JP2009504733A - 心血管(cv)事象を促進する医薬の投与に伴うcv有害事象のリスクを低減させる方法 - Google Patents
心血管(cv)事象を促進する医薬の投与に伴うcv有害事象のリスクを低減させる方法 Download PDFInfo
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Abstract
【選択図】 なし
Description
プロスタグランジンの病理的役割は、リウマチ様疾患及び骨関節炎、発熱、喘息、骨吸収、腎毒性、アテローム性動脈硬化、低血圧、ショック、疼痛、癌及びアルツハイマー病を含む多くのヒト疾患状態に関与している。NSAIDは、疼痛、炎症、及び急性・慢性炎症障害の治療に広く使用される。こうした化合物は、アラキドン酸をプロスタノイドに変換する酵素である酵素シクロオキシゲナーゼ(COX)(プロスタグランジンG/Hシンターゼとしても知られる。)の活性を阻害する。NSAIDは、他のプロスタグランジン、特に、プロスタグランジンG2、プロスタグランジンH2及びプロスタグランジンE2の産生も阻害し、それによりプロスタグランジン誘発性疼痛、及び炎症過程に伴う腫大を低減させる。
(1)1種又は複数種の第1の医薬を、CV有害事象のリスクを低減させるための1種又は複数種の予防医薬と共投与すること、及び
(2)勧告に従って、適切な体重の維持、運動、ストレス解消、及び健康な食習慣(これらに限られない。)を含む、より健全な生活習慣を始めること、
を含む全体計画に着手するように勧告することによって更に低減するであろう。
本明細書において、「心血管(CV)有害事象」又は単なる「心血管(CV)事象」という語は、一般に、進行性の血管損傷から生じる心血管系の障害又は疾患を指す。この事象は、かなり急に発症し得るが、このような障害又は疾患の進行性悪化を指すこともある。CV有害事象の例としては、これらに限定されないが、跛行、高血圧症、心停止、心筋梗塞、虚血、心発作、一過性脳虚血発作、狭心症の悪化、うっ血性心不全、左室肥大、心臓性突然死、不整脈、血栓塞栓症、動脈血栓症及び静脈血栓症が挙げられる。進行性血管疾患の例は、脳循環、冠循環、腎臓循環、又は抹消循環に影響を与える進行性血管疾患である。
虚血性心疾患(IHD)、高血圧症、及び他のCV有害事象を予防するための、現行の標準的な方法は、単にリスク因子の除去又は低減に基づくものである。証拠として、IHDのリスク因子は、変更可能か変更不可能かで2つのグループに分けられる。変更可能なリスク因子は、高血圧症、喫煙、糖尿病、肥満、身体活動、及びアテローム生成性食餌である。変更不可能なリスク因子は、年齢、男性、及び早発性IHDの家族歴である(Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults. Detection,evaluation,and treatment of high blood cholesterol in adults (Adult Treatment Panel III): third report of the National Cholesterol Education Program (NCEP) Expert Panel. Circulation 2002;106:3145−3421)。予想されるように、この報告でのリスク因子の考察は変更可能なグループに限られており、年齢という間違いなく変更不可能なリスク因子を変更することが明らかに不可能であることにより、より高齢の個体の疾患を予防することへの興味が制限されている。
本明細書において、「非ステロイド性抗炎症剤」及び「NSAID」という語は同義であり、抗炎症剤、鎮痛薬及び解熱薬として作用する非ステロイド性の薬物であることを特徴とする非オピオイド鎮痛薬を指す。このクラスの薬物は当分野で周知であり、例えば、Goodman,L.及びGilman,Aの第27章を参照されたい(“The Pharmacological Basis of Therapeutics”,9th edition,Pergamon press,New York,1996)。このクラスの薬物としては、アスピリン等のサリチル酸塩;フェニルブタゾン、オニフェンブタゾン(onyphenbutazone)、アンチピリン、アミノピリン、ジピロン、メタミゾール、フェナゾン、プロピフェナゾン、アパゾン等のピラゾロン誘導体;インドメタシン;スリンダク;メフェナム酸、メクロフェナム酸、フルフェナム酸、トルフェナム酸、エトフェナム酸(etofenamic acid)等のフェナメート;メロキシカム、ピロキシカム、セレコキシブ、バルデコキシブ、ロフェコキシブ等のCOX−2阻害剤;イブプロフェン、スプロフェン、オキサプロジン、カルプロフェン、フェノプロフェン、フェノプロフェンカルシウム等のアリール酢酸化合物及びプロピオン酸化合物;ナプロキセン;インドプロフェン;ケトプロフェン;フルルビプロフェン;並びにトルメチンが挙げられる。ゾメピラックナトリウム;ピロキシカム、テノキシカム、ジフルニサル又はプロクアゾン;アルクロフェナク、ジクロフェナク、エトドラク、ケトロラクトロメタミン、トラドール等のフェニル酢酸誘導体;及びナブメトンを含むクラス内の化合物もNSAIDに含まれる。
本明細書において、「COX−2阻害剤」(場合によっては、「選択的COX−2阻害剤」)及び「COX−2選択的NSAID」は同義であり、COX−2を特異的に阻害し、COX−1に対してほとんど又は全く影響しないNSAIDを指す。例えば、COX−2の50%の阻害を生じる用量では、COX−2阻害剤は、COX−1を10%未満しか阻害しないであろう。
HMG−CoA(3−ヒドロキシ−3−メチルグルタリル−補酵素A)還元酵素は、コレステロール生合成の律速段階を触媒する酵素である。スタチンとしても知られるHMG−CoA還元酵素阻害剤は、HMG−CoA還元酵素の酵素活性を阻害する分子であり、高コレステロール血症を患っている患者を治療するために使用されている。最初のこのような阻害剤(コンパクチン又はメバスタチン)は1976年に単離され(Endo,A. et al. F.E.B.S. Lett.,72: 323−326,1976)、それ以来、多くの他の天然の、又は化学的に修飾されたメバスタチンが同定され、臨床用途のために開発されている。
レニン−アンジオテンシン系(RAS)は、従来より、血液容量、血管緊張及びNaホメオスタシスを調節すると考えられている、内分泌カスケードである。このカスケードの最終の酵素であるアンジオテンシン変換酵素(ACE)は、ペプチドホルモンアンジオテンシンII(Ang II)の産生における重要な触媒である。この酵素は、不活性プロホルモンアンジオテンシンI(Ang I)から2つのアミノ酸を切断することにより、強力な血管収縮薬である、生体的に活性なオクタペプチドAng IIを形成する。更に、ACEは、最初に不活性ペプチドBK 1−7、続いて更にBK 1−5を切断する2段階切断過程で、ブラジキニン(BK)を失活させる(Stewart,Handbook of Inflammation,Volume 6: Mediators of the Inflammatory Process,pp. 189−217,Elsevier Science Publishers (1989))。ACEは、性腺刺激ホルモン放出ホルモン等のいくつかの神経ペプチドを含む他のペプチドを加水分解することもできる(Skigdel and Erdos,J Clin.and Exper.Theory and Practice 19987;A9(2&3):243−259)。
ACE阻害剤は、高血圧症及びCHFの血管拡張剤として主要な役割を有し、これらの障害を治療するための最も効率的な薬物の一つである(例えば、Opie et al. “Angiotensin Converting Enzyme Inhibitors and Conventional Vasodilators,” in Lionel H. Opie,Drugs for the Heart,Third Edition,WB Saunders Company,1991,p106を参照されたい)。いくつかの臨床試験により、心室機能障害に無症候性である患者から、症候性心不全を有するが、正常圧で血行力学的に安定である患者までを含む、心筋梗塞及び心不全を有する広範囲の患者で、ACE阻害剤が生存時間を延ばすことが示されている。例えば、一研究では、重篤な心不全の患者において6カ月での死亡率が40%低減することが実証されている(The CONSENSUS Trial Study Group,N.Engl.J.Med. 1987;316:1429; The CONSENSUS Trial Study Group,N.Engl.J.Med. 1991;325:293)。
アンジオテンシン産生の代替の代謝経路及びACE阻害剤の副作用は、アンジオテンシンIIを遮断する代替法の探索に導いた。アンジオテンシンIIの既知の全ての昇圧効果はAT1受容体によって媒介されるので、これらの受容体を遮断した薬物療法は、理論的にはACE阻害剤の治療効果を共有するであろう。この新しい手法は、アンジオテンシンII受容体拮抗薬(ARB)をもたらした。アンジオテンシンII受容体の最初の遮断は1970年代に酢酸サララシンで達成されたが、これは持続期間が短く、非経口的に投与しなければならなかった。経口的に投与された最初のアンジオテンシンIIタイプI(AT1)受容体拮抗薬であるロサルタンは、1995年に利用可能となった。
本発明の別の実施形態では、(1)NSAIDと、CV有害事象のリスクを低減させるための1種又は複数種の医薬と、を共投与すること、及び/又は(2)より健全な生活習慣を開始する勧告に従うこと、を含む、NSAIDの投与に伴うCV有害事象のリスクを低減させる全体計画である。本明細書で使用する「健全な生活習慣」及び「生活様式作用因子」という語は同義であり、CV有害事象のリスクを低減させる目的で、医師が勧告することができる任意の健全な生活習慣を含む。本発明の実施に適した健全な生活習慣としては、これらに限られないが、運動計画の履行、体重の減量、ストレス解消、適度な水準のアルコールの吸収、ポリミール(polymeal)食事、並びに/或いは、例えば、魚油若しくは魚、ナッツ、及び/又はフラボノイドの多い食事の摂取が挙げられる。勧告は、例えば、医師の勧告であっても、医薬又は添付文書に含まれる勧告であってもよい
前述の任意の活性薬剤は、塩、エステル、アミド、プロドラッグ、活性代謝産物等の形態で投与することができる。但し、塩、エステル、アミド、プロドラッグ、活性代謝産物等は、本発明との関連で、薬学的に許容可能で、薬理学的に活性であるものとする。活性薬剤の塩、エステル、アミド、プロドラッグ又は代謝産物は、有機合成化学の当業者に知られている標準的な方法、及び、例えばJ. March,Advanced Organic Chemistry: Reactions,Mechanisms and Structure,4th Edition (New York: Wiley−Interscience,1992)に記載されている標準的な方法を用いて調製することができる。
上記で検討した方法及び組成物は、任意の剤形又は投与経路に適合する。したがって、薬剤は、経口投与、鼻腔内投与、直腸投与、舌下投与、頬側投与、非経口投与又は経皮投与することができる。剤形としては、錠剤、トローチ、カプセル、カプレット、糖衣丸、ロゼンジ、非経口剤、液体、粉末、及び皮膚表面への埋込又は投与用に設計された製剤が挙げられる。一般に、経口製剤は最も好都合と考えられる。全ての製剤は、当分野で標準的な方法を用いて調製することができる(例えば、Remington’s Pharmaceutical Sciences,16th ed A. Oslo. ed.,Easton,Pa.(1980)、及びより最近の版を参照されたい)。
NSAID、特にCOX−2阻害剤は、疼痛、例えば、片頭痛による疼痛、及び炎症の治療に特に有用である。したがって、本発明は、NSAID、特にCOX−2阻害剤を組み合わせて、CV有害事象のリスクを低減させるための薬剤を投与することによって、これらの状態を治療する方法を含む。これらの薬剤は、共に適時に(co−timely manner)投与され、疼痛又は炎症を低減させるのに十分な量で送達される。一般に、薬物は、互いに24時間以内に投与されるであろう。
治療薬剤に関しては、経験のある医師であれば、臨床医学で十分に確立した方法を用いて、ケースバイケースで用量を調節するものと考えられる。しかし、場合によっては、NSAID、COX−2阻害剤、スタチン、ACE阻害剤及びARBに関する以下の一般指針が役立つ。
表4は、セレコキシブとアトルバスタチンとの共投与のための用量投与計画を提供する。表4に示したように、CELEBREX(登録商標)及びLIPITOR(登録商標)の比は、患者の有効な疼痛軽減の必要性、及び患者の重大なCV有害事象(例えば、心筋梗塞)のリスクに基づいて加減する。例えば、COX−2阻害剤療法の前に梗塞リスクの高い患者には、CELEBREX(登録商標)/LIPITOR(登録商標)を10:1の比で共投与する。COX−2阻害剤療法の前に梗塞リスクの低い患者には、CELEBREX(登録商標)/LIPITOR(登録商標)を20:1の比で共投与する。
表5は、ロフェコキシブとアトルバスタチンとの共投与のための用量投与計画を提供する。表4に示したように、VIOXX(登録商標)及びLIPITOR(登録商標)の比は、患者の有効な疼痛軽減の必要性、及び患者の重大なCV有害事象(例えば、心筋梗塞)のリスクに基づいて加減する。例えば、COX−2阻害剤療法の前に梗塞リスクの高い患者には、VIOXX(登録商標)/LIPITOR(登録商標)を0.625:1の比で共投与する。COX−2阻害剤療法の前に梗塞リスクの低い患者には、VIOXX(登録商標)/LIPITOR(登録商標)を1.25:1の比で共投与する。
表6は、バルデコキシブとアトルバスタチンとの共投与のための用量投与計画を提供する。表4に示したように、BEXTRA(登録商標)及びLIPITOR(登録商標)の比は、患者の有効な疼痛軽減の必要性、及び患者の重大なCV有害事象(例えば、心筋梗塞)のリスクに基づいて加減する。例えば、COX−2阻害剤療法の前に梗塞リスクの高い患者には、BEXTRA(登録商標)/LIPITOR(登録商標)を0.5:1の比で共投与する。COX−2阻害剤療法の前に梗塞リスクの低い患者には、BEXTRA(登録商標)/LIPITOR(登録商標)を1:1の比で共投与する。
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Claims (20)
- CV有害事象のリスクの誘発又は増大を伴う1種又は複数種の第1の医薬で治療される患者において、1種又は複数種のCV有害事象のリスクを低減させる方法であって、
(a)治療有効量の1種又は複数種の第1の医薬と、
(b)1種又は複数種のCV事象のリスクを低減させるのに有効な量の1種又は複数種の予防医薬と、
を含む組合せ薬剤を投与することを含む方法。 - CV有害事象のリスクを誘発又は増大する1種又は複数種の第1の医薬で慢性障害を治療し、同時に患者のCV有害事象のリスクを低減させる方法であって、
(a)治療有効量の1種又は複数種の第1の医薬と、
(b)1種又は複数種のCV事象のリスクを低減させるのに有効な量の1種又は複数種の予防医薬と、
を少なくとも2日間、繰り返し共投与することを含む方法。 - (a)1種又は複数種の第1の医薬がNSAID(アスピリンを除く。)を含み、
(b)1種又は複数種の予防医薬が、スタチン、ARB、ACE阻害剤、PPAR作動薬、血管拡張剤及びチアジドからなる群より選択される、
請求項1に記載の方法。 - 1種又は複数種の第1の医薬が、SERM、アセトアミノフェン、ムラグリタザール、及び交感神経刺激剤からなる群より選択される、請求項1に記載の方法。
- 交感神経刺激剤が、アスパラギン酸アンフェタミン、硫酸アンフェタミン、デキストロアンフェタミンサッカラート、硫酸デキストロアンフェタミン、メチルフェニデート、デキストロアンフェタミン、エフェドリン及びアトモキセチンからなる群より選択される、請求項4に記載の方法。
- SERMがラロキシフェンである、請求項4に記載の方法。
- 患者が健全な生活習慣を実践すべき旨の勧告を更に含む、請求項1に記載の方法。
- 1種又は複数種の第1の医薬と1種又は複数種の予防医薬とが、単位剤形として投与される、請求項1に記載の方法。
- 患者が他の点では健康である、請求項1に記載の方法。
- COX−2阻害剤で治療される患者において、1種又は複数種のCV有害事象のリスクを低減させる方法であって、
(a)治療有効量のCOX−2阻害剤と、
(b)1種又は複数種のCV事象のリスクを低減させるのに有効な量の1種又は複数種の予防医薬と、
を含む組合せ薬剤を投与することを含む方法。 - COX−2阻害剤が、セレコキシブ、ロフェコキシブ、バルデコキシブ、エトリコキシブ及びルマリコキシブからなる群より選択される、請求項10に記載の方法。
- 1種又は複数種の予防医薬が、スタチン、ARB、ACE阻害剤、PPAR作動薬、血管拡張剤及びチアジドからなる群より選択される、請求項10に記載の方法。
- 予防医薬が、アトルバスタチン、ロバスタチン、プラバスタチン、シンバスタチン、ロスバスタチン及びフルバスタチンからなる群より選択される、請求項12に記載の方法。
- COX−2阻害剤で治療される患者において、1種又は複数種のCV有害事象のリスクを低減させる方法であって、
(a)セレコキシブ、ロフェコキシブ、バルデコキシブ、エトリコキシブ及びルマリコキシブからなる群より選択される、治療有効量のCOX−2阻害剤と、
(b)1種又は複数種のCV事象のリスクを低減させるのに有効な量のスタチンと、
を含む組合せ薬剤を投与することを含む方法。 - CV有害事象のリスクの誘発又は増大を伴う1種又は複数種の第1の医薬で治療される患者において、1種又は複数種のCV有害事象のリスクを低減させるための医薬組成物であって、
(a)治療有効量の1種又は複数種の第1の医薬と、
(b)1種又は複数種のCV事象のリスクを低減させるのに有効な量の1種又は複数種の予防医薬と、
を含む単位剤形を含む医薬組成物。 - (a)1種又は複数種の第1の医薬がCOX−2阻害剤を含み、
(b)1種又は複数種の予防医薬が、スタチン、ARB、ACE阻害剤、PPAR作動薬、血管拡張剤及びチアジドからなる群より選択される、
請求項15に記載の医薬組成物。 - (a)COX−2阻害剤が、セレコキシブ、ロフェコキシブ、バルデコキシブ、エトリコキシブ及びルマリコキシブからなる群より選択され、
(b)1種又は複数種の予防医薬が、アトルバスタチン、ロバスタチン、プラバスタチン、シンバスタチン、ロスバスタチン及びフルバスタチンからなる群より選択される、
請求項16に記載の医薬組成物。 - (a)1種又は複数種の第1の医薬がSERMを含み、
(b)1種又は複数種の予防医薬が、スタチン、ARB、ACE阻害剤、PPAR作動薬、血管拡張剤及びチアジドからなる群より選択される、
請求項15に記載の医薬組成物。 - SERMがラロキシフェンである、請求項18に記載の医薬組成物。
- 繰返し共投与が少なくとも10日間実施される、請求項2に記載の方法。
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