JP5822724B2 - 疼痛、炎症、ニューロンもしくは血管損傷に対する生物学的マーカーおよび治療への応答、ならびにその使用方法 - Google Patents
疼痛、炎症、ニューロンもしくは血管損傷に対する生物学的マーカーおよび治療への応答、ならびにその使用方法 Download PDFInfo
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Landscapes
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Description
種々の態様のさらなる理解に役立つように、以下の非限定的な定義が提供される:
疾患の「治療(treating)」または「治療(treatment)」は、疾患の徴候または症状の緩和を目指してプロトコールを遂行することを指し、それには1またはそれより多くの薬物を患者(ヒトまたはその他)に投与することが含まれてもよい。緩和は、疾患の徴候または症状が現れる前、ならびにその出現後に行うことが可能である。このように、「治療(treating)」または「治療(treatment)」には、疾患の「予防(preventing)」または「予防(prevention)」が含まれる。加えて、「治療(treating)」または「治療(treatment)」は、徴候または症状の完全な緩和を必要とせず、治癒を必要とせず、そして、患者にほんのわずかな効果のあるプロトコールを特に含む。
「専門家」の語は、本態様の方法、キットおよび組成物を対象に実施する人を意味する。該語には、これに限定されないが、医師、その他の医療関係者および研究者が含まれる。
「痛覚過敏」の語は、通常の疼痛刺激に対する感受性が増加することを指す。一次痛覚過敏は、損傷の直近領域を冒す。
「ニューロン損傷」の語は、中枢もしくは末梢神経系の要素への傷害を指す。ニューロン損傷は、物理的(機械的、電気的または熱的を含む)、虚血性、出血性、化学的、生物学的、生化学的または血管性の傷害から生じ得る。ニューロン損傷の例としては、これに限定されないが、虚血性および出血性脳卒中、脊髄、脳、脳神経および末梢神経の損傷が挙げられる。
生物活性剤、生体膜シーリング剤およびマーカーを非限定的に含む化合物に対するすべての言及には、これらの化合物のすべての形態(すなわち、塩、エステル、水和物、エタノラート、ラジオアイソトープ、画像診断プローブ等)が含まれ、前記形態は、それぞれの化合物の活性を少なくとも部分的に有する。
生物学的マーカーまたはバイオマーカーは、生体組織および/もしくは体液中に見いだされ、かつ、単純な分子から複合的な構造までの範囲が含まれてもよい。例えば、生物学的マーカーとしては、イオン、アミノ酸、神経伝達物質、糖類、脂質、炭水化物、タンパク質、ペプチド、酵素、サイトカイン類、受容体、ホルモン、ステロイド類、遺伝子、リボヌクレオチド等、またはそれらの組み合わせが挙げられてもよい。その他のより具体的なバイオマーカーとしては、マグネシウム、カルシウム、グルタメート、グルタミン、コリン、アセチルコリンエステラーゼ、タウ、c−タウ、ニューロン特異的エノラーゼ、ユビキチン、およびユビキチン加水分解酵素などのユビキチン酵素、n−アセチルアスパルテート、ニューロン線維、ミオ−イノシトール、S100B、インターロイキン類、PEGに対する抗体などのポリマーに対する抗体が挙げられる。本質的には、バイオマーカーは、特定の身体もしくは疾患の状態の指標として特徴付けられる。すなわち、バイオマーカーは、ホメオスタシスにおいても、疾患状態においても、生物体の状態の指標であり得る。例えば、バイオマーカーは、ニューロン損傷の後に起こる二次相の進行を示すことが可能である。このように、バイオマーカーは、一般に、個体の組織、細胞または体液における細胞的、生化学的、生理学的もしくは分子的な状態、またはそのようなパラメーターの変化の尺度である。
40年以上もの間、種々の分子量の生体膜シーリング剤が、流体力学的な損傷から細胞を保護するその能により、培地への付加物として利用されている。これらの薬剤としては、ポリオキシエチレン類、ポリアルキレングリコール、ポリエチレングリコール類(PEG)、ポリビニルアルコールなどの親水性ポリマー、プルロニック類またはポロキサマーP−188(CytRx Corp社、ロサンゼルス、カリフォルニア州から入手可能なCRL−5861としても公知である)(MichaelsおよびPapoutsakis、1991年)を含むポロキサマー類などの両親媒性ポリマー、ならびに、メチルセルロース(Kuchlerら、1960年)、カルボキシメチルセルロースナトリウム、ヒドロキシエチルでんぷん、ポリビニルピロリジンおよびデキストラン類(MizrahiおよびMoore、1970年;Mizrahi、1975年;Mizrahi、1983年)が挙げられる。
上記に論じたように、発明者は、生体膜シーリング剤とマグネシウム化合物との組み合わせがニューロン外傷および疼痛状態の治療に有用であることを見いだした。したがって、本発明の一態様では、少なくとも1種の生物活性剤はマグネシウム化合物を含んでなる。マグネシウムは、細胞機能の広範な多様性に重要な役割を果たしている。例えば、マグネシウムは、細胞におけるエネルギー産生およびエネルギー消費反応を補助する解糖および酸化的リン酸化に必要である。タンパク質合成ならびに膜の構造および機能もまたマグネシウムに依存的である。マグネシウムのレベルは、グルタメートおよびアセチルコリン放出を含む神経伝達物質の放出に影響を及ぼすであろう。それはまた、カルシウム輸送体の活性およびノン−メチル−D−アスパラギン酸(NMDA)グルタメート受容体の開口も制御する。マグネシウムは、抗酸化抗アポトーシス作用を有し、かつ脂質の形成および輸送を調節することが知られている。細胞での作用に加えて、マグネシウムは、血流および浮腫発現の制御に関与する生理学的機能を調節することが可能である。
血流モジュレーターの適切な非限定例は、ATL−146eなどのアデノシン受容体モジュレーター、およびCM101などの新規血管形成の調節剤である。
本態様の医薬組成物を含んでなる治療用製剤を、少なくとも1種の生体膜シーリング剤と少なくとも1種の生物活性剤とを、所望により生理学的に許容可能なキャリア、賦形剤または安定化剤とともに混合することによって(例えば、Remington’s Pharmaceutical Sciences、第16版、Osol,A.編(1980年))、凍結乾燥製剤または水溶液の形態で貯蔵用に製造することが可能である。許容可能なキャリア、賦形剤または安定化剤は、使用される投与量および濃度ではレシピエントに対して非毒性であり、かつ、リン酸、クエン酸および他の有機酸などのバッファー;アスコルビン酸およびメチオニンを含む抗酸化剤;保存剤(塩化オクタデシルジメチルベンジルアンモニウム;塩化ヘキサメトニウム;塩化ベンザルコニウム、塩化ベンゼトニウム;フェニル、ブチルもしくはベンジルアルコール;メチルもしくはプロピルパラベンなどのアルキルパラベン類;カテコール;レソルシノール;シクロヘキサノール;3−ペンタノール;およびm−クレゾールなど);低分子量(約10残基未満)ポリペプチド;血清アルブミン、ゼラチンまたはイムノグロブリン類などのタンパク質;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニンまたはリジンなどのアミノ酸;グルコース、マンノースまたはデキストリン類を含む単糖類、二糖類およびその他の炭水化物;EDTAなどのキレート剤;ショ糖、マンニトール、トレハロースまたはソルビトールなどの糖類;ナトリウムなどの塩形成カウンターイオン;ならびに/あるいは金属錯体(例えば、Zn−タンパク質錯体)を含む。
別の側面では、病的状態を治療する方法が提供され、該方法は、病的状態に関連するバイオマーカーを測定し、治療有効量の少なくとも1種の生体膜シーリング剤および治療有効量の少なくとも1種の生物活性剤をそれを必要とする対象に送達し、その後再びバイオマーカーを測定し、そして次いで測定手順の結果を比較して治療を評価することを含んでなる。異なる態様では、病的状態は、ニューロン損傷、組織損傷、外科的介入、炎症およびそれらの任意の組み合わせからなる群より選択される。
病的状態を治療するための手順を、特定の状態に関連する特定のバイオマーカーをまず同定することにより、実施してもよい。次いで、該バイオマーカーを測定し、そして定量する。治療的介入を行い、そして次いで、同定されたバイオマーカー(単数もしくは複数)を再び定量して、疾患の進行期または回復期を決定する。介入前のバイオマーカーのレベルを、治療後のレベルと比較する。治療的介入は、非経口投与によるポリマー溶液中マグネシウムの適用を含んでなってもよく、ここで、マグネシウムは、硫酸マグネシウム、塩化マグネシウム、グルコン酸マグネシウムまたはATPマグネシウムの1またはそれより多くを含んでなる塩の形態である。
治療的介入前のバイオマーカーの測定が第一の測定手順であり、そして、第二の測定手順は、バイオマーカー、もしくはバイオマーカーと相互作用する分子の構造、活性またはレベルの少なくとも1つを検出することを含んでなる。第一と第二の測定手順を比較し、そしてバイオマーカーを定量的または定性的に評価してもよく、次いで、有効性、または介入により引き起こされた病的状態の変化の示差尺度が提供される。介入後に順次実施されるバイオマーカーのさらなる測定手順は、病的状態の進行または退縮をもたらすさらなる時間関係測定値を提供するであろう。あるいは、患者におけるバイオマーカーのレベルを、ホメオスタシスまたは病的状態の参照標準値指標と比較することが可能である。
第一の測定手順から得た結果は、例えば、療法に用いられるべき投薬およびレジメンを示し得る。あるいは、該結果は、特定の治療剤による治療が患者に有益でないだろうということを示し得る。
Claims (20)
- 病的状態を治療するための医薬組成物であって、ポリマー溶液中、硫酸マグネシウムまたは塩化マグネシウムからなる生物活性剤を含む治療用化合物を含み、治療が、以下の工程
病的状態に関連するバイオマーカーを測定するための第一の測定手順を実施すること;
ポリマー溶液中マグネシウムを含む治療有効量の治療用化合物を投与することにより、病的状態を治療すること;
病的状態に関連するバイオマーカーを測定するための第二の測定手順を実施すること;および、
少なくとも第一の測定手順の結果と少なくとも第二の測定手順の結果とを比較して、病的状態の治療を評価すること;
を含むことにより行われ、ここで当該ポリマー溶液はPEGを含み、当該病的状態はニューロン損傷、虚血性および出血性脳卒中、脊髄損傷、脳損傷、脳神経損傷、または末梢神経損傷である、前記医薬組成物。 - 第一および第二の測定手順が、血液、脳脊髄液、細胞間液、細胞もしくは組織試料の1またはそれより多くから得られた試料においてバイオマーカーを検出することを含む、請求項1に記載の医薬組成物。
- バイオマーカーが、マグネシウム、カルシウム、グルタメート、グルタミン、コリン、アセチルコリンエステラーゼ、タウ、c-タウ、ニューロン特異的エノラーゼ、ユビキチンおよびユビキチン加水分解酵素、n-アセチルアスパルテート、ニューロンフィラメント、ミオ-イノシトール、S100B、インターロイキン類、抗酸化剤、PEGに対する抗体などのポリマーに対する抗体の少なくとも1種である、請求項1に記載の医薬組成物。
- バイオマーカーが、イオン、アミノ酸、糖、脂質、タンパク質、ペプチド、受容体、神経伝達物質、酵素、遺伝子またはリボヌクレオチドの少なくとも1種である、請求項1に記載の医薬組成物。
- 第一の測定手順または第二の測定手順が、バイオマーカーのもしくはバイオマーカーと相互作用する分子の、構造、活性またはレベルの少なくとも1種を検出することを含む、請求項1に記載の医薬組成物。
- 治療が、病的状態に関連するバイオマーカーを検出するための第三の測定手順を実施すること、ならびに、少なくとも第二の測定手順の少なくとも結果を少なくとも第三の測定手順の少なくとも結果と比較して病的状態の治療を評価することをさらに含む、請求項1に記載の医薬組成物。
- 治療が、少なくとも第二の測定手順の少なくとも結果と少なくとも第三の測定手順の少なくとも結果または予め決定された参照基準の結果との比較に応じて病的状態の治療を変更することをさらに含む、請求項6に記載の医薬組成物。
- 硫酸マグネシウムまたは塩化マグネシウムからなる生物活性剤を含む治療有効量の治療用化合物を投与することによる病的状態の治療が、第一の測定工程の少なくとも結果または予め決定された参照基準にしたがって実施される、請求項1に記載の医薬組成物。
- 病的状態を治療するための医薬組成物であって、PEG溶液中、硫酸マグネシウムまたは塩化マグネシウムからなる生物活性剤を含む治療用化合物を含み、治療が、以下の工程
病的状態または病的状態に対する治療に関連する生物学的マーカーを測定するための第一の測定手順を実施すること;および、
第一の測定手順の1またはそれより多くの結果にしたがって、PEG溶液中マグネシウムを含む治療有効量の治療用化合物を投与することにより、病的状態を治療すること;
を含むことにより行われ、ここで、当該病的状態はニューロン損傷、虚血性および出血性脳卒中、脊髄損傷、脳損傷、脳神経損傷、または末梢神経損傷である、前記医薬組成物。 - バイオマーカーが、マグネシウム、カルシウム、グルタメート、グルタミン、コリン、アセチルコリンエステラーゼ、タウ、c-タウ、ニューロン特異的エノラーゼ、ユビキチンおよびユビキチン加水分解酵素、n-アセチルアスパルテート、ニューロンフィラメント、ミオ-イノシトール、S100B、インターロイキン類、抗酸化剤ならびにポリマーに対する抗体の少なくとも1種である、請求項9に記載の医薬組成物。
- 病的状態を治療するための医薬組成物であって、PEG溶液中、硫酸マグネシウムまたは塩化マグネシウムからなる生物活性剤を含む治療用化合物を含み、治療が、以下の工程
PEG溶液中マグネシウムを含む治療有効量の治療用化合物を投与することにより、病的状態を治療すること;
病的状態または病的状態に対する治療に関連する生物学的マーカーを測定するための第一の測定手順を実施すること;および、
第一の測定手順の結果を病的状態の治療を評価するために利用すること;
を含むことにより行われ、ここで、バイオマーカーがマグネシウム、カルシウム、グルタメート、グルタミン、コリン、アセチルコリンエステラーゼ、タウ、c-タウ、ニューロン特異的エノラーゼ、ユビキチンおよびユビキチン加水分解酵素、n-アセチルアスパルテート、ニューロンフィラメント、抗酸化剤、ミオ-イノシトール、S100B、インターロイキン類、ならびにポリマーに対する抗体の少なくとも1種であり、ここで、当該病的状態はニューロン損傷、虚血性および出血性脳卒中、脊髄損傷、脳損傷、脳神経損傷、または末梢神経損傷である、前記医薬組成物。 - 病的状態が、脊髄損傷である、請求項1に記載の医薬組成物。
- 病的状態が、虚血性脳卒中である、請求項1に記載の医薬組成物。
- 病的状態が、出血性脳卒中である、請求項1に記載の医薬組成物。
- 病的状態が、脳損傷である、請求項1に記載の医薬組成物。
- 病的状態が、脳神経損傷である、請求項1に記載の医薬組成物。
- 病的状態が、末梢神経損傷である、請求項1に記載の医薬組成物。
- 病的状態が、ニューロン損傷である、請求項1に記載の医薬組成物。
- PEGが1,400〜20,000 Daの分子量を有する、請求項1に記載の医薬組成物。
- PEGが組成物の30%〜50%を構成する、請求項1に記載の医薬組成物。
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-
2008
- 2008-04-18 US US12/105,666 patent/US20090263507A1/en not_active Abandoned
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2009
- 2009-04-13 EP EP09733658.0A patent/EP2278981A4/en not_active Withdrawn
- 2009-04-13 CA CA2720670A patent/CA2720670A1/en not_active Abandoned
- 2009-04-13 CN CN200980113809.2A patent/CN102083446B/zh active Active
- 2009-04-13 CN CN201410471552.0A patent/CN104306395A/zh active Pending
- 2009-04-13 WO PCT/US2009/040316 patent/WO2009129163A2/en active Application Filing
- 2009-04-13 AU AU2009236427A patent/AU2009236427A1/en not_active Abandoned
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JP2011518165A (ja) | 2011-06-23 |
EP2278981A4 (en) | 2020-07-22 |
EP2278981A2 (en) | 2011-02-02 |
WO2009129163A2 (en) | 2009-10-22 |
CN104306395A (zh) | 2015-01-28 |
CN102083446B (zh) | 2014-10-22 |
CA2720670A1 (en) | 2009-10-22 |
AU2009236427A1 (en) | 2009-10-22 |
US20090263507A1 (en) | 2009-10-22 |
CN102083446A (zh) | 2011-06-01 |
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