JP2020063264A - 持続性抑制を増加させ、二次性不眠症を治療する方法 - Google Patents
持続性抑制を増加させ、二次性不眠症を治療する方法 Download PDFInfo
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Abstract
Description
患者、特に脆弱X症候群またはアンジェルマン症候群を有する患者におけるニューロンの持続性抑制を増加させる方法を提供する。神経変性疾患または中枢神経系障害を有する患者における二次性不眠症を治療する方法を提供する。方法は、典型的には、患者におけるニューロンにおける持続性抑制を増加させるため、徐波睡眠(SWS)および/または徐波活動(SWA)を増加させ、睡眠構築を正常化し、二次性不眠症を減少させ、ノンレム(非急速眼球運動(non-rapid eye movement))(NREM)睡眠を増加させ、睡眠の連続性を高め、ノンレム(NREM)睡眠を増加させ、睡眠の連続性を高め、NREM内のデルタ活動を強化し、総睡眠時間(TST)を増加または改善し、睡眠効率を増加または改善し、総覚醒時間(TAA)を短縮し、覚醒回数を減らし(NWA)、持続睡眠潜時(LPS)を短縮するか、または中途覚醒(WASO)を減少させるため、または患者におけるそれらの任意の組合せのために、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を患者に投与することを包含する。
I.定義
本明細書で用いる用語「担体」または「賦形剤」は、1種以上の活性成分と組合わせる、製剤中の有機または無機成分、天然または合成不活性成分を意味する。
患者における二次性不眠症、乱れた睡眠構築、またはその組合せを治療するための4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)、その誘導体、またはその医薬的に許容しうる塩を用いる方法を開示する。一部の実施態様において、患者は、神経変性疾患または中枢神経系障害を有するか、または発症する危険性がある。最も好ましい実施態様において、患者は、神経変性疾患または中枢神経系障害による二次性不眠症および/または乱れた睡眠構築に苦しむ。以下により詳細に説明するように、方法は、典型的に、徐波睡眠を増加させ、睡眠構築を正常化するため、またはその組合せのために、有効量の有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)、その誘導体、またはその医薬的に許容しうる塩を、それを必要とする患者に投与することを包含する。一部の実施態様において、神経変性疾患または中枢神経系障害の臨床症状が、低減化される。
開示する二次性不眠症を治療する方法において用いるための組成物は、4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIPおよびガボキサドールとも称される)、その誘導体、またはその医薬的に許容しうる塩、または構造的関連化合物を包含する。THIP、ならびに誘導体および構造的関連化合物、およびその製造方法は、当技術分野で公知である。たとえば、米国特許第4,278,676、4,362,731、4,353,910号、およびWO 2005/094820を参照(これらのそれぞれは、その全体において参照することによって本明細書に援用される)。特に好ましい化合物を以下により詳細に考察する。
で示される化合物、またはその互変異性体、異性体、エピマーもしくはジアステレオマーである。
で示される化合物およびその塩。
脳内への化合物の侵入を強化することができると考えられる。また、R”が水素ではない化合物のその場での分解を介して、化合物(Ia)の長期効果が得られ、親化合物を生成することができる。
一般式(I)で示される化合物は、式(I'):
[式中、Rは、1〜17個の炭素原子を有する分枝または非分枝のアルキル基;低級アルキル、低級アルキルオキシおよびハロゲンから選ばれる1または2個の基で任意に置換されたフェニル基;フェニルアルキル基;低級アルキルオキシ基;または-NHR1基(ここで、R1は、水素、低級アルキル、フェニルまたはシクロヘキシルである)]
で示される化合物ならびにその医薬的に許容しうる酸付加塩である。
開示の化合物は、医薬組成物中に製剤化することができる。医薬組成物は、投与の非経口(筋肉内、腹腔内、静脈内(IV)または皮下注射)、経腸、経皮(受動的またはイオン導入法もしくはエレクトロポレーションを使用して)または経粘膜(経鼻、肺、膣、直腸または舌下)の投与経路によって、または生体内分解性インサートを用いて投与することができ、各投与経路に適した投与剤形に製剤することができる。
組成物は、全身投与することができる。
化合物およびその医薬組成物は、水溶液で、非経口注射によって投与することができる。製剤は、懸濁液または乳液の形態であってもよい。一般に、有効量の活性剤を含む医薬組成物が提供され、任意に、医薬的に許容しうる希釈剤、保存剤、可溶化剤、乳化剤、アジュバントおよび/または担体を含む。このような組成物として、希釈剤滅菌水、さまざまな緩衝内容(たとえば、Tris-HCl、酢酸塩、リン酸塩)、pHおよびイオン強度の緩衝生理食塩水;および任意に、界面活性剤および可溶化剤(たとえば、POLYSORBATE(登録商標)20または80とも称されるTWEEN(登録商標)20、TWEEN(登録商標)80);抗酸化剤(たとえば、アスコルビン酸、メタ重亜硫酸ナトリウム);および保存剤(たとえば、チメルソール、ベンジルアルコール)および増量剤(たとえば、ラクトース、マンニトール)が挙げられる。非水性溶媒またはビヒクルの例は、プロピレングリコール、ポリエチレングリコール、オリーブ油およびトウモロコシ油などの植物油、ゼラチン、およびオレイン酸エチルのような注射可能な有機エステルである。製剤は、凍結乾燥し、使用直前に再溶解/再懸濁することができる。製剤は、たとえば、細菌保持フィルターによる濾過、組成物への滅菌剤の組み込み、組成物の放射線照射、または組成物の加熱によって滅菌することができる。
適切な経口投与剤形として、錠剤、カプセル剤、液剤、懸濁液剤、シロップ剤およびロゼンジが挙げられる。錠剤は、当技術分野で周知の圧縮または成形技術を用いて作成することができる。ゼラチンカプセル剤または非ゼラチンカプセル剤は、当技術分野において周知の技術を用いて、液体、固体および半固体の充填材料を封入することができる硬質または軟質カプセルシェルとして製造することができる。
「徐放性製剤は、一般に、たとえば、Remington-The science and practice of pharmacy」(20th ed.、Lippincott Williams & Wilkins、Baltimore、MD、2000)に記載されるように、拡散または浸透システムとして製造される。拡散システムは、典型的には、2つのタイプのデバイス、すなわち、リザーバおよびマトリックスからなり、当技術分野で周知であり、記載されている。マトリックスデバイスは、一般に、ゆっくりと溶解するポリマー担体を用いて薬剤を錠剤の形態に圧縮することによって製造される。マトリックスデバイスの製造に使用される3つの主なタイプの材料は、不溶性プラスチック、親水性ポリマーおよび脂肪族化合物である。プラスチックマトリックスとして、メチルアクリレート-メチルメタクリレート、ポリ塩化ビニルおよびポリエチレンが挙げられるが、これらに限定されるものではない。親水性ポリマーとして、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、カルボポール934、ポリエチレンオキシドが挙げられるが、これらに限定されるものではない。脂肪族化合物として、カルナウバワックス、グリセリルトリステアレートなどのさまざまなワックスが挙げられるが、これらに限定されるものではない。
遅延放出製剤は、胃の酸性環境に不溶性であり、小腸の中性環境に可溶性であるポリマーのフィルムで固体剤形をコーティングすることによって作成される。
当業者に理解されるように、関連するテキストおよび文献に記載されているように、さまざまな薬物放出プロファイルを提供する薬物含有錠剤、ビーズ、顆粒または粒子を製造するための多くの方法が利用可能である。このような方法として、以下のものが挙げられるが、これらに限定されるものではない:典型的にはポリマー材料を組み込む必要はないが、薬物または薬物含有組成物を適切なコーティング材料で被覆すること、薬物粒子サイズを増大させること、マトリックス内に薬物を置くこと、および適当な錯化剤と薬物の複合体を形成すること。
投与
活性剤およびその組成物を、肺または粘膜投与用に製剤化することができる。投与は、肺、鼻、口(舌下、頬側)、膣または直腸粘膜への組成物のデリバリーを含むことができる。特定の実施態様において、組成物は患者への舌下用に製剤され、デリバリーされる。
経皮製剤を製造することもできる。これらは典型的には、ゲル、軟膏、ローション、スプレーまたはパッチであり、これらはすべて標準技術を用いて製造することができる。経皮製剤は、浸透増強剤を含むことができる。
このような添加剤の例として、ミリスチン酸イソプロピル、酢酸エチル、C12〜C15アルキル安息香酸塩、鉱物油、スクワラン、シクロメチコン、カプリン酸/カプリル酸トリグリセリド、およびそれらの組み合わせが挙げられるが、これらに限定されるものではない。
BRIJ(登録商標)76(ステアリルポリ(10オキシエチレンエーテル)、BRIJ(登録商標)78(ステアリルポリ(20)オキシエレチンエーテル)、BRIJ(登録商標)96(オレイルポリ(10)オキシエチレンエーテル)およびBRIJ(登録商標)721(ステアリルポリ(21)オキシエチレンエーテル)(ICI Americas Inc. Corp.)が挙げられる。化学的浸透および経皮ドラッグデリバリーの増強方法は、Inayatraら、Tropical Journal of Pharmaceutical Research、8(2):173-179(2009)およびFoxら、Molecules、16:10507-10540(2011)に記載されている。一部の実施態様において、浸透強化剤は、エタノールなどのアルコール、または本明細書に開示されるか、または当技術分野で公知である他のものであるか、またはそれを包含する。
二次性不眠症を治療する方法を提供する。方法は、睡眠中断を減少させ、徐波睡眠(SWS)および/または徐波活動(SWA)を増加させ、睡眠構築を正常化し、二次性不眠症を減少させ、ノンレム(NREM)睡眠を増加させ、睡眠の連続性を高め、NREM内のデルタ活動を増強し、総睡眠時間(TST)を増加または改善し、睡眠効率を向上または改善し、総覚醒時間(TAA)を減少させ、覚醒回数(NWA)を減少させ、持続睡眠潜時(LPS)を短縮し、睡眠開始後の覚醒(WASO)を減少させるため、またはそれらの任意の組み合わせのために、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体を患者に投与することを含みうる。好ましい実施態様において、REM睡眠は実質的に減少されない。一部の実施態様において、方法は、神経変性疾患または中枢神経系疾患または障害の1つ以上の他の臨床症状を軽減、遅延、または予防するのに有効である。
THIPおよびその誘導体を用いて二次性不眠症を治療することができることが発見された。二次性不眠症は、感情的、神経学的またはその他の医学的または睡眠障害などの、もう1つの問題である症状または副作用である。したがって、治療される患者は、典型的に、不眠症および不眠症の原因となる基礎疾患、障害または状態の両方に苦しんでいる。
一部の実施態様において、患者は、徐波睡眠の低下、睡眠構築の中断を有しているか、またはそれを発症する危険にあり、あるいは徐波睡眠の増加の利益を受ける。したがって、一部の実施態様において、組成物は、1つ以上の睡眠関連症状を軽減、緩和、または予防するために有効量で投与される。好ましい実施態様において、THIPまたはその誘導体は、睡眠中断を減少させ、徐波睡眠(SWS)および/または徐波活動(SWA)を増加させ、睡眠構築を正常化し、二次性不眠症を減少させ、ノンレム(NREM)睡眠を増加させ、睡眠の連続性を高め、NREM内のデルタ活動を増強し、総睡眠時間(TST)を増加または改善し、睡眠効率を向上または改善し、総覚醒時間(TAA)を減少させ、覚醒回数(NWA)を減少させ、持続睡眠潜時(LPS)を短縮し、睡眠開始後の覚醒(WASO)を減少させるため、またはそれらの任意の組み合わせのために、有効量で患者に投与される。好ましい実施態様において、レム睡眠は実質的に減少されない。
各段階の基準および睡眠中の患者の段階を決定する方法および患者の睡眠構築をプロファイリングする方法は、Iberら、「The AASM Manual for the Scoring of Sleep and Associated Events、American Academy of Sleep Medicine」、pg. 1-57(2007)に記載されており、この文献は、その全体において参照することによって本明細書に援用される
開示する二次性不眠症を治療する方法は、典型的には、それを必要とする患者に、有効量のTHIPまたはその誘導体を投与することを含み、好ましくは、上記でより詳細に考察される医学的に許容される組成物である。
一部の実施態様において、組成物は、静脈内注射または点滴によって投与される。経口投与される場合、ガボキサドールの腸から門脈循環への輸送は、輸送体PAT1を介して行われる。プロリン、トリプトファン、アラニン、およびグリシンなどが挙げられるがこれらに限定されるものではないPAT1輸送体のアミノ酸基質は食物中に存在するので、経口投与中のそれらの存在は、ガボキサドールの吸収に影響を及ぼしうる。さらに詳しくは、L-トリプトファンなどのPAT1阻害剤は、ガボキサドールの吸収速度定数kaおよびCmaxを減少させ、Tmaxを増加させることができる(たとえば、Larsenら、Br. J. Pharmacol.、157(8):1380-1389(2009)およびWO 2009/056146を参照)。したがって、経口経路によるガボキサドール摂取の有意な変動ゆえに、静脈内投与は、経口投与よりも血漿レベル(および脳レベル)の制御を改善することができると考えられる。さらに、素因のある個体におけるガボキサドールの高いピーク濃度は、幻覚を引き起こし、一部の患者への薬物投与の中止をもたらしている。静脈内デリバリーは、高いピークCmaxが観察されないことを確実にする用量を漸増する能力を提供し、この潜在的な有害事象を回避するのに役立つ。
開示する組成物は、典型的には、神経変性疾患または障害または中枢神経系障害、特に患者に二次性不眠症をもたらすものを有する患者に投与される。神経変性は、ニューロンの死などのニューロンの構造または機能の進行性喪失を意味する。例示的な疾患および障害を以下に示す。一部の実施態様において、組成物は、神経変性疾患または障害を有していない患者に投与される。
一部の実施態様において、開示する組成物は、神経変性疾患の1つ以上の分子または臨床症状、または神経変性を引き起こす1つ以上のメカニズムを低減化または防止するために有効量で、それを必要とする患者に投与される。神経変性疾患の症状は、当技術分野では公知であり、疾患によって異なる。一部の実施態様において、疾患は、以下の症状または疾患の1つまたは任意の組み合わせを示すか、またはそれによって特徴付けられる:ストレス、不安症、季節性うつ病、不眠症および疲労、統合失調症、パニック発作、憂鬱、食欲の調節における機能不全、不眠症、精神病性障害、てんかん、老人性認知症、正常または病的老化に起因する種々の障害、片頭痛、記憶喪失、脳循環障害、心臓血管の病状、消化器系の病状、食欲障害による疲労、肥満、疼痛、精神病性障害、糖尿病、老人性認知症、または性機能障害が挙げられる。一部の実施態様において、患者は、上記の症状の1つ以上を示さない。
本明細書に開示する方法は、神経変性疾患または障害を有する患者を治療するために使用されうる。例示的神経変性疾患として、パーキンソン病(PD)およびPD関連障害、ハンチントン病(HD)、筋萎縮性側索硬化症(ALS)、アルツハイマー病(AD)および他の認知症、クロイツフェルト・ヤコブ病などのプリオン病、大脳皮質基底核変性症、前頭側頭型認知症、HIV関連認知障害、軽度認知障害、運動ニューロン疾患(MND)、脊髄小脳失調症(SCA)、脊髄性筋萎縮症(SMA)、フリードライヒ失調症、レヴィー小体病、アルパース病、バタン病、脳・眼・顔・骨格症候群、大脳皮質基底核変性症、ゲルストマン-ストロイスラー-シャインカー症候群、クール、リー病、単子葉筋萎縮症、多系統萎縮症、起立性低血圧による多系統萎縮(Shy-Drager症候群)、多発性硬化症(MS)、脳の鉄蓄積を伴う神経変性、オプソクロナス・ミオクローヌス、後皮質萎縮症、原発性進行失調、進行性核上麻痺、血管性認知症、進行性多巣性白質脳症、レビー小体による認知症、ラクナ症候群、水頭症、ヴェルニケ・コルサコフ症候群、脳炎後認知症、癌および化学療法に関連する認知障害および認知症、およびうつ病誘発性認知症および偽認知症が挙げられるが、これらに限定されるものではない。
本明細書に開示する方法を用いて、ハンチントン病の患者を治療することができる。ハンチントン病(HD)は、筋肉調整に影響を及ぼし、認知低下および精神医学的問題を引き起こす神経変性疾患である。HDの慢性病理は、認知機能障害、より具体的には思考および精神的表現における機能不全、判断や推論における変化などの多数の関連する支障につながる。HDは、個体の2コピーのハンチンチン(HTT)遺伝子のいずれかの常染色体優性突然変異によって引き起こされる。この遺伝子の一部は、トリヌクレオチドリピートと呼ばれる反復部分であり、個体間で長さが異なり、世代間で長さが変化する可能性がある。反復が健常な遺伝子に存在する場合、動的突然変異は反復回数を増加させ、遺伝子欠損をもたらす可能性がある。この繰り返し部分の長さが一定の閾値に達すると、それは突然変異ハンチンチンタンパク質(mHtt)と呼ばれる変化した形態のタンパク質を産生する。これらのタンパク質の異なる機能が、疾患の症状を引き起こす病理学的変化の原因である。ハンチントン病の突然変異は、遺伝的に優性でほぼ完全に浸透性である。ヒトのHTT遺伝子のいずれかの突然変異は、この疾患を引き起こし得る。ハンチントン病の身体的症状は、乳児期から老齢期までのあらゆる年齢で開始しうるが、通常、35〜44歳で開始する(Walkerら、Lancet、369(9557):218-28(2007))。
特定の実施態様において、開示する組成物は、パーキンソン病の患者またはパーキンソニズムもしくはパーキンソン症候群に苦しむ患者を治療するために用いられる。PDは中枢神経系の変性疾患である。一部の実施態様において、患者は、本明細書および他の文献で考察したものなどの、1つ以上のPDの臨床症状、1つ以上のPDの分子症状、またはそれらの組み合わせを示す。PDの症状は、当技術分野で公知であり、Jankovicら、J. Neurol. Neurosurg. Psychiatr.、79(4): 368-76(2007)に概説されている。パーキンソン病の運動症状は、中脳の領域である黒質中のドーパミン生成細胞の死に起因する。細胞死の原因は不明のままである。この病気の初期には、最も顕著な症状は運動関連の症状であり、振戦、こわばり、動きの遅さ、歩行および足取りの困難性が挙げられるが、これらに限定されるものではない。特に、PDの特徴である4つの運動症状は、振戦、こわばり、動きの遅さ、および姿勢の不安定性である。主な運動症状は、まとめてパーキンソニズムまたは「パーキンソン症候群」と呼ばれる。
本明細書中に開示する方法は、筋萎縮性側索硬化症を有する患者を治療するために使用され得る。筋萎縮性側索硬化症(ALS)は、致命的な運動ニューロン疾患であり、一次および二次運動ニューロンに影響を及ぼす。ALSの進行は、脊髄の前角における脱髄に関連する運動ニューロンの変性を特徴とする。病因は部分的にしか理解されていない。5〜10%の家族性症例のうち、20%がスーパーオキシドジスムターゼ1(SOD1)遺伝子の変異を有する。この突然変異は、散発性症例の5%にも存在する(Rowlandら、New Engl J Med、44:1688-1700(2001))。家族性症例の3〜4%は、TDP-43またはFUS遺伝子の病原性変異体によるものである(Mackenzieら、Lancet Neurol.、9:995-1007(2010))。
本明細書に開示する方法を用いて、アルツハイマー病の患者を治療することができる。アルツハイマー病(AD)は、最も一般的な型の認知症である。ADの原因と進行は完全には解明されていないが、研究から、脳内のプラークおよび絡みが病態生理学的役割を果たすことが示されている。現在の治療は、疾患の症状を支援するのみであり、病気の進行を停止または逆行させる利用可能な治療法はない。
もう1つの特定の実施形態において、開示する組成物は、外傷性脳損傷(TBI)に罹患している患者を治療するために使用される。外傷性脳損傷は、外部からの機械的な力、典型的には頭部外傷が、脳機能障害を引き起こす場合に起こる。
持続性抑制を増加させるための4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)、その誘導体、またはその医薬的に許容しうる塩を用いる方法も提供される。方法は、持続性抑制における欠乏または欠陥を特徴とする障害を有する患者における持続性抑制を増加させるために使用することができる。例示的な疾患として、脆弱X症候群またはアンジェルマン症候群などの神経原性疾患が挙げられる。
1.持続性抑制
患者における持続性抑制を増加させるための開示する方法は、典型的に、患者の脳における持続性抑制を増加させるために、それを必要とする患者に、有効量のTHIPまたはその誘導体を投与することを含む。
開示される持続性抑制を増加させる方法は、典型的には、それを必要とする患者に、有効量のTHIPまたはその誘導体を投与することを含み、好ましくは、上記でより詳細に考察されたものなどの医薬的に許容しうる組成物である。
一部の実施態様において、持続性抑制を必要とする患者は、神経原性疾患を有する患者である。一部の実施態様において、組成物は、疾患の1つ以上の症状または表現型を低減化または予防するために有効量で投与される。疾患および症状については、以下でより詳細に考察する。
一部の実施態様において、組成物は、アンジェルマン症候群を有する患者を治療するために使用される。アンジェルマン症候群は、母系遺伝性染色体15上の遺伝子の欠失または不活性化によって引き起こされる神経原性障害であり、正常な配列であってもよい父系コピーは刷り込まれ、沈黙する。プラダー・ウィリー症候群は、父系遺伝性遺伝子の同様の欠失および母系刷り込みによって引き起こされる。
組成物は、脆弱X症候群(FXS)を有する患者を治療するために使用される。脆弱X症候群は、神経原性障害である。それは、最も一般的な単一遺伝子を原因とする自閉症であり、特に少年における知的障害の遺伝的原因である。FXSは、X染色体上の脆弱X精神遅滞1(FMR1)遺伝子に影響を及ぼすCGGトリヌクレオチドリピートの拡大に関連する。正常な個人において、このDNAセグメントは5〜約40回反復される。脆弱X症候群を有する人々では、CGGセグメントは200回以上繰り返され、遺伝子のサイレンシングをもたらす。FMR1の喪失または不足(欠陥)は、神経系機能を崩壊させ、脆弱X症候群の徴候や症状を引き起こす。
一部の実施態様において、組成物は、脳萎縮高アンモニア血症(cerebroatrophic hyperammonemia)とも呼ばれるレット症候群を有する患者を治療するために使用される。レット症候群は、ほとんどの場合、女性に影響を与える神経発達障害である。遺伝的に、レット症候群は、最も典型的には、X染色体上に位置する遺伝子MECP2の突然変異によって引き起こされる。この突然変異は、散発的にまたは生殖系列突然変異から生じうるが、典型的には遺伝されない。10%未満のレット症候群では、遺伝子CDKL5またはFOXG1の突然変異も見出されている。レット症候群は、最初は臨床観察によって診断されるが、MECP2遺伝子に遺伝的欠損がある場合には診断は確定的である。
一部の実施態様において、組成物は、アスペルガー症候群、広汎性発達障害、他に特定されていない広汎性発達障害(PDD-NOS)、自閉症障害、または別の自閉症スペクトラムを有する患者を治療するために使用される。
一部の実施態様において、THIPまたはその誘導体は、1つ以上のさらなる活性薬剤と組み合わせて投与される。併用療法として、同じ混合物中で、または別々の混合物中での活性薬剤の共投与を挙げることができる。したがって、一部の実施態様において、医薬組成物は、2種、3種、またはそれ以上の活性薬剤を含む。そのような製剤は、典型的には、有効量のTHIPまたは誘導体を含む。異なる活性薬剤は、同一または異なる作用機序を有することができる。一部の実施態様において、併用は、疾患または障害の治療に対して相加的な効果をもたらす。一部の実施態様において、併用は、疾患または障害の治療に対して相乗効果をもたらす。
本発明の態様には、以下のものが含まれる。
[1] 患者のニューロンの持続性抑制を増加させるために、神経変性疾患、神経原性障害または中枢神経系障害を有するヒト患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者におけるニューロンの持続性抑制を増加させる方法。
[2] 患者が、脆弱X症候群または脆弱X関連振戦/運動失調症候群(FXTAS)を有する、[1]に記載の方法。
[3] 患者が、アンジェルマン症候群を有する、[1]に記載の方法。
[4] 患者におけるニューロンの持続性抑制を増加させるために、脆弱X症候群または脆弱X関連振戦/運動失調症候群を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者における脆弱X症候群または脆弱X関連振戦/運動失調症候群を治療または予防する方法。
[5] 患者におけるニューロンの持続性抑制を増加させるために、アンジェルマン症候群を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者におけるアンジェルマン症候群を治療または予防する方法。
[6] THIPまたはその誘導体の量が、患者において副作用を引き起こすのに有効でない、[1]〜[5]のいずれか1つに記載の方法。
[7] 患者における徐波睡眠(SWS)および/または徐波活動(SWA)を増加させ、睡眠構築を正常化し、二次性不眠症を減少させ、ノンレム(非急速眼球運動(non-rapid eye movement))(NREM)睡眠を増加させ、睡眠の連続性を高め、NREM内のデルタ活動を強化し、総睡眠時間(TST)を増加または改善し、睡眠効率を増加または改善し、総覚醒時間(TAA)を短縮し、覚醒回数を減らし(NWA)、持続睡眠潜時(LPS)を短縮し、中途覚醒(WASO)を減少させるため、または患者におけるそれらの任意の組合せのために、神経変性疾患または中枢神経系障害を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者における二次性不眠症を治療する方法。
[8] 患者における徐波睡眠を増加させるために、神経変性疾患または中枢神経系障害を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者における徐波睡眠を増加させる方法。
[9] 神経変性疾患が、パーキンソン病(PD)およびPD関連障害、アルツハイマー病(AD)および他の認知症、クロイツフェルト・ヤコブ病などのプリオン病、大脳皮質基底核変性症、前頭側頭型認知症、HIV関連認知障害、軽度認知障害、運動ニューロン疾患(MND)、脊髄小脳失調症(SCA)、脊髄性筋萎縮症(SMA)、フリードライヒ失調症、レヴィー小体病、アルパース病、バタン病、脳・眼・顔・骨格症候群、大脳皮質基底核変性症、ゲルストマン-ストロイスラー-シャインカー症候群、クール、リー病、単子葉筋萎縮症、多系統萎縮症、起立性低血圧による多系統萎縮(Shy-Drager症候群)、多発性硬化症(MS)、脳の鉄蓄積を伴う神経変性、オプソクロナス・ミオクローヌス、後皮質萎縮症、原発性進行失調、進行性核上麻痺、血管性認知症、進行性多巣性白質脳症、レビー小体による認知症、ラクナ症候群、水頭症、ヴェルニケ・コルサコフ症候群、脳炎後認知症、癌および化学療法に関連する認知障害および認知症、およびうつ病誘発性認知症および偽認知症からなる群より選ばれる、[7]または[8]のいずれかに記載の方法。
[10] 神経変性疾患が、ハンチントン病である、[9]に記載の方法。
[11] 神経変性疾患が、パーキンソン病である、[9]に記載の方法。
[12] 神経変性疾患が、筋萎縮性側索硬化症である、[9]に記載の方法。
[13] 神経変性疾患が、アルツハイマー病である、[9]に記載の方法。
[14] 患者が、神経変性疾患と臨床的に診断されていない、[7]〜[13]のいずれか1つに記載の方法。
[15] 患者が、神経変性疾患の有意な身体症状を有しないか、または臨床症状が、神経変性疾患の肯定的な診断には軽度すぎる、[7]〜[13]のいずれか1つに記載の方法。
[16] 患者が、神経変性疾患であると臨床的に診断されている、[7]〜[13]のいずれか1つに記載の方法。
[17] THIPまたはその誘導体が、THIPまたはその医薬的に許容しうる塩である、[1]〜[16]のいずれか1つに記載の方法。
[18] THIPまたはその誘導体が、唯一の活性剤である、[1]〜[17]のいずれか1つに記載の方法。
[19] 医薬組成物が、有効量のTHIPまたはその誘導体および1種以上の医薬的に許容しうる担体もしくは賦形剤からなる、[1]〜[18]のいずれか1つに記載の方法。
[20] 医薬組成物が、持続放出用に製剤化される、[1]〜[19]のいずれか1つに記載の方法。
[21] 医薬組成物が、24〜48時間毎に1回投与される、[1]〜[20]のいずれか1つに記載の方法。
[22] 医薬組成物が、経皮的に投与される、[1]〜[21]のいずれか1つに記載の方法。
[23] 医薬組成物が、医薬組成物を含む経皮パッチを患者の皮膚に接触させることによって投与される、[22]に記載の方法。
[24] 医薬組成物が、患者に朝または夕方に投与される、[1]〜[23]のいずれか1つに記載の方法。
[25] THIPまたはその誘導体の1日投与量が、約1 mg〜20 mgである、[1]〜[24]のいずれか1つに記載の方法。
[26] 医薬組成物が、患者に静脈内投与される、[1]〜[24]のいずれか1つに記載の方法。
[27] 患者が投与される、THIPまたはその誘導体の1日投与量が約0.001 mg〜30 mgである、[26]に記載の方法。
[28] THIPまたはその誘導体が、0.001mg/kg/時間〜1 mg/kg/時間の速度で投与される、[27]に記載の方法。
Claims (28)
- 患者のニューロンの持続性抑制を増加させるために、神経変性疾患、神経原性障害または中枢神経系障害を有するヒト患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者におけるニューロンの持続性抑制を増加させる方法。
- 患者が、脆弱X症候群または脆弱X関連振戦/運動失調症候群(FXTAS)を有する、請求項1に記載の方法。
- 患者が、アンジェルマン症候群を有する、請求項1に記載の方法。
- 患者におけるニューロンの持続性抑制を増加させるために、脆弱X症候群または脆弱X関連振戦/運動失調症候群を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者における脆弱X症候群または脆弱X関連振戦/運動失調症候群を治療または予防する方法。
- 患者におけるニューロンの持続性抑制を増加させるために、アンジェルマン症候群を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者におけるアンジェルマン症候群を治療または予防する方法。
- THIPまたはその誘導体の量が、患者において副作用を引き起こすのに有効でない、請求項1〜5のいずれか1つに記載の方法。
- 患者における徐波睡眠(SWS)および/または徐波活動(SWA)を増加させ、睡眠構築を正常化し、二次性不眠症を減少させ、ノンレム(非急速眼球運動(non-rapid eye movement))(NREM)睡眠を増加させ、睡眠の連続性を高め、NREM内のデルタ活動を強化し、総睡眠時間(TST)を増加または改善し、睡眠効率を増加または改善し、総覚醒時間(TAA)を短縮し、覚醒回数を減らし(NWA)、持続睡眠潜時(LPS)を短縮し、中途覚醒(WASO)を減少させるため、または患者におけるそれらの任意の組合せのために、神経変性疾患または中枢神経系障害を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者における二次性不眠症を治療する方法。
- 患者における徐波睡眠を増加させるために、神経変性疾患または中枢神経系障害を有する患者に、有効量の4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)またはその誘導体および医薬的に許容しうる担体もしくは賦形剤を含む医薬組成物を投与することを含む、患者における徐波睡眠を増加させる方法。
- 神経変性疾患が、パーキンソン病(PD)およびPD関連障害、アルツハイマー病(AD)および他の認知症、クロイツフェルト・ヤコブ病などのプリオン病、大脳皮質基底核変性症、前頭側頭型認知症、HIV関連認知障害、軽度認知障害、運動ニューロン疾患(MND)、脊髄小脳失調症(SCA)、脊髄性筋萎縮症(SMA)、フリードライヒ失調症、レヴィー小体病、アルパース病、バタン病、脳・眼・顔・骨格症候群、大脳皮質基底核変性症、ゲルストマン-ストロイスラー-シャインカー症候群、クール、リー病、単子葉筋萎縮症、多系統萎縮症、起立性低血圧による多系統萎縮(Shy-Drager症候群)、多発性硬化症(MS)、脳の鉄蓄積を伴う神経変性、オプソクロナス・ミオクローヌス、後皮質萎縮症、原発性進行失調、進行性核上麻痺、血管性認知症、進行性多巣性白質脳症、レビー小体による認知症、ラクナ症候群、水頭症、ヴェルニケ・コルサコフ症候群、脳炎後認知症、癌および化学療法に関連する認知障害および認知症、およびうつ病誘発性認知症および偽認知症からなる群より選ばれる、請求項7または8のいずれかに記載の方法。
- 神経変性疾患が、ハンチントン病である、請求項9に記載の方法。
- 神経変性疾患が、パーキンソン病である、請求項9に記載の方法。
- 神経変性疾患が、筋萎縮性側索硬化症である、請求項9に記載の方法。
- 神経変性疾患が、アルツハイマー病である、請求項9に記載の方法。
- 患者が、神経変性疾患と臨床的に診断されていない、請求項7〜13のいずれか1つに記載の方法。
- 患者が、神経変性疾患の有意な身体症状を有しないか、または臨床症状が、神経変性疾患の肯定的な診断には軽度すぎる、請求項7〜13のいずれか1つに記載の方法。
- 患者が、神経変性疾患であると臨床的に診断されている、請求項7〜13のいずれか1つに記載の方法。
- THIPまたはその誘導体が、THIPまたはその医薬的に許容しうる塩である、請求項1〜16のいずれか1つに記載の方法。
- THIPまたはその誘導体が、唯一の活性剤である、請求項1〜17のいずれか1つに記載の方法。
- 医薬組成物が、有効量のTHIPまたはその誘導体および1種以上の医薬的に許容しうる担体もしくは賦形剤からなる、請求項1〜18のいずれか1つに記載の方法。
- 医薬組成物が、持続放出用に製剤化される、請求項1〜19のいずれか1つに記載の方法。
- 医薬組成物が、24〜48時間毎に1回投与される、請求項1〜20のいずれか1つに記載の方法。
- 医薬組成物が、経皮的に投与される、請求項1〜21のいずれか1つに記載の方法。
- 医薬組成物が、医薬組成物を含む経皮パッチを患者の皮膚に接触させることによって投与される、請求項22に記載の方法。
- 医薬組成物が、患者に朝または夕方に投与される、請求項1〜23のいずれか1つに記載の方法。
- THIPまたはその誘導体の1日投与量が、約1 mg〜20 mgである、請求項1〜24のいずれか1つに記載の方法。
- 医薬組成物が、患者に静脈内投与される、請求項1〜24のいずれか1つに記載の方法。
- 患者が投与される、THIPまたはその誘導体の1日投与量が約0.001 mg〜30 mgである、請求項26に記載の方法。
- THIPまたはその誘導体が、0.001mg/kg/時間〜1 mg/kg/時間の速度で投与される、請求項27に記載の方法。
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