JP2017519778A - 片頭痛の治療または改善方法 - Google Patents
片頭痛の治療または改善方法 Download PDFInfo
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- JP2017519778A JP2017519778A JP2016575106A JP2016575106A JP2017519778A JP 2017519778 A JP2017519778 A JP 2017519778A JP 2016575106 A JP2016575106 A JP 2016575106A JP 2016575106 A JP2016575106 A JP 2016575106A JP 2017519778 A JP2017519778 A JP 2017519778A
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Abstract
Description
本出願は、2014年6月23日出願の米国仮出願第62/015,727号及び2015年1月29日出願の米国仮出願第62/109,386号の利益及び優先権を主張するものであり、同出願はそれぞれその全体が参照により本明細書に組み込まれる。
若しくはその薬学的に許容される塩、またはNMDAR部分アゴニスト活性を有するその誘導体を有する。
片頭痛は1988年に初めて包括的に分類された。直近では2004年にInternational Headache Societyがその頭痛分類を更新した。この分類によれば、片頭痛は、その中でも緊張型頭痛及び群発頭痛とならび一次性頭痛に分類されている。
GLYX−13は、N−メチル−D−アスパラギン酸型グルタミン酸受容体(NMDAR)の活性化に対して、先例のない調節作用を有する新開発の即効性、長期持続性の抗うつ剤である。この抗うつ剤は、NMDA受容体の活性化に必要なNMDA受容体上の必須コアゴニストグリシン部位に作用し、この重要な受容体の活性を正常化し、低すぎる場合は増加させ、高すぎる場合は抑制する。この作用によってGLYX−13は、LTDを抑制しつつシナプス強度の長期増強(LTP)の誘発を増強できると共に、加齢動物からの海馬スライスにおいて正常なLTPを回復させることができる。
式I
一態様では、本発明はそれを必要とする患者の片頭痛を治療する方法に関し、該方法は前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む。
本発明のどの組成物も、患者の症状、年齢及び体重、治療及び予防される障害の性質及び重度、投与経路、ならびに対象組成物の形態に応じて用量が異なる。どの対象製剤も単一用量または分割用量で患者に投与して良い。本開示の組成物の用量は、当業者に既知の手法によって、または本明細書で教示する手法によって容易に決定することができる。一般に、本化合物は、例えば0.05mg〜3000mg(固体形態として測定)、例えば約10mg〜約500mg、または例えば約1〜約200mg/kgの1日用量でヒトに投与されるとき満足な結果を得ることができる。用量範囲には、例えば10〜1000mg(例えば50〜800mg)を含む。いくつかの実施形態では、50、100、150、200、225、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950または1000mgの化合物が投与される。あるいは、患者の体重を用いて用量を算出することができる。例えば、患者に投与される化合物、またはその医薬組成物の用量は、1〜500mg/kg(例えば5〜250mg/kg)の範囲内であって良い。例示的非限定的実施形態では、用量は5〜200mg/kg(例えば、1、2、2.5、5、10、15、20、25、30、35、40、45または50mg/kg)、または15〜100mg/kg(例えば、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190または200mg/kg)の範囲内であって良い。例示的非限定的実施形態では、用量は、1〜15mg/kg、50〜100mg/kg、60〜90mg/kgまたは70〜80mg/kgの範囲内であって良い。
本開示のGLYXペプチドは、使用目的に応じて、当該技術分野において周知である各種手段によって投与することができる。例えば、本開示の組成物を経口投与しようとする場合、組成物を錠剤、カプセル、顆粒、粉末またはシロップとして製剤化することができる。あるいは、本開示の製剤を注射(静脈内、筋肉内または皮下)、滴下注入製剤または坐剤として非経口的に投与しても良い。眼の粘膜経路による適用の場合、本開示の組成物を点眼薬または眼軟膏として処方しても良い。これらの製剤は従来の手段によって調製でき、必要に応じて、任意の従来的添加剤、例えば賦形剤、バインダー、崩壊剤、潤滑剤、矯味剤、可溶化剤、懸濁助剤、乳化剤またはコーティング剤と混合しても良い。
本明細書に記載するGLYXペプチド(例えば、GLYX−13)はいずれも、単独でまたは他の薬剤と組み合わせて使用することで、本明細書で述べる疾患または病態のいずれをも治療または予防することができる。例えば一部の併用療法において、1種以上の治療化合物の用量を、単独で投与されたときの標準用量よりも低減することができる。
本明細書に記載する試験には、インビトロ海馬スライスにおける、細胞外複数部位でのSD伝播速度の電気生理学的モニタリング、及びSDが誘発する樹状突起スパインのサイズ変化をリアルタイムにイメージングするための2光子レーザー走査顕微鏡を利用した。NMDAR受容体グリシン部位に機能する新規部分アゴニストであるGLYX−13の効果を、SD伝播の閾値及び速度、ならびに樹状突起スパインのモルホロジーに与えるSDのリアルタイム効果に基づいて検討した。GLYX−13は、場合により細胞外カリウム濃度の局所的増加によるSDの誘発を完全に防止し、かつSDの伝搬速度を持続的に低下させた。海馬CA1領域をSDが通過すると、樹状突起スパインは急速な収縮を生じ、ニューロン脱分極の復帰後に逆進した。GLYX−13は、樹状突起スパインがSD後に元のサイズ及び位置に戻る速度及び程度を改善した。これは、NMDA受容体活性を調節する薬物及びその他が、反復性片頭痛発作で起こり得る損傷から脳のシナプス接続を保護できることを示す。
薬物
外部溶液及びパッチピペット溶液は全て、脱イオン蒸留水(抵抗率>18MΩcm-2;Milli−Qシステム)を用いて作製した。細胞外及び細胞内溶液を作製するための化学物質は、Sigma−Aldrich(St.Louis,MO,USA)から購入した。AlexaFluor 594はMolecular Probesから購入した。
14〜21日齢のSprague−Dawley(登録商標)ラット(Taconic Farms、Hudson,NY)からの海馬スライスで実験を実施した。ラットをイソフルオレンで深麻酔して犠牲死させ、素早く脳を切除し、酸素化した(95%O2―5%CO2)氷冷人工脳脊髄液(ACSF)中に配置した。ACSFはNaCl 126、KCl 2.5、CaCl2 2.6、MgCl2 1.3、NaH2PO4 1.25、NaHCO3 26及びグルコース 11(単位mM)を含有する。脳を二等分して前頭葉を切除し、個々の脳半球をシアノアクリレート接着剤を使用してステージに固定し、スライスする間、連続して酸素添加された氷冷ACSF中に浸漬した。ビブラトーム(Leica 1200s)を使用して、海馬を含む400μm厚の冠状スライスを切り出して、インターフェイス式保持チャンバーに移し、室温にて最低1時間培養した後、Haas型インターフェイス式チャンバーに移して32℃で記録した。実験開始前に95%O2/5%CO2で飽和させたACSF(4mL/min、ACSF(mM):NaCl 126;KCl 3;NaH2PO4 1.25;MgCl 1.3;CaCl2 2.5;NaHCO3 26;グルコース 10)をスライスに灌流させ、全ての薬物を浴適用した。
海馬の尖端冠状スライスを顕微鏡ステージ上の浸漬した記録チャンバーに移し、温めたACSF(32℃)を灌流させ、3mL/minの灌流速度で細胞外[K+]を8mMまで上昇させた。ガラスピペットによって3MのKClを加圧注入パフ(pressure−injecting puff)して拡延性抑制を開始した。50〜100ms持続する8〜10psiの圧力パルスを、Picospritzer II(Parker Hannifin、Hollis,NH)によって作動させた。3MのKClを充填したときのピペット抵抗は、2±0.2MΩであった。
海馬スライスのCA1錘体神経にAlexa Fluor 594(100μM)を15分間充填した後、以前に記載されているように(Zhangら,2008)、60x/1.1nAの水浸赤外線対物レンズ及び4倍デジタルズームを備えるカスタマイズされた2光子レーザー走査顕微鏡Olympus BX61WIを使用して3次樹状突起を撮像した。移動誤差を回避するために、0.5μmのzステップ間隔で、焦点層から+/−3μm範囲のXYZ走査モードを使用した。各画像の完了まで0.45秒を要し、単一の深さプロファイル時間は7秒であった。蛍光の飽和と、過剰な励起光からの小さい樹状突起スパインに対する何らかの光毒性の徴候の両方を回避するように十分に注意した。起こり得る色素の光退色及び光毒性を低減するため、深さプロファイルを5分間隔で反復した。810nmに調整したMai/Taiレーザー(Solid−State Laser、Mountain View,CA)を励起に使用し、Olympus FluoviewFV300ソフトウェア(Olympus America,Melville,NY)によって画像取得を制御した。ピンホールを最大開口し、発光スペクトル窓を背景上の信号に最適化した共焦点レーザー走査ヘッドの光電子増倍管によって落射蛍光を検出した。トランス蛍光経路において、565nmのダイクロイックミラーを使用して、緑と赤の蛍光を分離し、それぞれHQ525/50及びHQ605/50発光フィルター(Chroma Technology、Rockingham,VT)を通過させて、透過または反射された励起光を除去して、2つの光電子増倍管によって同時に検出した。図は6μmの全体的なZプロファイルからの圧縮画像を示し、及び各投影を使用して、スパインの体積指数としての強度を算出した。
1kHzの遮断周波数を有する8極ベッセル低域フィルターを通して記録信号をフィルタリングし、100μs間隔でClampex(V.9)によってサンプリングした。Clampfit(V.9)によってfEPSP傾きを算出した後、そのデータをOrigin 6.1(Microcal Software、MA)によって更に処理し、CorelDraw 10(Corel、Ottawa,Ontario,Canada)を用いて表示した。全データをSPSSソフトウェア(SPSS Inc.,Chicago,IL)を使用して、一元配置分散分析(ANOVA)またはスチューデントのt検定によって分析した。統計的有意差は、p<0.05に指定した。データは、実験全体の平均±SEMを表す。
限局性の高[K+]によって海馬スライスのCA1野に誘発される拡延性抑制
[K+]oを32℃で8mMまで上昇させた人工脳脊髄液(ACSF)中で、CA1放線状層(図1、左上)の領域上に3M[K+]oを1回、局所的にパフ(100ms)すると、海馬のCA1全領域にわたって9±5.4mm/min(n=16)の伝搬速度で広がるSDが確実に誘発された。負電位シフト(図1、右上)を特徴とするSDは、海馬CA1領域の放線状層シナプス層で−8±1.5mV(n=30)の最大シフトを示し、通常これは45秒以上持続した。
NMDA受容体グリシンコアゴニスト部位の新規部分アゴニストGLYX−13が、NMDA受容体の活性化を生理学的範囲内に調節し、過剰な活性化を防止することにより、SDの閾値を上げること、またはSDを阻止することができるという仮説を検証するために、GLYX−13を1、10または50μmで海馬スライスに30分間、浴適用した後、CA1領域の放線状層に高[K+]を短時間放出(パッチピペットで1mM)し、SDの誘発を試みた。ナイーブスライスに高[K+]が最初に放出されたときと、それから30分間、それぞれ3つの試験濃度(1、10または50μM)のGLYX−13で浴適用した後に基づいて用量反応関係を確定し、一方でSDを検出するためにDC電位を記録した。
SDにより、脱分極された細胞に流体が流出し、細胞が膨張するにつれ、細胞外空間体積の大きな収縮を誘発する。これはインビボの内在的光学濃度の変化として表れ得る。このような輝度強度の変化は、透過光DIC顕微鏡を使用して脳スライス中に容易に検出することもできる。図4Aは、SD「前兆」である輝度の増加が開始ピペットから広がり、スライス全体に伝播していることを示し、更にこれはSD伝導速度の算出に使用できる(図4B)。電気生理学的記録を使用した、SDの負の最大電位シフトと、輝度増加の時間経過とは良好に相関した。このように、距離を用いて輝度変化の時間経過を算出することは、SD伝導速度を測定する正確かつ利便な方法を提供する。
脳内の錘体神経樹状突起の解剖学的微細構造は、意外にも多様な刺激に応答して不安定化する。脱分極、酸素/グルコース欠乏及びN−メチル−D−アスパラギン酸は全て、インビボの海馬CA1錘体神経の樹状突起スパインの収縮をもたらすことが示されている。SDに対するスパインの応答を検討するために、単一のCA1錘体神経に蛍光色素AlexaFluor−594を充填して、2光子レーザー走査顕微鏡から収集された連続したzスタック断面(5μmにわたり0.2μmステップずつ)を利用して樹状突起スパインの形状を撮像した。AlexaFluror−594をCA1錘体神経に充填して30分後、ニューロン内で平衡分布に到達したら、海馬スライスのCA1領域の放線状層に、高[K+]を短時間放出(パッチピペットで1M)することによりSDを開始させた。このときシャファー側枝アクソンがCA1錘体神経の先端樹状突起にシナプスを形成する。図6A及び6Bに示すように、SDによって生じる脱分極は、圧縮されたzスタック層の蛍光振幅によって測定される、実質的なスパイン収縮を誘発した。スパイン体積は最初のSD後20〜30分で完全に回復する。これにより、SDが誘発する脱分極の後遺症の1つが、樹状突起スパインのモルホロジーの変化であることが確認された。
最後に、GLYX−13の効果を、SDに対する樹状突起スパインの動的なモルホロジー応答について検討した。GLYX−13がSDに応答してスパインの収縮を低減できるか、またはスパインの回復を改善できるかを調べた。図6Aは、対照の錘体神経内での2回のSD現象出現に応答したスパイン収縮を示し、一方の図6Bは10μMのGLYX−13存在下での同様の過程を示す。図6C上部に示されたように、反復測定ANOVAによると、樹状突起スパインから測定した蛍光強度は有意に達した(F(8,64)=17.53、p<0.001)。更にこの有意性は、主にSD後の時間経過に起因したものであった(F(8,64)=6.18、p<0.01)。このことは、GLYX−13(黒丸)がSDによって引き起こされた収縮を変化させなかったが、SD後のスパインのサイズの回復を助けることを明らかにしている(F(8,64)=2.81、p<0.05)。
海馬スライスの調製:14〜21日齢のSprague−Dawley(登録商標)ラット(Taconic Farms)を使用して実験を実施した。ラットをイソフルオレンで深麻酔して犠牲死させ、素早く脳を切除し、酸素化した(95%O2―5%CO2)氷冷人工脳脊髄液(ACSF)中に配置した。ACSFはNaCl 126、KCl 2.5、CaCl2 2.6、MgCl2 1.3、NaH2PO4 1.25、NaHCO3 26及びグルコース 11(単位mM)を含有する。脳を二等分して前頭葉を切除し、個々の脳半球をシアノアクリレート接着剤を使用してステージに固定し、スライスする間、連続して酸素添加された氷冷ACSF中に浸漬した。ビブラトーム(Leica 1200s)を使用して海馬を含む400μm厚の冠状スライスを切り出して、インターフェイス式保持チャンバーに移し、実験開始前に最低1時間室温にて培養した。
表1
方法
動物
成体雄(2〜3か月齢)Sprague−Dawley(登録商標)(SD)ラットをHarlan(USA)から購入した。ポプラ材チップの寝床を有するLucite製ケージにラットを収容し、12時間:12時間の明暗サイクル(午前5時に点灯)を維持し、研究期間を通じて、随時Purina(登録商標)ラット用餌(USA)及び水道水を摂取できるようにした。
Goldsteinら(Goldstein,L.E.ら.(2012)「Chronic traumatic encephalopathy in blast−exposed military veterans and a blast neurotrauma mouse model」,Science Translational Medicine 4:134ra160)のプロトコルに従って、ラットで使用するために改変し、一次爆風誘発性の外傷性脳損傷を誘発させた。成体雄Sprague−Dawley(登録商標)ラットをイソフルランで麻酔して、ラットの両耳に耳栓を挿入し、0.014インチのポリエステルフィルムを穿孔して生じるヘリウムの一次爆風(約42PSI)をラットに与える。シャム対照を爆風半径外に配置した。以降、爆風を受けた1時間後、動物にrapastinel(3mg/kgをIV)または0.9%の無菌生理食塩水ビヒクル(1mL/kgをIV)を投与し、ラットを最初に3.5〜4%のイソフルランを使用して麻酔した後、両耳を1.5×1.5mmの発泡プラグ(Pura−Fit耳栓、Moldex−Metric INC、Culver City,California)で保護した。頭部入口付き齧歯類用胸部拘束装置(Stoelting、USA)にラットを入れて胴体を保護すると同時に、アルミニウム衝撃波管(183×61cm;L−3 Applied Technologies、USA)の端から10cmに頭部を置き、頭部は自由に動くようにした。ラットに0.014インチのポリエステルフィルムを穿孔して生じるヘリウムの一次爆風(約42PSI)を与えた。シャム対照を爆風半径外に配置した。爆風を受けた1時間後、動物にrapastinel(3mg/kgをIV)または0.9%の無菌生理食塩水ビヒクル(1mL/kgをIV)を投与した。麻酔から回復するまでの潜在時間を記録した(図11A)。回復は、瞬目反射及び正向反射の表れ、ならびに通常の歩行(標準的な周期ゲート、非環状ゲート、完全な体重支持、何らかの嗅ぐ動作及び探索行動の徴候)と定義した。爆風を受けた1時間後、動物にGLYX−13(3mg/kgをIV)または0.9%の無菌生理食塩水ビヒクル(1mL/kgをIV)を投与した。群当たりN=4−6、*P<0.05(図11A)ANOVA。
図11Aに示すように、TBIを受けた動物は、シャム対照動物と比較して、麻酔からの回復時間が長かった[F(1,13)=41.7、P<0.05]。図11Bに示すように、rapastinel(3mg/kgをIV)は、積極的感情学習のTBI誘発性抑制を改善した[F(2,12)=10.0、P<.05、FisherのPLSD事後検定、rapastinel+TBI対ビヒクル+TBI、シャム対ビヒクル+TBI対、P<0.05]。加えて、麻酔回復時間は、PELの率と有意に相関しなかった[r(15)=−0.14、P>.05]。積極的感情学習試験において、単一用量のrapastinel(3mg/kgをIV)は、TBIによって誘発される学習及び感情の欠如を完全に改善した。このように、この臨床前モデルでは、rapastinelがTBIの中枢認知及び情緒的症状の治療に効果的であり、rapastinelはPTSD治療に対する治療的可能性を有すると思われる。
本開示の具体的実施形態を示したが、上記の具定例は例示的なものであり、限定的はでない。本開示の多くの変形は、本明細書を確認すれば当業者に明らかであろう。本開示の完全な範囲は、等価物の完全な範囲を併記した特許請求の範囲、及びこのような変形を併記した本明細書を参照することにより特定されるものである。
Claims (26)
- それを必要とする患者の片頭痛の治療方法であって、前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む、前記方法。
- 前記化合物が約0.01mg/kg〜約1000mg/kgまたは約1mg/kg〜約500mg/kgの用量で患者に投与される、請求項1に記載の方法。
- 前記片頭痛が、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群または群発性頭痛である、請求項1または2に記載の方法。
- 前記片頭痛が、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛または群発性頭痛である、請求項1または2に記載の方法。
- 前記片頭痛が前兆のある片頭痛(古典的片頭痛)である、請求項1〜4のいずれか1項に記載の方法。
- 前記片頭痛が前兆のない片頭痛(一般的な片頭痛)である、請求項1〜4のいずれか1項に記載の方法。
- 前記片頭痛がアロディニアを伴う、請求項1〜6のいずれか1項に記載の方法。
- 約1mg/kg〜約10mg/kg、約10mg/kg〜約250mg/kg、約20mg/kg〜約150mg/kg、約30mg/kg〜約125mg/kg、約40mg/kg〜約110mg/kg、約50mg/kg〜約100mg/kg、約60mg/kg〜約90mg/kgまたは約70mg/kg〜約90mg/kgの化合物を投与することを含む、請求項1〜7のいずれか1項に記載の方法。
- 約1mg/kg、約2.5mg/kg、約5mg/kg、約10mg/kg、約20mg/kg、約25mg/kg、約30mg/kg、約50mg/kg、約75mg/kgまたは約100mg/kgの化合物を投与することを含む、請求項1〜7のいずれか1項に記載の方法。
- 前記化合物を1日2回、ほぼ毎日、2日毎、3日毎、4日毎、5日毎、約週1回、約2週毎または約月1回投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- それを必要とする患者の皮質拡延性抑制の治療、抑制及び/または予防方法であって、前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む、前記方法。
- それを必要とする患者での片頭痛後の長期後遺症の治療及び/または改善方法であって、前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む、前記方法。
- 前記化合物が約0.01mg/kg〜約1000mg/kgまたは約1mg/kg〜約500mg/kgの化合物の用量で患者に投与される、請求項11〜12のいずれか1項に記載の方法。
- 約1〜約20mg/kg、約2〜約15mg/kg、約5〜約10mg/kg、約10mg/kg〜約250mg/kg、約20mg/kg〜約150mg/kg、約30mg/kg〜約125mg/kg、約40mg/kg〜約110mg/kg、約50mg/kg〜約100mg/kg、約60mg/kg〜約90mg/kgまたは約70mg/kg〜約90mg/kgの化合物を投与することを含む、請求項11〜12のいずれか1項に記載の方法。
- 約1mg/kg、約2.5mg/kg、約5mg/kg、約10mg/kg、約21mg/kg、約25mg/kg、約30mg/kg、約50mg/kg、約70mg/kgまたは約10mg/kgの化合物を投与することを含む、請求項11〜12のいずれか1項に記載の方法。
- 前記化合物を1日2回、ほぼ毎日、2日毎、3日毎、4日毎、5日毎、約週1回、約2週毎または約月1回投与することを含む、請求項11〜15のいずれか1項に記載の方法。
- オピオイド、抗うつ剤、抗てんかん薬、非ステロイド性抗炎症薬(NSAID)、セロトニン5HT1B/1Dアゴニスト、N−メチル−D−アスパラギン酸アンタゴニストまたは抗炎症化合物との共投与を更に含む、請求項1〜16のいずれか1項に記載の方法。
- 前記患者がヒトである、請求項1〜17のいずれか1項に記載の方法。
- 前記患者が女性である、請求項1〜18のいずれか1項に記載の方法。
- 前記患者が小児または青年期の患者である、請求項1〜19のいずれか1項に記載の方法。
- それを必要とする患者での外傷性脳損傷の治療及び/または改善方法であって、前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む、前記方法。
- 前記化合物が約0.01mg/kg〜約1000mg/kgまたは約1mg/kg〜約500mg/kgの化合物の用量で患者に投与される、請求項21に記載の方法。
- 約1〜約20mg/kg、約2〜約15mg/kg、約5〜約10mg/kg、約10mg/kg〜約250mg/kg、約20mg/kg〜約150mg/kg、約30mg/kg〜約125mg/kg、約40mg/kg〜約110mg/kg、約50mg/kg〜約100mg/kg、約60mg/kg〜約90mg/kgまたは約70mg/kg〜約90mg/kgの化合物を投与することを含む、請求項21〜22のいずれか1項に記載の方法。
- 前記化合物を1日2回、ほぼ毎日、2日毎、3日毎、4日毎、5日毎、約週1回、約2週毎または約月1回投与することを含む、請求項21〜23のいずれか1項に記載の方法。
- ステロイド、抗うつ剤、オピオイド、抗てんかん薬、抗発作薬、抗けいれん剤、非ステロイド性抗炎症薬(NSAID)、セロトニン5HT1B/1Dアゴニスト、利尿剤及び/または抗炎症化合物との共投与を更に含む、請求項21〜24のいずれか1項に記載の方法。
- 前記患者がヒトである、請求項21〜25のいずれか1項に記載の方法。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995006468A1 (en) * | 1993-09-01 | 1995-03-09 | Smithkline Beecham Corporation | Method for treating migraine headaches |
JP2007528352A (ja) * | 2003-03-06 | 2007-10-11 | ボツリヌム・トクシン・リサーチ・アソシエイツ・インコーポレイテッド | 洞炎に関連する慢性の顔面痛および頭痛のボツリヌス毒素での治療 |
WO2010010908A1 (ja) * | 2008-07-23 | 2010-01-28 | 協和発酵キリン株式会社 | 片頭痛治療剤 |
WO2011044089A2 (en) * | 2009-10-05 | 2011-04-14 | Joseph Moskal | Methods of treating depression and other related diseases |
WO2012149389A2 (en) * | 2011-04-27 | 2012-11-01 | Northwestern University | Methods of treating alzheimer's disease, huntington's disease, autism, or other disorders |
US20120295852A1 (en) * | 2009-10-05 | 2012-11-22 | Joseph Moskal | Methods of treating depression and other related diseases |
JP2013519683A (ja) * | 2010-02-11 | 2013-05-30 | ノースウエスタン ユニバーシティ | Nmda受容体モジュレータを安定化させる二次構造及びその使用 |
WO2014059326A2 (en) * | 2012-10-12 | 2014-04-17 | Northwestern University | Methods of identifying compounds for treating depression and other related diseases |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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DE60131032T2 (de) * | 2000-08-25 | 2008-08-14 | Research Corp. Technologies, Inc., Tucson | Verwendung von antikonvulsiven Aminosäure zur Behandlung von Migräne |
AU2002227929A1 (en) * | 2000-11-17 | 2002-05-27 | Bayer Aktiengesellschaft | Regulation of human nmda receptor |
WO2011003064A2 (en) * | 2009-07-02 | 2011-01-06 | Naurex, Inc. | Methods of treating neuropathic pain |
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Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995006468A1 (en) * | 1993-09-01 | 1995-03-09 | Smithkline Beecham Corporation | Method for treating migraine headaches |
JP2007528352A (ja) * | 2003-03-06 | 2007-10-11 | ボツリヌム・トクシン・リサーチ・アソシエイツ・インコーポレイテッド | 洞炎に関連する慢性の顔面痛および頭痛のボツリヌス毒素での治療 |
WO2010010908A1 (ja) * | 2008-07-23 | 2010-01-28 | 協和発酵キリン株式会社 | 片頭痛治療剤 |
WO2011044089A2 (en) * | 2009-10-05 | 2011-04-14 | Joseph Moskal | Methods of treating depression and other related diseases |
US20120295852A1 (en) * | 2009-10-05 | 2012-11-22 | Joseph Moskal | Methods of treating depression and other related diseases |
JP2013519683A (ja) * | 2010-02-11 | 2013-05-30 | ノースウエスタン ユニバーシティ | Nmda受容体モジュレータを安定化させる二次構造及びその使用 |
WO2012149389A2 (en) * | 2011-04-27 | 2012-11-01 | Northwestern University | Methods of treating alzheimer's disease, huntington's disease, autism, or other disorders |
WO2014059326A2 (en) * | 2012-10-12 | 2014-04-17 | Northwestern University | Methods of identifying compounds for treating depression and other related diseases |
Non-Patent Citations (1)
Title |
---|
BRITISH J PHARMACOLOHY., 2011, VOL.165, P.235-244, JPN6019006177, ISSN: 0003984547 * |
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RU2017101410A3 (ja) | 2019-01-21 |
KR20170018072A (ko) | 2017-02-15 |
AU2015280108B2 (en) | 2019-11-28 |
EP3157943A1 (en) | 2017-04-26 |
RU2017101410A (ru) | 2018-07-24 |
BR112016030375A2 (pt) | 2017-08-15 |
AU2015280108A1 (en) | 2017-01-19 |
EP3157943A4 (en) | 2018-01-24 |
WO2015200322A1 (en) | 2015-12-30 |
RU2721401C2 (ru) | 2020-05-19 |
CN106661085A (zh) | 2017-05-10 |
MX2016017388A (es) | 2018-02-19 |
BR112016030375A8 (pt) | 2021-07-13 |
JP2020114863A (ja) | 2020-07-30 |
CA2953170A1 (en) | 2015-12-30 |
JP6688748B2 (ja) | 2020-04-28 |
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