JP2008255059A - ミトコンドリア障害脳疾患治療剤及び診断剤 - Google Patents
ミトコンドリア障害脳疾患治療剤及び診断剤 Download PDFInfo
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- JP2008255059A JP2008255059A JP2007099508A JP2007099508A JP2008255059A JP 2008255059 A JP2008255059 A JP 2008255059A JP 2007099508 A JP2007099508 A JP 2007099508A JP 2007099508 A JP2007099508 A JP 2007099508A JP 2008255059 A JP2008255059 A JP 2008255059A
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- iron
- cerebral
- disease
- ferrous
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- MDXRFOWKIZPNTA-UHFFFAOYSA-L butanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)CCC([O-])=O MDXRFOWKIZPNTA-UHFFFAOYSA-L 0.000 claims description 2
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 claims description 2
- VEPSWGHMGZQCIN-UHFFFAOYSA-H ferric oxalate Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O VEPSWGHMGZQCIN-UHFFFAOYSA-H 0.000 claims description 2
- IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical compound [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 claims description 2
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- 239000011773 ferrous fumarate Substances 0.000 claims description 2
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- 229960001604 ferrous succinate Drugs 0.000 claims description 2
- 150000003278 haem Chemical class 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- ATEAWHILRRXHPW-UHFFFAOYSA-J iron(2+);phosphonato phosphate Chemical compound [Fe+2].[Fe+2].[O-]P([O-])(=O)OP([O-])([O-])=O ATEAWHILRRXHPW-UHFFFAOYSA-J 0.000 claims description 2
- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 claims description 2
- YPJCVYYCWSFGRM-UHFFFAOYSA-H iron(3+);tricarbonate Chemical compound [Fe+3].[Fe+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O YPJCVYYCWSFGRM-UHFFFAOYSA-H 0.000 claims description 2
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Abstract
【解決手段】
(A)一般式(1)
R2R1NCH2COCH2CH2COR3 (1)
(式中、R1及びR2は各々独立に、水素原子、アルキル基、アシル基、アルコキシカルボニル基、アリール基又はアラルキル基を示し;R3はヒドロキシ基、アルコキシ基、アシルオキシ基、アルコキシカルボニルオキシ基、アリールオキシ基、アラルキルオキシ基又はアミノ基を示す。)
で表されるδ−アミノレブリン酸、その誘導体又はそれらの塩、と(B)鉄化合物とを組み合せてなることを特徴とするミトコンドリア障害脳疾患治療剤。
【選択図】なし
Description
しかし、これらの治療法を施行しても、施行が遅れたり、施行の誤認により、何らかの後遺症(意識障害、運動知覚障害、高次脳機能障害、記銘力障害、情動症障害)が残る場合があり、血栓溶解治療と同時に疾患部位を治療する薬剤は存在していないのが現状である。
R2R1NCH2COCH2CH2COR3 (1)
(式中、R1及びR2は各々独立に、水素原子、アルキル基、アシル基、アルコキシカルボニル基、アリール基又はアラルキル基を示し;R3はヒドロキシ基、アルコキシ基、アシルオキシ基、アルコキシカルボニルオキシ基、アリールオキシ基、アラルキルオキシ基又はアミノ基を示す。)
で表されるδ−アミノレブリン酸、その誘導体又はそれらの塩、と(B)鉄化合物とを組み合せてなることを特徴とするミトコンドリア障害脳疾患治療剤を提供するものである。
(脳梗塞モデルラットの作成)
Wister7週齢、雄、ラットの右中大脳動脈に直径1.5mmナイロン糸を留置し、血流を2時間遮断し、その後ナイロン糸を抜去し、右中大脳動脈閉塞モデル(脳梗塞モデルラット)を作成した。
作成した中大脳動脈腹閉塞モデルラットは、作成前、作成直後(0日目)、作成後1日目、3日目、5日目、7日目、10日目、14日目にNSS(Neurological Severity Scores:神経重症度スコア)に従って評価した。図1に示すように作成したモデルラット(6匹)が重度の脳梗塞状態を示していることを確認した。
中大脳動脈腹閉塞モデルラット作成して6時間、12時間、24時間、42時間後に、それぞれ別々のモデルラットにδ−アミノレブリン酸塩酸塩を生理食塩水に溶解しラットの体重1kgあたり100mgとなるように腹腔投与した。投与4時間後、脳内に405nmの蛍光をあて赤色光部位を全てのモデルラットで観察し、δ−ALAが代謝されてプロトポルフィリンIXに変換されたことを確認した。また、赤色光部位が脳梗塞状態であることも確認した。同様の実験を正常ラットにおいても行ったが、脳内に405nmの蛍光をあてても赤色光部位を確認することはできなかった。従って、本発明の脳疾患診断剤は、術中に疾患組織と正常組織とを明確に判別できる診断剤であることが分かった。
脳梗塞モデルラットであることをNSSで確認した後、ラットを断頭し、直ちに脳を取り出した。脳をカミソリの刃を用いて厚さ2〜3mmの一定の断面で切断した。ミトコンドリア活性染色剤であるTTC(2,3,5−triphenyltetrazolium hydrochloride)の生食溶液(2%)の中で37℃、30分間インキュベートし、直ちに割面の写真を撮影し、梗塞範囲を記録した。図2により、ミトコンドリア活性を有するところは赤く染色され、ミトコンドリア活性がないところは白くなっていることがわかり、右中大脳動脈閉塞を起こしているところが白くなっていることを確認した。
実施例1で作成した一過性中大脳動脈閉塞モデルのラットを用いて、1)閉塞直後に5−ALAを体重1kgあたり100mgとなるように腹腔内投与し、2時間後含糖酸化鉄(商品名フェジン)を体重1kgあたり2mgを静脈内投与した群(3匹)と、2)閉塞直後に生理食塩水を腹腔内投与し、2時間後に生理食塩水を静脈内投与した群(3匹)の2群で比較した。
モデル作成前、作成3時間後、1日後、3日後、5日後、7日後に各々、NSSの評価と体重測定を行った。図3のように、2)群に比べて1)群では、3日後より6〜8点に改善し経過した。また体重については2群で有意な差はみられなかった(図4)。以上の結果より、δ−アミノレブリン酸塩酸塩と鉄化合物によるミトコンドリア障害脳疾患治療剤としての効果が確認された。
Claims (5)
- (A)一般式(1)
R2R1NCH2COCH2CH2COR3 (1)
(式中、R1及びR2は各々独立に、水素原子、アルキル基、アシル基、アルコキシカルボニル基、アリール基又はアラルキル基を示し;R3はヒドロキシ基、アルコキシ基、アシルオキシ基、アルコキシカルボニルオキシ基、アリールオキシ基、アラルキルオキシ基又はアミノ基を示す。)
で表されるδ−アミノレブリン酸、その誘導体又はそれらの塩、と(B)鉄化合物とを組み合せてなることを特徴とするミトコンドリア障害脳疾患治療剤。 - (B)鉄化合物が、塩化第二鉄、三二酸化鉄、鉄クロロフィリンナトリウム、フェリチン鉄、クエン酸第一鉄、クエン酸鉄ナトリウム、クエン酸鉄アンモニウム、フマル酸第一鉄、ピロリン酸第一鉄、ピロリン酸第二鉄、含糖酸化鉄、酢酸鉄、シュウ酸鉄、コハク酸第一鉄、コハク酸クエン酸鉄ナトリウム、ヘム鉄、デキストラン鉄、乳酸鉄、グルコン酸第一鉄、ジエチレントリアミン五酢酸鉄ナトリウム、ジエチレントリアミン五酢酸鉄アンモニウム、ジエチレンジアミン四酢酸鉄ナトリウム、ジエチレンジアミン五酢酸鉄アンモニウム、トリエチレンテトラアミン鉄、ジカルボキシメチルグルタミン酸鉄ナトリウム、ジカルボキシメチルグルタミン酸鉄アンモニウム、クエン酸鉄コリン、蟻酸第一鉄、蟻酸第二鉄、シュウ酸カリウム第二鉄アンモニウム、硫酸第一鉄、硫酸第二鉄、硫酸鉄アンモニウム、炭酸第二鉄、塩化第一鉄及び酸化鉄から選ばれる1種又は2種以上の化合物である請求項1記載のミトコンドリア障害脳疾患治療剤。
- ミトコンドリア障害脳疾患が、筋萎縮性側索硬化症、ミトコンドリア脳筋症、片頭痛、パーキンソン病、低酸素脳症、脳動脈硬化症、躁うつ病、慢性疲労症候群、頭蓋内圧亢進症、正常圧水頭症、クモ膜下出血後の脳血管攣縮、手術及び血管内手術時の脳虚血の防止、アテローム血栓性脳梗塞、ラクナ梗塞、心原性脳塞栓症、又はアルツハイマー症である請求項1又は2記載のミトコンドリア障害脳疾患治療剤。
- 一般式(1)
R2R1NCH2COCH2CH2COR3 (1)
(式中、R1及びR2は各々独立に、水素原子、アルキル基、アシル基、アルコキシカルボニル基、アリール基又はアラルキル基を示し;R3はヒドロキシ基、アルコキシ基、アシルオキシ基、アルコキシカルボニルオキシ基、アリールオキシ基、アラルキルオキシ基又はアミノ基を示す。)
で表されるδ−アミノレブリン酸、その誘導体又はそれらの塩を含有することを特徴とするミトコンドリア障害脳疾患診断剤。 - ミトコンドリア障害脳疾患が、筋萎縮性側索硬化症、ミトコンドリア脳筋症、片頭痛、パーキンソン病、低酸素脳症、脳動脈硬化症、躁うつ病、慢性疲労症候群、頭蓋内圧亢進症、正常圧水頭症、クモ膜下出血後の脳血管攣縮、手術及び血管内手術時の脳虚血の防止、アテローム血栓性脳梗塞、ラクナ梗塞、心原性脳塞栓症、又はアルツハイマー症である請求項4記載のミトコンドリア障害脳疾患診断剤。
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EP17193845.9A EP3281642B1 (en) | 2007-04-05 | 2008-03-27 | Diagnostic agent for mitochondrial dysfunction brain diseases |
US12/594,672 US20100120916A1 (en) | 2007-04-05 | 2008-03-27 | Therapeutic agent and diagnostic agent for mitochondrial dysfunction brain diseases |
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BRPI0810081-0A2A BRPI0810081A2 (pt) | 2007-04-05 | 2008-03-27 | Agente terapêutico e agente diagnóstico para doenças cerebrais de disfunção mitocondrial |
KR1020097020513A KR101250576B1 (ko) | 2007-04-05 | 2008-03-27 | 미토콘드리아 장애 뇌질환 치료제 및 진단제 |
AU2008239234A AU2008239234B2 (en) | 2007-04-05 | 2008-03-27 | Remedy and diagnostic for mitochondrial dysfunction brain disease |
PCT/JP2008/055959 WO2008126693A1 (ja) | 2007-04-05 | 2008-03-27 | ミトコンドリア障害脳疾患治療剤及び診断剤 |
EP08739088.6A EP2135613B1 (en) | 2007-04-05 | 2008-03-27 | Remedy for mitochondrial dysfunction brain diseases |
NZ580138A NZ580138A (en) | 2007-04-05 | 2008-03-27 | THERAPEUTIC AGENT AND DIAGNOSTIC AGENT FOR MITOCHONDRIAL DYSFUNCTION BRAIN DISEASEs |
RU2009136582/15A RU2435595C2 (ru) | 2007-04-05 | 2008-03-27 | Терапевтический агент и диагностический агент для заболеваний мозга, обусловленных дисфункцией митохондрий |
CN2008800108818A CN101678047B (zh) | 2007-04-05 | 2008-03-27 | 用于线粒体功能障碍性脑疾病的治疗剂和诊断剂 |
KR1020127034024A KR101383418B1 (ko) | 2007-04-05 | 2008-03-27 | 미토콘드리아 장애 뇌질환 치료제 및 진단제 |
US13/613,565 US8927532B2 (en) | 2007-04-05 | 2012-09-13 | Therapeutic agent and diagnostic agent for mitochondrial dysfunction brain diseases |
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Also Published As
Publication number | Publication date |
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EP2135613B1 (en) | 2017-11-22 |
CN101678047A (zh) | 2010-03-24 |
EP2135613A1 (en) | 2009-12-23 |
AU2008239234A1 (en) | 2008-10-23 |
KR101383418B1 (ko) | 2014-04-08 |
AU2008239234B2 (en) | 2012-11-08 |
KR20130004943A (ko) | 2013-01-14 |
RU2435595C2 (ru) | 2011-12-10 |
BRPI0810081A2 (pt) | 2014-10-21 |
RU2009136582A (ru) | 2011-04-10 |
CA2682855A1 (en) | 2008-10-23 |
EP2135613A4 (en) | 2010-07-21 |
CA2682855C (en) | 2015-06-23 |
WO2008126693A1 (ja) | 2008-10-23 |
NZ580138A (en) | 2011-04-29 |
US8927532B2 (en) | 2015-01-06 |
US20100120916A1 (en) | 2010-05-13 |
EP3281642A1 (en) | 2018-02-14 |
US20130011337A1 (en) | 2013-01-10 |
CN101678047B (zh) | 2013-05-22 |
EP3281642B1 (en) | 2019-05-01 |
JP5098051B2 (ja) | 2012-12-12 |
KR101250576B1 (ko) | 2013-04-03 |
KR20100014718A (ko) | 2010-02-10 |
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