JP5512275B2 - 放射線傷害治療のための三置換グリセロール化合物の使用 - Google Patents
放射線傷害治療のための三置換グリセロール化合物の使用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
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- Epidemiology (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Medicinal Preparation (AREA)
Description
病率を低下させ、プラチナ含有剤に関連する累積的腎毒性を軽減し、頭部または頸部癌のために放射線療法を受けている患者の口腔乾燥症の発生率を低下させるために、アミフォスチンを使用する。しかしながらアミフォスチンは、放射線への曝露のすぐ前に投与した場合にのみ、放射線防護剤として有効であることが示されている。放射線への曝露後に投与しても療法的効果はない。さらに、アミフォスチンまたは関連チオール化合物の投与は、全身性の細胞毒性に加えて悪心および嘔吐のような胃腸不適合のような、目立つ有害な副作用と関連性がある。
血小板活性化因子(PAF;1−O−アルキル−2−アセチル−sn−グリセロ−3−ホスホコリン)の合成類似体を代表するもので、血小板凝集、炎症およびアナフィラキシーを含めた多くの白血球機能の、強力な燐脂質活性化剤兼媒介剤である。従来のほとんどの化学療法薬とは異なり、これらの合成エーテル脂質は、細胞DNAを直接の標的とせず、むしろ、原形質膜の脂質組成に影響を与え、かつ様々なシグナル伝達経路を妨害する、もしくはそのいずれかを行う。よって、それらの作用形態は、特定の細胞受容体の存在に依存しないものであるか、または細胞周期に依存する。
しくはそのいずれかの医薬品の製造のための使用に関するものであり、式中、
Xは、燐酸塩および硫酸塩から成る群から選択され、
R1は、C16〜C20アルキルから成る群から選択され、
R2は、C1〜C3アルキルおよびC1〜C3ヒドロキシアルキルから成る群から選択され、
R3は、水素およびC1〜C3アルキルから成る群から選択され、
R4は、C1〜C3アルキルおよびC3〜C6シクロアルキルから成る群から選択され、R5は、水素およびメチルから成る群から選択される。
い。
好ましくは、固体剤型は腸溶剤型である。つまり、固体剤型は、胃内、すなわちpH値が2.5以下の範囲の酸性環境では、安定したままである。これは、被膜を有する固体剤型を提供することにより達成してもよい。例えば、本発明の剤型は、いわゆるフィルム錠剤の形であってもよい。
。
中性子線は、しばしば、間接電離放射線と呼ばれる。中性子線は、陽子、光子および電子と同じやり方では原子を電離させない。その理由は、中性子には電荷がないためである。しかしながら、例えば、中性子吸収によりガンマ線が放出され、その後、ガンマ線により原子から電子が取り除かれるか、または中性子相互作用により反跳する原子核が電離し
、その後、その他の原子で、より従来型の電離が生じる場合、中性子相互作用は大部分が電離している。中性子は、荷電していないため、アルファ線(ヘリウム原子核)およびベータ線(電子または陽電子)より貫通性がある。いくつかの事例では、中性子はガンマ線(電磁放射線)より貫通性があり、ガンマ線は、高い原子番号の物質内では妨げられる。
(半)致死放射線量により引き起こされた急性放射線傷害の治療での、放射線防護剤としての1−O−オクタデシル−2−O−メチル−グリセロ−3−ホスホコリン(以下「ET18−OCH3」と呼ぶ)の効力を、マウス生存率と、様々な種類の放射線に応じた放射線傷害の血液症候群とに対するその影響を割り出すことにより分析した。
(実施例1)X線に対するET18−OCH3の効力
650cGy(センチグレイ)のX線量への曝露の12時間後に、25匹のマウスに、25mg/kgのET18−OCH3の単回投与を一度に静脈内投与した。処置マウスでは25匹中1匹だけが死亡したのに比べ、対照群のマウスでは25匹中6匹が死亡した。
(表1)照射の各々6時間後および12時間後に2×25mg/kgのET18−OCH3を投与した後の、X線照射マウスの生存率
から749±37.1cGyに増加した。X線が媒介する致死は、対照マウスに比べて処置マウスでは遅くなった。
(実施例2)中性子線に対するET18−OCH3の効力
ヴァンドグラーフ起電機を用いて3〜8MeV中性子でマウスを照射した。以下の分析で用いた放射線量は、処置および対照マウスの各3分の1について、各々400、410および420cGyであった。マウスの半分に、50mg/kgのET18−OCH3の単回投与を皮下注射により投与した。得られた結果を表2に示す。
(表2)400〜420cGyの中性子線に曝露し様々な時点で50mg/kgのET18−OCH3を皮下注射した後の、マウスの生存率。処置動物対対照動物を比較するためにカイ二乗検定を用いた。
(表3)300cGyの中性子照射に曝露し照射の各々2時間後および30分後に50mg/kgのET18−OCH3を皮下注射した後、7日目および14日目のマウスの末梢血内の細胞数の変化。様々な種類の1μL当たり細胞について、メジアン/四分位間距離を示す。血小板については、1000細胞/μL単位で数値を示す。ウィルコクソン・マン・ホイットニーのU検定を、対照動物対処置動物の比較に用いた(p値)。
ET18−OCH3による予防処置の、ガンマ線照射マウスの生存率に対する効果を、表4に要約する。
(表4)ガンマ線を照射し各々照射への曝露前または放射線照射後(a.r.)の様々な時点でET18−OCH3の単回投与を投与した後の、マウスの生存率。処置動物対対照動物を比較するためにカイ二乗検定を用いた。
(実施例4)中性子線適用前のET18−OCH3の効力
異なる中性子線量の適用前のET18−OCH3の、マウスの生存率に対する効果を、表5に要約する。
(表5)中性子照射の1日前に皮下投与したET18−OCH3の効果。処置動物対対照動物を比較するためにカイ二乗検定を用いた。
各々50mg/kgおよび70mg/kgのET−18−OCH3を投与し中性子照射に曝露した後、白血球数(リンパ球と顆粒球との両方)の減少が、無処置対照に比べ、わずかに増大した(統計的に有意ではない;5実験、n=90)。
う承認ではない。
Claims (10)
- 下記式(I)に従った三置換グリセロール化合物、
Xが、
R1が、C16〜C20アルキルから成る群から選択され、
R2が、C1〜C3アルキルおよびC1〜C3ヒドロキシアルキルから成る群から選択され、
R3が、水素およびC1〜C3アルキルから成る群から選択され、
R4が、C1〜C3アルキルおよびC3〜C6シクロアルキルから成る群から選択され、
R5が、水素およびメチルから成る群から選択され、前記医薬品は経口投与用の固体の剤型である、医薬品。 - Xが
- 前記医薬品内の前記三置換グリセロール化合物の量が、30〜250mgの範囲である、請求項1〜2のいずれかに記載の医薬品。
- 前記三置換グリセロール化合物の1日用量が、50〜350mgの範囲である、請求項1〜3のいずれかに記載の医薬品。
- 前記放射線損傷または傷害が電離放射線により引き起こされる、請求項1〜4のいずれかに記載の医薬品。
- 前記放射線損傷または傷害が癌療法に関連するものである、請求項1〜5のいずれかに記載の医薬品。
- 前記放射線損傷または傷害が、または癌療法中の骨髄移植に関連するものである、請求項1〜6のいずれかに記載の医薬品。
- 1つ以上の細胞の放射線損傷または傷害を予防する生体外での方法であって、前記1つ以上の細胞を、放射線への曝露の前に、請求項1〜7のいずれかに定義した通りの医薬品に接触させるステップを有する生体外での方法(人間を手術、治療する方法を除く)。
- 1つ以上の細胞の放射線損傷または傷害を治療する生体外での方法であって、前記1つ以上の細胞を、請求項1〜7のいずれかに定義した通りの医薬品に接触させるステップを有する生体外での方法(人間を手術、治療する方法を除く)。
- 前記1つ以上の細胞が非癌性細胞である、請求項8または9に記載の生体外での方法(人間を手術、治療する方法を除く)。
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JP2013227341A (ja) * | 2006-11-10 | 2013-11-07 | Radioprotect Alphaptose Ug (Haftungsbeschraenkt) & Co Kg | 放射線傷害治療のための三置換グリセロール化合物の使用 |
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DE3827974A1 (de) * | 1988-08-18 | 1990-02-22 | Boehringer Mannheim Gmbh | Kombinationspraeparate von proteinkinase-c-inhibitoren mit lipiden, lipid-analoga, cytostatica oder inhibitoren von phospholipasen |
DE3918082A1 (de) * | 1989-06-02 | 1991-01-24 | Max Planck Gesellschaft | Mittel gegen autoimmunerkrankungen |
US5082846A (en) * | 1990-08-30 | 1992-01-21 | Sandoz Ltd. | Use of the R-(+)-isomer of 2-methoxy-3-octadecyloxy-propanol-(1)-phosphoric acid, monocholine ester in treating multiple sclerosis |
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US20020102208A1 (en) * | 1999-03-01 | 2002-08-01 | Paul Chinn | Radiolabeling kit and binding assay |
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DK2089401T3 (da) | 2012-09-17 |
RU2448973C2 (ru) | 2012-04-27 |
AU2007316589B2 (en) | 2013-03-07 |
EP2089401B1 (en) | 2012-07-25 |
US20100130449A1 (en) | 2010-05-27 |
EP2089401A1 (en) | 2009-08-19 |
CA2668923A1 (en) | 2008-05-15 |
JP2010509294A (ja) | 2010-03-25 |
WO2008055997A1 (en) | 2008-05-15 |
CA2668923C (en) | 2015-01-13 |
AU2007316589A1 (en) | 2008-05-15 |
RU2009121836A (ru) | 2010-12-20 |
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