JP2007509920A - 神経変性疾患の治療におけるヒドロキシム酸クロライドの使用 - Google Patents
神経変性疾患の治療におけるヒドロキシム酸クロライドの使用 Download PDFInfo
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
Description
以下の生物試験は、試験化合物として、(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライド・シトレートで行った。当該化学化合物は化合物Aと称することとする。
疾患の進行の程度、等尺性張力の記録、及び運動単位数のアセスメントを測定するために、後肢筋機能の生体のin vivo 電気生理アセスメントを両後肢筋中の長指伸(EDL)筋において行った。
EDLは通常速筋であるため、特徴的な疲労パターンを生じるように継続的に刺激すると直ぐに疲労する。これらの実験におけるEDLの疲労パターンを調査するため、両後肢の筋肉を250ms間40Hzにおいて、毎秒、3分間刺激し、そして筋収縮を記録した。
実験の最後に両肢のEDL筋を除去し、秤量し、そして融解イソペンタン中でスナップ凍結させた。当該筋肉は組織分析を行うまで−80℃で保管した。
生理的実験の完了後、腰髄の断面からの前角中の坐骨運動プールにおける運動ニューロンの数をカウントすることにより、運動ニューロンの生存を評価した(White, C.M.,Greensmith, L. & Vrbova, G. Repeated stimuli for axonal growth causes motoneuron death in adult rats: the effect of botulinum toxin followed by partial denervation. Neuroscience 95,1101-1109 (2000) )。マウスを深く麻酔し(4%抱水クロラール、1ml/100g体重、腹腔内)、そして4%パラホルムアルデヒドを含む固定液で経心的に灌流させた。脊髄を除去し、そして同じ固定液中で腰部領域を2時間固定(postfixed)し、スクロース(MPB中30%)において凍結保護し、そして凍結横断面をニッスル染色(ガロシアニン)で明るく対比染色した。両前角中のニッスル染色した運動ニューロンの数を光学顕微鏡下でカウントした。連続切片中の同じ細胞を2回カウントすることを避けるために、運動ニューロンの生存はレベルL2〜L5間の脊髄の腰部の全ての三番目のセクションにおける坐骨運動プールにおいて評価した。核小体が高拡大率において明確に見えるこれらのニューロンのみをカウントに入れた。
評価される全てのパラメーターのために、当該結果は独立な試料の比較のために Mann-Whitney U 検定を用いて分析した。全ての例において両側検定を使用し、そして有意性は、P<0.05に設定した。
35日齢におけるmSOD1(G93A)遺伝子導入マウスは、腰部運動ニューロン変性の顕微鏡的特徴をすでに示し、110日齢までの後肢麻痺は明らかである。mSOD1(G93A)遺伝子導入マウスが当該疾患の後期になると、120日齢において、後肢筋機能における化合物Aでの治療効果、並びに運動単位及び運動ニューロンの生存を評価した。
野生型マウスにおいて、通常、EDL筋中に28+/−0.6(平均値+/−S.E.M、n=11)の運動単位が存在する。120日齢のmSOD1(G93A)遺伝子導入マウスにおいては、たった8.3+/−0.7(平均値+/−S.E.M、n=10)の運動単位が存在した。しかしながら、化合物Aで処理したmSOD1(G93A)遺伝子導入マウスにおいては、運動単位の生存において有意な向上が存在し、120日齢において、14.3+/−0.6(平均値+/−S.E.M、n=10)の運動単位が生存した(p=0.003)。
i)EDL筋の半緩和時間
単収縮張力の記録から、我々は処理及び未処理mSOD1(G93A)遺伝子導入マウスにおいて、いくつかのEDL筋の収縮特徴を調査した。EDLは、通常、速性、疲労性筋肉であり、そして野生型マウスのEDLの半緩和時間、筋肉が収縮後弛緩するまでにかかる時間の長さは、25.8ms+/−2.4(平均値+/−S.E.M、n=10)である。一方、未処理マウスにおいては、半緩和時間は除神経及び筋萎縮の結果を示し、そして43.3ms+/−6.93(平均値+/−S.E.M、n=10)であった。化合物Aで処理したマウスにおいては、半緩和時間は有意に向上し、32.2ms+/−1.80(平均値+/−S.E.M、n=10)であった(p=0.030)。
EDLは通常速筋であるため、特徴的な疲労パターンを生じるように継続的に刺激すると直ぐに疲労する。EDL筋の疲労パターンは、野生型、mSOD1(G93A)遺伝子導入マウス、及び処理型mSOD1(G93A)遺伝子導入マウスにおいて検査した。3分間の刺激後の張力における低下が測定され、そして疲労指標(FI)が計算された。120日齢のmSOD1(G93A)遺伝子導入マウスにおいて、運動ニューロンの変性、除神経、及び筋繊維表現型において生じる変化の結果としてEDL筋は疲労耐性となる。従って、120日齢におけるmSOD1(G93A)遺伝子導入マウスにおいて、EDLは、野生型マウスにおける0.848+/−0.028(平均値+/−S.E.M、n=10)と比較して、0.255+/−0.04(平均値+/−S.E.M、n=10)の疲労指標を有する。しかしながら、化合物Aで処理したマウスにおいては、EDLは0.416+/−0.07(平均値+/−S.E.M、n=10)の疲労指標を有する。従って、EDLの疲労指標は、未処理型mSOD1(G93A)同腹仔と比較して、処理型mSOD1(G93A)遺伝子導入マウスにおいて有意に向上した(p=<0.05)。
生理実験の比較後、腰部脊髄の横断面由来の前角における坐骨運動プール中の運動ニューロンの数をカウントすることにより、運動ニューロンの生存をアッセイした。運動単位の生存において観察された増加と一致して、処理型mSOD1(G93A)遺伝子導入マウスの坐骨運動プールにおいて生存している運動ニューロンの数も、未処理型mSOD1(G93A)同腹仔と比較して有意に増加した。野生型マウスにおいて、検査された坐骨運動プールのセグメント中、593+/−15.8(平均値+/−S.E.M、n=13)であった。120日齢の未処理型mSOD1(G93A)遺伝子導入マウスにおいて、有意な数の運動ニューロンが死に、273+/−14(平均値+/−S.E.M、n=7)の運動ニューロンのみが生存した。しかしながら、化合物Aで処理されたmSOD1(G93A)遺伝子導入マウスにおいては、120日齢にも関わらず、412+/−28(平均値+/−S.E.M、n=4)の運動ニューロンの生存を伴う運動ニューロン生存が劇的に増加した(p=0.002)。
マウスの別々のグループ中、120日齢における処理型mSOD1(G93A)遺伝子導入マウスにおいて観察される運動単位数及び運動ニューロン生存率における有意な向上の観点において、我々は化合物Aでの処理が、mSOD1(G93A)遺伝子導入マウスの寿命において有効性を有するか否かを調査した。その側面を着けたときに正常に戻れないこと、及び約20%の体重の喪失の両方により測定されたとおり、我々は未処理のmSOD1(G93A)遺伝子導入マウスが、125+/−1.8(平均値+/−S.E.M、n=18)日の平均寿命を有したことを見出した。しかしながら、化合物Aで処理したグループにおいて、体重の減少は遅延し、且つ寿命は有意に向上し、mSOD1(G93A)マウスは平均153+/−2.6(平均値+/−S.E.M、n=7)日間生存した。これは、22%以上の寿命の有意な増加を示す(p=<0.001)。
Claims (10)
- 神経変性疾患の治療又は予防のための医薬組成物の調製における、N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライド、その光学的に活性なエナンチオマー又はエナンチオマーの混合物、及びラセミ化合物又は光学的に活性な化合物の医薬的に受容可能な塩から成る群から選択される化学物質の使用。
- 前記化学物質が、(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライドである、請求項1に記載の使用。
- 前記化学物質が、(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライドの塩である、請求項2に記載の使用。
- 前記化学物質が、(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライド・シトレートである、請求項3に記載の使用。
- 前記神経変性疾患が、筋萎縮性側索硬化症である、請求項1〜4のいずれか一項に記載の使用。
- N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライド、その光学的に活性なエナンチオマー又はエナンチオマーの混合物、及びラセミ化合物又は光学的に活性な化合物の医薬的に受容可能な塩から成る群から選択される化学物質の治療的有効量が患者に投与される、神経変性疾患の治療又は予防の方法。
- 前記化学物質が(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライドである、請求項6に記載の方法。
- 前記化学物質が、(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライドの塩である、請求項7に記載の方法。
- 前記化学物質が、(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシミドイル・クロライド・シトレートである、請求項8に記載の方法。
- 前記神経変性疾患が、筋萎縮性側索硬化症である、請求項6〜9のいずれか一項に記載の方法。
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2003
- 2003-10-30 HU HU0303584A patent/HUP0303584A3/hu unknown
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2004
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WO2003026653A1 (en) * | 2001-09-27 | 2003-04-03 | Biorex Kutató És Fejlesztö Rt. | Pharmaceutical composition comprising metformin and n-`2-hydroxy-3-(1-piperidinyl)-propoxy! pyridine-1-oxide-3-carboximidoyl chloride |
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JP2017528521A (ja) * | 2014-09-15 | 2017-09-28 | オーファザイム エーピーエス | アリモクロモル製剤 |
JP2019518725A (ja) * | 2016-04-29 | 2019-07-04 | オーファザイム エー/エス | グルコセレブロシダーゼ関連障害を治療するためのアリモクロモル |
JP2021059586A (ja) * | 2016-04-29 | 2021-04-15 | オーファザイム エー/エス | グルコセレブロシダーゼ関連障害を治療するためのアリモクロモル |
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