JP6684264B2 - 心不全の予防又は治療のための医薬 - Google Patents
心不全の予防又は治療のための医薬 Download PDFInfo
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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Description
(1)4−[5−(ピリジン−4−イル)−1H−1,2,4−トリアゾール−3−イル]ピリジン−2−カルボニトリル(一般名:トピロキソスタット)を有効成分とする、心不全の予防又は治療のための医薬。
(2)前記心不全が、慢性心不全、慢性心不全の急性増悪、及び急性心不全からなる群から選択される(1)に記載の医薬。
[研究方法]
種々の基礎心疾患により、心不全重症度分類NYHAII〜IVに相当する患者で、かつキサンチンオキシダーゼ阻害薬(XO阻害剤)の類薬であるアロプリノール又はフェブキソスタット投与中の患者を対象に、それまでの心不全治療を継続した上で、アロプリノール又はフェブキソスタットからトピロキソスタット投与に切り替えることによって、心機能マーカーである血中BNP値に対する影響を評価した。また、類薬非投与の患者についても、同様に、トピロキソスタット投与による血中BNP値低下の影響を6か月間に亘り評価した。尚、トピロキソスタット投与中は、特に血中BNP値に影響するとされる利尿剤等の新たな追加や用法・用量の変更などは行わなかった。尚、対象とした患者は15例で男性13例、女性2例であり、年齢は67-94歳であった。そのうち、トピロキソスタット投与前の類薬別症例13例の内訳は、アロプリノール2例、フェブキソスタット11例であった。類薬非投与患者は2例であった。また、トピロキソスタット投与前のアロプリノール又はフェブキソスタット投与期間中(3か月間)の血中BNP値は有意な変動を示さなかった。
対象とした15例全例のトピロキソスタット投与による血中BNP値の推移は、投与前469±278pg/ml(平均±SD)、投与3か月後には296±232pg/mlへと著明に低下し、投与6か月後(最終評価時)には254±129pg/mlとさらに低下した。15例の最終評価時における投与開始前からの血中BNP値の変化量の平均値とその95%信頼区間は、-215±238pg/ml(-347pg/ml, -83pg/ml)と有意に低下した(t検定、P=0.0036)。
同様に、類薬であるアロプリノール又はフェブキソスタット投与中の心不全患者13例を対象にトピロキソスタットに切り替えた場合の血中BNP値の推移は、投与前431±272pg/ml(平均±SD)から、投与3か月後には293±243pg/mlへと著明に低下し、投与6か月後(最終評価時)には248±136pg/mlとさらに低下した。
また、類薬非投与の患者2例の投与前から投与6か月後(最終評価時)の血中BNP値の変化量は、各々-184pg/ml及び-660pg/mlと顕著な低下を示した。
対象とした15例の血中BNP値のトピロキソスタット投与後の推移を図1に示した。心機能マーカーである血中BNP値の変化量は、投与3か月という早期に平均で-173pg/mlと45%も低下させた。中等度以上の心不全ではBNP 10pg/mlの上昇で心血管死亡率が6年あたり3%ずつ上昇するとの報告(非特許文献2)からすると、トピロキソスタット投与による血中BNP値低下量は驚くべきことである。また、投与前値の平均値469pg/mlはNYHA分類ではおよそIII度に相当する心不全重症度であり、3、6か月後の血中BNP値の各々の平均値296pg/ml、254pg/mlはおよそII度に相当する。この血中BNP値の低下量(平均-215pg/ml)は心不全重症度(NYHA重症度)を1度相当改善したという点で、特に心血管死亡率の低下の可能性など医療上のメリットのみならず、再入院率の低下の可能性等、医療経済的なメリットも大きいことが示唆された。
従来治療での血中BNP値低下が不十分な患者に対しても、トピロキソスタットの併用、あるいは類薬からの切替により、優れた血中BNP値低下、即ち、心不全に対する予防及び治療効果が得られた。これらの効果は、当業者の予測を遙かに超えたものである。
Claims (2)
- 4−[5−(ピリジン−4−イル)−1H−1,2,4−トリアゾール−3−イル]ピリジン−2−カルボニトリル(一般名:トピロキソスタット)を有効成分とする、心不全の予防又は治療のための医薬。
- 前記心不全が、慢性心不全、慢性心不全の急性増悪、及び急性心不全からなる群から選択される請求項1記載の医薬。
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JP2015028707 | 2015-02-17 | ||
JP2015028707 | 2015-02-17 | ||
PCT/JP2016/054392 WO2016133069A1 (ja) | 2015-02-17 | 2016-02-16 | 心不全の予防又は治療のための医薬 |
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JPWO2016133069A1 JPWO2016133069A1 (ja) | 2018-01-25 |
JP6684264B2 true JP6684264B2 (ja) | 2020-04-22 |
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WO (1) | WO2016133069A1 (ja) |
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Publication number | Priority date | Publication date | Assignee | Title |
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DK1471065T3 (da) * | 2002-01-28 | 2008-03-25 | Fuji Yakuhin Co Ltd | Hidtil ukendt 1,2,4-triazolforbindelse |
US20040122067A1 (en) * | 2002-12-20 | 2004-06-24 | Lin Zhao | Treatment of chronic heart failure |
JP2008088107A (ja) * | 2006-10-02 | 2008-04-17 | Fujiyakuhin Co Ltd | 新規ピリダジン誘導体 |
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- 2016-02-16 WO PCT/JP2016/054392 patent/WO2016133069A1/ja active Application Filing
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JPWO2016133069A1 (ja) | 2018-01-25 |
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