JP2015180639A - Kcnq1遺伝子の多型に基づいた治療方法 - Google Patents
Kcnq1遺伝子の多型に基づいた治療方法 Download PDFInfo
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- JP2015180639A JP2015180639A JP2015093382A JP2015093382A JP2015180639A JP 2015180639 A JP2015180639 A JP 2015180639A JP 2015093382 A JP2015093382 A JP 2015093382A JP 2015093382 A JP2015093382 A JP 2015093382A JP 2015180639 A JP2015180639 A JP 2015180639A
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- patient
- genotype
- kcnq1
- individual
- reference sequence
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- 238000000034 method Methods 0.000 title claims abstract description 47
- 108090000623 proteins and genes Proteins 0.000 title abstract description 12
- 102000054765 polymorphisms of proteins Human genes 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 101150061256 KCNQ1 gene Proteins 0.000 claims abstract description 14
- 108010011185 KCNQ1 Potassium Channel Proteins 0.000 claims description 29
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Abstract
【解決手段】患者の電位開口型カリウムチャンネルに関連するKCNQ1遺伝子配列の少なくとも一部を決定するステップと、患者のシトクロムP450 2D6(CYP2D6)遺伝子配列の少なくとも一部を決定するステップを更に含む、患者のKCNQ1遺伝子配列に基づく量の向精神薬である化合物を患者に投与するステップとを含む方法。
【選択図】なし
Description
本出願は、これによって本明細書に組み込まれる2009年4月6日出願の同時係属の米国特許仮出願第61/167,136号の利益を主張する。
[技術分野]
本発明は、概して、抗精神病薬を投与すること、より具体的には、個体のKCNQ1遺伝子型に基づいて抗精神病薬を投与することに関する。
心電図のQT間隔の延長(Q波の始めからT波の終わりまでの間の時間)は、QT延長症候群(LQTS)と称される。LQTSは遺伝要素を含む可能性がある。一部のLQTS患者では、QT延長は慢性的な状態になり得る。一部の人では、LQTSはQT間隔を延長する活性医薬成分の投与によって誘発され得る。
本発明は、QTc間隔を延長する能力がある化合物を投与するための方法及び個体がそのようなQTc延長の素因を持つかどうかを予測するための方法を提供する。
上に示したように、本発明は、抗精神病薬を個体のKCNQ1遺伝子型に基づいて投与するための方法を提供する。
Claims (30)
- 患者を、QT間隔を延長する能力がある化合物で処置する方法であって、
患者のKCNQ1遺伝子配列の少なくとも一部を決定するステップと、
患者のKCNQ1遺伝子配列に基づく量の前記化合物を患者に投与するステップと
を含む方法。 - 投与される化合物の量が、参照配列AJ006345.1の79764位における患者のKCNQ1遺伝子型がGGである場合に、患者の遺伝子型がGGでない場合よりも少ない、請求項1に記載の方法。
- 投与される化合物の量が、参照配列AJ006345.1の286414位における患者のKCNQ1遺伝子型がAAである場合に、患者の遺伝子型がAAでない場合よりも少ない、請求項1に記載の方法。
- 投与される化合物の量が、参照配列AJ006345.1の78927位における患者のKCNQ1遺伝子型がCCである場合に、患者の遺伝子型がCCでない場合よりも少ない、請求項1に記載の方法。
- 化合物が、アミオダロン、三酸化ヒ素、ベプリジル、クロロキン、クロルプロマジン、シサプリド、クラリスロマイシン、ジソピラミド、ドフェチリド、ドンペリドン、ドロペリドール、エリスロマイシン、ハロファントリン、ハロペリドール、イブチリド、イロペリドン、レボメタジル、メソリダジン、メサドン、ペンタミジン、ピモジド、プロカインアミド、キニジン、ソタロール、スパルフロキサシン、チオリダジン、
アルフゾシン、アマンタジン、アジスロマイシン、抱水クロラール、クロザピン、ドラセトロン、フェルバメート、フレカイニド、ホスカルネット、ホスフェニトイン、ガチフロキサシン、ゲミフロキサシン、グラニセトロン、インダパミド、イスラジピン、レボフロキサシン、リチウム、モエキシプリル、モキシフロキサシン、ニカルジピン、オクトレオチド、オフロキサシン、オンダンセトロン、クエチアピン、ラノラジン、リスペリドン、ロキシスロマイシン、タクロリムス、タモキシフェン、テリスロマイシン、チザニジン、バルデナフィル、ベンラファキシン、ボリコナゾール、ジプラシドン、
アルブテロール、アミトリプチリン、アモキサピン、アンフェタミン、デキストロアンフェタミン、アトモキセチン、クロロキン、シプロフロキサシン、シタロプラム、クロミプラミン、コカイン、デシプラミン、デクスメチルフェニデート、ドブタミン、ド−パミン、ドキセピン、エフェドリン、エピネフリン、フェンフルラミン、フルコナゾール、フルオキセチン、ガランタミン、イミプラミン、イソプロテレノール、イトラコナゾール、ケトコナゾール、レバルブテロール、メタプロテレノール、メチルフェニデート、メキシレチン、ミドドリン、ノルエピネフリン、ノルトリプチリン、パロキセチン、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、プロトリプチリン、プソイドエフェドリン、リトドリン、サルメテロール、セルトラリン、シブトラミン、ソリフェナシン、テルブタリン、トルテロジン、トリメトプリム−サルファ、トリミプラミン、並びにそれらの代謝産物、薬学的に許容される塩及び組合せからなる群から選択される、請求項1に記載の方法。 - 化合物が下式
[式中、Rは、独立に、水素、低級アルキル、低級アルコキシ、ヒドロキシル、カルボキシル、低級ヒドロキシケトン、低級アルカノール、ヒドロキシル酢酸、ピルビン酸、エタンジオ−ル、塩素、フッ素、臭素、ヨウ素、アミノ、低級モノアルキルアミノ又は低級ジアルキルアミノ、ニトロ、低級アルキルチオ、トリフルオロメトキシ、シアノ、アシルアミノ、トリフルオロメチル、トリフルオロアセチル、アミノカルボニル、モノアルキルアミノカルボニル、ジアルキルアミノカルボニル、ホルミル、
であり、
アルキルは、分岐又は直鎖の、飽和又は不飽和の低級アルキルであり、
アシルは、カルボニルによって結合した低級アルキル又は低級アルキルオキシであり、
アリールは、フェニル又は、少なくとも1つの基R5で置換されたフェニルであり、それぞれのR5は、独立に、水素、低級アルキル、低級アルコキシ、ヒドロキシ、塩素、フッ素、臭素、ヨウ素、低級モノアルキルアミノ、低級ジアルキルアミノ、ニトロ、シアノ、トリフルオロメチル又はトリフルオロメトキシであり、
ヘテロアリールは、少なくとも1つのヘテロ原子Q3を有する五員アリール環又は六員アリール環であり、それぞれのQ3は、独立に、−O−、−S−、−N(H)−又は−C(H)=N−であり、
WはCH2又はCHR8又はN−R9であり、
R1は−H、低級アルキル、−OH、ハロ、低級アルコキシ、トリフルオロメチル、ニトロ又はアミノであり、
R2はC2〜C5のアルキレン、アルケニレン(シス又はトランス)又はアルキニレンであり、少なくとも1つのC1〜C6の線状アルキル基、フェニル基又は
(式中、Z1は低級アルキル、−OH、低級アルコキシ、−CF3、−NO2、−NH2又はハロゲンである)
で置換されていてもよく、
R3は低級アルキル又は水素であり、
R7は水素、低級アルキル又はアシルであり、
R8は低級アルキルであり、
R9はヒドロキシ、低級アルコキシ、又は−NHR10であり、
R10は水素、低級アルキル、C1〜C3のアシル、アリール、
であり、
X1、X2及びX3は、独立に、−O−、−S−、=N−又は−N(R3)−である、又は、X1及びX2は互いに共有結合しておらず、独立に、−OH、=O、−R3又は=NR3であり、
低級とは炭素原子1〜4個であり、
mは1、2又は3であり、
nは1又は2である]
を有する、請求項5に記載の方法。 - 患者のCYP2D6遺伝子配列の少なくとも一部を決定するステップをさらに含む、請求項1に記載の方法。
- 投与される化合物の量が、患者のCYP2D6G1846A遺伝子型がAA又はGAである場合に、患者の遺伝子型がGGである場合よりも少ない、請求項10に記載の方法。
- 投与される化合物の量が、患者のCYP2D6C100T遺伝子型がTT又はCTである場合に、患者の遺伝子型がCCである場合よりも少ない、請求項10に記載の方法。
- 患者が、統合失調症、統合失調感情障害、鬱病、双極性躁/鬱病、心不整脈、トゥレット症候群、精神障害、妄想性障害及び統合失調症様障害からなる群から選択される少なくとも1つの状態に罹患している、請求項1に記載の方法。
- 患者が、妄想性統合失調症、緊張性統合失調症、解体型統合失調症、未分化統合失調症及び残遺型統合失調症からなる群から選択される少なくとも1つの状態に罹患している、請求項13に記載の方法。
- 患者が、短期精神障害、特定不能の精神障害、全身病状による精神障害及び物質誘発精神障害からなる群から選択される少なくとも1つの状態に罹患している、請求項13に記載の方法。
- 個体がQTc間隔の延長の素因を持つかどうかを決定する方法であって、個体のKCNQ1遺伝子配列の少なくとも一部を決定するステップを含む方法。
- 決定するステップが、参照配列AJ006345.1の79764、参照配列AJ006345.1の286414位及び参照配列AJ006345.1の78927位からなる群から選択される少なくとも1つの一塩基多型(SNP)遺伝子座における個体の遺伝子型を決定するサブステップを含む、請求項16に記載の方法。
- 個体のKCNQ1遺伝子型が、
参照配列AJ006345.1の79764位におけるGG、
参照配列AJ006345.1の286414位におけるAA、又は
参照配列AJ006345.1の78927位におけるCC
のいずれかを含む場合に、個体がQTc間隔の延長の素因を持つと結論付けるステップをさらに含む、請求項16に記載の方法。 - 個体のCYP2D6遺伝子配列の少なくとも一部を決定するステップをさらに含む、請求項16に記載の方法。
- 決定するステップが、個体のCYP2D6遺伝子配列がCYP2D6G1846A多型を含むかどうかを決定するサブステップを含む、請求項19に記載の方法。
- 決定するステップが、個体のCYP2D6遺伝子配列がCYP2D6C100T多型を含むかどうかを決定するサブステップを含む、請求項19に記載の方法。
- 患者を、QT間隔を延長する能力がある化合物で処置する方法であって、
患者のKCNQ1遺伝子の発現産物を特徴づけるステップと、
特徴づけられた発現産物に基づく量の前記化合物を患者に投与するステップと
を含む方法。 - 特徴づけられた発現産物が、
参照配列AJ006345.1の79764位におけるGG KCNQ1遺伝子型、
参照配列AJ006345.1の286414位におけるAA KCNQ1遺伝子型、又は
参照配列AJ006345.1の78927位におけるCC KCNQ1遺伝子型
のいずれかに対応する場合に化合物の量を減少させる、請求項22に記載の方法。 - 患者のCYP2D6遺伝子の発現産物を特徴づけるステップをさらに含む、請求項22に記載の方法。
- 特徴づけられた発現産物が、CYP2D6G1846A及びCYP2D6C100Tからなる群から選択されるCYP2D6多型に対応するかどうかを決定するステップをさらに含む、請求項24に記載の方法。
- 化合物が、アミオダロン、三酸化ヒ素、ベプリジル、クロロキン、クロルプロマジン、シサプリド、クラリスロマイシン、ジソピラミド、ドフェチリド、ドンペリドン、ドロペリドール、エリスロマイシン、ハロファントリン、ハロペリドール、イブチリド、イロペリドン、レボメタジル、メソリダジン、メサドン、ペンタミジン、ピモジド、プロカインアミド、キニジン、ソタロール、スパルフロキサシン、チオリダジン、
アルフゾシン、アマンタジン、アジスロマイシン、抱水クロラール、クロザピン、ドラセトロン、フェルバメート、フレカイニド、ホスカルネット、ホスフェニトイン、ガチフロキサシン、ゲミフロキサシン、グラニセトロン、インダパミド、イスラジピン、レボフロキサシン、リチウム、モエキシプリル、モキシフロキサシン、ニカルジピン、オクトレオチド、オフロキサシン、オンダンセトロン、クエチアピン、ラノラジン、リスペリドン、ロキシスロマイシン、タクロリムス、タモキシフェン、テリスロマイシン、チザニジン、バルデナフィル、ベンラファキシン、ボリコナゾール、ジプラシドン、
アルブテロール、アミトリプチリン、アモキサピン、アンフェタミン、デキストロアンフェタミン、アトモキセチン、クロロキン、シプロフロキサシン、シタロプラム、クロミプラミン、コカイン、デシプラミン、デクスメチルフェニデート、ドブタミン、ド−パミン、ドキセピン、エフェドリン、エピネフリン、フェンフルラミン、フルコナゾール、フルオキセチン、ガランタミン、イミプラミン、イソプロテレノール、イトラコナゾール、ケトコナゾール、レバルブテロール、メタプロテレノール、メチルフェニデート、メキシレチン、ミドドリン、ノルエピネフリン、ノルトリプチリン、パロキセチン、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、プロトリプチリン、プソイドエフェドリン、リトドリン、サルメテロール、セルトラリン、シブトラミン、ソリフェナシン、テルブタリン、トルテロジン、トリメトプリム−サルファ、トリミプラミン、並びにそれらの代謝産物、薬学的に許容される塩及び組合せからなる群から選択される、請求項22に記載の方法。 - 個体がQTc間隔の延長の素因を持つかどうかを決定する方法であって、
個体のKCNQ1遺伝子の発現産物を特徴づけるステップ
を含む方法。 - 特徴づけられた発現産物が、
参照配列AJ006345.1の79764位におけるGG KCNQ1遺伝子型、
参照配列AJ006345.1の286414位におけるAA KCNQ1遺伝子型、又は
参照配列AJ006345.1の78927位におけるCC KCNQ1遺伝子型
のいずれかに対応するかどうかを決定するステップをさらに含む、請求項27に記載の方法。 - 個体のCYP2D6遺伝子の発現産物を特徴づけるステップをさらに含む、請求項27に記載の方法。
- 特徴づけられた発現産物が、CYP2D6G1846A及びCYP2D6C100Tからなる群から選択されるCYP2D6多型に対応するかどうかを決定するステップをさらに含む、請求項29に記載の方法。
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