{"created":"2022-01-28T01:03:09.780786+00:00","id":2005148,"links":{},"metadata":{"_buckets":{"deposit":"f0bf013b-c47b-4106-8392-aa1da802ab0a"},"_deposit":{"id":"2005148","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"2005148"},"status":"published"},"_oai":{"id":"oai:u-ryukyu.repo.nii.ac.jp:02005148","sets":["1642838403123","1642838403551:1642838407795"]},"author_link":[],"item_1617186331708":{"attribute_name":"Title","attribute_value_mlt":[{"subitem_1551255647225":"心血管薬の薬効評価システムの開発と臨床試験に向けた代替エンドポイントの評価","subitem_1551255648112":"ja"},{"subitem_1551255647225":"Sorrogate biomarker for evaluation of cardiovascular drugs","subitem_1551255648112":"en"}]},"item_1617186419668":{"attribute_name":"Creator","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"植田, 真一郎","creatorNameLang":"ja"}]},{"creatorNames":[{"creatorName":"大屋, 祐輔","creatorNameLang":"ja"}]},{"creatorNames":[{"creatorName":"浦田, 秀則","creatorNameLang":"ja"}]},{"creatorNames":[{"creatorName":"Ueda, Shinichiro","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Ohya, Yusuke","creatorNameLang":"en"}]},{"creatorNames":[{"creatorName":"Urata, Hidenori","creatorNameLang":"en"}]}]},"item_1617186476635":{"attribute_name":"Access Rights","attribute_value_mlt":[{"subitem_1522299639480":"open access","subitem_1600958577026":"http://purl.org/coar/access_right/c_abf2"}]},"item_1617186609386":{"attribute_name":"Subject","attribute_value_mlt":[{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"血管内皮機能"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"インスリン抵抗性"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"αグルコシダーゼ阻害薬"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"食後内皮機能低下"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"レニン－アンジオテンシン"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"遊離脂肪酸"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"NO"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"酸化ストレス"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"Free fatty acid"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"Endothelial function"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"Renin-angiotensin"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"Nitric Oxide"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"Post-prandial endothelial dysfunction"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"alpha glucosidase inhibitor"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"Oxidative stress"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"Insulin resistance"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"脈波伝播速度"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"PWV"},{"subitem_1522299896455":"en","subitem_1522300014469":"Other","subitem_1523261968819":"HOMA-IR"},{"subitem_1522299896455":"ja","subitem_1522300014469":"Other","subitem_1523261968819":"高脂肪食"}]},"item_1617186626617":{"attribute_name":"Description","attribute_value_mlt":[{"subitem_description":"科研費番号: 16590439","subitem_description_type":"Other"},{"subitem_description":"平成16年度～平成18年度科学研究費補助金(基盤研究(C))研究成果報告書","subitem_description_type":"Other"},{"subitem_description":"研究概要:1.抗動脈硬化薬の薬効評価モデルとしての遊離脂肪酸負荷内皮機能測定われわれは抗動脈硬化治療薬を評価する系として、ヒト遊離脂肪酸負荷時の内皮機能低下モデルを作成した。脂肪とヘパリンを静注すると、血中遊離脂肪酸濃度が5-7倍に上昇する。このときアセチルコリンの血管拡張作用は減弱することから、遊離脂肪酸上昇は血管内皮機能低下を来すことが考えられる。しかしL- NMMAの同時動注を行うとアセチルコリンの血管拡張作用減弱は認められず、遊離脂肪酸はNOの産生を選択的に阻害することが明らかになった。またビタミンC動注下にはやはりアセチルコリンの血管拡張作用は減弱せず、酸化ストレスの関与も考えられた。アセチルコリンの血管拡張作用の遊離脂肪酸上昇による減弱は、ARBロサルタンやACE阻害薬のペリンドプリルの全投与により防止された。これらの結果により遊離脂肪酸上昇はレニン-アンジオテンシン系の活性亢進から酸化ストレスの亢進を来たし、NO産生を卸制する等内皮機能を低下させることが明らかになった。またこの系を抗動脈硬化薬の薬効評価のひとつとして使用できる可能性が示唆された(論文1)。また動物実験により、遊離脂肪酸(palmitate)によるMADPH oxidaseの発現亢進など酸化ストレス亢進の機序の一部が解明されてきた(論文2)。また遊離脂肪酸上昇は血清あるいは血漿中のレニン活性、ACE活性には影響しないものの、単核球のアンジオテンシンII産生を亢進させることを見いだした(論文執筆中) 2.食事負荷による内皮機能低下モデルの開発と薬剤の効果食事負荷による食後高脂血症、食後高血糖は血管内皮機能を低下させることが知られている。検査食のひとつであるクッキーテストは耐糖能低下患者において食後の血管内皮機能を低下させる。αグルコシダーゼ阻害薬投与はクッキー負荷後の血糖、インスリンの上昇を低下させ、内皮機能の低下を防止した(論文3)。また健常人ではクッキーテストでは内皮機能は低下しないが、高脂肪負荷食により遊離脂肪酸の上昇が認められる場合、血管内皮機能が低下した(論文4)。","subitem_description_type":"Other"},{"subitem_description":"要約(欧文):1. FFA induced endothelial dysfunction in humans experimental model mimicking metabolic syndrome/insulin sensitivity and possible roles in evaluating anti atherosclerotic effect of drugs. An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction. Elevated FFA significantly reduced the response to acetylcholine without L-NMMA., but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction. Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resistance, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition inpatients with high FFA levels. Our other study in rats and isolated vessels suggest that FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatia or NADPH oxidase inhibitors. 2. Postprandial endothelial dysfunction and alpha glucosidase inhibitor We evaluated effect of acarbose on post-prandial glucose and lipid metabolism and endothelial function. Patients with impaired glucose tolerance received the single dose of 100mg of acarbose or placebo in cross-over design before test meal. Metabolic parameters including serum glucose, triglyceride, and remnant lipoprotein were measured and endothelial function was evaluated by the measurement of changes in forearm blood flow during reactive hyperemia before and after the test meal. There were significant elevation in metabolic parameters and endothelial function was significantly impaired in patients with impaired glucose tolerance but not in healthy subjects. The single dose acarbose significantly inhibited the elevation in metabolic parameters and prevented post-prandial endothelial dysfunction in patients with impaired-glucose tolerance. Our results suggest that acarbose may improve post--prandial metabolic abnormalities and, consequently, improve endothelial function in subjects with impaired glucose tolerance. On the other hand, Postprandial endothelial function in normal volunteers was impaired only after high-fat diet, but not after high-carbohydrate and standard test meal. Since such endothelial dysfunction after high-fat meal was closely correlated with FFA concentrations, postprandial 'state could be hazardous mostly through acute hyperlipacidenia in healthy subjects.","subitem_description_type":"Other"},{"subitem_description":"未公開：P.3以降(別刷論文のため)","subitem_description_type":"Other"},{"subitem_description":"研究報告書","subitem_description_type":"Other"}]},"item_1617186643794":{"attribute_name":"Publisher","attribute_value_mlt":[{"subitem_1522300295150":"ja","subitem_1522300316516":"植田真一郎"}]},"item_1617186702042":{"attribute_name":"Language","attribute_value_mlt":[{"subitem_1551255818386":"eng"}]},"item_1617186783814":{"attribute_name":"Identifier","attribute_value_mlt":[{"subitem_identifier_type":"HDL","subitem_identifier_uri":"http://hdl.handle.net/20.500.12000/13948"}]},"item_1617186920753":{"attribute_name":"Source Identifier","attribute_value_mlt":[{"subitem_1522646500366":"NCID","subitem_1522646572813":"BA82738907"}]},"item_1617187056579":{"attribute_name":"Bibliographic Information","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2007-05","bibliographicIssueDateType":"Issued"}}]},"item_1617258105262":{"attribute_name":"Resource Type","attribute_value_mlt":[{"resourcetype":"research report","resourceuri":"http://purl.org/coar/resource_type/c_18ws"}]},"item_1617265215918":{"attribute_name":"Version Type","attribute_value_mlt":[{"subitem_1522305645492":"VoR","subitem_1600292170262":"http://purl.org/coar/version/c_970fb48d4fbd8a85"}]},"item_1617605131499":{"attribute_name":"File","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_access","filename":"16590439.pdf","mimetype":"application/pdf","url":{"objectType":"fulltext","url":"https://u-ryukyu.repo.nii.ac.jp/record/2005148/files/16590439.pdf"},"version_id":"2f97c71d-8d90-401c-80bf-89b186c4830a"}]},"item_title":"心血管薬の薬効評価システムの開発と臨床試験に向けた代替エンドポイントの評価","item_type_id":"15","owner":"1","path":["1642838403123","1642838407795"],"pubdate":{"attribute_name":"PubDate","attribute_value":"2009-12-15"},"publish_date":"2009-12-15","publish_status":"0","recid":"2005148","relation_version_is_last":true,"title":["心血管薬の薬効評価システムの開発と臨床試験に向けた代替エンドポイントの評価"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2022-10-31T02:30:33.144666+00:00"}