JP2006513998A - 疼痛軽減のための組成物および方法 - Google Patents
疼痛軽減のための組成物および方法 Download PDFInfo
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Abstract
Description
本発明は疼痛管理に関する。
本発明は、腰椎椎間板ヘルニアに由来する坐骨痛が単なる神経圧迫以上のものに関係しているとの発見に基づいている。化学成分の一つである、変性軟骨から放出される遊離グルタミン酸は、腰部神経根障害および力学的腰痛の他の局面に関与していることが見いだされた。
遊離グルタミン酸は、間葉由来の線維性結合組織である変性軟骨(硝子軟骨、線維軟骨、弾性軟骨などのいくつかの形態で存在する)から放出される。遊離グルタミン酸は神経伝達物質としてはたらく。グルタミン酸はニューロン表面のグルタミン酸受容体に結合し、疼痛の一因となる。グルタミン酸アンタゴニスト(硬膜外または脊髄に投与される)は、脊柱管内に脱出した腰椎椎間板物質によって引き起こされる坐骨痛および他の種類の背痛などの疼痛を軽減する。ヒトにおいて脱出した椎間板物質は、高い濃度の細胞外グルタミン酸を含む。
グルタミン酸受容体を、標的ニューロンにおいて誘発された活性化経路の型に基づいてカテゴリーに分類する。イオンチャネル型受容体は受容体チャネルであり、他の特異的アゴニストのグルタミン酸が受容体タンパク質へ結合することにより受容体の孔形成サブユニットが開口される。イオンチャネル型受容体には、NMDA受容体、AMPA受容体、およびカイニン酸受容体が含まれる。代謝調節型受容体はGタンパク質に結合した受容体であり、グルタミン酸または特異的アゴニストの結合がGタンパク質を活性化し、いくつかは別の細胞内シグナル伝達(signalling)経路(InsP3/Ca2+反応またはcAMP)を誘発または調節する。
腰椎椎間板ヘルニアに由来する坐骨痛は、腰部脊椎管狭窄のような骨圧迫の状態で見られるものよりも、神経に対する腫瘤効果(mass effect)の程度が軽いと思われる場合でさえ、患者にとっては我慢できないことがある。腰椎椎間板手術を受けている覚醒患者において、根への圧迫は疼痛として知覚されない。神経への圧迫は、虚血ならびに、神経周膜および後根神経節の基底膜構造の破壊を起こすことがある。この基底膜の破壊により、通常はそこでは見られない小分子が神経細胞膜を通過できるようになる。
椎間板軟骨および一般的軟骨は、一つの特定の観点において独特である。これは、細胞膜および細胞内代謝による制約を受けない大きな細胞外貯蔵器に炭水化物の基質およびタンパク質部分を含む、体内で唯一の組織である。この細胞外基質の分子構造は解明されている。健康な軟骨の親水性は、アグリカン、すなわち、大きなプロテオグリカン基質の一部であるリンクおよびコアタンパク質の存在に関係している。これらのタンパク質の配列決定試験により、アミノ酸鎖内の組成の30%〜50%がグルタミン酸およびアスパラギン酸であることが明らかにされている。グルタミン酸およびアスパラギン酸内で見いだされるカルボキシル部分が、これらのタンパク質の親水性を維持している。これらのタンパク質を酵素的に切断しうる多くのメタロプロテイナーゼ成分が硬膜外腔を構成しており、椎間板破壊はアグリカンの損失に強く相関している。
遊離グルタミン酸がヒト外科的椎間板試料中に有意な濃度で存在するかどうかを判定するために、試験を実施した。これは二つの様式で行った。第一に、抗グルタミン酸抗体を用いて免疫蛍光染色を実施した。一次抗体および二次抗体を含む関心対象の領域が、同じ椎間板試料由来の一次抗体だけを含む切片に比べて強い免疫蛍光を示す場合、椎間板物質はグルタミン酸を含むと定義した。関心対象の領域は、10,000ピクセルよりも大きくかつ軟骨細胞を含まないとして定義された。この方法により、脱出した椎間板試料は椎間板基質において特異的グルタミン酸免疫染色を示したが、サブスタンスPに対する特異的免疫染色は見られなかった。
移植から72時間後にグルタミン酸を02 mM、0.02 mM、および0.002mMの濃度で注入して、行動試験で見られた濃度依存性に相関しうる、受容体発現における濃度関連の変化があるかどうかを判定するために、免疫組織化学および濃度測定試験を行う。濃度測定分析は、各濃度で片側につき合計25の観察に対して動物あたり5切片(n5)で盲検的に行う。次いで、受容体アゴニストAMPA、NMDA、およびカイニン酸の使用に注目して、行動試験を、当技術分野において公知の方法、例えば、Hu et al., 1998, Pain 77:15-23に記載の方法を用い、2.0mM〜0.002mMの範囲の注入濃度で実施する。いくつかの実験において、カテーテルチップのレベルで同側の神経孔にスペーサーを置くという、追加の条件も含める。
300グラムから500グラムの雌Sprague-Dawleyラットに、L5/S1レベルで、皮下に移植したAlzetミニ浸透圧ポンプによって0.002mM、0.02mM、0.2mM、または2mM濃度のグルタミン酸を硬膜外の一側に72時間注入する。この範囲は、脱出したヒトの椎間板物質の平均グルタミン酸濃度が0.18mMであり、硬膜外腔における基準グルタミン酸濃度がマイクロモル濃度よりも低いことから選択される。
行動試験-フォンフライ繊維力学的異痛アッセイ法-を、術前24時間と、術後24時間、72時間、および144時間の時点で行う。各足の足底表面の疼痛反応について試験する。フォンフライ繊維試験キットには、異なる幅のプラスティック製繊維が含まれ、それぞれ異なる量の力を伝える。合計10の繊維をこの実験で用いる。0.6グラムの力から始めて、1、1.4、2、4、6、8、10、15、および最終的に26グラムまで上げて、各足の反応を記録する。より低い力の印加における足を引っ込める動きを、フォンフライ繊維による突きに対する痛覚過敏反応と考える。
動物をペントバルビタール150mg/kgで麻酔して安楽死させる。胸郭内で横隔膜上切開を行い、縦隔内に心臓を露出する。右心室に16ゲージ灌流針を突き刺し、クランプで固定して、緩衝化4%パラホルムアルデヒド溶液を灌流ポンプで少なくとも2分間、組織が十分に硬化するまで注入する。
組織調製物の必要性に応じて、動物を二つの方法で屠殺する。即時固定を必要とする分析のためには、脊髄組織を組織固定液の心臓灌流により固定することになる。ペントバルビタール過量投与後の心臓灌流は、ヘパリン加生理食塩水200mlの左心室へのボーラス投与後、10%中性緩衝化ホルマリンまたは4%パラホルムアルデヒド溶液300mlの灌流からなる。脊髄組織をDNAおよびタンパク質分析のために採取する場合、深く麻酔したラットを断頭する以外は、同様の手順である。次いで、脊髄を液体窒素に短時間浸漬する。3分間解凍した後、脊髄を横切し、神経根および硬膜外脂肪ならびに静脈から分離する。組織を-70℃のメチルブタン浴に30秒間置き、パラフィルムおよびフォイルで包み、液体窒素中に保存する。
本明細書に記載のグルタミン酸受容体アンタゴニスト化合物は、椎間板または関節組織の軟骨破壊に由来する遊離グルタミン酸が神経細胞上のグルタミン酸受容体に結合するのを阻害するために有用である。ペプチドをアンタゴニストとして用いる場合、薬学的に許容される担体中のペプチド溶液の形態で患者に投与する。そのような方法は当業者には公知である。ペプチドは1日に体重1kgあたりポリペプチド約1μmolから100μmolの静脈内用量で投与される。本発明の組成物は静脈内投与、皮下投与、筋肉内投与、腹腔内投与、または関節もしくは脱出椎間板周囲の領域への直接投与などの、非経口投与のために有用である。好ましくは、アンタゴニストは硬膜外投与、脊髄投与、または関節腔(例えば、膝関節腔または肘関節腔)に直接投与される。ペプチドの疼痛軽減用量は0.1 mgから100mgの範囲で、これを患者に1回投与してもよく、繰り返し投与してもよい。複数のペプチドを一緒に投与してもよい(同時または逐次)。
Claims (21)
- 軟骨性組織のニューロン細胞をグルタミン酸受容体のアンタゴニストと接触させる段階を含む、哺乳動物における疼痛緩和法であって、ニューロン細胞上の受容体への遊離グルタミン酸の結合阻害が疼痛を緩和する方法。
- グルタミン酸受容体がイオンチャネル型グルタミン酸受容体である、請求項1記載の方法。
- イオンチャネル型グルタミン酸受容体アンタゴニストが、非-N-メチル-D-アスパラギン酸(NMDA)型受容体アンタゴニストである、請求項2記載の方法。
- 非-NMDA受容体アンタゴニストが、(S)-a-アミノ-3-ヒドロキシ-5-メチル-4-イソキサロンプロピオネート(AMPA)受容体アンタゴニストおよびカイニン酸活性化(KA)受容体アンタゴニストからなる群より選択される、請求項2記載の方法。
- アンタゴニストがNMDA受容体アンタゴニストである、請求項1記載の方法。
- NMDA受容体アンタゴニストがMK-801である、請求項5記載の方法。
- AMPA受容体アンタゴニストが、GYK152466、CNQX、およびNBQXからなる群より選択される、請求項4記載の方法。
- KA受容体アンタゴニストが、LY294486、LY382884およびACEA-1011からなる群より選択される、請求項4記載の方法。
- グルタミン酸受容体が代謝調節型グルタミン酸受容体である、請求項1記載の方法。
- アンタゴニストが、L(+)-2-アミノ,3-ホスホノプロピオン酸(LAP-3)および(S)4-カルボキシ,3-ヒドロキシフェニルグリシン(CHPG)からなる群より選択される代謝調節型グルタミン酸受容体アンタゴニストである、請求項1記載の方法。
- アンタゴニストが遊離グルタミン酸のmGlu2受容体への結合を優先的に阻害する、請求項1記載の方法。
- 疼痛が、背痛、関節痛、および坐骨痛からなる群より選択される、請求項1記載の方法。
- ニューロン細胞が後根神経節細胞である、請求項1記載の方法。
- 軟骨性組織が椎間板組織である、請求項1記載の方法。
- 軟骨性組織が連結関節(articulating joint)組織である、請求項1記載の方法。
- 連結関節組織が膝関節組織である、請求項1記載の方法。
- 連結関節組織が肘関節組織である、請求項1記載の方法。
- グルタミン酸アンタゴニストを硬膜外腔に直接投与する、請求項1記載の方法。
- グルタミン酸アンタゴニストを脊髄液中に投与する、請求項1記載の方法。
- グルタミン酸アンタゴニストを連結関節の関節腔に投与する、請求項1記載の方法。
- 連結関節または椎間板腔への注射に適した形態のグルタミン酸受容体アンタゴニストを含む組成物。
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TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
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JP5433579B2 (ja) | 2007-09-14 | 2014-03-05 | ジャンセン ファーマシューティカルズ, インコーポレイテッド. | 1,3−二置換−4−フェニル−1h−ピリジン−2−オン |
CN101861316B (zh) | 2007-11-14 | 2013-08-21 | 奥梅-杨森制药有限公司 | 咪唑并[1,2-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途 |
AU2009289784B2 (en) | 2008-09-02 | 2012-03-22 | Addex Pharma S.A. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
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