JP2023071900A - Nmdarアンタゴニスト-応答性精神神経障害のための併用療法 - Google Patents
Nmdarアンタゴニスト-応答性精神神経障害のための併用療法 Download PDFInfo
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Abstract
Description
その開示内容の全体を参照によって援用する、2017年5月25日出願の米国仮特許出願第62/510,801号及び2017年6月12日出願の米国仮特許出願第62/518,020号に対する利益を主張する。
別段の説明がない限り、本明細書で使用される全ての技術用語及び科学用語は、本開示が属する技術分野の当業者によって一般に理解されるのと同じ意味を有する。「a」、「an」、及び「the」という単数形の用語には、文脈が明確に示さない限り、複数の参照を含む。同様に、「又は」という言葉は、文脈が明確に示さない限り、「及び」を含むことを意図している。更に、核酸又はポリペプチドに与えられた全ての塩基サイズ又はアミノ酸サイズ、及び全ての分子量又は分子質量の値は、おおよそであり、説明のために提供されることが理解される。本明細書に記載のものと類似又は同等の方法及び材料を本開示の実施又は試験に使用することができるが、適切な方法及び材料を以下に記載する。「comprises」という用語は、「includes」を意味する。「consisting essentially of」は、リストされた特徴のみをアクティブ又は必須な要素として含む組成物、方法、又はプロセスを示すが、更に非アクティブ要素を含むことができる組成物、方法、又はプロセスを示す。略語「e.g.」は、ラテン語のexempli gratiaに由来し、非限定的な例を示すために本明細書中で使用される。したがって、略語「e.g.」は、「for example」などの用語と同義である。
矛盾する場合、用語の説明を含む本明細書が考慮される。更に、全ての材料、方法、及び例は例示的であり、限定することを意図したものではない。
本明細書において記載されるのは、ヒト対象におけるNMDA受容体精神神経障害の治療における使用のための組成物であって、治療的有効量の、NMDA受容体アンタゴニストである第1の剤と、レボミルナシプラン、ミルナシプラン、ビラゾドン、ボルチオキセチン、S-ミルタザピン、及びR-ミルタザピンから選択される抗うつ剤である第2の剤とを含み、前記NMDA受容体精神神経障害は、うつ病、強迫性障害、及び不安障害から選択される。
アンタゴニストのD-サイクロセリン血漿レベルが齧歯類の抗うつ効果に関連するという知見が、本明細書中で実証されている。また、自発運動亢進のD-サイクロセリンの増大の最初の実証も提供され、抗うつ剤の種々のクラスは、正味アンタゴニスト用量で提供されるD-サイクロセリンと組み合わせて自発運動亢進を特異的に調節することができる最初の実証は、特異的な臨床有効性を示唆する。これらの知見は、ヒトの精神神経障害の治療のためのD-サイクロセリンにおける予期しない投与戦略の開発を可能にし、特定のタイプの抗うつ病医薬、特に最近開発された抗うつ剤と、D-サイクロセリンの予期しない有益な組合せ効果を示唆する。これら及び他の記載された観察の点で、過剰なNMDR神経伝達、特にうつ病、強迫性障害、及び不安障害に関連する神経精神状態の治療のための組成物及び方法が、本明細書において提供される。
実施例
この研究では、抗うつ剤の存在下又は非存在下で、D-サイクロセリン投与後の齧歯類のオープンフィールド試験を用いて、D-サイクロセリンの精神運動効果を評価した。
・D-サイクロセリン(300mg/kg)をPTS溶媒(5%PEG200:5%Tween80:90%NaCl)に溶解し、オープンフィールド試験において10mL/kgの用量体積でIP投与をした。
・ブプロピオン(10mg/kg)を食塩水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・デシプラミン(10mg/kg)を食塩水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・セルトラリン(20mg/kg)を滅菌水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・ベンラファキシン(40mg/kg)を食塩水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・デュロキセチン(40mg/kg)を食塩水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・フルオキセチン(10mg/kg)を食塩水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・イミプラミン(10mg/kg)を食塩水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・シタロプラム(10mg/kg)を食塩水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・レボミルナシプラン(40mg/kg)を滅菌水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前にmL/kgの用量体積でIP投与した。
・ミルナシプラン(40mg/kg)を滅菌水に溶解し、オープンフィールド試験においてD-サイクロセリン30分前にmL/kgの用量体積でIP投与した。
・ビラゾドン(1mg/kg)をPTS溶媒(5%PEG200:5%Tween80:90%NaCl)に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
・ボルチオキセチン(10mg/kg)をPTS溶媒(5%PEG200:5%Tween80:90%NaCl)に溶解し、オープンフィールド試験においてD-サイクロセリン30分前に10mL/kgの用量体積でIP投与した。
この研究では、齧歯類の強制水泳試験を用いて、NMDARアンタゴニストの抗うつ病効果を評価した。NMDARアンタゴニストは、単独で及び特定の抗うつ剤と組み合わせて研究された。
・D-サイクロセリン(DCS300mg/kg)をPTS溶媒に溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
・ブプロピオン(10mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・デシプラミン(10mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・イミプラミン(10mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・セルトラリン(20mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・ベンラファキシン(40mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・デュロキセチン(40mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・フルオキセチン(10mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・シタロプラム(10mg/kg)を食塩水に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・レボミルナシプラン(40mg/kg)を滅菌水に溶解し、試験30分前にmL/kgの用量体積でIP投与した。
・ミルナシプラン(40mg/kg)を滅菌水に溶解し、試験30分前にmL/kgの用量体積でIP投与した。
・ビラゾドン(1mg/kg)をPTS溶媒に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・ボルチオキセチン(10mg/kg)をPTS溶媒に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
・ミルタザピン(5mg/kg)をPTS溶媒に溶解し、試験30分前に10mL/kgの用量体積でIP投与した。
この研究では、齧歯類におけるD-サイクロセリンの薬物動態を評価した。この研究では、上記の実施例で示されたDCSの抗うつ病効果が、>25マイクログラム/mLの持続された血中DCSレベルをもたらす処置レベルで特異的に観察されるという仮説を試験する。
実施例1で述べられるように、ミルタザピン+D-サイクロセリンの組合せでは、有意な有益な効果が観察された。ミルタザピンは、R-ケタミンとS-ケタミンの2つの立体異性体からなるラセミ化合物である。ここでは、強制水泳試験の活性における異性体の相対的効果を評価した。
・D-サイクロセリン(Sigma、DSC;30mg/kg及び300mg/kg)を5%PEG200:5%Tween80:90%食塩水(PTS)に溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
・ミルタザピン(Sigma、5.5mg/kg)を5%PEG200:5%Tween80:90%食塩水(PTS)に溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
・パロキセチン(Sigma、5mg/kg)をガラス玉覆い隠し試験におけるポジティブリファレンスとして用いた。この化合物を20%シクロデキストリンに溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
・組合せDSC(300mg/kg)+ミルタザピン(5.5mg)を、試験30分前に10ml/kgの用量体積で単回投与におけるカクテルとして、IP投与した。
下記の試験グループのそれぞれにおいて、10頭のマウスを試験した。
・溶媒(5%PEG200;5%Tween80;90%食塩水)
・パロキセチン(5mg/kg)
・ミルタザピン(5.5mg/kg)
・D-サイクロセリン(30mg/kg)
・D-サイクロセリン(300mg/kg)
・D-サイクロセリン(300mg/kg)+(ミルタザピン5.5mg/kg)
ミルタザピンは、別々のR(-)異性体及びS(+)異性体のラセミ混合物である。追跡研究では、2つの異性体の相対的な効果を個別に評価した。方法は、実施例3と同じである。試験化合物は、下記の通りである。
・5%PEG200:5%Tween80:90%食塩水(PTS)を試験30分前に10ml/kgの体積用量でIP投与した。
・パロキセチン(5mg/kg)を食塩水に溶解し、試験30分前に10ml/kgの体積用量でIP投与した。
・D-サイクロセリン(Sigma、DSC;300mg/kg)を5%PEG200:5%Tween80:90%食塩水(PTS)に溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
・ミルタザピン(Sigma、1mg/kg、2.5mg/kg、5.0mg/kg、及び10mg/kg)を5%PEG200:5%Tween80:90%食塩水(PTS)に溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
・S-ミルタザピン(TRC、1mg/kg、2.5mg/kg、5.0mg/kg、及び10mg/kg)を5%PEG200:5%Tween80:90%食塩水(PTS)に溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
・R-ミルタザピン(TRC、1mg/kg、2.5mg/kg、5.0mg/kg、及び10mg/kg)を5%PEG200:5%Tween80:90%食塩水(PTS)に溶解し、試験30分前に10ml/kgの用量体積でIP投与した。
Claims (17)
- それを必要とするヒト対象におけるNMDA受容体精神神経障害の治療における使用のための組成物であって、前記組成物が、治療的有効量の、
NMDA受容体アンタゴニストからなる第1の剤と;
レボミルナシプラン、ミルナシプラン、ビラザドン(vilazadone)、ボルチオキセチン、S-ミルタザピン、及びR-ミルタザピンからなる群から選択される抗うつ剤からなる第2の剤と、
を含み、
前記NMDA受容体精神神経障害が、うつ病、強迫性障害、及び不安障害からなる群から選択されることを特徴とする組成物。 - 前記第1の剤が、正味アンタゴニスト用量(net antagonistic dose)で提供されるD-サイクロセリンである請求項1に記載の組成物。
- 前記D-サイクロセリンが、≧500mg/日~≦1000mg/日の用量で投与され、前記対象において、25μg/mL超の平均血漿レベルをもたらすように配合される請求項2に記載の組成物。
- 前記D-サイクロセリンが、7.5mg/kg/日~12.5mg/kg/日の用量で投与される請求項2から3のいずれかに記載の組成物。
- 前記第1の剤が、ケタミン、GlyX-13、NRX-1074、NYX-2925、AGN-241751、及びガベスチネルからなる群から選択される請求項1に記載の組成物。
- 前記NMDA受容体精神神経障害が、うつ病である請求項1に記載の組成物。
- 前記うつ病が、大うつ病、大うつ病性障害、非定型うつ病、激越性うつ病、メランコリー型うつ病、又は気分変調性障害である請求項6に記載の組成物。
- 前記うつ病が、双極性障害である請求項1に記載の組成物。
- 前記双極性障害が、双極型I又は双極型2のうつ病性障害である請求項8に記載の組成物。
- 前記双極性障害が、双極性うつ病に関連したうつ病エピソード又は混合性エピソードに関連する請求項8に記載の組成物。
- 前記組成物が、前記対象におけるうつ病の症状を軽減する、自殺の発生を軽減する、又は自殺念慮を治療する請求項1から10のいずれかに記載の組成物。
- 前記障害が、自殺傾向に関連する請求項1から10のいずれかに記載の組成物。
- NMDA受容体アンタゴニストからなる第1の剤と;
レボミルナシプラン、ミルナシプラン、ビラザドン(vilazadone)、ボルチオキセチン、S-ミルタザピン、及びR-ミルタザピンからなる群から選択される抗うつ剤からなる第2の剤と、
を含むことを特徴とする組成物。 - 前記第1の剤が、正味アンタゴニスト用量で提供されるD-サイクロセリンである請求項13に記載の組成物。
- 前記D-サイクロセリンが、≧500mg/日~≦1000mg/日の用量で提供するように、対象において、25μg/mL超の平均血漿レベルをもたらすように配合される請求項14に記載の組成物。
- 前記D-サイクロセリンが、7.5mg/kg/日~12.5mg/kg/日の用量を提供するように配合される請求項14から15のいずれかに記載の組成物。
- 前記第1の剤が、ケタミン、GlyX-13、AGN-241751、及びガベスチネルからなる群から選択される請求項13に記載の組成物。
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KR102608479B1 (ko) * | 2017-05-25 | 2023-12-01 | 글리테크 엘엘씨. | Nmdar 길항제-반응성 신경정신 질환을 위한 병용 요법 |
JPWO2019160057A1 (ja) | 2018-02-15 | 2021-02-04 | 国立大学法人千葉大学 | 炎症性疾患若しくは骨疾患の予防又は治療剤及び医薬組成物 |
MX2020011653A (es) | 2018-05-04 | 2021-02-09 | Perception Neuroscience Inc | Métodos de tratamiento para el abuso de sustancias. |
US20210386689A1 (en) * | 2018-10-31 | 2021-12-16 | Sunovion Pharmaceuticals Inc. | Methods of treating central nervous system disorders |
KR20220045929A (ko) * | 2019-04-09 | 2022-04-13 | 비스타젠 쎄라퓨틱스, 인크. | 신경 질환의 치료 반응과 관련된 유전적 변이 |
KR20220164470A (ko) * | 2020-01-03 | 2022-12-13 | 유니버시티 오브 파도바 | 신경정신 장애 및 질병에 대한 질병-조절 치료제로서의 덱스트로메타돈 |
CN115677519A (zh) * | 2021-07-22 | 2023-02-03 | 立科时代(武汉)生物科技有限公司 | L-4-溴-犬尿氨酸及其在制备治疗抑郁症药物中的应用 |
CN113648320A (zh) * | 2021-08-16 | 2021-11-16 | 中国人民解放军军事科学院军事医学研究院 | 赛洛西宾抗创伤后应激障碍的医药用途 |
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CA2556216A1 (en) | 2004-02-13 | 2005-09-01 | Neuromolecular, Inc. | Combination of a nmda receptor antagonist and an anti-depressive drug mao-inhibitor or a gadph-inhibitor for the treatment of psychiatric conditions |
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US20100216805A1 (en) * | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
WO2012104852A1 (en) * | 2011-01-31 | 2012-08-09 | Serotech, Llc | Dosage regimen, medication dispensing package and uses thereof for the treatment of major depressive disorder |
US9737531B2 (en) * | 2012-07-12 | 2017-08-22 | Glytech, Llc | Composition and method for treatment of depression and psychosis in humans |
CA2871782A1 (en) | 2012-04-27 | 2013-10-31 | Indiana University Research And Technology Corporation | Compositions and methods for treating ptsd and related diseases |
PL3057595T3 (pl) * | 2013-10-18 | 2021-03-08 | Emalex Biosciences, Inc. | Skondensowane benzazepiny do leczenia jąkania |
US20180271869A1 (en) | 2014-09-22 | 2018-09-27 | Jie Liu | Treatment of anxiety disorders and autism spectrum disorders |
WO2016061320A2 (en) * | 2014-10-15 | 2016-04-21 | Rowan University | Timber therapy for post-traumatic stress disorder |
US20180221315A1 (en) | 2015-08-04 | 2018-08-09 | Confluence Pharmaceuticals, Llc | Combination therapy using acamprosate and d-cycloserine |
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