JP5363152B2 - グリシン捕捉性アンタゴニストを用いる拒絶性および認知性精神分裂病症候群の処置 - Google Patents
グリシン捕捉性アンタゴニストを用いる拒絶性および認知性精神分裂病症候群の処置 Download PDFInfo
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Description
本発明は、グリシン捕捉性アンタゴニストを用いる拒絶性および認知性精神分裂病症候群の処置に関する。
本発明が解決しようとする課題は、新規なNMDAレセプター仲介神経伝達を促進させる方法を提供することである。
方法:この研究はブロンクス(ニューヨーク)にあるブロンクス・精神病センターにおいておこなわれた。インフォームド・コンセントを得た後でこの研究に参加してあらかじめ二重盲検法においてグリシンを0.4g/kg/日の割合で投与された5人の精神分裂病患者(DSM−IV)を採用した。患者の平均年令は45.0±7.6才であり、慢性的な平均病歴は24.2±5.9年であった。いずれの患者も重度の病状を示した(CG1>4)。すべての患者には試験の少なくとも4週間前から抗精神病薬(クロザピン2、リペリドン2およびハロペリドール1)を投与した。
結果:グリシンの経口投与による処置によってグリシンの血中濃度は著しく増加し(6.3倍)、この値は2〜6週にわたって安定に維持された(図1参照)。6〜8週にかけては統計的に意義のある程度ではないが、グリシンの血中濃度に明らかな低下がみられた。8週間の試験期間中には不都合な効果、例えば衰弱、嘔気および鎮静はみられなかった。SANSを用いたときには拒絶性症候において著しい改善効果がみられた(ベースライン:75.8±7.2、試験後: 72.2±8.6、t=2.79、p=0.049)。一方、PANSSを用いたときには拒絶性症候において改善傾向がみられた(ベースライン:31.0±2.3、試験後: 27.4±3.2、t=2.21、p=0.092)。5人のうちの2人の患者においては拒絶性症候において20%以上の低減効果がみられた。処置応答と全患者のグリシン濃度または個々の患者のグリシン濃度の経時変化との間には著しい関連性はみられなかった。
方法:被験者としてはサラー・ヘルツォグ記念病院の研究病棟(エルサレム、イスラエル)の入院患者を採用した。これらの患者はDSM−III−R(米国精神医学協会、1987年)の精神分裂病と診断されていた。さらに、これらの患者は従来の神経弛緩薬に対する応答が弱いために抗療性があるとみなされていた。試験を開始する前に、少なくとも3カ月間にわたって常套の神経弛緩薬またはクロザピンを臨床的に最適な投与量でこれらの患者に定期的に経口投与した。付加的なDSM−III−R診断を受けた精神分裂病患者の場合には付加的な向精神薬もしくは併用薬を投与するか、または神経学的症状を解消させた。12人の患者をこの研究においては採用した。全ての患者からはこの研究に参加することについて書面によるインフォームド・コンセントを得た。また、この研究は病院の審査委員会の認可を受けた。
PANSSの伝統的分析法においては、症候は従命自動性症候、拒絶性症候および一般的症候に分類されるが、5因子または7因子を組み込む別の分析法が提案されている。5因子モデルによれば症候は従命自動性のもの、拒絶性のもの、認知性のもの、うつ病性のもの、および興奮性のものに分類される。従命自動性および拒絶性症候以外の精神分裂病の程度に及ぼすグリシンの影響度を測定するために、5因子成分を用いてデータの二次分析をおこなった(図4参照)。3因子分析の場合のように、PANSS従命自動性症候に関してはグリシンまたはプラセボ処置中においては著しい低減効果はみられなかったが、プラセボ処置期間ではなくてグリシン処置期間においては著しく漸進的な改善効果がみられた[経時処置F(3,8)=19.5、p<0.0001]。しかしながら、5因子分析法によれば、うつ症候[F(3,8)=7.23、p<0.02]および認知性症候[F(3,8)=4.74、p<0.05]に対しても著しい低減効果がみられた。うつ症候[F(3,5)=2.13、p=0.22]に対しても著しい認知性症候[F(3,5)=0.89、p=0.51]における改善効果は拒絶性症候における変化に対する共変によって維持されなかった。
グリシルドデシルアミド(GDA)は1986年の非特許文献20に最初に報告されたグリシン誘導体である。当時、この化合物はPCP誘発機能高進の転換に関してはグリシンよりも著しく高い効能をもたらすことが示された。さらに、GDAの投与によって脳内の全グリシン濃度は増加しないことが示され、このことはGDAがグリシンの前駆体として作用しなかったことを示す。当時、PCP誘発機能高進に対するGDA誘発抑制機構は仮定されていなかった。
Claims (8)
- NMDAレセプター仲介神経伝達を促進するのに十分な量のグリシン捕捉アンタゴニストを含む、ヒトにおけるNMDAレセプター仲介神経伝達促進剤であって、グリシン捕捉アンタゴニストは、グリシルアルキルアミド、グリシンアルキルエステルおよびサルコシンから選択される、上記NMDAレセプター仲介神経伝達促進剤。
- 精神病で患うヒトの患者用処置剤であって、NMDAレセプター仲介神経伝達を促進するのに十分な量のグリシン捕捉アンタゴニストを含み、ここで、精神病は、情動障害と関係する精神病、一時的な精神的ストレスによる精神病、情動分裂性精神病、精神病NOS、精神分裂病スペクトル障害、または分裂質もしくは分裂型性格障害であり、グリシン捕捉アンタゴニストは、グリシルアルキルアミド、グリシンアルキルエステルおよびサルコシンから選択される、上記処置剤。
- 精神分裂病で患うヒトの患者用処置剤であって、NMDAレセプター仲介神経伝達を促進するのに十分な量のグリシン捕捉アンタゴニストを含む処置剤であって、グリシン捕捉アンタゴニストは、グリシルアルキルアミド、グリシンアルキルエステルおよびサルコシンから選択される、上記処置剤。
- さらに抗精神病薬を含む、請求項3記載の処置剤。
- 抗精神病薬が神経遮断薬である請求項4記載の処置剤。
- GLYT1またはGLYT2仲介グリシン捕捉を抑制する請求項1記載の処置剤。
- GLYT1またはGLYT2仲介グリシン捕捉を抑制する請求項2記載の処置剤。
- GLYT1またはGLYT2仲介グリシン捕捉を抑制する請求項3記載の処置剤。
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CN114805139B (zh) * | 2018-01-10 | 2023-10-20 | 凯瑞康宁生物工程(武汉)有限公司 | 氯胺酮的前药、其组合物和用途 |
US20220087970A1 (en) * | 2019-01-18 | 2022-03-24 | The Johns Hopkins University | Prevention of anesthetic-induced neurocognitive dysfunction |
BR112022007676A2 (pt) * | 2019-11-18 | 2022-08-09 | Nestle Sa | Composições e métodos para aumentar glutationa para uso na saúde cerebral |
CN117881394A (zh) | 2021-08-13 | 2024-04-12 | 凯瑞康宁生物工程(武汉)有限公司 | 氯胺酮衍生物的药物组合物和口服剂型 |
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US4904681A (en) * | 1987-12-01 | 1990-02-27 | G. D. Searle & Co. | D-cycloserine and its prodrugs as cognitive enhancers |
JPH07103018B2 (ja) * | 1988-09-16 | 1995-11-08 | 武田薬品工業株式会社 | 精神分裂病治療剤 |
JP2757960B2 (ja) * | 1988-10-17 | 1998-05-25 | サントリー株式会社 | (2R,3S,4S)−α−(カルボキシシクロプロピル)グリシン |
US5187171A (en) * | 1989-01-09 | 1993-02-16 | G. D. Searle & Co. | Use of a glycine b partial agonist as an antipsychotic |
US5179085A (en) * | 1989-03-15 | 1993-01-12 | Warner-Lambert Company | N-substituted α-amino acids and derivatives thereof having pharmaceutical activity |
JPH03236315A (ja) * | 1989-12-05 | 1991-10-22 | Nippon Oil & Fats Co Ltd | 抗精神病薬 |
US5260324A (en) * | 1990-02-06 | 1993-11-09 | G. D. Searle & Company | Composition containing D-cycloserine and D-alanine for memory and learning enhancement or treatment of a cognitive or psychotic disorder |
US5086072A (en) * | 1990-06-18 | 1992-02-04 | The United States Of America As Represented By The Department Of Health And Human Services | Treatment of mood disorders with functional antagonists of the glycine/nmda receptor complex |
CA2123323A1 (en) | 1991-11-12 | 1993-05-27 | Neurogenetic Corporation | Dna encoding a glycine transporter and uses thereof |
US5428069A (en) * | 1993-01-11 | 1995-06-27 | The United States Of America As Represented By The Department Of Health & Human Services | Treating cognition with, aminocyclopropanecarboxylic derivatives |
US5656608B1 (en) * | 1995-02-23 | 2000-09-26 | Novartis Nutrition Ltd | Amino acid compositions and methods of treatment using same |
IL124536A (en) * | 1995-12-07 | 2001-03-19 | Daniel C Javitt | Pharmaceutical compositions containing a glycine uptake antagonist |
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- 1996-12-05 PT PT96941518T patent/PT871440E/pt unknown
- 1996-12-05 EP EP96941518A patent/EP0871440B1/en not_active Revoked
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ATE320804T1 (de) | 2006-04-15 |
JP2009167205A (ja) | 2009-07-30 |
US6162827A (en) | 2000-12-19 |
EP0871440A1 (en) | 1998-10-21 |
US5837730A (en) | 1998-11-17 |
WO1997020552A1 (en) | 1997-06-12 |
WO1997020553A1 (en) | 1997-06-12 |
US5854286A (en) | 1998-12-29 |
EP0871440A4 (en) | 1999-01-20 |
EP0871440B1 (en) | 2006-03-22 |
DE69635959T2 (de) | 2006-12-07 |
DE69635959D1 (de) | 2006-05-11 |
DK0871440T3 (da) | 2006-07-10 |
JP2013056918A (ja) | 2013-03-28 |
IL124536A0 (en) | 1998-12-06 |
IL124536A (en) | 2001-03-19 |
JP2000501707A (ja) | 2000-02-15 |
PT871440E (pt) | 2006-07-31 |
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