  • the most notable in the present invention is to transform cell functions into adipocytes by activation.
  • the present inventors observed an abdominal aortic aneurysm of a surgical patient by mass microscopy and further examined by HE staining and the like, and confirmed that an innumerable fat cell was accumulated in the lesion.
  • fibroblasts expressed PPAR ⁇ and differentiated into adipocytes, suggesting the involvement of PPAR ⁇ in the pathology of abdominal aortic aneurysms.
  • PPAR ⁇ adipates outer membrane fibroblasts, which play an important role in maintaining blood vessel strength in the arterial wall, and lowers blood vessel wall strength, which leads to an increase in aneurysm diameter and rupture. It is done.
  • PPAR ⁇ inhibition suppresses adipogenesis of fibroblasts in vivo as well as in vitro in a plurality of animal models.
  • administration of a PPAR ⁇ inhibitor is useful as a pharmacotherapy for the prevention or treatment of aneurysms.
  • the action of factors that promote the adipogenesis of fibroblasts constituting the arterial wall is inhibited, and the adipogenesis of the arterial wall is directly suppressed, This suppresses the decrease in blood vessel wall strength and prevents the enlargement and rupture of the aneurysm diameter.
  • the aneurysm referred to in the present invention usually includes all pathological conditions called aneurysms.
  • Aneurysms are classified in various ways depending on their origin, their cause, or their shape. For example, the classification according to their origin includes aortic aneurysms including thoracic aortic aneurysms and abdominal aortic aneurysms, cerebral aneurysms and renal aneurysms An aneurysm or an aneurysm that occurs in a peripheral artery is exemplified. Depending on the wall structure, it is classified as a true aneurysm, a dissecting aneurysm, a pseudoaneurysm, or the like.
  • the classification by cause includes infectious aneurysms typified by arteriosclerotic aneurysms, inflammatory aneurysms, traumatic aneurysms or bacterial aneurysms, fungal aneurysms, syphilitic aneurysms, and the like.
  • infectious aneurysms typified by arteriosclerotic aneurysms, inflammatory aneurysms, traumatic aneurysms or bacterial aneurysms, fungal aneurysms, syphilitic aneurysms, and the like.
  • classification by shape include saccular aneurysm and spindle-shaped aneurysm. The present invention is not particularly limited to any of these.
  • Aneurysm prevention refers to “expansion prevention” that prevents further enlargement of small-diameter aneurysms that are unlikely to rupture the aneurysm, and further prevents weakening of the vascular wall. Prevention also includes prevention.
  • the substance having PPAR ⁇ inhibitory activity may be used alone or mixed with a solubilizer, a bulking agent, an excipient or a carrier, and injected, tablet, granule, fine granule, powder, capsule, patch , Ointments, sprays, solutions, sustained-release preparations and the like.
  • a solubilizer such as an excipient or a carrier
  • a pharmaceutically acceptable one is selected, and its kind and composition are determined by the administration route and the administration method.
  • saccharides such as sodium chloride, glucose and mannitol are generally desirable.
  • starch, lactose, crystalline cellulose, magnesium stearate and the like are desirable.
  • the administration route is systemically administered orally or parenterally by injection or external preparation.
  • it may be administered directly to the lesion or the vicinity of the lesion using an ointment, solution, patch, spray, etc., or may be administered remotely to the lesion or the vicinity of the lesion using a catheter, etc.
  • the drug may be bound to a graft or an integrated stent graft.
  • it may be administered in a sustained release manner by placing it in or near the lesion.
  • an aneurysm preventive agent oral administration is particularly preferable.
  • an aneurysm therapeutic agent not only an oral agent but also an injection or a drug-bonded stent graft is desirable depending on the risk of rupture.
  • candidate substances for the prevention and / or treatment of aneurysm progression can be selected using the expression of PPAR ⁇ as an index.
  • the test substance is brought into contact with cells expressing PPAR ⁇ , and the expression of PPAR ⁇ is measured.
  • Expression can be measured by designing a probe or primer based on the sequence of the gene encoding PPAR ⁇ and measuring the amount of mRNA in the cell.
  • the amount of PPAR ⁇ protein in the cell may be measured using an antibody against PPAR ⁇ . The principles and techniques of these measurement methods are well known in the art. If the expression of PPAR ⁇ is lower in the presence of the test substance than in the absence, the test substance is considered a candidate substance for the prevention and / or treatment of aneurysm progression.
  • Example 1 Open surgery using matrix-assisted laser desorption / ionization imaging mass spectrometry (MALDI-IMS), a recently developed non-targeted metabolomic molecular imaging method. A tissue sample of the wall of the abdominal aortic aneurysm (artificial blood vessel replacement) was observed.From MALDI-IMS, a patient with abdominal aortic aneurysm who underwent open surgery, from the subrenal artery to the left and right iliac bifurcation The distribution of metabolites in the aortic wall up to was investigated.
  • MALDI-IMS matrix-assisted laser desorption / ionization imaging mass spectrometry
  • the leftmost image is an image obtained by computed tomography (CT).
  • CT computed tomography
  • the maximum diameter of the aneurysm was measured by preoperative contrast CT.
  • the specimen to be extracted was designed as described below from a three-dimensional (3D) -multidetector (MD) CT. That is, the aorta from the non-expanded part of the part about 2 cm below the renal artery to the right and left iliac artery bifurcation was excised in a strip shape on the midline.
  • the section 1 is the most central side of the excised specimen, and is the aortic wall where no pathological aneurysm is observed.
  • the section 3 is a portion having the maximum aneurysm diameter.
  • Section 2 is an intermediate part between the two.
  • HE staining and fat staining correspond to MALDI-IMS tissue sections.
  • PC phosphatidylcholine
  • CE cholesterol ester
  • TG was quantified in 10 cases of abdominal aortic aneurysm (AAA). The results are shown in FIG. The amount of TG in the outer membrane of the largest aneurysm wall was 6.1 times higher than that in the inner-media. There was no difference between the adventitia and intima in the non-aneurysm under the renal artery. The adventitia of the largest aneurysm wall was 5 times more TG than the normal adrenal aortic wall adventitia. These results were consistent with the results obtained with IMS.
  • Example 2 In order to clarify the mechanism in which many cells containing fat droplets exist in the aneurysm, a tissue specimen of the aortic aneurysm wall was stained (FIG. 3). When the section of the outer membrane dyed with Elastica-Wangeson staining or Picrosirius red staining was observed, the structure of collagen fibers and elastic fibers was maintained in the non-lumped area (neck), whereas Adipocytes were observed in the sac, where the structure of elastic fibers and collagen fibers broke down, and the area of collagen fibers and the number of elastic fibers decreased. Furthermore, fibroblast marker (prolyl-4-hydroxylase) -positive cells expressing PPAR ⁇ 2 were present at the aneurysm site.
  • fibroblast marker prolyl-4-hydroxylase
  • PPAR ⁇ 2 was not expressed in the outer membrane fibroblasts of the normal part of the same specimen. From the above, it was revealed that fibroblasts expressed PPAR ⁇ at the site of aneurysm and became adipocytes.
  • Example 3 We measured the HemB value, which is an index of circulatory disturbance, and the patency rate of the vegetative blood vessels (vasa vasorum) responsible for circulation in the outer membrane region by MALDI-IMS, and examined the presence or absence of circulatory disturbance in the aneurysm. HemB, which is a molecule constituting hemoglobin, was obtained from integration of HemB ionic strength obtained by MALDI-IMS. The patency rate of vasa vasorum was measured by the ratio of the area of the blood vessel lumen to the area surrounded by the perivascular connective tissue after dyeing with HE staining. The results are shown in FIG.
  • the HemB value was lower at the aneurysm site than the non-aneurysm part under the renal artery, and a difference was observed in the blood circulation between the two.
  • the vegetative blood vessels were narrowed and occluded due to marked fiber growth around the blood vessels at the aneurysm.
  • the patency rate was 95% at the subrenal artery site and 27% at the aneurysm site, significantly decreasing at the aneurysm site. From the above, it was suggested that lipid accumulation starts from circulatory disturbance.
  • Example 4 In order to confirm that fat cells are deposited on the blood vessel wall due to vascular wall circulation disorder, an experiment using an animal model was performed. A male rat (Slc: WsRC-+ / +; Nippon SLC Co., Ltd.) weighing 700-900 g was incised in the midline of the neck under anesthesia, and the connective tissue around the blood vessel was peeled to expose one carotid artery. A peripheral vascular wall circulatory disturbance model was created by ligating the central 5 cm from the internal and external carotid artery branches with 4-0 silk thread.
  • the arterial wall was removed, and the amount of triglyceride contained in the vascular tissue was measured with a mass microscope and a colorimetric method (FIG. 5). Compared with the subject group, the lipid and adipocytes in the vascular wall were significantly elevated in the vascular wall circulation disorder model.
  • Examples 1 to 4 indicate that adipocyte deposition on the blood vessel wall is caused by the expression of PPAR ⁇ in fibroblasts starting from circulatory disturbance.
  • Example 5 Next, it was investigated whether PPAR ⁇ inhibitors show an effect of suppressing adipocyte deposition on blood vessel walls.
  • a male rat (Slc: WsRC-+ / +; Nippon SLC Co., Ltd.) weighing 700-900 g was incised in the midline of the neck under anesthesia, and the connective tissue around the blood vessel was peeled to expose one carotid artery.
  • a peripheral vascular wall circulatory disturbance model was created by ligating the central 5 cm from the internal and external carotid artery branches with 4-0 silk thread.
  • a PPAR ⁇ inhibitor (GW9662, G3335) was administered 1.5 ⁇ g daily from 3 days before surgery until 14 days after surgery to remove the artery.
  • FIG. 6 shows the results of the ratio of TG and PC, the amount of TG on the blood vessel wall (TG content), and the deposition of adipocytes (adipocyte) for the group (model) and control group (control) administered GW9662.
  • FIG. 7 shows the results of the TG content of the blood vessel wall for the group administered with G3335 (malperfusion) and the control group (contralateral).
  • CMC is carboxymethylcellulose (G3335 dissolving drug).
  • the TG amount in the blood vessel wall and the deposition of adipocytes showed a significant decrease. This indicates that the inhibition of PPAR ⁇ could significantly suppress outer membrane adipocyte deposition involved in the progression of aortic aneurysms. Both GW9662 and G3335 PPAR ⁇ inhibitors suppressed blood vessel wall triglyceride levels and adipocyte deposition.

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Abstract

La présente invention porte sur un médicament pour prévenir et/ou traiter un anévrisme, lequel médicament comprend un inhibiteur de PPARγ comme ingrédient actif. Il a été récemment trouvé que, en raison d'une insuffisance circulatoire à l'intérieur d'une paroi vasculaire, des fibroblastes constituant l'adventice anévrismal aortique abdominal expriment PPARγ et se différencient en cellules de type adipocyte, ce qui provoque une accumulation anormale de triglycérides dans la paroi vasculaire et affaiblit la paroi vasculaire. L'inhibiteur de PPARγ peut corriger entièrement ces facteurs et empêcher le début, le progrès ou la rupture de l'anévrisme. Ainsi, le pronostic vital d'un patient avec un anévrisme peut être amélioré.
PCT/JP2010/004570 2009-07-15 2010-07-14 PRÉVENTION ET TRAITEMENT D'UN ANÉVRISME À L'AIDE D'INHIBITEUR DE PPARγ WO2011007565A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014175287A1 (fr) * 2013-04-26 2014-10-30 国立大学法人 京都大学 Composition médicinale destinée à empêcher la formation et/ou l'expansion d'un anévrisme cérébral ou réduire un tel anévrisme
JP2015072237A (ja) * 2013-10-04 2015-04-16 株式会社島津製作所 質量分析を用いたアンモニア測定方法
WO2020256095A1 (fr) 2019-06-21 2020-12-24 学校法人近畿大学 Composition pharmaceutique pour la prophylaxie d'un anévrisme aortique et aliment traité
WO2022124390A1 (fr) * 2020-12-11 2022-06-16 学校法人近畿大学 Composition pharmaceutique pour la prévention et le traitement d'un anévrisme aortique et aliment traité

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DENG, G. ET AL.: "Tryptophan-containing dipeptide derivatives as potent PPARgamma antagonists: design, synthesis, biological evaluation, and molecular modeling", EUR J MED CHEM, vol. 43, no. 12, 2008, pages 2699 - 2716, XP025714716, DOI: doi:10.1016/j.ejmech.2008.01.032 *
YASUNARI SAKOMURA ET AL.: "Daidomyaku Nojo Chumaku Hensei ni Kansuru Bunshi Byori Soshikigakuteki Kenkyu -Daidomyakuryu.Kairi no Yakubutsuteki Yoboho no Kaihatsu", JAPAN RESEARCH PROMOTION SOCIETY FOR CARDIOVASCULAR DISEASE KENKYU GYOSEKISHU, no. 18, 2003, pages 19 - 22 *
YE, F. ET AL.: "The dipeptide H-Trp-Glu-OH shows highly antagonistic activity against PPARgamma: bioassay with molecular modeling simulation", CHEMBIOCHEM, vol. 7, no. 1, 2006, pages 74 - 82 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014175287A1 (fr) * 2013-04-26 2014-10-30 国立大学法人 京都大学 Composition médicinale destinée à empêcher la formation et/ou l'expansion d'un anévrisme cérébral ou réduire un tel anévrisme
JPWO2014175287A1 (ja) * 2013-04-26 2017-02-23 国立大学法人京都大学 脳動脈瘤の形成および／または増大の抑制若しくは縮小用医薬組成物
US9629834B2 (en) 2013-04-26 2017-04-25 Kyoto University Medicinal composition for inhibiting formation and/or enlargement of cerebral aneurysm or shrinking same
JP2015072237A (ja) * 2013-10-04 2015-04-16 株式会社島津製作所 質量分析を用いたアンモニア測定方法
WO2020256095A1 (fr) 2019-06-21 2020-12-24 学校法人近畿大学 Composition pharmaceutique pour la prophylaxie d'un anévrisme aortique et aliment traité
JPWO2020256095A1 (fr) * 2019-06-21 2020-12-24
JP7236119B2 (ja) 2019-06-21 2023-03-09 学校法人近畿大学 大動脈瘤の予防用医薬組成物および加工食品
WO2022124390A1 (fr) * 2020-12-11 2022-06-16 学校法人近畿大学 Composition pharmaceutique pour la prévention et le traitement d'un anévrisme aortique et aliment traité
JP7541674B2 (ja) 2020-12-11 2024-08-29 学校法人近畿大学 大動脈瘤の予防および治療用医薬組成物および加工食品

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