JP5551581B2 - 成長ホルモン分泌促進物質を用いる嘔吐の治療又は予防方法 - Google Patents
成長ホルモン分泌促進物質を用いる嘔吐の治療又は予防方法 Download PDFInfo
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- JP5551581B2 JP5551581B2 JP2010503058A JP2010503058A JP5551581B2 JP 5551581 B2 JP5551581 B2 JP 5551581B2 JP 2010503058 A JP2010503058 A JP 2010503058A JP 2010503058 A JP2010503058 A JP 2010503058A JP 5551581 B2 JP5551581 B2 JP 5551581B2
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- C07—ORGANIC CHEMISTRY
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Description
本願は、2007年4月10日に出願された米国仮出願第60/922,742号の利益を請求する。上記出願の全体の内容は、本明細書に参考として明白に援用される。
本発明は、嘔吐の危険性を有するか又はその危険性にある対象を治療するための方法及び組成物に関する。本発明はまた、ASAS試験によって測定される癌症状の苦痛の治療のための方法及び組成物を提供する。該方法は、成長ホルモン分泌促進化合物又はその薬学的に許容される塩、水和物もしくは溶媒和物の治療上有効量をそれを必要としている対象に投与することを含む。
R1は、水素、又は場合により1以上のアリール又はヘタリールで置換されたC1-6アルキルであり;
a及びdは、独立に0、1、2又は3であり;
b及びcは、b+cが3、4又は5であることを条件に、独立に0、1、2、3、4又は5であり;
Dは、R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-
ここで、R2、R3、R4及びR5は、独立に、水素、場合により1以上のハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;又は
R2及びR3、又はR2及びR4、又はR3及びR4は、場合により、-(CH2)i-U-(CH2)j-を形成し(ここで、i及びjは独立に1又は2であり、Uは-O-、-S-又は原子価結合である);
h及びfは、独立に0、1、2又は3を示し;
g及びeは、独立に0又は1を示し;
Mは、原子価結合、-CR6=CR7-、アリーレン、ヘタリーレン、-O-又は-S-であり;
R6及びR7は、独立に、水素、又は場合により1以上のアリール又はヘタリールで置換されたC1-6アルキルであり;
Gは、-O-(CH2)k-R8、
Jは、-O-(CH2)l-R13、
k及びlは独立に0、1又は2であり;
Eは、-CONR18R19、-COOR19、-(CH2)m-NR18SO2R20、-(CH2)m-NR18-COR20、-(CH2)m-OR19、-(CH2)m-OCOR20、-CH(R18)R19-(CH2)m-NR18-CS-NR19R21、又は-(CH2)m-NR18-CO-NR19R21;又は
Eは、-CONR22NR23R24であり、ここで、R22は、水素、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキル、又は1以上のC1-6アルキルで置換されたアリール又はヘタリールであり;R23は、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキル、又はC1-7アシルであり;及びR24は、水素、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキルであり;又は
R22及びR23は、それらが結合されている窒素原子と一緒になって、場合により、1以上のC1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;又は
R22及びR24は、それらが結合されている窒素原子と一緒になって、場合により、1以上のC1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;又は
R23及びR24は、それらが結合されている窒素原子と一緒になって、場合により、1以上のC1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;
mは、0、1、2又は3であり;
R18、R19及びR21は、独立に、水素、場合によりハロゲン、-N(R25)R26(R25及びR26は、独立に、水素又はC1-6アルキルである)
で置換されたC1-6アルキル、ヒドロキシ、C1-6アルコキシ、C1-6アルコキシカルボニル、C1-6アルキルカルボニルオキシ又はアリールであり;又は
R19は、
Qは、-CH<、又は-N<であり;
K及びLは、独立に-CH2-、-CO-、-O-、-S-、-NR27-、又は原子価結合であり、R27は水素又はC1-6アルキルであり;n及びoは、独立に0、1、2、3又は4である);
R20は、C1-6アルキル、アリール又はヘタリールである)である。]
で表される化合物又はその薬学的に許容される塩である。但し、Mが原子価結合である場合には、Eが-CONR22NR23R24である。
R1は、水素又はC1-6アルキルであり;
R2は、水素又はC1-6アルキルであり;
Lは、
R4は、水素又はC1-6アルキルであり;
pは、0又は1であり;
q、s、t、uは、独立に0、1、2、3又は4であり;
rは、1であり;
q + r + s + 1 + uの合計は、0、1、2、3又は4であり;
R9、R10、R11及びR12は、独立に水素又はC1-6アルキルであり;
Qは、>N-R13、又は
oは、0、1又は2であり;
Tは、-N(R15)(R16)又はヒドロキシルであり;
R13、R15及びR16は、独立に水素又はC1-6アルキルであり;
R14は、水素、アリール又はヘタリールであり);あるいは
Lは
pは、0又は1であり;
q、s、t、uは、独立に0、1、2、3又は4であり;
rは、0又は1であり;
q + r + s + 1 + uの合計は、0、1、2、3又は4であり;
R9、R10、R11及びR12は、独立に水素又はC1-6アルキルであり;
Qは、>N-R13、又は
oは、0、1又は2であり;
Tは、-N(R15)(R16)又はヒドロキシルであり;
R13、R15及びR16は、独立に水素又はC1-6アルキルであり;
R14は、水素、アリール又はヘタリール、
Gは、-O-(CH2)-R17
ここで、
R17、R18、R19、R20、及びR21は、独立に水素、ハロゲン、アリール、ヘタリール、C1-6アルキル又はC1-6アルコキシであり;
kは、0、1又は2であり;
Jは、-O-(CH2)t-R22、
aは、O、1又は2であり;
bは、O、1又は2であり;
cは、O、1又は2であり;
dは、0又は1であり;
eは、0、1、2又は3であり;
fは、O又は1であり;
R5は、水素、又は場合により1以上のヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;
R6及びR7は、独立に水素、又は1以上のハロゲン、アミノ、ヒドロキシ、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;
R8は、水素、又は1以上のハロゲン、アミノ、ヒドロキシ、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;
R6及びR7、又はR6及びR8、又はR7及びR8は、場合により-(CH2)i-U-(CH2)j-を形成することができ(ここで、i及びjは、独立に1、2又は3であり、Uは、-O-、-S-又は原子価結合であり;
Mは、アリーレン、ヘタリーレン、-O-、-S-又は-CR27 = CR28-であり、
R27及びR28は、独立に水素、又は1以上のヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルである。]
によって示される化合物、又はその薬学的に許容される塩である。
本発明は、経口投与されたグレリン受容体作動薬が、癌患者に投与された時に悪心を減少させ、癌を有する及び/又は癌治療を経験する対象の癌症状の苦痛を減少させる、という予想しない発見に基づいている。従って、本発明は、悪心の治療又は予防のための、及び対象の癌症状の苦痛を減少させるための、方法及び組成物を提供する。該方法は、成長ホルモン分泌促進物質又はその薬学的に許容される塩、水和物もしくは溶媒和物の治療上有効量をそれを必要としている対象に投与することを含む。成長ホルモン分泌促進物質は、式I〜XVIのいずれか1つによって示される化合物、又はその薬学的に許容される塩、水和物もしくは溶媒和物である。
本明細書で使用される「成長ホルモン分泌促進物質」は、成長ホルモン分泌促進物質受容体(GHS受容体)の少なくとも1つの機能的特徴を促進(誘導又は亢進)する物質(例えば、分子、化合物)を意味する。成長ホルモン分泌促進物質の例は、グレリン模倣体、例えばグレリン作動薬である。1つの実施態様では、成長ホルモン分泌促進物質化合物又はグレリン受容体は、GHS受容体又はグレリン受容体(すなわち、グレリン又はGHS受容体作動薬)と結合し、成長ホルモンの分泌を誘発する。GHS受容体作動薬活性を有する化合物(例えば、GHS受容体又はグレリン受容体作動薬)は、任意の好適な方法によって同定されそして評価され得る。例えば、GHS受容体作動薬のGHS受容体への結合親和性は、受容体結合アッセイを用いて決定され、成長ホルモン刺激は、本明細書に参考として援用される米国特許第6,919,315号明細書に記載されているようにして評価され得る。
R1は、水素、又は場合により1以上のアリール又はヘタリールで置換されたC1-6アルキルであり;
a及びdは、独立に0、1、2又は3であり;
b及びcは、b+cが3、4又は5であることを条件に、独立に0、1、2、3、4又は5であり;
Dは、R2-NH-(CR3R4)e-(CH2)f-M-(CHR5)g-(CH2)h-
ここで、R2、R3、R4及びR5は、独立に、水素、場合により1以上のハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;又は
R2及びR3、又はR2及びR4、又はR3及びR4は、場合により、-(CH2)i-U-(CH2)j-を形成し(ここで、i及びjは独立に1又は2であり、Uは-O-、-S-又は原子価結合である);
h及びfは、独立に0、1、2又は3を示し;
g及びeは、独立に0又は1を示し;
Mは、原子価結合、-CR6=CR7-、アリーレン、ヘタリーレン、-O-又は-S-であり;
R6及びR7は、独立に、水素、又は場合により1以上のアリール又はヘタリールで置換されたC1-6アルキルであり;
Gは、-O-(CH2)k-R8、
k及びlは独立に0、1又は2であり;
Eは、-CONR18R19、-COOR19、-(CH2)m-NR18SO2R20、-(CH2)m-NR18-COR20、-(CH2)m-OR19、-(CH2)m-OCOR20、-CH(R18)R19-(CH2)m-NR18-CS-NR19R21、又は-(CH2)m-NR18-CO-NR19R21であり;又は
Eは、-CONR22NR23R24であり、ここで、R22は、水素、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキル、又は1以上のC1-6アルキルで置換されたアリール又はヘタリールであり;R23は、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキル、又はC1-7アシルであり;及びR24は、水素、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキルであり;又は
R22及びR23は、それらが結合されている窒素原子と一緒になって、場合により、1以上のC1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;又は
R22及びR24は、それらが結合されている窒素原子と一緒になって、場合により、1以上のC1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;又は
R23及びR24は、それらが結合されている窒素原子と一緒になって、場合により、1以上のC1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;
mは、0、1、2又は3であり;
R18、R19及びR21は、独立に、水素、場合によりハロゲン、-N(R25)R26(R25及びR26は、独立に、水素又はC1-6アルキルである)
で置換されたC1-6アルキル、ヒドロキシ、C1-6アルコキシ、C1-6アルコキシカルボニル、C1-6アルキルカルボニルオキシ又はアリールであり;又は
R19は、
Qは、-CH<、又は-N<であり;
K及びLは、独立に-CH2-、-CO-、-O-、-S-、-NR27-、又は原子価結合であり、R27は水素又はC1-6アルキルであり;n及びoは、独立に0、1、2、3又は4である);
R20は、C1-6アルキル、アリール又はヘタリールである)である。]
で表される化合物又はその薬学的に許容される塩である。但し、Mが原子価結合である場合には、Eが-CONR22NR23R24である。
[式中、
R2、R3、R4及びR5は、独立に、水素、場合により1以上のハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;又は
R2及びR3、又はR2及びR4、又はR3及びR4は、場合により、-(CH2)i-U-(CH2)j-(ここで、i及びjは独立に1又は2であり、Uは-O-、-S-又は原子価結合である);
h及びfは独立に0、1、2、又は3であり;
g及びeは独立に0又は1であり;
Mは、-CR6=CR7-、アリーレン、ヘタリーレン、-O-又は-S-であり;そして
R6及びR7は独立にハロゲン又はC1-6アルキルである。]
で表される。
[式中、
R2、R3、R4及びR5は、独立に、水素、場合により1以上のハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;又は
R2及びR3、又はR2及びR4、又はR3及びR4は、場合により、-(CH2)i-U-(CH2)j-(ここで、i及びjは独立に1又は2であり、Uは-O-、-S-又は原子価結合である);
h及びfは独立に0、1、2、又は3であり;
g及びeは独立に0又は1であり;
Mは、原子価結合である。]
である。
でよい。
でよい。
(ここで、
mは0、1、2又は3であり;
R18及びR19は、独立に、水素又は場合によりハロゲンによって置換されたC1-6アルキル、-N(R25)R26(ここで、R25及びR26は、独立に水素又はC1-6アルキルである)、ヒドロキシル、C1-6アルコキシ、C1-6アルコキシカルボニル、C1-6アルキルカルボニルオキシ又はアリールである。)
でよい。
(ここで、
R22は、水素、場合によりアリール又はヘタリールで置換されたC1-6アルキル、又はC1-6アルキルで置換されたアリール又はヘタリールであり;
R23は、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキル、又はC1-7アシルであり;及び
R24は、水素、場合により1以上のアリール又はヘタリールで置換されたC1-6アルキル、又はC1-6アルキルで置換されたアリール又はヘタリールであり;
R22及びR23は、それらが結合されている窒素原子と一緒になって、場合により、C1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;又は
R22及びR24は、それらが結合されている窒素原子と一緒になって、場合により、C1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができ;又は
R23及びR24は、それらが結合されている窒素原子と一緒になって、場合により、C1-6アルキル、ハロゲン、アミノ、ヒドロキシ、アリール又はヘタリールで置換された複素環式系を形成することができる。)
でよい。
R1は、水素又はC1-6アルキルであり;
R2は、水素又はC1-6アルキルであり;
Lは、
R4は、水素又はC1-6アルキルであり;
pは、0又は1であり;
q、s、t、uは、独立に0、1、2、3又は4であり;
rは、1であり;
q + r + s + 1 + uの合計は、0、1、2、3又は4であり;
R9、R10、R11及びR12は、独立に水素又はC1-6アルキルであり;
Qは、>N-R13、又は
oは、0、1又は2であり;
Tは、-N(R15)(R16)又はヒドロキシルであり;
R13、R15及びR16は、独立に水素又はC1-6アルキルであり;
R14は、水素、アリール又はヘタリールであり);あるいは
Lは
pは、0又は1であり;
q、s、t、uは、独立に0、1、2、3又は4であり;
rは、0又は1であり;
q + r + s + 1 + uの合計は、0、1、2、3又は4であり;
R9、R10、R11及びR12は、独立に水素又はC1-6アルキルであり;
Qは、>N-R13、又は
oは、0、1又は2であり;
Tは、-N(R15)(R16)又はヒドロキシルであり;
R13、R15及びR16は、独立に水素又はC1-6アルキルであり;
R14は、水素、アリール又はヘタリール、
Gは、-O-(CH2)-R17
ここで、
R17、R18、R19、R20、及びR21は、独立に水素、ハロゲン、アリール、ヘタリール、C1-6アルキル又はC1-6アルコキシであり;
kは、0、1又は2であり;
Jは、-O-(CH2)t-R22、
aは、O、1又は2であり;
bは、O、1又は2であり;
cは、O、1又は2であり;
dは、0又は1であり;
eは、0、1、2又は3であり;
fは、O又は1であり;
R5は、水素、又は場合により1以上のヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;
R6及びR7は、独立に水素、又は1以上のハロゲン、アミノ、ヒドロキシ、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;
R8は、水素、又は1以上のハロゲン、アミノ、ヒドロキシ、アミノ、ヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルであり;
R6及びR7、又はR6及びR8、又はR7及びR8は、場合により-(CH2)i-U-(CH2)j-を形成することができ(ここで、i及びjは、独立に1、2又は3であり、Uは、-O-、-S-又は原子価結合であり;
Mは、アリーレン、ヘタリーレン、-O-、-S-又は-CR27 = CR28-であり、
R27及びR28は、独立に水素、又は1以上のヒドロキシ、アリール又はヘタリールで置換されたC1-6アルキルである。]
によって示される化合物、又はその薬学的に許容される塩である。
R4は、水素又はC1-6アルキルであり;
pは、0又は1であり;
q、s、t、uは、独立に0、1、2、3又は4であり;
rは、1であり;
q + r + s + 1 + uの合計は、0、1、2、3又は4であり;
R9、R10、R11及びR12は、独立に水素又はC1-6アルキルであり;
Qは、>N-R13、又は
oは、0、1又は2であり;
Tは、-N(R15)(R16)又はヒドロキシルであり;
R13、R15及びR16は、独立に水素又はC1-6アルキルであり;
R14は、水素、アリール又はヘタリールであり);あるいは
Lは
pは、0又は1であり;
q、s、t、uは、独立に0、1、2、3又は4であり;
rは、0又は1であり;
q + r + s + 1 + uの合計は、0、1、2、3又は4であり;
R9、R10、R11及びR12は、独立に水素又はC1-6アルキルであり;
Qは、>N-R13、又は
oは、0、1又は2であり;
Tは、-N(R15)(R16)又はヒドロキシルであり;
R13、R15及びR16は、独立に水素又はC1-6アルキルであり;
R14は、水素、アリール又はヘタリールである。)
でよい。
でよい。
でよい。
1-{(2R)-2-[N-((2E)-5-アミノ-5-メチルヘキ-2-エノイル)-N-メチルアミノ]-3-(2-ナフチル)プロピオニル}-4-ベンジルピペリジン-4-カルボン酸メチルアミド
投与は、嘔吐症状を予防又は治療するために必要に応じて行える。成長ホルモン分泌促進物質の投与は、悪心又は嘔吐を起こしそうである化学療法剤の投与の前に、後に又は同時に行える。
本発明の成長ホルモン分泌促進物質(本明細書では、「活性化合物」とも称される)は、医薬組成物に組み込まれる。かかる組成物は、典型的には、成長ホルモン分泌促進物質及び薬学的に許容される担体を含む。本明細書で用いられる用語「薬学的に許容される担体」は、医薬組成物と適合し得る、溶媒、分散媒体、コーティング、抗菌剤及び抗真菌剤、等張剤及び吸収遅延剤等を含む。補助的な活性化合物も、該組成物に組み込まれる。
本明細書に記載の化合物の多くは、1以上のキラル中心を有し、そのため、異なったエナンチオマー体で存在し得る。必要ならば、キラル炭素はアスタリスク(*)で表示される。キラル炭素への結合が本発明の式において直線で示されるときには、キラル炭素の(R)及び(S)配置の両方、並びにその両エナンチオマー及びその混合物は、式中に包含される。当該分野で使用されるように、キラル炭素についての絶対配置を特定することが望ましい時には、キラル炭素への結合の1つは、(平面上で原子に結合する)くさびとして表示され、他の結合は、(平面上で原子に結合する)一組の短い平行線又は短い平行線のくさびとして表示され得る。カーン・インゴルド・プレローグ順位則は、キラル炭素に対して(R)又は(S)配置を指定するために使用され得る。
上記の構造式において及び本明細書の全体において、以下の用語は所定の意味を有する。
嘔吐症状の処置のために使用されるべき成長ホルモン分泌促進物質の能力を研究するために、二重盲検のプラセボ制御された無作為化試験を設計した。
フェレットにおけるイパモレリンの抗-嘔吐活性の評価の薬理学的試験
この試験の目的は、シスプラチンで治療されたフェレットにおける単回静脈内投与(遅延型ボーラス)に従ってイパモレリンの抗-嘔吐反応を評価することであった。
この実験では30匹の雌性フェレット(24週齢)を使用した。到着後に、正常な健康状態を確認するために、資格のある獣医スタッフメンバーによる全身的な健康状態試験に、すべての動物を供した。動物を研究室環境に慣れさせるために、動物の受け入れと処置開始との間に少なくとも1週間の順応期間を設けた。
投薬前に、被検物質の好適な量をビヒクルに溶解して4 mg/mLのストック溶液を調製し、ストック溶液(4 mg/mL)を調合する時に2当量の氷酢酸を加え、1 N NaOHを加えて7.5±0.2(必要に応じて)にpHを調整した。次いで、0.22 μm PVDFフィルターを用いてストック溶液を殺菌濾過し、毎日の投薬のために等分し、投薬製剤調製のために使用するまで冷凍保存した(約-20℃)。
投与
フェレットを、好適な16時間、投薬前に終夜絶食させた。
投薬後、10分おきに約4時間、嘔吐の兆候についてフェレットを監視、観察した。全体の観察時間(4時間投薬)に渡って10分間隔で、吐き気又は嘔吐の最初の兆候の前の時間(潜伏期間)、並びに吐き気及び嘔吐時間の総数を記録した。
動物から得られた数値データを、群平均及び標準偏差(SEM)の計算に供した。以下の統計的比較を行った。
全体の動物観察期間中、吐き気又は嘔吐の兆候がなかった時はいつでも、潜伏期間を4時間に設定し、吐き気/嘔吐の存在を有する、間隔当たりの吐き気/嘔吐の兆候の平均をゼロに設定した。これらの7個のパラメータの各々を以下の統計的比較の供した。
死亡及び臨床的兆候
投薬に関するこの試験において死亡及び臨床的兆候は認められなかった。
生食対照動物は、4時間の観察時間中、それぞれ、平均して4.89と1.78の吐き気及び嘔吐の兆候を示した。
結論として、1.0 mg/kg/用量で雄性フェレット静脈内投与されたイパモレリンは、生食処置対照と比べた時に、吐き気兆候の数を有意に減少させた(p<0.05)。嘔吐兆候の数を減少させることに対するイパモレリンの効果は、生食処置対照群動物に対して統計的有意に達しなかった。
Claims (6)
- 癌の化学療法を受けている対象がヒトである、請求項1記載の医薬組成物。
- 前記式IIIの化合物が25 mg/日〜150 mg/日の量で投与される、請求項1又は2記載の医薬組成物。
- 前記式IIIの化合物が50 mg/日〜100 mg/日の量で投与される、請求項1又は2記載の医薬組成物。
- 前記式IIIの化合物が50 mg/日の量で投与される、請求項1又は2記載の医薬組成物。
- 経口投与のための形態の、請求項1〜5のいずれか1項記載の医薬組成物。
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US8288427B2 (en) | 2012-10-16 |
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CA2680948A1 (en) | 2008-10-16 |
KR20150061026A (ko) | 2015-06-03 |
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US8394833B2 (en) | 2013-03-12 |
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