JP2011521908A - チオレドキシンが細胞における一酸化窒素放出を調節するという知見に基づく疾患の治療法 - Google Patents
チオレドキシンが細胞における一酸化窒素放出を調節するという知見に基づく疾患の治療法 Download PDFInfo
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- JP2011521908A JP2011521908A JP2011508506A JP2011508506A JP2011521908A JP 2011521908 A JP2011521908 A JP 2011521908A JP 2011508506 A JP2011508506 A JP 2011508506A JP 2011508506 A JP2011508506 A JP 2011508506A JP 2011521908 A JP2011521908 A JP 2011521908A
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- nitric oxide
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Classifications
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Abstract
Description
本願は、2008年5月9日出願の、米国仮出願第61/071631号の優先権を主張し、その全体を出典明示により本明細書の一部とする。
本発明は、1の実施態様において、一酸化窒素欠乏に付随する疾患または一酸化窒素の要求の治療法を対象とし、第2の実施態様において、一酸化窒素シンターゼ過剰発現または活性増大に付随する疾患の治療法を対象とする。
ストレス状態では、タンパク質ジスルフィドは、正常なタンパク質の機能を妨害する体内において形成する。体内に存在するチオレドキシン系(すなわち、チオレドキシン/チオレドキシンレダクターゼ)がジスルフィド基をシステインに還元することによって、正常なタンパク質の機能を回復させることは知られている。この還元の結果として、チオレドキシンは酸化され、一時的に不活性になる。体内に存在するチオレドキシンレダクターゼが酸化チオレドキシンの還元を引き起こすことによって、その活性および機能を回復させることは知られている。
チオレドキシン系(特に文章中に明記しない限り、以下、Trx)がシステイン含有タンパク質の脱ニトロソ化によって細胞における内因性一酸化窒素の放出を調節することは本発明にて見出された。その結果として、Trxレダクターゼ阻害薬が細胞における一酸化窒素の増大をもたらし、TrxレダクターゼアップレギュレーションおよびTrx阻害薬が細胞における一酸化窒素の低下をもたらすことになる。
現在、本発明者らは本明細書における第1の実施態様を検討する。
治療に対して反応しなかった大細胞リンパ腫を罹患している50歳は、1ヵ月ごとに6mgオーラノフィンおよび50mg二硝酸イソソルビドを1日1回経口投与された。CATスキャンによって測定されるように、腫瘍組織量は減少する。
再発性再狭窄を罹患している60歳は、0.15mg/kg/日の三酸化ヒ素静注および60mg一硝酸イソソルビド/日または1日最大4回1〜2インチのニトログリセリンパッチのいずれかを投与される。1ヵ月後、疾患は軽減し、血栓性合併症の発症は消失し、再狭窄は再発しない。
パーキンソン病を罹患している70歳は、30日間、300mgのN−アセチルシステインおよび髄液への注入量(範囲が10μg〜2mgの体重でありうる)0.3mgのパーキンを対象とするアプタマーが経口投与される。運動を改善する。次いで、アスコルビン酸塩1mg/日を加え、器用性をさらに改善する。
次いで、アルツハイマー病を罹患している75歳は、1日3回、NAC(300mg/日)、アスコルビン酸塩1mg/日およびミノサイクリン100mgの組み合わせで開始され、記憶力を改善する。
筋ジストロフィーを罹患している13歳は、デプレニル10mg/日+二硝酸イソソルビド(ISDN)10mg/日を投与され、筋力低下を改善する。1日2回ミノサイクリン300mgを加え、6分の歩行試験においてさらに改善される。
アルツハイマー病を罹患している65歳は、デプレニル15mgおよびS−ニトロソグルタチオン10mgを1日3回経口投与される。血圧は変化しないが、記憶力は改善される。
関節リウマチを罹患している40歳は、デプレニル10mg+アスコルビン酸塩1mg+ISDN 5mgまたは+システインもしくはNaHS(10μM〜1mMの血中最終濃度)を1日2回経口投与される。疾患の進行を遅くする。
セントラルコア病を罹患している40歳は、悪性高熱(MH)を伴う膵臓癌および経過の手術を受ける。患者は、デプレニル10mgおよびISDN 5mgを1日2回経口投与され、MHを急激に軽減し、筋機能を徐々に改善する。
敗血症性ショックを罹患している40歳は、TrxIPの遺伝子療法を受け、15mg/kg L−NMMA(2mg/kgの1日2回静注)を静注される。血圧を増大させ、安定にする。
膵臓癌を罹患している40歳は、TrxIPの遺伝子療法を受け、1日当たり10mgのアスコルビン酸ナトリウムを注入される。癌を退縮させる。
膠芽細胞腫を罹患している70歳は、6時間ごとに投与される6mgオーラノフィンおよび50mg二硝酸イソソルビドまたは6mgオーラノフィンおよび150mg/m2 BCNUまたは2.5mgオーラノフィンおよび2mg L−BSOを含有するカプセルを経口投与される。癌の退縮が起こる。
前述の本発明の説明は、ある使用可能なおよび好ましい実施態様を記載することを示している。その変更および修正が当業者に自明であり、そのすべてが本発明の精神および範囲内にあるので、本発明は非常に限定されるべきものであることを意図とするものではない。
Claims (10)
- 高レベルのチオレドキシン系もしくは一酸化窒素の要求に付随する疾患を罹患している患者または一酸化窒素から恩恵を受ける患者の治療方法であって、治療上有効な量のチオレドキシン系阻害薬および一酸化窒素供与化合物または内因性一酸化窒素レベルを上昇させる化合物を投与することを含む、方法。
- 疾患が、アポトーシス、高レベルのチオレドキシン系または一酸化窒素の治療的要求に付随する癌、鎌状赤血球病、心不全、インポテンス、ぜんそく、嚢胞性線維症、高血圧、再狭窄、および感染症からなる群より選択される、請求項1記載の方法。
- 一酸化窒素供与化合物が、一硝酸イソソルビド、二硝酸イソソルビド、亜硝酸エチル、亜硝酸アミル、ニトログリセリン、ニトロソチオールおよびニトロプルシドからなる群より選択され、チオレドキシン系阻害薬が、ヒ素剤、オーラノフィンおよび他の金化合物、Trx系に対するアンチセンス、チオレドキシンレダクターゼ発現を阻害するsiRNAおよびチオレドキシンレダクターゼ発現を抑制するshRNAからなる群より選択される、請求項2記載の方法。
- 一酸化窒素シンターゼの過剰発現または活性増大に付随する疾患を罹患している患者の治療方法であって、治療上有効な量のチオレドキシン系アップレギュレーターもしくはアクチベーターおよび/またはチオレドキシン系のアップレギュレーターもしくはアクチベーターおよび体内の一酸化窒素の喪失をもたらす物質を患者に投与することを含む、方法。
- 疾患が、パーキンソン病、骨格筋の先天性疾患、筋力低下/疲労性糖尿病、敗血症性ショック、一酸化窒素シンターゼの過剰発現または活性増大に付随する癌、潰瘍性大腸炎、関節炎および成人呼吸窮迫症候群(ARDS)からなる群より選択される、請求項4記載の方法。
- チオレドキシン系アップレギュレーターまたはアクチベーターが、チオレドキシンレダクターゼ発現のための遺伝子療法剤、チオレドキシンレダクターゼ阻害薬を阻害するタンパク質の阻害薬、チオレドキシンレダクターゼ阻害薬に対するアンチセンス、低用量のNO、または硫化水素、およびチオレドキシンレダクターゼ阻害薬に結合するアプタマーからなる群より選択され、体内の一酸化窒素の喪失をもたらす薬剤が、一酸化窒素シンターゼ阻害薬、アスコルビン酸塩、L−システイン、硫化水素、デプレニルおよびN−アセチルシステインからなる群より選択される、請求項4記載の方法。
- 治療上有効な量のチオレドキシン系阻害薬およびニトロソ化ストレスを増大する物質を含む組成物。
- ニトロソ化ストレスを増大する物質が一酸化窒素供与化合物である、請求項7記載の組成物。
- ニトロソ化ストレスを増大する物質がデニトロシラーゼ阻害薬である、請求項7記載の方法。
- ニトソロ化ストレスを増大する物質がグルタチオン合成阻害薬である、請求項7記載の方法。
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PCT/US2009/002825 WO2009137071A1 (en) | 2008-05-09 | 2009-05-07 | Treatment for diseases relying on discovery that thioredoxin mediates nitric oxide release in cells |
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WO2009137071A1 (en) | 2009-11-12 |
AU2009244790A1 (en) | 2009-11-12 |
EP2297183A4 (en) | 2012-07-04 |
EP2297183A1 (en) | 2011-03-23 |
US20110104308A1 (en) | 2011-05-05 |
US20160106773A1 (en) | 2016-04-21 |
AU2009244790B2 (en) | 2013-09-12 |
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