JP2019533692A - チャネル病を引き起こす薬物に対するdmpc、dmpg、dmpc/dmpg、lysopg及びlysopcの防護効果 - Google Patents
チャネル病を引き起こす薬物に対するdmpc、dmpg、dmpc/dmpg、lysopg及びlysopcの防護効果 Download PDFInfo
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- JP2019533692A JP2019533692A JP2019522785A JP2019522785A JP2019533692A JP 2019533692 A JP2019533692 A JP 2019533692A JP 2019522785 A JP2019522785 A JP 2019522785A JP 2019522785 A JP2019522785 A JP 2019522785A JP 2019533692 A JP2019533692 A JP 2019533692A
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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Abstract
Description
1−DMPC
2−DMPG
3−DMPC/DMPG 90:9
4−14:0 LysoPC
5−14:0 LysoPG
6−DMPC+ニロチニブ(0.1μM)
7−DMPG+ニロチニブ(0.1μM)
8−DMPC/DMPG 90:9+ニロチニブ(0.1μM)
9−14:0 LysoPC+ニロチニブ(0.1μM)
10−14:0 LysoPG+ニロチニブ(0.1μM)
ベースライン条件で行われる記録1
濃度1の存在下で行われる記録1
ベースライン条件で行われる記録1
正の対照の存在下で行われる記録1
n=上記全プロトコールを適用することができたパッチした応答細胞の数。
1.評判の悪い薬物曝露の時間枠
2.封の不安定性
3.パッチした細胞により発生するテール電流なし
4.正の対照の有意な効果なし
5.研究の持続期間にわたるキャパシタンス過渡振幅における10%を超える可変性
1- DMPC (水溶液中)
2- DMPG (水溶液中)
3- DMPC/DMPG90:9 (水溶液中)
4- 14:0 LysoPC (水溶液中)
5- 14:0 LysoPG(水溶液中)
6- DMPC + ニロチニブ (0.1 μM) (水溶液中)
7- DMPG + ニロチニブ (0.1 μM) (水溶液中)
8- DMPC/DMPG90:9 + ニロチニブ (0.1 μM) (水溶液中)
9- 14:0 LysoPC + ニロチニブ (0.1 μM) (水溶液中)
10- 14:0 LysoPG + ニロチニブ (0.1 μM) (水溶液中)
11- ニロチニブ単独 (DMSO中)
米国特許公開第2010/0004549号明細書:System and Method of Serial Comparison for Detection of Long QT Syndrome (LQTS)。
米国特許公開第2008/0255464号明細書:System and Method for Diagnosing and Treating Long QT Syndrome。
米国特許公開第2007/0048284号明細書:Cardiac Arrhythmia Treatment Methods。
米国特許公開第2001/00120890号明細書:Ion Channel Modulating Activity I。
Claims (36)
- 対象において心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を誘導する1又は2以上の薬理学的活性剤と、前記1又は2以上の薬理学的活性剤により引き起こされる前記心臓パターンにおける前記不規則性又は変化に起因する前記心臓チャネル病又は前記状態を予防又は低減するのに十分な量で供給される1又は2以上の脂質と
を含む組成物であって、組合せが、薬学的に許容される媒介物、溶媒、又は媒体中に分散しており、前記活性剤、前記脂質又は両方が、前記媒介物、前記溶媒、又は前記媒体中に溶解、分散又は懸濁しており、前記活性剤と前記脂質の1又は2以上の薬理学的比が、10:1〜1:10、1:5〜5:1、3:1〜1:3であり、前記心臓パターンにおける前記不規則性又は変化に起因する前記心臓チャネル病又は前記状態に対する防護が1〜24時間続く、前記組成物。 - 脂質が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を予防又は低減する量で供給されるが、前記脂質が血流から取り除かれている、請求項1に記載の組成物。
- 1又は2以上の薬理学的活性剤が、セロトニン結合を遮断する5−HT3アンタゴニスト、5−HT4受容体アゴニスト、ヒスタミンアンタゴニスト、カルシウムチャネル遮断薬、抗マラリア剤、抗精神病薬、ハロドール、抗生物質、抗不整脈薬、抗がん剤、オピオイド、又は抗高脂血症薬のうちの少なくとも1つから選択される、請求項1又は2に記載の組成物。
- 脂質が、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルグリセロール、カルジオリピン、ホスファチジルイノシトール又はこれらの前駆体のうちの少なくとも1つを含む、請求項1〜3のいずれかに記載の組成物。
- 脂質が、リゾホスファチジルグリセロール、リゾホスファチジルコリン、ラウロイル−リゾホスファチジルコリン、ミリストイル−リゾホスファチジルコリン、パルミトイル−リゾホスファチジルコリン、ステアロイル−リゾホスファチジルコリン、アラキドイル−リゾホスファチジルコリン、オレオイル−リゾホスファチジルコリン、リノレオイル−リゾホスファチジルコリン、リノレノイル−リゾホスファチジルコリン、エルコイル−リゾホスファチジルコリン、1−ミリストイル−2−ヒドロキシ−sn−グリセロ−3−ホスホコリン(DMPC)、12−ミステロイル−2−ヒドロキシ−sn−グリセロ−3−[ホスホ−rac−(グリセロール)](DMPG)、DMPC/DMPG、1−ミリストイル−2−ヒドロキシ−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール)(LysoPG)、又は1−ミリストイル−2−ヒドロキシ−sn−グリセロ−3−ホスホコリン(LysoPC)を含む、請求項1〜4のいずれかに記載の組成物。
- 脂質が、短鎖脂肪酸が5個以下の炭素、中鎖が6〜12個の炭素、長鎖が13〜21個の炭素、及び超長鎖脂肪酸が22個を超える炭素であり、偶数及び奇数鎖の両方の脂肪酸を含むとさらに規定されるリゾホスファチジルグリセロールである、請求項1〜5のいずれかに記載の組成物。
- 脂質が、飽和又は不飽和である3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、35、40、45、50、55又は56個以上の炭素を有する短鎖脂肪酸を含む、請求項1〜6のいずれかに記載の組成物。
- 心臓パターンにおける不規則性若しくは変化に起因する心臓チャネル病若しくは状態が、心臓内の遅延整流性K+電流に関与するイオンチャネルの阻害、多形性心室性頻拍、QTc、LQT2、LQTSの延長、若しくはトルサード・ド・ポアンツである、請求項1〜7のいずれかに記載の組成物。
- 活性剤薬物が、クリゾチニブ、ニロチニブ、テルフェナジン、アステミゾール、グリパフロキサシン、テロジレン、ドロペリドール、リドフラジン、レボメタジル、セルチンドール又はシサプリドのうちの少なくとも1つから選択される、請求項1〜8のいずれかに記載の組成物。
- 組成物が、経腸、非経口、静脈内、腹腔内、皮内、皮下、経肺、直腸内、膣内、又は経口投与用に適合される、請求項1〜9のいずれかに記載の組成物。
- 活性剤が、リポソームに形成される脂質中に供給され、脂質が、ホスファチジルコリン(レシチン)、リゾレシチン、リゾホスファチジルエタノール−アミン、ホスファチジルセリン、ホスファチジルイノシトール、スフィンゴミエリン、ホスファチジルエタノールアミン(セファリン)、カルジオリピン、ホスファチジン酸、セレブロシド、リン酸ジセチル、ホスファチジルコリン、及びジパルミトイル−ホスファチジルグリセロール、ステアリルアミン、ドデシルアミン、ヘキサデシル−アミン、パルミチン酸アセチル、リシノール酸グリセロール、ステアリン酸ヘキサデシル、ミリスチン酸イソプロピル、両性アクリルポリマー、脂肪酸、脂肪酸アミド、コレステロール、コレステロールエステル、ジアシルグリセロール、又はコハク酸ジアシルグリセロールのうちの少なくとも1つから選択される、請求項1〜10のいずれかに記載の組成物。
- 活性剤が、アルブテロール、アルフゾシン、アマンタジン、アミオダロン、アミスルプリド、アミトリプチリン、アモキサピン、アンフェタミン、アナグレリド、アポモルヒネ、アルフォルモテロール、アリピプラゾール、三酸化ヒ素、アステミゾール、アタザナビル、アトモキセチン、アジスロマイシン、ベダキリン、ベプリジル、ボルテゾミブ、ボスチニブ、抱水クロラール、クロロキン、クロルプロマジン、シプロフロキサシン、シサプリド、シタロプラム、クラリスロマイシン、クロミプラミン、クロザピン、コカイン、クルクミン、クリゾチニブ、ダブラフェニブ、ダサチニブ、デシプラミン、デクスメデトミジン、デクスメチルフェニデート、デキストロアンフェタミン、d−アンフェタミン、ジヒドロアルテミシニン+ピペラキン、ジフェンヒドラミン、ジソピラミド、ドブタミン、ドフェチリド、ドラセトロン、ドンペリドン、ドーパミン、ドキセピン、ドロネダロン、ドロペリドール、エフェドリン、エピネフリン、アドレナリン、エリブリン、エリスロマイシン、エスシタロプラム、ファモチジン、フェルバメート、フェンフルラミン、フィンゴリモド、フレカイニド、フルコナゾール、フルオキセチン、ホルモテロール、ホスカルネット、ホスフェニトイン、フロセミド、フルセミド、ガランタミン、ガチフロキサシン、ゲミフロキサシン、ゲラニセトロン、ハロファントリン、ハロペリドール、ヒドロクロロチアジド、イブチリド、イロペリドン、イミプラミン、メリプラミン、インダパミド、イソプロテレノール、イスラジピン、イトラコナゾール、イバブラジン、ケトコナゾール、ラパチニブ、レブアルブテロール、レボフロキサシン、レボメタジル、リスデキサンフェタミン、リチウム、メソリダジン、メタプロテレノール、メサドン、メタンフェタミン(Methamphetamine)(メタンフェタミン(methamfetamine))、メチルフェニデート、ミドドリン、ミフェプリストン、ミラベグロン、ミルタザピン、モエキシプリル/HCTZ、モキシフロキサシン、ネルフィナビル、ニカルジピン、ニロチニブ、ノルエピネフリン(ノルアドレナリン)、ノルフロキサシン、ノルトリプチリン、オフロキサシン、オランザピン、オンダンセトロン、オキシトシン、パリペリドン、パロキセチン、パシレオチド、パゾパニブ、ペンタミジン、パーフルトレン脂質ミクロスフェア、フェンテルミン、フェニレフリン、フェニルプロパノールアミン、ピモジド、ポサコナゾール、プロブコール、プロカインアミド、プロメタジン、プロトリプチリン、プソイドエフェドリン、クエチアピン、キニジン、硫酸キニーネ、ラノラジン、リルピビリン、リスペリドン、リトドリン、リトナビル、ロキシスロマイシン、サルブタモール、サルメテロール、サキナビル、セルチンドール、セルトラリン、セボフルラン、シブトラミン、ソリフェナシン、ソラフェニブ、ソタロール、スパルフロキサシン、スルピリド、スニチニブ、タクロリムス、タモキシフェン、テラプレビル、テラバンシン、テリスロマイシン、テルブタリン、テルフェナジン、テトラベナジン、チオリダジン、チザニジン、トルテロジン、トレミフェン、トラゾドン、トリメトプリム−サルファ、トリミプラミン、バンデタニブ、バルデナフィル、ベムラフェニブ、ベンラファキシン、ボリコナゾール、ボリノスタット、又はジプラシドンから選択される、請求項1〜11のいずれかに記載の組成物。
- 脂質が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を、少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、又は24時間予防する、請求項1〜12のいずれかに記載の組成物。
- ヒト又は動物対象において疾患を治療するために使用される薬理学的活性剤により引き起こされる心臓パターンにおける不規則性又は変化に起因する1又は2以上の心臓チャネル病又は状態を予防又は治療する方法であって、
心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を低減又は予防するのに有効な投与用に適合された脂質を活性剤とともに含む組成物を調製するステップであって、脂質の量は、活性剤により引き起こされる心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を低減又は排除するのに十分であり、活性剤と脂質の1又は2以上の薬理学的比が10:1〜1:10、1:5〜5:1、3:1〜1:3であり、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態に対する防護が1〜24時間続く、ステップ;及び
ヒト又は動物対象に前記組成物を、疾患を治療するのに十分な量で投与するステップを含む、前記方法。 - 脂質が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を予防又は低減する量で供給されるが、前記脂質が血流から取り除かれている、請求項14に記載の方法。
- 脂質が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を、少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、又は24時間予防する、請求項14に記載の方法。
- 1又は2以上の薬理学的活性剤が、セロトニン結合を遮断する5−HT3アンタゴニスト、5−HT4受容体アゴニスト、ヒスタミンアンタゴニスト、カルシウムチャネル遮断薬、抗マラリア剤、抗精神病薬、ハロドール、抗生物質、抗不整脈薬、抗がん剤、オピオイド、又は抗高脂血症薬のうちの少なくとも1つから選択される、請求項14に記載の方法。
- 脂質が、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルグリセロール、カルジオリピン、ホスファチジルイノシトール又はこれらの前駆体のうちの少なくとも1つを含む、請求項14に記載の方法。
- 脂質が、リゾホスファチジルグリセロール、リゾホスファチジルコリン、ラウロイル−リゾホスファチジルコリン、ミリストイル−リゾホスファチジルコリン、パルミトイル−リゾホスファチジルコリン、ステアロイル−リゾホスファチジルコリン、アラキドイル−リゾホスファチジルコリン、オレオイル−リゾホスファチジルコリン、リノレオイル−リゾホスファチジルコリン、リノレノイル−リゾホスファチジルコリン、エルコイル−リゾホスファチジルコリン、1−ミリストイル−2−ヒドロキシ−sn−グリセロ−3−ホスホコリン(DMPC)、12−ミステロイル−2−ヒドロキシ−sn−グリセロ−3−[ホスホ−rac−(グリセロール)](DMPG)、DMPC/DMPG、1−ミリストイル−2−ヒドロキシ−sn−グリセロ−3−ホスホ−(1’−rac−グリセロール)(LysoPG)、又は1−ミリストイル−2−ヒドロキシ−sn−グリセロ−3−ホスホコリン(LysoPC)のうちの少なくとも1つを含む、請求項14に記載の方法。
- 脂質が、短鎖脂肪酸が5個以下の炭素、中鎖が6〜12個の炭素、長鎖が13〜21個の炭素、及び超長鎖脂肪酸が22個を超える炭素であり、偶数及び奇数鎖の両方の脂肪酸を含むとさらに規定されるリゾホスファチジルグリセロールである、請求項14に記載の方法。
- 脂質が、飽和又は不飽和である3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、35、40、45、50、55又は56個以上の炭素を有する短鎖脂肪酸を含む、請求項14に記載の方法。
- 心臓パターンにおける不規則性若しくは変化に起因する心臓チャネル病若しくは状態が、心臓内の遅延整流性K+電流に関与するイオンチャネルの阻害、多形性心室性頻拍、QTc、LQT2、LQTSの延長、若しくはトルサード・ド・ポアンツである、請求項14に記載の方法。
- 1又は2以上の活性剤が、クリゾチニブ、ニロチニブ、テルフェナジン、アステミゾール、グリパフロキサシン、テロジレン、ドロペリドール、リドフラジン、レボメタジル、セルチンドール又はシサプリドのうちの少なくとも1つから選択される、請求項14に記載の方法。
- 経腸、非経口、静脈内、腹腔内、皮内、皮下、経肺、直腸内、膣内、又は経口投与用に適合させることをさらに含む、請求項1に記載の組成物。
- 活性剤が、アルブテロール、アルフゾシン、アマンタジン、アミオダロン、アミスルプリド、アミトリプチリン、アモキサピン、アンフェタミン、アナグレリド、アポモルヒネ、アルフォルモテロール、アリピプラゾール、三酸化ヒ素、アステミゾール、アタザナビル、アトモキセチン、アジスロマイシン、ベダキリン、ベプリジル、ボルテゾミブ、ボスチニブ、抱水クロラール、クロロキン、クロルプロマジン、シプロフロキサシン、シサプリド、シタロプラム、クラリスロマイシン、クロミプラミン、クロザピン、コカイン、クルクミン、クリゾチニブ、ダブラフェニブ、ダサチニブ、デシプラミン、デクスメデトミジン、デクスメチルフェニデート、デキストロアンフェタミン、d−アンフェタミン、ジヒドロアルテミシニン+ピペラキン、ジフェンヒドラミン、ジソピラミド、ドブタミン、ドフェチリド、ドラセトロン、ドンペリドン、ドーパミン、ドキセピン、ドロネダロン、ドロペリドール、エフェドリン、エピネフリン、アドレナリン、エリブリン、エリスロマイシン、エスシタロプラム、ファモチジン、フェルバメート、フェンフルラミン、フィンゴリモド、フレカイニド、フルコナゾール、フルオキセチン、ホルモテロール、ホスカルネット、ホスフェニトイン、フロセミド、フルセミド、ガランタミン、ガチフロキサシン、ゲミフロキサシン、ゲラニセトロン、ハロファントリン、ハロペリドール、ヒドロクロロチアジド、イブチリド、イロペリドン、イミプラミン、メリプラミン、インダパミド、イソプロテレノール、イスラジピン、イトラコナゾール、イバブラジン、ケトコナゾール、ラパチニブ、レブアルブテロール、レボフロキサシン、レボメタジル、リスデキサンフェタミン、リチウム、メソリダジン、メタプロテレノール、メサドン、メタンフェタミン(Methamphetamine)(メタンフェタミン(methamfetamine))、メチルフェニデート、ミドドリン、ミフェプリストン、ミラベグロン、ミルタザピン、モエキシプリル/HCTZ、モキシフロキサシン、ネルフィナビル、ニカルジピン、ニロチニブ、ノルエピネフリン(ノルアドレナリン)、ノルフロキサシン、ノルトリプチリン、オフロキサシン、オランザピン、オンダンセトロン、オキシトシン、パリペリドン、パロキセチン、パシレオチド、パゾパニブ、ペンタミジン、パーフルトレン脂質ミクロスフェア、フェンテルミン、フェニレフリン、フェニルプロパノールアミン、ピモジド、ポサコナゾール、プロブコール、プロカインアミド、プロメタジン、プロトリプチリン、プソイドエフェドリン、クエチアピン、キニジン、硫酸キニーネ、ラノラジン、リルピビリン、リスペリドン、リトドリン、リトナビル、ロキシスロマイシン、サルブタモール、サルメテロール、サキナビル、セルチンドール、セルトラリン、セボフルラン、シブトラミン、ソリフェナシン、ソラフェニブ、ソタロール、スパルフロキサシン、スルピリド、スニチニブ、タクロリムス、タモキシフェン、テラプレビル、テラバンシン、テリスロマイシン、テルブタリン、テルフェナジン、テトラベナジン、チオリダジン、チザニジン、トルテロジン、トレミフェン、トラゾドン、トリメトプリム−サルファ、トリミプラミン、バンデタニブ、バルデナフィル、ベムラフェニブ、ベンラファキシン、ボリコナゾール、ボリノスタット、又はジプラシドンから選択される、請求項14に記載の方法。
- ヒト又は動物対象において活性剤により引き起こされる心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を予防又は治療する方法であって、
心臓チャネル病を引き起こす前記活性剤で治療可能な疾患について、治療を必要とする対象を特定するステップ;及び
心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を低減又は予防するのに有効な量の脂質を、前記疾患を治療するのに十分な有効量の前記活性剤とともに含む組成物を供給するステップであって、活性剤と脂質の1又は2以上の薬理学的比が10:1〜1:10、1:5〜5:1、3:1〜1:3であり、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態に対する防護が1〜24時間続く、ステップ
を含む、前記方法。 - 活性剤が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態が原因で、以前に臨床試験に失敗している、請求項26に記載の方法。
- 薬物により引き起こされる心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態が原因で失敗した、又は臨床的使用を制限している臨床試験での薬物を特定するステップ、及び前記薬物により引き起こされる前記心臓パターンにおける不規則性又は変化に起因する前記心臓チャネル病又は状態を低減又は排除するために、前記薬物を脂質とともに再配合するステップをさらに含む、請求項26に記載の方法。
- 前記活性剤が、アルブテロール、アルフゾシン、アマンタジン、アミオダロン、アミスルプリド、アミトリプチリン、アモキサピン、アンフェタミン、アナグレリド、アポモルヒネ、アルフォルモテロール、アリピプラゾール、三酸化ヒ素、アステミゾール、アタザナビル、アトモキセチン、アジスロマイシン、ベダキリン、ベプリジル、ボルテゾミブ、ボスチニブ、抱水クロラール、クロロキン、クロルプロマジン、シプロフロキサシン、シサプリド、シタロプラム、クラリスロマイシン、クロミプラミン、クロザピン、コカイン、クルクミン、クリゾチニブ、ダブラフェニブ、ダサチニブ、デシプラミン、デクスメデトミジン、デクスメチルフェニデート、デキストロアンフェタミン、d−アンフェタミン、ジヒドロアルテミシニン+ピペラキン、ジフェンヒドラミン、ジソピラミド、ドブタミン、ドフェチリド、ドラセトロン、ドンペリドン、ドーパミン、ドキセピン、ドロネダロン、ドロペリドール、エフェドリン、エピネフリン、アドレナリン、エリブリン、エリスロマイシン、エスシタロプラム、ファモチジン、フェルバメート、フェンフルラミン、フィンゴリモド、フレカイニド、フルコナゾール、フルオキセチン、ホルモテロール、ホスカルネット、ホスフェニトイン、フロセミド、フルセミド、ガランタミン、ガチフロキサシン、ゲミフロキサシン、ゲラニセトロン、グリパフロキサシン、ハロファントリン、ハロペリドール、ヒドロクロロチアジド、イブチリド、イロペリドン、イミプラミン、メリプラミン、インダパミド、イソプロテレノール、イスラジピン、イトラコナゾール、イバブラジン、ケトコナゾール、ラパチニブ、レブアルブテロール、レボフロキサシン、レボメタジル、リスデキサンフェタミン、リチウム、メソリダジン、メタプロテレノール、メサドン、メタンフェタミン(Methamphetamine)(メタンフェタミン(methamfetamine))、メチルフェニデート、ミドドリン、ミフェプリストン、ミラベグロン、ミルタザピン、モエキシプリル/HCTZ、モキシフロキサシン、ネルフィナビル、ニカルジピン、ニロチニブ、ノルエピネフリン(ノルアドレナリン)、ノルフロキサシン、ノルトリプチリン、オフロキサシン、オランザピン、オンダンセトロン、オキシトシン、パリペリドン、パロキセチン、パシレオチド、パゾパニブ、ペンタミジン、パーフルトレン脂質ミクロスフェア、フェンテルミン、フェニレフリン、フェニルプロパノールアミン、ピモジド、ポサコナゾール、プロブコール、プロカインアミド、プロメタジン、プロトリプチリン、プソイドエフェドリン、クエチアピン、キニジン、硫酸キニーネ、ラノラジン、リルピビリン、リスペリドン、リトドリン、リトナビル、ロキシスロマイシン、サルブタモール、サルメテロール、サキナビル、セルチンドール、セルトラリン、セボフルラン、シブトラミン、ソリフェナシン、ソラフェニブ、ソタロール、スパルフロキサシン、スルピリド、スニチニブ、タクロリムス、タモキシフェン、テラプレビル、テラバンシン、テリスロマイシン、テルブタリン、テルフェナジン、テトラベナジン、チオリダジン、チザニジン、トルテロジン、トレミフェン、トラゾドン、トリメトプリム−サルファ、トリミプラミン、バンデタニブ、バルデナフィル、ベムラフェニブ、ベンラファキシン、ボリコナゾール、ボリノスタット、又はジプラシドンから選択される、請求項26に記載の方法。
- 疾患又は状態の治療用候補薬物を評価する方法であって、前記候補薬物が、候補剤により引き起こされる心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を引き起こし、前記方法が、
(a)患者の第1のサブセットにある量の脂質、リポソーム、又は脂質前駆体及び候補薬物を、患者の第2のサブセットにある量のプラセボを投与するステップであって、前記脂質、リポソーム又は脂質前駆体が、前記候補薬物により引き起こされる心臓パターンにおける不規則性又は変化に起因する1又は2以上の心臓チャネル病又は状態を低減又は予防するのに有効な量で供給され、活性剤と脂質の1又は2以上の薬理学的比が10:1〜1:10、1:5〜5:1、3:1〜1:3であり、前記心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態に対する防護が1〜24時間続く、ステップ;
(b)前記第1及び第2のセットの患者からの、前記心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態のレベルを測定するステップ;並びに
(c)前記脂質、リポソーム、又は脂質前駆体及び前記候補薬物の組合せが、前記心臓パターンにおける不規則性又は変化に起因する前記チャネル病又は状態を、プラセボを服用した患者のサブセットで生じる任意の低減、又は前記心臓パターンにおける不規則性又は変化に起因する既知の心臓チャネル病又は状態と比較して、統計的に有意に低減するかどうかを決定するステップであって、統計的に有意な低減が、前記脂質、リポソーム、又は脂質前駆体及び前記候補薬物の組合せが、前記心臓パターンにおける不規則性又は変化に起因する薬物誘導性心臓チャネル病又は状態も低減又は排除しながら、疾患状況又は状態を治療するのに有用であることを示す、ステップ
を含む、前記方法。 - 脂質が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を予防又は低減する量で供給されるが、脂質が血流から取り除かれている、請求項30に記載の方法。
- 脂質が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態を、少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、又は24時間予防する、請求項30に記載の方法。
- 薬物が、以前に臨床試験に、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態が原因で失敗している、請求項30に記載の方法。
- 薬物が、心臓パターンにおける不規則性又は変化に起因する心臓チャネル病又は状態が原因で市場から取り下げられている、請求項30に記載の方法。
- ある期間の後にステップ(a)〜(c)を繰り返すステップをさらに含む、請求項30に記載の方法。
- 活性剤が、アルブテロール、アルフゾシン、アマンタジン、アミオダロン、アミスルプリド、アミトリプチリン、アモキサピン、アンフェタミン、アナグレリド、アポモルヒネ、アルフォルモテロール、アリピプラゾール、三酸化ヒ素、アステミゾール、アタザナビル、アトモキセチン、アジスロマイシン、ベダキリン、ベプリジル、ボルテゾミブ、ボスチニブ、抱水クロラール、クロロキン、クロルプロマジン、シプロフロキサシン、シサプリド、シタロプラム、クラリスロマイシン、クロミプラミン、クロザピン、コカイン、クルクミン、クリゾチニブ、ダブラフェニブ、ダサチニブ、デシプラミン、デクスメデトミジン、デクスメチルフェニデート、デキストロアンフェタミン、d−アンフェタミン、ジヒドロアルテミシニン+ピペラキン、ジフェンヒドラミン、ジソピラミド、ドブタミン、ドフェチリド、ドラセトロン、ドンペリドン、ドーパミン、ドキセピン、ドロネダロン、ドロペリドール、エフェドリン、エピネフリン、アドレナリン、エリブリン、エリスロマイシン、エスシタロプラム、ファモチジン、フェルバメート、フェンフルラミン、フィンゴリモド、フレカイニド、フルコナゾール、フルオキセチン、ホルモテロール、ホスカルネット、ホスフェニトイン、フロセミド、フルセミド、ガランタミン、ガチフロキサシン、ゲミフロキサシン、グラニセトロン、ハロファントリン、ハロペリドール、ヒドロクロロチアジド、イブチリド、イロペリドン、イミプラミン、メリプラミン、インダパミド、イソプロテレノール、イスラジピン、イトラコナゾール、イバブラジン、ケトコナゾール、ラパチニブ、レブアルブテロール、レボフロキサシン、レボメタジル、リスデキサンフェタミン、リチウム、メソリダジン、メタプロテレノール、メサドン、メタンフェタミン(methamfetamine)、メチルフェニデート、ミドドリン、ミフェプリストン、ミラベグロン、ミルタザピン、モエキシプリル/HCTZ、モキシフロキサシン、ネルフィナビル、ニカルジピン、ニロチニブ、ノルエピネフリン(ノルアドレナリン)、ノルフロキサシン、ノルトリプチリン、オフロキサシン、オランザピン、オンダンセトロン、オキシトシン、パリペリドン、パロキセチン、パシレオチド、パゾパニブ、ペンタミジン、パーフルトレン脂質ミクロスフェア、フェンテルミン、フェニレフリン、フェニルプロパノールアミン、ピモジド、ポサコナゾール、プロブコール、プロカインアミド、プロメタジン、プロトリプチリン、プソイドエフェドリン、クエチアピン、キニジン、硫酸キニーネ、ラノラジン、リルピビリン、リスペリドン、リトドリン、リトナビル、ロキシスロマイシン、サルブタモール、サルメテロール、サキナビル、セルチンドール、セルトラリン、セボフルラン、シブトラミン、ソリフェナシン、ソラフェニブ、ソタロール、スパルフロキサシン、スルピリド、スニチニブ、タクロリムス、タモキシフェン、テラプレビル、テラバンシン、テリスロマイシン、テルブタリン、テルフェナジン、テトラベナジン、チオリダジン、チザニジン、トルテロジン、トレミフェン、トラゾドン、トリメトプリム−サルファ、トリミプラミン、バンデタニブ、バルデナフィル、ベムラフェニブ、ベンラファキシン、ボリコナゾール、ボリノスタット、又はジプラシドンから選択される、請求項30に記載の方法。
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