970 707
( Renin Inhibitors )
ၡāāࢋ
- ( renin-angiotensin system RAS )
( angiotensin convert- ing enzyme inhibitor, ACEI ) AT1 ( angiotensin AT1-receptor blocker, ARB ) RAS
RAS RAS
aliskiren Aliskiren ( plasma renin activity,
PRA ) I II aliskiren
ACEI ARB
ᙯᔣෟĈඪ৵-ҕგچᑅ৵ր ( Renin-angiotensin system, RAS ) ඪ৵ ( Renin )
ඪ৵Ժט ( Renin inhibitors, ˫Ⴭ Direct renin inhibitors, DRI ) Aliskiren
݈֏
ඪ৵-ҕგچᑅ৵ր ( renin-angiotensin sys- temĂ RAS ) дҕᑅ۞ଠט˯Էႊޝࢦࢋ۞֎
ҒĄ࿅ޘ۞ R A S ߿ّົֹҕგچᑅ৵ I I ( a n - giotensin IIĂ Ang II ) ᆧΐĂ Ang II ົֹҕᑅ˯̿
ͷѣܳซࡪϠܜүϡซ҃ጱጡء๋̝चĄኜ тҕგچᑅ৵ᖼೱᅔ৵Ժט ( angiotensin con- verting enzyme inhibitorĂ ACEI )ăҕგچᑅ৵
AT1ତצጡܡᕝ ( angiotensin AT1-receptor blockerĂ ARB ) ̏జᙋ၁Ξͽڼᒚҕᑅă͕
აᄃ࠹ᙯ۞͕ҕგ়ঽ1, 2Ą҃ϫ݈Ξϡ۞ᘽۏ
̙֭ਕѣड़гԺט RAS ĂЯࠎ ACEI ă ARB ă ӀԌౌົ߿̼ᐺّ۞ͅ㒝፟ᖼ҃ጱඪ৵ᛖ
ᄃҕඪ৵߿ّ ( plasma renin activity Ă PRA ) ᆧ3, 4Ą ACEI ົጱҕგچᑅ৵ I ( angiotensin IĂ Ang I ) ᆧΐĂ҃ Ang I ΞϤϏజܡᕝ۞ҕგچ ᑅ৵ᖼೱᅔ৵ ( angiotensin converting enzyme in-
hibitor, ACE ) ٕܧ ACE ֶᏥྮश ( ACE-indepen- dent pathwayĂּт chymase ) តೱј Ang II Ą ARBăӀԌ˵ౌົᆧΐ Ang I ă Ang II 5( ֍ܑ
˘ )Ą
ඪ৵ߏ๊̼ R A S ۞ௐ˘ᄃిதࢨט ( r a t e limiting ) ՎូĂͷ၆ٺצኳęҕგچᑅ৵ࣧ
( angiotensinogen, AGT ) ѣޘ۞পளّĂٙͽ ඪ৵Ժט ( renin inhibitors ) ೩ֻ˞дኑᗔ۞
R A S߿̼ؕᕇಶܡᕝι۞ΞਕّĄГ۰Ăඪ
৵Ժט̙ᇆᜩ k i n i n ᔁĂٙͽ̙ົѣтТ ACEI͔ݜăҕგৠགྷّͪཚ ( angioneurotic edema ) ۞ઘүϡĂ˵̙ົ͔ Ang I ă Ang II ᆧ ΐ6Ą
࿅Ν 3 0 ѐֽĂࡁտ۰˧ٺࡁ൴ඪ৵Ժט
Ăܐ۞ဘྏߏϡඪ৵ԩវٕඪ৵Аᜭۏ̝
prosegment۞ᙷҬۏ ( analogs of the prosegment of the renin precursor )7Ăޢҡᐌჟ۞̼ጯԼ ซăࢫҲ̶̄ณ҃ࡁ൴ enalkiren8ă remikiren 9ă zankiren10ă ciprokiren11ඈඪ৵ԺטĄֱѝഇ
۞ᷴ ّ ( ٕᙷᷴ ّ ) ඪ৵ԺטགྷϤրّ
Ը̟̝ޢѣ֝ిࢫҲҕᑅ۞ड़ڍĂҭ࿅Ҳ۞˾
ڇϠۏӀϡޘ ( bioavailability, Ŵ 2% )ăൺड़ăઐ
۞ЪјјώĂЯѩտ՟ѣјࠎથݡĄ ܕѐֽགྷϤ̶̄ሀݭԫఙᄃඕវ̶ژጯ҃
யϠೀૻޘăඕЪᏐ˧ăҲ̶̄ณ۞ܧ
ᷴ ّඪ৵ԺטĄ̚ Aliskiren ( ࡁ൴ቅĈ SPP 100 ) தАԆјᓜԖྏរĂٺ 2007 ѐ 3 ͡ז
઼࡚ࢴݡᘽۏგநԊ( Food and Drug Administration, FDA ) ٚᄮĂ҃јࠎܕ˩ѐֽ˯ξ۞າᙷҕ ᑅڼᒚᘽĄώ̬͛̚۞ඪ৵Ժטͽ Aliskiren ࠎĄ
RASϠநጯ
RASࢋϤඪ৵ᄃҕგچᑅ৵ၹј( ֍ဦ˘)Ą RASٺܜഇአ༼ҕटณ ( blood volume ) ᄃրҕ ᑅԷႊޝࢦࢋ۞֎ҒĂ༊ҕटณഴٕ͌ҕᑅ˭
ࢫॡ RAS ಶజ߿ֽ̼ĂࢵАߏඪᛖඪ
৵ٺҕ୵̚Ą
˘ăඪ৵
ඪ৵ߏϤඪ۞ඪක౭ጡࡪ ( j u x t a - glomerular cell, JGࡪ ) ̶ک۞కϨኳ̶ྋᅔ
৵Ą JG ࡪགྷϤˬᙷו፬҃ᛖඪ৵ٺҕ୵ೈ
ᒖ̚Ĉ
1.Ϲຏৠགྷ߿̼ĈགྷϤ JG ࡪ۞ɘ1-ඪ˯ཛྷ צጡ ( ɘ1-adrenoreceptor )Ą
2.ඪજਔҲҕᑅ ( ּтϤրّҲҕᑅٕඪજ ਔব৫͔ٙ )Ĉ็ˢ̈જਔ ( afferent arteriole ) ᑅ
˧˭ࢫ͔ඪ৵ᛖĂ҃็ˢ̈જਔᑅ˧˯̿
ဦ˘Ĉඪ৵- ҕგچᑅ৵րĄ N E P Ĉ n e u t r a l e n - dopeptidaseć PEP Ĉ prolyl-endopeptidase ć ACEĈ angiotensin converting enzyme ć ACE 2Ĉ angiotensin converting enzyme 2 ć Ang Ĉ angiotensinogenć AT1R Ĉ angiotensin AT1-re- ceptorć AT2R Ĉ angiotensin AT2-receptor Ą
ܑ˘Ĉֹϡ̙Тᘽۏ͔ٙ۞ЧϠ̼ࣃត̼
ಏ˘ RAS Ժט
ACEI ARB ඪ৵Ժט
ᅔ৵ΐ
PRA ᆧΐ ᆧΐ Ժט
PRC ᆧΐ ᆧΐ ᆧΐ
Prorenin ᆧΐ ᆧΐ ᆧΐ
Plasma ACE Ժט Ժט Ժט
צኳ፧ޘ
AGT ࢫҲ ࢫҲ ត̼
Ang I ᆧΐ ᆧΐ ࢫҲ
Bradykinin ᆧΐ ត̼ ត̼
ბயۏ
Ang II ࢫҲ ᆧΐ ࢫҲ
Aldosterone ࢫҲ ࢫҲ ࢫҲ
Ang ( 1-7 ) ᆧΐ ᆧΐ ࢫҲ
RAS: renin-angiotensin system; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin AT1-re- ceptor blocker; PRA: plasma renin activity; PRC: plas- ma renin concentration; ACE: angiotensin converting en- zyme; AGT: angiotensinogen; Ang: angiotensinĄ
Ժטඪ৵ᛖĄ
3.็ᏮҌඪᅈѡ̈გ ( distal tubule ) ۞ท፧
ޘഴ͌Ĉᅈѡ̈გ۞ቜ ( macula densa ) ዐ ତ ٺ JG ࡪĂቜΞຏᑕทăന፧ޘĂ༊ᅈѡ
̈გ۞ทăന፧ޘ˭ࢫॡቜགྷϤᛖ݈Еཛྷ
৵ֹܳ JG ࡪᛖඪ৵Ă҃༊ᅈѡ̈გ۞ทă ന፧ޘ̿ॡԺטඪ৵ᛖĄ
༊ඪ৵జ JG ࡪᛖĂιಶགྷϤకϨኳ̶
ྋ ( proteolytic cleavage ) ֹ҃дҕ୵ೈᒖ̚۞
AGTෘྋј Ang I Ąҕგ̰ϩࡪ̶ک ACE Ang Iෘྋј Ang II ĂϠј Ang II ۞Վូд۱
ҕგপҾពĄ
ඪ৵۞Аᜭۏߏ̙߿ّ۞ preprorenin Ă preproreninГᖼតјඪ৵ࣧ ( prorenin )ĄొЊ۞
ඪ৵ࣧགྷకϨኳ̶ྋјࠎඪ৵҃జᐼхٺ̶کᔺ
( secretory granula )ĂΩ˘ొЊ۞ඪ৵̙ࣧགྷక Ϩኳ̶ྋ҃ۡତᛖҌҕ୵ೈᒖ̚Ąдϒ૱ଐڶ
˭Ăҕ̚۞ඪ৵ࣧ፧ޘߏඪ৵፧ޘ۞˩ࢺĄк ᇴ۞ඪ৵ࣧజ prosegment ᄏҝ߿ّొҜ ( active site ) ̙҃߿ّ ( ֍ဦ˟ )Ąѩ prosegment Ξᇶ ॡχฟ҃ѣ߿ّĂΞਗ਼ّ۞ՎូჍࠎܧక Ϩኳ̶ྋّ߿̼ ( non-proteolytic activation )12Ą дҋېၗ˭ ( pH 7.4 ă 37 ƨ )Ă߿ّ̝ඪ৵
ࣧࡗ 2% Ă҃дྵҲăҲ pH ࣃॡѺ̶ͧົ
ᆧΐ ( Ƃ 15% )Ą
Ҍ̫ѣ࣎ඪ৵ତצጡజ൴னĄௐ˘࣎ߏ M6PR ( mannose-6-phosphate receptor )ĂΞඕЪඪ
৵ࣧăඪ৵̝҃ৼˢ ( internalize ) ࡪ̚Ăߏ
˘ੵّତצጡ ( clearance receptor )13ĄΩ˘࣎
পҾ۞ତצጡߏ ( P ) RR ( ( pro ) renin receptor )Ă ᄃ̝ඕЪޢඪ৵۞๊̼߿ّົᆧΐĂͷඪ৵ࣧ˵
ԆБ߿ّ̼Ą(P)RR ۞߿̼Ξᆧΐ plasminogen activator inhibitor-1 ( PAI-1 )ă TGF-ɘ1Ъјซ҃
͔ fibronectin ă collagen I ᆧΐ14( ֍ဦˬ )Ą
˟ă Ang I ᄃࢉϠۏăᖼೱᅔ৵
AGT ( ӣ 453 ࣎ঊૄᅕ ) Ϥքᄦౄ҃ᛖ
ٺҕ୵ೈᒖ̚Ăజඪ৵ෘྋ̬ٺ leucine ( Leu ) ᄃ valine ( Val ) ̝ม۞ᷴ ᔣ҃யϠ 10 ࣎ঊૄ
ᅕ۞ Ang I Ą Ang I ̙Ϡۏ߿ّĂᐌޢགྷϤ̙Т शྮயϠ̙Т۞ᷴ ( ֍ဦ˘ )Ą
ဦ˟Ĉඪ৵ࣧజ p r o s e g m e n t ᄏҝ߿ّొҜ̙҃߿
ّĂѩ prosegment Ξᇶॡχฟ҃ѣ߿ّĂ
Ξ ਗ਼ ّ ۞ Վ ូ Ⴭ ࠎ ܧ క Ϩ ኳ ̶ ྋ ّ ߿ ̼ Ğnon-proteolytic activationğĂ߿̼۞ඪ৵ࣧ
๊̼ਕ˧Ξజඪ৵ԺטԺטĄొЊ۞ඪ৵ࣧགྷ కϨኳ̶ྋّ߿̼Ğproteolytic activationğј ࠎඪ৵Ą
ဦˬĈඪ৵ࣧăඪ৵࠰ᄃତצጡ(PRR)ඕЪĄඕЪޢĂ ඪ৵๊̼ҕგچᑅ৵ࣧ(AGT)ԛјҕგچᑅ৵-I (Ang I)۞߿ّᆧΐĄᄃତצጡඕЪޢĂࣧώ๊
̼үϡ۞ඪ৵ࣧயϠԛၗ˯۞ԼតĂซ҃யϠт Тඪ৵ਠ۞๊̼ਕ˧Ąҕგچᑅ৵-I Гགྷҕგچ ᑅ৵ᖼೱᅔ৵( A C E ) үϡ҃யϠҕგچᑅ৵- II(Ang II)Ă Ang II ᄃ AT1ତצጡඕЪĄඕЪޢ۞
ତצጡ፬൴కϨ፬∰(protein kinase)-ERK1/2 Ă ซ҃ᆧΐࡪል৵ࣧ߿̼Ժט-1(plasminogen activator inhibitor-1Ă PAI-1)ăᖼ̼јܜЯ̄-ɘ1 (transforming growth factorɘ1Ă TGF-ɘ1)Ą T- GF-ɘ1Ξ͔ fibronectin ă collagen I ۞ᆧΐĄ P R RĈ(pro)rennin receptor ć ACE Ĉ an- giotensin converting enzymeć Ang Ĉ an- giotensinogenć ERK Ĉ extracellular regulated kinasesć AGT Ĉ angiotensinogen ć AT1 Ĉ angiotensin AT1-receptorĄ
1.Ang Iགྷ ACE யϠ Ang II
ACEΞ๊̼ Ang I ᖼೱј Ang II Ă˵Ξෘྋ
ҕგᕖૺ˧۞ bradykinin Ąٙͽ ACEI ۞ࢫҕ ᑅड़ڍੵ˞Яࠎഴ͌ A n g I I Ϡј̝γĂԺט bradykininజෘྋ˵ԷႊొЊ֎ҒĄ
2.Ang Iགྷܧ ACE ҃யϠ Ang II
Ang IΞགྷϤ chymotrypsin-like angiotensin- generating enzyme ( CAGE ) ٕ chymase ඈᅔ৵ᖼ ೱј Ang II Ą
3.Iགྷ ACE2 யϠ Ang-( 1-9 )
ACE2 ( angiotensin converting enzyme 2 ) ᄃ ACEѣ 42% ۞࠹ҬޘĂхдٺ͕ăඪ۞ҕ გ̰ϩࡪĂΞ Ang I ̶ྋј̙Ϡۏ߿ّ۞
Ang-( 1-9 )15Ą Ang-( 1-9 ) Гགྷ ACE ٕ neutral en- dopeptidase ( NEP )̶ྋј Ang-( 1-7 )16Ą ACE2 ̙
ົజ ACEI ԺטĄ
4.Ang Iགྷ NEP யϠ Ang-( 1-7 )
Ang-( 1-7 ) д RAS ̚ߏԷႊͅШአ༼۞֎
ҒĂιΞ၆ԩ Ang II ۞ ( ҕგќᒺăࡪᆧത ) үϡ17Ą Ang-( 1-7 ) хдٺҕ୵ă͕ăҕგ
̚ĄϤ Ang-( 1-7 ) ͔ᛖٸ۞ҕგᕖૺ̶̄ѣ݈
Еཛྷ৵ᙷ ( prostanoids )ă NO ( nitric oxide )ă̰
ϩϤֽ࿅ໂ̼Я̄ ( endothelium-derived hyperpo- larizing factorĂ EDHF ) ඈ18,19Ą Ang-( 1-7 ) ˵
ԩҕংԛј۞পّ20Ą Ang-( 1-7 )˵ΞϤ Ang II གྷ ACE2 ̶ྋֽ҃Ăٙͽдֹϡ ACEI ٕ ARB ॡ Ξᆧΐ Ang-( 1-7 ) ྿ 25 ࢺ21Ą Ang-( 1-7 ) ۞ତ צጡߏ Mas22Ą
5.Ang IIགྷ aminopeptidase யϠ Ang-III ă Ang IVĄ
Aliskiren̝ᘽநጯ
Aliskiren۞̼ጯ̶̄ёࠎ C30H53N3O6 Ć 0.5 C4H4O4Ă̶̄ณ 609.8 ( ̼ጯၹౄ֍ဦα )Ă ࠎϨҒเৰϐĂޘͪ໘ّĂથݡͽᏺݭ ё˯ξĄ
˘ăᘽۏજ˧ጯ ( pharmacokinetics )
ॲፂ Nussberge ඈˠ۞ࡁտĂ aliskiren ˾ڇ ϠۏӀϡޘࠎ 2.5% Ăҕ̚ыप፧ޘߏдڇᘽޢ 3Ƃ 6 ̈ॡĂҕ̚۞ΗഇπӮ 23.7 ̈ॡ ( 20 Ƃ 4 5̈ॡ ) Ăᜈڇϡ 5 Ƃ 8 ͇ޢ྿זᘦؠېၗ
ဦ̣Ĉڇϡᘽۏޢҕඪ৵፧ޘĞactive renin concen- trationğĞဦ˯ğăҕგچᑅ৵ů I ፧ޘĞဦ̚ğă ҕგچᑅ৵ů II ፧ޘĞဦ˭ğҡᐌॡม۞ត̼Ą A300 (aliskiren 300 mg)ć V160 (valsartan 160 mg)ć A150+V80 (aliskiren 150 mg+ valsartan 80 mg)Ą
ဦαĈ Aliskiren ۞̼ጯၹౄ
( steady state )23Ąᄃ۩ཛڇϡ࠹ྵĂ۹ࢴ
̚Тॡڇϡ aliskiren Ă AUC ( area under the curve ) ົࢫҲ 62% Ăҭ̙ົᇆᜩ၆ٺ PRA ̝ Ժט24Ą Aliskiren ࢋͽϏᔁݭၗགྷᓙଵڴĂ
̈ٺ 1% གྷϤ̈ܮଵĄڇϡ 150 ă 300 ă 600 mg aliskiren̝ trough-to-peak ratios ( T/P ratio )̶
Ҿࠎ 0.64 ă 0.98 ă 0.8625Ą
ᄃ irbesartan ׀ϡॡĂ aliskiren ҕ̚፧ޘົ
ࢫҲĂ҃ᄃ atorvastatin ă ketoconazole ׀ϡॡĂ a l i s k i r e nҕ̚፧ޘົ˯̿Ą A l i s k i r e n ົࢫҲ furosemide̝ҕ̚፧ޘĄ
дҁѐˠ ( Ÿ 65 years ) ڇϡ aliskiren ޢҕ
̚፧ޘྵѐᅅˠரĂҭߏ̙ᅮࢋአፋณ26Ą Aliskiren۞ᘽۏજ˧ጯдˠมमҾ27Ą
˟ăᘽड़ጯ ( pharmacodynamics )
дϒ૱ҕᑅշّצྏ۰ڇϡ aliskiren ޢĂ PRAă Ang I ă Ang II ࠰ࢫҲ҃˭ࢫޘᄃ˾
ڇ aliskiren ۞ณӔϒ࠹ᙯĄҕᄃԌ୵̚۞ al- dosterone፧ޘϺࢫҲĄᄃщᇐ̈́ enalapril ࠹
ྵĂ aliskiren Ξͽѣड़۞ᆧΐӀԌทүϡ ( natri- ureisis ) ҃ӀԌ࿔үϡ ( kaliuresis )Ą၆ٺ Angiotensin II ۞ԺטүϡޘĂڇϡ aliskiren 160 mg۰ᄃڇϡ enalapril 20 mg ۰࠹༊Ąᄃщᇐ
࠹ͧĂֹϡณ۞ aliskiren ΞͽࢫҲ Ang II
྿ 80% Ăݒֹҕඪ৵፧ޘ ( plasma renin con- c e n t r a t i o n , P R C ) ˯̿࿅ 1 0 ࢺĄՏ͇ڇϡ aliskiren 160 mgٕ Enalapril 20 mg ၆ٺҕ̚ Ang II
፧ޘ۞˭ࢫޘߏ࠹Ҭ۞Ą Aliskiren ࢫҲҕ
ᄃԌ୵̚ aldosterone ྿ 40 Ƃ 50%23Ą
Aliskirenͧ valsartan Հਕו፬ඪ৵ᛖٸҌೈ
ᒖ̚Ą Aliskiren Ξܡᕝ valsartan ಏֹϡॡ۞
PRAă Ang I ă Ang II ᆧΐĂٙͽ۰׀ϡົѣ םТүϡ ( synergistic effect ) ( ֍ဦ̣ )28Ą
Aliskiren۞ᓜԖྏរ
˘ăಏֹϡ
[ ̙Тณ̝ aliskiren vs щᇐ ]
Oh BHඈˠࡁտ aliskiren ۞ड़ڍĂצྏ۰ࠎ ᅅޘٕ̚ޘ۞ҕᑅଈ۰ 672 ˠĂᐌ̶፟Ҿڇϡ ˣฉ aliskiren 150mg ă 300mg ă 600mg ăٕщᇐ
Ă̝ޢαГઃᘽฉ៍၅Ąˣฉ̝ޢĂ
α ঽ ˠ ќ ᒺ ᑅ Ɲ න ૺ ᑅ ۞ ࢫ Ҳ ̶ Ҿ ࠎ 13.0/10.3ă 14.7/11.1 ă 15.8/12.5 mmHg ă 3.8/4.9 mmHgĄͧྵࣃڦຍ۞ߏĂдઃᘽฉޢĂ၁ រ̙ҭ՟ѣͅᇅன෪҃ͷֶΞͽ៍၅זࢫᑅ ड़ڍ25Ą
[ aliskiren vs losartan ]
Stantonͽᐌ፟ăᗕ۠ྏរࡁտ aliskiren ̝ࢫ ᑅड़ڍᄃщБّĄ 226 Ҝᅅޘٕ̚ޘҕᑅঽˠ ᐌ̶፟ј 5 ̶ҾՏ͇˾ڇ 37.5 mg ă 75 mg ă 150 mgă 300 mg ۞ aliskiren ٕ 100 mg ۞ losartan αฉĄඕڍពϯ a l i s k i r e n ࢫҲ P R A 5 5 % Ƃ 83%Ă҃ losartan ߏᆧΐ PRA 110% Ąҕᑅ˭
ࢫ۞ޘд aliskiren 300 mg ᄃ losartan 100 mg ߏ
࠹༊۞29Ą
[ aliskiren vs irbesartan vs щᇐ ]
Gradmanͽᐌ፟ăᗕ۠ăщᇐ၆ྏរࡁ տ 652 ҜᅅޘҌ̚ޘҕᑅঽˠĂᐌ፟Տ͇ග̟
˘Ѩ aliskiren ( 150 ٕ 300 ٕ 600 mg )Ăٕ irbesar- tan 150 mgĂٕщᇐĄඕڍពϯڇϡ aliskiren 150 mg۞ࢫҕᑅड़ڍߏᄃڇϡ irbesartan 150 mg ۰࠹ҬĂ҃ڇϡ aliskiren 300 mg ٕ 600 mg ̝න
ૺഇҕᑅࢫҲड़ڍͧڇϡ irbesartan 150 mg рĄ
щБޘăटצޘඈઘүϡ൴Ϡத࠰ᄃ irbesar- tanٕщᇐ࠹Ҭ30Ą
[ aliskiren vs irbesartan vs amlodipine vs щᇐ
]
JordanඈˠАϡՏ͇ hydrochlorothiazide ( HCTZ ) 25 mgڼᒚනૺഇҕᑅࠎ 95 Ƃ 109 mm Hgͷ֗វኳณᇴ ( body mass index Ă BMI )ŵ 30 ۞ঽˠĂ 4 ฉ̝ޢГଂ̚Ա၆ٺѩڼᒚ
ͅᑕ۰ ( nonresponder ) В 489 ҜĄ 489 Ҝঽˠ
ੵ˞ᚶᜈග̟Տ͇ HCTZ 25 mg ̝γĂᐌ፟ăᗕ
̶۠ј 4 ĂՏ̶͇Ҿΐ aliskiren 150 mg ă irbesartan 150 mgă amlodipine 5 mg ăٕщᇐ
ڼᒚαฉĂତԯ aliskiren ă irbesartan ă am- lodipineՏ͇۞ณᆧΐ˘ࢺГᖸˣฉĄඕ ڍពϯ Aliskiren+HCTZ ۞ࢫҕᑅड़ڍᄃ irbesar- tan+HCTZă amlodipine+HCTZ ࠹Ҭ ( ќᒺƝන
ૺഇҕᑅ˭ࢫࣃ̶Ҿࠎ 15.8/11.9 ă 15.4/11.3 ă 13.6/10.3 mm Hg )Ąд۲ࡡ۞ҕᑅঽˠֹϡௐ
˘ቢ thiazide ӀԌڱ྿јҕᑅଠטॡĂЪ׀
ֹϡ aliskiren ߏޘѣड़۞31Ą [ aliskiren vs lisinopril ]
Strasser۞ࡁտߏᐌ፟ăᗕ۠ྏរĂනૺഇҕ ᑅ̬ٺ 105 Ƃ 120 mm Hg ۞ 183 Ҝঽˠᐌ̶፟ј aliskiren 150 mg ( n=125 ) ᄃ lisinopril 20 mg ( n=58 )
ڼᒚ 8 ฉĄඕڍពϯĂ aliskiren ᄃ lisino- pril၆ٺනૺഇҕᑅ۞ࢫҲޘ ( -18.5 mm Hg vs -20.1 mm Hg )ăќᒺഇҕᑅ۞ࢫҲޘ ( -20.0 mm Hg vs -22.3 mm Hg )ă၆ڼᒚѣͅᑕ۰൴Ϡத ( re- sponder rate, 81.5% vs 87.9% ) ౌߏ࠹Ҭ۞Ą Aliskiren
ᄃ lisinopril Яઘүϡ҃ઃᘽ۞ͧதߏ࠹Ҭ۞
( 3.2% vs 3.4% )Ă૱֍۞ઘүϡߏᐝ൭ăᆄݟۆ ( nasopharyngitis )ăᐝຶ ( dizziness ) 32Ą
˟ă׀ϡࢫᑅᘽ
[ aliskiren vs HCTZ vs aliskiren/HCTZ vs щᇐ
]
Villamilඈˠࡁտֹϡ aliskiren ă HCTZ ٕ aliskiren/HCTZ۞ѣड़ّăщБّᄃ၆ٺ PRA ̝ ᇆᜩĄВ 2776 Ҝනૺഇҕᑅ̬ٺ 95-109 mm Hg
۞ঽˠᐌ፟ăᗕ̶۠јڇϡ a l i s k i r e n ( 7 5 ă 150ă 300 mg )ă HCTZ ( 6.25 ă 12.5 ă 25 mg )ă aliskiren+ HCTZăщᇐα̂Ą 8 ฉޢඕڍព ϯࢫᑅड़ڍдಏֹϡ aliskiren ֹͧϡщᇐ
рĄ҃дࢫҲҕᑅޘă၆ڼᒚѣͅᑕ۰൴Ϡ தăҕᑅᒔଠטத͞ࢬĂ aliskiren+ HCTZ ͧ ಏֹϡ aliskiren ٕ HCTZ ౌֽрĄಏֹϡ aliskirenॡ PRA ࢫҲ 65% Ăಏֹϡ HCTZ ॡ PRAᆧΐ 72% Ă҃ aliskiren+ HCTZ ົࢫҲ P R AĄ A l i s k i r e n + H C T Z ΞͽࢫҲಏֹϡ HCTZॡٙயϠҲҕ࿔۞൴Ϡத33Ą
[aliskiren vs aliskiren/HCTZ vs aliskiren/irbe- sartan vs aliskiren/ramipril]
O'Brienඈˠ۞ࡁտߏᅅޘҌ̚ޘ۞ҕᑅ ଈ۰Ăග̟ aliskiren ( ঽˠᇴĂ n = 6 ) ٕ aliskiren + HCTZ ( n = 17 ) ٕ aliskiren + ramipril ( n = 21 )
ٕ aliskiren + irbesartan ( n = 23 )Ąඕڍពϯ aliskiren + HCTZ ͧಏֹϡ aliskiren ѣՀр۞ࢫ ᑅड़ڍ ( ќᒺഇƝනૺഇҕᑅ -18.4/ -10.6 vs -10.4 / -5.8Ă p=0.0007 )Ąд Aliskiren + ramipril ͧಏ
ֹϡ ramipril рć aliskiren + irbesartan ˵ͧಏ
ֹϡ i r b e s a r t a n ѣՀр۞ࢫᑅड़ڍĄಏֹϡ
Aliskiren 150 mg ࢫҲ PRA 65% ( P<0.0001 ) ҃ ramiprilă irbesartan ۞ಏֹϡົ͔ PRA Чᆧ ΐ 90% ă 175% Ą༊ HCTZ ă ramipril ă irbesar- tanᄃ aliskiren Ъ׀ֹϡॡĂ PRA ̙ົᆧ34Ą
[ a l i s k i r e n v sщᇐ v s v a l s a r t a n v s aliskiren/valsartan vs valsartan/HCTZ ]
Poolඈˠ 1123 ҜᅅޘҌ̚ޘ۞ҕᑅଈ ۰ᐌ̶፟јщᇐăಏϡ aliskiren ăಏϡ v a l s a r t a nă aliskiren/valsartan ă valsartan/
HCTZĄ 8 ฉޢĂಏϡ aliskiren ۰ͧϡщᇐ
۰ѣࢍຍཌྷ۞ࢫҲҕᑅ ( p < .0001 )Ą၆ᘽۏய Ϡઘүϡ۞൴ϠதЧӮᄃщᇐពम ளĂ૱֍۞ઘүϡߏᐝ൭ăཛᕫĄ Aliskiren/val- sartan̝ࢫҕᑅޘͧ۰࣎ҾಏֹϡॡՀਕࢫ ҲҕᑅĂ҃ᄃ valsartan/HCTZ ̝ࢫҕᑅޘ࠹༊ͷ щБّ۰मҾ35Ą
ᔵ Pool ඈˠ۞ྏរពϯಏϡ aliskiren ۰
ͧϡщᇐ۰ѣࢍຍཌྷ۞ࢫҲҕᑅĂҭЯࠎщ ᇐड़ڍ࿅̂ ( ќᒺૺഇҕᑅƝනૺഇҕᑅࠎ -10.0Ɲ-8.6 mmHg Ăֹ҃ϡ aliskiren 300 mg ۰ࠎ -15.0Ɲ-12.3 ) ҃జᘃႷѣϨҗّҕᑅ۞צྏ
۰Ąࠎ˞ଵੵѣϨҗّҕᑅ۞ΞਕّĂ Oparil ඈˠֹϡᛸݭҕᑅాᜈႾീϨ͇ˣ̈ॡ۞ҕ ᑅĂޢᏴፄනૺഇҕᑅŸ 90 mmHg ͷπӮ ळҜනૺഇҕᑅࠎ 95 Ƃ 109 mmHg ۞ 1797 Ҝঽ ˠซˢྏរĄঽˠᐌ̶፟јαĂ̶ҾՏ͇ගᄃ aliskiren 150 mg ( 437ˠ)ă valsartan 160 mg ( 455 ˠ)ă aliskiren 150 mg + valsartan 160 mg ( 446ˠ )ăщᇐ
( 459ˠ )Ąαߐഇ̝ޢĂЧڇϡ۞ณౌΐࢺ ГڇϡαߐഇĄඕڍពϯ aliskiren 300 mg + val- sartan 320 mg۞නૺഇҕᑅ˭ࢫޘ ( 12.2 mmHg )
ͧ aliskiren 300 mg ( 9.0 mmHg )ă valsartan 320 mg ( 9.7 mmHg )ăщᇐ ( 4.1 mmHg )ౌֽ
рĄΩγĂڇᘽˣฉޢঽˠ۞ҕ࿔፧ޘ ŵ 5.5 mmol/LдЧ۞൴Ϡத̶ҾࠎĈщᇐ( 3% )ă aliskiren ( 2% )ă valsartan ( 2% )ă aliskiren + valsartan ( 4% )36Ą
ˬăซҖ̝̚ aliskiren ᓜԖྏរ
1.AVOID ( Aliskiren in the eValuation of prOteinuria in Diabetes ) ྏរĈдకϨԌ۞ௐ˟
ݭ Ꭴ Ԍ ঽ ͷ ̏ ֹ ϡ A R B ڼ ᒚ ۞ ঽ ˠ Ă ග ̟
aliskiren 300 mgٕщᇐ̱̝࣎͡ड़ڍͧྵĄ 2.ALLAY ( ALiskiren in Left ventricular Assessment of hypertrophY )Ĉдѣν͕ވ۲̂۞
ঽˠĂග̟ aliskiren 300 mg ٕ losartan ٕ۰׀
ϡ˝̝࣎͡ޢĂͽ MRI ͧྵν͕ވ۞ኳณ ( LV mass )Ą
3.ALOFT ( ALiskiren Observation of heart Failure Treatment )Ĉдѐ᛬Ÿ 18 ໐̝Тॡҕ ᑅᄃᘦؠېၗ͕აͷ BNP ( brain natriuretic pep- tide )ŵ 100 pg/mL ۞ঽˠĂੵ˞ᇾڼᒚ̝γĂ ග̟˩˟ฉ aliskiren 150 mg ٕщᇐĂͧྵड़ ڍ ( BNP ̝˭ࢫޘ ) ᄃщБّĄܐՎ۞ඕڍ̏д 2007ѐ 9 ͡ٺለ߷͕ጯົ۞ 2007 ѐᗁጯົᛉ
൴ܑĄ Aliskiren ពгࢫҲ BNP ࣃ ( ֍ܑ˟ )Ă
͕ࢰگᑭߤ˵ពϯν͕ވ·ᑅពԼච ( p=0.047 vs щᇐ )Ą
4.AVIATOR ( Aliskiren in Visceral Obesity AT risk patients Outcomes Research )Ĉࠎܐ৺ّ֨
ྏរĂෞҤ aliskiren ߏӎΞؼᏵПᐍঽˠௐ˘
Ѩ൴Ϡࢦ͕̂ҕგְІ ( first major cardiovascular event )۞ॡมĄࢍќᐂ 15000 ˠĄ
5.ALTITUDE ( ALiskiren Trial In Type 2 Diabetic nephropathy )ĈࠎГ൴ّ֨ྏរĂ
ࢍќᐂ 6000 ˠĂෞҤ aliskiren ߏӎΞؼᏵᎤԌ ঽ׀൴াன۞ॡมĄ
ͽ˯݈˟ีྏរ̝ඕڍࢍ 2007 ѐ൴ܑĂ
҃ޢ۰̝ඕڍҤࢍࡗд 2011 Ƃ 2013 ѐ൴ܑĄ
າ͵ඪ৵Ժט
ᔵ aliskiren జҤΞͽдඪ৵Ժט۞ξ ಞ˯ᅳࢲᛢ̣ѐĂҭߏາ˘۞ඪ৵Ժט˵
̏णฟᓜԖྏរĂּтฟ൴ቅࠎ SPP635 ۞ᘽ ۏ̏дซҖ phase IIa ྏរĂ SPP635 ۞˾ڇϠۏ ӀϡޘΞ྿ 30% ćฟ൴ቅࠎ SPP1148 ۞ᘽۏ
̏дซҖ phase I ྏរĄΩγ˵ѣᇴछᘽᇄ˵ϒ дࡁᄦඪ৵ԺטĄ
ֹϡඪ৵Ժט۞҂ณ
˘ăѣड़ّ
дధкᓜԖྏរ˘ͯ࠻рᓏ̚Ă S e a le y ᄃ L a r a g h೩˞ᖰຕ۞ෞኢĄࣇ੫၆ᓁᇴ࿅
5000ˠ۞̱࣎ᓜԖྏរ ( ώ͛ણ҂͛ᚥ̚۞25, 29, 30, 33, 34, 35
) ۞ඕڍઇ̶ژ൴னĈ( a ) ಏֹϡ aliskiren ॡĈ 600 mg ۞ࢫᑅޘ̙ͧ 300 mg ֽрćณ
ͅᑕ ( dose response ) តளޝ̂ćᄃ ARB ăӀԌ
࠹ྵ֭ܧࠎՀѣड़̝ԩҕᑅᘽć( b ) ׀ϡڼ ᒚॡĈ a l i s k i r e n / ӀԌ۞ࢫᑅड़ڍҬͼͧ
aliskiren/ARBٕ aliskiren/ACEI рć࿅ˬ̶̝
˘۞ڼᒚঽˠҕᑅ̙ਕ˭ࢫҌҲٺ 140/90 ć
ࡶщᇐड़ڍৼˢ҂ᇋĂ၆ڼᒚѣͅᑕ۰ Ŵ 50% ĄΩγĂࣇΞਕߏ aliskiren ͔ඪ
৵ͅᑕّ͉̿к҃ٯঐొ̶۞ࢫᑅड़ڍĄ
ࣇ۞ඕኢߏĈֹϡ aliskiren ѣΞਕ͔҃ͅҕᑅ
˯̿ĂдΞਕّإϏঐੵ̝݈Ăֹϡ̏జ ᇃھֹϡͷྵܮآ۞ࢫҕᑅᘽٕధߏᖎಏᄃ
щБ37Ą
੫၆ Laragh ۞ෞኢĂܜഇࡁտ RAS ۞ڱ઼
ˠ Azizi д Lancet ൴ܑ˞˘ቔаᑕ۞͛ౢ38Ą͛
̚Ĉ( a ) Laragh ͔ٙϡ̝ྏរᇴྵ͌ ( В̱
࣎ )Ă҃၆ٺྏរ̚۞ aliskiren ࢫᑅड़ڍ՟ѣͽ
̳ϒ۞͞ёઇ̶ژĂͷ၆ٺྤफ़۞ҿѣᄱć( b )
ྏរฟ݈̝ؕૄҕᑅ̙ٽޙϲ ( צА݈ڇϡ۞
ᘽۏٕࢴۏඈᇆᜩ ) ć( c ) ҕᑅঽˠග̟
aliskiren̝ޢଂϏѣٙᏜĶaliskiren ͔۞ҕ ᑅķ ۞ன෪ĂЯࠎࢫҕᑅड़ڍࠤҌΞͽдઃ
ᘽฉޢ៍၅זĄ̙࿅Ă Azizi ˵Тຍ Laragh ۞
࠻ڱĈĶ тڍΪࢦٺଠטҕᑅĂ՟ѣᙋፂព ϯಏՏֹ͇ϡ aliskiren 150 Ƃ 300 mg ͔ٙ
۞ ҕ ᑅ ˭ ࢫ ޘ ົ ͧ ϫ ݈ Ξ ϡ ۞ Ї ˘ ࢫ ҕ ᑅ ᘽ рķĄ
ܑ˟Ĉ ALOFT ྏរֹ̚ϡ aliskiren ͔ٙ۞ЧϠ̼
ࣃត̼
Marker Aliskiren, Placebo,
n=156 n=146 p
Plasma renin(ng/mL/h) -5.71 -0.97 Ŵ 0.000
BNP (pg/mL) -61 -12.2 0.016
NT-proBNP (pg/mL) -243.6 761.7 0.0106 Urinary aldosterone (nmol/d) -9.2 -7 0.015 ALOFTĈ Aliskiren Observation of Heart Failure Treatmentć
BNPĈ brain natriuretic peptide ć NT-proBNP Ĉ N- terminal proBNPĄ
˟ăщБّ
дઘүϡ༊̚Ă૱֍۞ѣཛᕫăᐝ൭ăᆄݟ ۆăᐝຶ ( dizziness )Ă͔̚ˠڦϫ۞ߏཛᕫ ( ˘ਠಡӘࡗࠎ 2% Ă҃ Oh BH ۞ಡӘߏдֹϡ aliskiren 600 mg۰ཛᕫ൴Ϡத྿ 11.4% ) 25Ą Яࠎдҁဂྏរॡ൴ன aliskiren ၆ඕབᕆቯѣֱ
ו፬ّĂٙͽ FDA дઇᆶߤॡĂؼܜˬ࣎͡ឰ Ϧኛ˯ξ۞̳ΦГྃ· 3 0 Ҝઉצྏ۰ڇϡ aliskirenޢ۞̰ෛᙡᑭߤಡӘ ( ඕڍពϯඕབᕆ ቯត̼ )Ąдֹϡ aliskiren 150 Ƃ 300 mg ॡ
ன۞ᐝ൭ăᆄݟۆăཛᕫඈઘүϡజᄮࠎ̂кᇴ ᄃ aliskiren ᙯ ( ֍ဦ̱ )39Ą
ΩγĂдϦኛ˯ξ۞ॡ࣏Ă̏ڇϡ aliskiren
࿅˘ѐ۞ঽˠΪѣ 1250 ˠĂܜഇֹϡ̝щБ
ّ̪ϏۢĄ
ˬăኑᗔ۞ሕдّᐹăК๕
Яࠎඪ৵Ժט۞ᓜԖᑕϡ̖ࣣฟؕâֱ
ٺજۏăˠᙷ၁រٙពϯ۞ᘽۏүϡإѣޞٺᓜ Ԗ˯జᙋ၁Ąඪ৵Ժטٙѣ۞ሕдّᐹ๕ ࠎĈ
1.ΞࢫҲҋّҕᑅဂ ( spontaneous hy- pertensive ratĂ SHR ) ൴Ϡν͕ވ۲̂40ć
2.ֹϡඪ৵Ժטٺ͕҉ୟ۞ҁဂĂԼ චν͕ވϐഇᑅăᙝҕგܡԩăඪҕ߹ณ۞
ޘĂᄃֹϡ ACEI ॡ۞ޘߏ࠹Ҭ۞41ć 3.၆ٺ၁រဂ۞͕ăඪѣ᜕ܲड़ڍ42ć 4.Ξᆧΐҕᑅঽˠ۞ඪҕ߹ณ43ć 5.ΞពࢫҲకϨԌ44Ą
ඪ৵Ժטٙѣ۞ሕдّК๕ࠎĈ ( 1 ) ˾ڇϠۏӀϡޘҲ ( າ˘ඪ৵Ժט
Ξ྿ 30% )ć
( 2 ) ڇϡ̙Тณ۞ aliskiren ̝ޢĂҕ̚
፧ޘᐌณᆧΐ҃ᆧ ( dose-response )23Ăҭ ߏдࢫҲҕᑅ͞ࢬĂᆧΐณ ( 300mg Ɩ 600mg ) ݒ՟ѣ dose-response ன෪25,30Ą Laragh ᄮࠎΞਕ ߏ aliskiren ͔ඪ৵ͅᑕّ͉̿к҃ٯঐొ
̶۞ࢫᑅड़ڍ37Ăҭߏৌϒ۞፟ᖼ̪̙ځĄ ( 3 ) ACEIă ARB ̿ PRA ᄃ PRC Ăඪ৵Ժ טᔵֹ PRA ࢫҲĂҭ̿ PRC ۞ޘߏ A- CEIă ARB ۞ࢺͽ˯23, 36Ąඪ৵ࣧăඪ৵ᄃତ צጡ ( ݈̝( P )RR ) ඕЪޢΞਕົ͔ܳញჯ
̼ăܳҕड़ڍĂڇϡඪ৵Ժטޢͅᑕّ̿
͉к۞ඪ৵տౣѣңᇆᜩ̪̙ځĄ
( 4 ) ܕѐֽϤٺࡊጯछ۞Ӆ˧Ăֹԧࣇᒢྋ ז RAS ᔘѣ ACE2 ă Ang-( 1-7 ) ඈјЊĂֹ
R A S ЧјЊม۞Ϲ̢үϡតՀტኑᗔĄ Ang-( 1-7 ) Ξ͔ҕგᕖૺĂΞԺט͕҉ࡪϠ ܜ45ĂΞࢫҲᎤԌঽ၁រજۏ̝కϨԌ46Ąтڍ Ang-( 1-7 ) ̝ϠјពࢫҲॡĂົֹ͕Αਕצຫ47Ą ACEIă ARB Ξᆧΐ Ang-( 1-7 )Ă҃ඪ৵Ժט
ົֹ Ang-( 1-7 ) ˭ࢫ ( ֍ܑ˘ )Ă၆ٺࢫҕ ᑅड़ڍă͕Αਕඈѣңᇆᜩ̪̙ځĄ
( 5 ) Aliskiren 300 mg̝ಏᆊࠎ 2.8 ࡚̮Ăд
̏൴ܑ۞ᓜԖྏរ̚Ăᄃ aliskiren 300 mg ࢫᑅड़ ڍ࠹Ҭ۞ᘽಏᆊ̶ҾࠎĈ ARB ᙷů Losartan ( 100 mg ) 2.82࡚̮ă Valsartan ( 320 mg ) 2.71 ࡚
̮ć ACEI ᙷů Ramipril ( 10 mg ) 2.35 ࡚̮ćӀԌ
ᙷů hydrochlorothiazide ( 25 mg ) 0.19 ࡚̮ ( ˯
Чಏᆊߏ 2007 ѐ 9 ઼࡚͡৸ࡗߙछშྮᘽԊ
۞ಡᆊ )Ą ACEI ă ARB ̏జᙋ၁ੵ˞ࢫҲҕᑅ
̝γĂ˵ΞԼච͕აăࢫҲ͕ҕგ়ঽĄ̙ͧ
ACEIă ARB ܮآ۞ aliskiren ੵ˞ࢫҲҕᑅ̝
γĂߏӎѣड़ৈإ၁ᙋĄ
ඕኢ
ဦ̱Ĉֹϡ aliskiren 150 mg (ALI 150)Ă aliskiren 300 mg (ALI 300)Ăщᇐ(PL)̝ޢᐝ൭ăᆄݟۆă ཛᕫඈઘүϡ۞൴ϠதĄ *p <0.05 vs ALI 150 and ALI 300Ą
R A S၆ٺአ༼ҕᑅԷႊޝࢦࢋ۞֎ҒĄ кѐֽĂԺט RAS ۞ᘽۏ ( ACEI Ă ARB ) ̏జ
ځΞͽѣड़гڼᒚҕᑅăԼච͕ҕგăඪ
়ঽĄགྷϤԺטඪ৵҃ܡᕝ RAS ᐝ۞៍ه̏
хд 30 ѐĂдкีᅳા۞ࡁտ۰۞Ӆ˧̝˭Ă
ٺѣௐ˘࣎˾ڇඪ৵Ժטę aliskiren ˯ξĄ дڼᒚҕᑅ͞ࢬĂᇴ࣎ᓜԖྏរពϯĂд ಏֹϡॡĂ aliskiren ( 150 Ƃ 300 mg ) ۞ࢫҲҕ ᑅड़ڍͧщᇐр҃ᄃӀԌă ACEI ă ARB ۞ ड़ڍߏ࠹ܕ۞ ( ֍ܑˬ )Ąд aliskiren ׀ϡᘽ ۏॡĂᔵ࠰ͧщᇐՀѣड़гࢫҲҕᑅĂ҃
ιٙᆧΐ۞ҕᑅ˭ࢫޘݒࢍጯ˯̝ຍཌྷĂͷ
಼̂ᆧΐᘽᆊĄд၁ᙋᗁጯҖ۞னĂтڍֶ
ፂ aliskiren ࠎᇴ̙к۞ᓜԖྏរඕڍĂࢋଯᖧ aliskirenઇࠎڼᒚҕᑅ۞ௐ˘ቢᘽۏ ( ಏ˘ֹ
ϡٕЪ׀ᘽۏ ) Ҭͼ̪ѣޞથၻĄͧྵᖰຕ
۞ઇڱߏĈдֹϡ࿅ڼᒚҕᑅᘽۏ҃ड़ڍ
̙рٕயϠઘүϡ ( ݜမăͪཚăᘽۏ࿅ୂඈ ) ॡĂ̖҂ᇋֹϡ aliskiren Ąдܧϡ aliskiren ̙Ξ ͷڇϡޢᘽड़ָ̙҃ࢋ҂ᇋ׀ϡᘽۏॡĂӀ Ԍߏௐ˘Ᏼፄ ( ੵ˞ड़ৈ/ᘽᆊ۞҂ณ̝γĂ aliskiren۞̿ҕ࿔үϡΞᄃӀԌ۞ࢫҲҕ࿔
үϡ̢࠹ٯঐ )33Ą
2007ѐ 3 ͡Ă aliskiren జ FDA ८఼ࣞ࿅۞
ዋᑕাΪѣڼᒚҕᑅĂณࠎ 150 Ƃ 300 mg Ą
ܑˬĈ Aliskiren ۞ᓜԖྏរඕڍ
ү۰ ͛ᚥ ഇมߐഇ ᘽۏ ณ צྏˠᇴ නૺᑅត̼ mmHg ࢍ
Oh BH 25 8 ALI 150 167 - 10.3 p < 0.0001 vs PL
ALI 300 166 - 11.1 p < 0.0001 vs PL
PL 163 - 4.9
Gradman 30 8 ALI 150 127 - 9.3 p < 0.005 vs PL
ALI 300 130 - 11.8 p < 0.0001 vs PL, p < 0.01 vs IRB
IRB 150 133 - 8.9 p < 0.05 vs PL
PL 130 - 6.3
Oparil 36 4 ALI 150 430 - 7.5 p < 0.0001 vs PL; p < 0.0001 vs ALI + VAL VAL 160 453 - 8.7 p < 0.0001 vs PL; p < 0.001 vs ALI + VAL ALI 150 + VAL 160 438 - 10.5 p < 0.0001 vs PL
PL 455 - 4.8
Jordan 31 8 ALI 300 + HCTZ 25 113 - 11.9 p < 0.0001 vs PL + HCTZ 25 IRB 300 + HCTZ 25 117 - 11.3
AML 10 + HCTZ 25 122 - 10.3
PL + HCTZ 25 117 - 7.9
Villamil 33 8 ALI 150 183 - 8.9 p < 0.05 vs PL
ALI 300 180 - 10.3 p < 0.0001 vs PL
ALI 150 + HCTZ 25 187 - 12.7 p < 0.0001 vs PL; p < 0.05 vs Чಏ˘ᘽ ALI 300 + HCTZ 25 173 - 14.3 p < 0.0001 vs PL; p < 0.05 vs Чಏ˘ᘽ
HCTZ 25 173 - 9.4 p < 0.05 vs PL
PL 192 - 6.3
Pool 35 8 ALI 150 177 - 10.3
ALI 300 175 - 12.3 p < 0.0001 vs PL
VAL 160 58 - 11.0 p < 0.05 vs ALI 150 (ො)
VAL 320 60 - 11.3 p < 0.05 vs ALI 150 (ො)
ALI 300 + VAL 320 58 - 12.9 p < 0.001 vs PL (ො)
PL 176 - 8.6
ALIĈ aliskiren ć PL Ĉ placebo ć IRB Ĉ irbesartan ć VAL Ĉ valsartan ć HCTZĈ hydrochlorothiazide ć AML Ĉ amlodipine Ą
(ො)Ĉᒣϒщᇐड़ڍޢ̝ࢍ̶ژĄ
ੵ˞ࢫҲҕᑅ̝γĂ၆ٺ͕ăඪߏӎѣт Т ( ࠤҌ ) ACEI ă ARB ਠ۞ड़ৈإ၁ ᙋĄдඈޞՀкăՀᚑᖰ۞ᓜԖྏរඕڍ൴ܑ۞
ഇมĂ၆ٺҕᑅͷЪ׀ѣ͕ҕგăඪ়ঽ
۞ঽˠĂֶዋᑕা҃ග̟̏జᇃھֹϡͷѣ၁ ᙋ۞ᘽۏ ( ּт ARB ă ACEI )ĂҬͼߏྵЪآ˫
щБ۞ઇڱĄ
ણ҂͛ᚥ
1.Chung O, Unger T. Angiotensin II receptor blockade and end- organ protection. Am J Hypertens 1999; 12: 150 S-6.
2.Sleight P, Yusuf S. New evidence on the importance of the renin- angiotensin system in the treatment of higher-risk patients with hypertension. J Hypertens 2003; 21: 1599-608.
3.Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and an- giotensin II type 1 receptor antagonists. Circulation 2004; 109:
2492-9.
4.Goldberg MR, Bradstreet TE, McWilliams EJ, et al. Biochemical effects of losartan, a nonpeptide angiotensin II receptor antag- onist, on the renin-angiotensin-aldosterone system in hyperten- sive patients. Hypertension 1995; 25: 37-46.
5.Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 1998; 32: 387-92.
6.Wood JM, Cumin F, Maibaum J. Pharmacology of renin in- hibitors and their application to the treatment of hypertension.
Pharmacol Ther 1994; 61: 325-44.
7.Lin C, Frishman WH. Renin inhibition: a novel therapy for car- diovascular disease. Am Heart J 1996; 131: 1024-34.
8.Delabays A, Nussberger J, Porchet M, et al. Hemodynamic and humoral effects of the new rennin inhibitor enalkiren in normal humans. Hypertension 1989; 13: 941-7.
9.Kobrin I, Viskoper RJ, Laszt A, Bock J, Weber C, Charlon V.
Effects of an orally active rennin inhibitor, Ro 42-5892, in pa- tients with essential hypertension. Am J Hypertens 1993; 6: 349- 56.
10.Menard J, Boger RS, Moyse DM, Guyene TT, Glassman HN, Kleinert HD. Dose-dependent effects of the renin inhibitor zankiren HCl after a single oral dose in mildly sodium-deplet- ed normotensive subjects. Circulation 1995; 91: 330-8.
11.Fischli W, Clozel JP, Breu V, et al. Cirprokiren (Ro 44-9375): A renin inhibitor with increasing effects on chronic treatment.
Hypertension 1994; 24: 163-9.
12.Derkx FHM, Deinum J, Lipovski M, et al. Nonproteolytic "ac- tivation" of prorenin by active site-directed renin inhibitors as demonstrated by renin-specific monoclonal antibody. J Biol Chem 1992; 267: 22837-42.
13.Van Kesteren CAM, Danser AHJ, Derkx FHM, et al. Mannose
6-phosphate receptor-mediated internalization and activation of prorenin by cardiac cells. Hypertension 1997; 30: 1389-96.
14.Huang Y, Wongamorntham S, Kasting J, et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix pro- teins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 2006; 69: 105-13.
15.Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000; 87: E1-9.
16.Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM.
Evaluation of angiotensin converting enzyme (ACE), its homo- logue ACE2 and neprilysin in angiotensin peptide metabolism.
Biochem J 2004; 383: 45-51.
17.Santos RAS, Ferreira AJ, Pinheiro SV, Sampaio WO, Touyz R, Campagnole-Santos MJ. Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs. Expert Opin Investig Drugs 2005; 14: 1019-31.
18.Li P, Chappell MC, Ferrario CM, Brosnihan KB. Angiotensin- (1-7) augments bradikinin-induced vasodilation by competing with ACE and releasing nitric oxide. Hypertension 1997; 29:
394-400.
19.Iyer SN, Yamada K, Diz DI, Ferrario CM, Chappel MC.
Evidence that prostaglandins mediate the antihypertensive ac- tions of angiotensin-(1-7) during chronic blockade of the renin- angiotensin system. J Cardiovasc Pharmacol 2000; 36: 109-17.
20.Kucharewicz I, Chabielska E, Pawlak D, Matys T, Rolkowski R, Buczko W. The antithrombotic effect of angiotensin-(1-7) closely resembles that of losartan. J Renin Angiotensin Aldosterone Syst 2000; 1: 268-72.
21.Iyer SN, Ferrario CM, Chappell MC. Angiotensin-(1-7) con- tributes to the antihypertensive effects of blockade of the renin- angiotensin system. Hypertension. 1998; 31: 356-61.
22.Tallant EA, Ferrario CM, Gallagher PE. Angiotensin-(1-7) in- hibits growth of cardiac myocytes through activation of the Mas receptor. Am J Physiol Heart Circ Physiol. 2005; 289: H1560- 6.
23.Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension 2002; 39: E1-8.
24.Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibi- tion with aliskiren: where are we now, and where are we going?
J Hypertens 2006; 24: 243-56.
25.Oh BH, Mitchell J, Herron JR, et al. Aliskiren, an oral renin in- hibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007 Mar 20; 49: 1157-63.
26.Vaidyanathan S, Reynolds C, Yeh CM, et al. Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects. J Clin Pharmacol 2007; 47:
453-60.
27.Vaidyanathan S, Jermany J, Yeh C, Bizot MN, Camisasca R.
Aliskiren, a novel orally effective renin inhibitor, exhibits sim-
ilar pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects. Br J Clin Pharmacol 2006; 62: 690-8.
28.Azizi M, Menard J, Bissery A, et al. Pharmacologic demonstra- tion of the synergistic effects of a combination of the renin in- hibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II - renin feedback interruption. J Am Soc Nephrol 2004; 15: 3126-33.
29.Stanton A, Jensen C, Nussberger J, O'Brien E: Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003; 42: 1137-43.
30.Gradman AH, Schmeider RE, Lins RL, et al. Alisiren, a novel orally effective renin inhibitor, provides dose-dependent anti- hypertensive efficacy and placebo-like tolerability in hyperten- sive patients. Circulation 2005; 111: 1012-8.
31.Jordan J, Engeli S, Boye SW, Le Breton S, Keefe DL. Direct Renin inhibition with aliskiren in obese patients with arterial hy- pertension. Hypertension 2007; 49: 1047-55.
32.Strasser RH, Puig JG, Farsang C, Croket M, Li J, van Ingen H.
A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension. J Hum Hypertens 2007 ; 21: 780-7.
33.Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007; 25:
217-26.
34.O'Brien E, Barton J, Nussberger J, et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme in- hibitor, or an angiotensin receptor blocker. Hypertension 2007;
49: 276-84.
35.Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally ef- fective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007; 20:
11-20.
36.Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007; 370: 221-9.
37.Sealey JE, Laragh JH. Aliskiren, the first Renin inhibitor for treating hypertension: reactive Renin secretion may limit its ef- fectiveness. Am J Hypertens 2007; 20: 587-97.
38.Menard J, Azizi M. The difficult conception, birth and delivery of a renin inhibitor: controversies around aliskiren. J Hypertens 2007; 25: 1775-82.
39.Gradman AH, Traub D. The efficacy of aliskiren, a direct renin inhibitor, in the treatment of hypertension. Rev Cardiovasc Med 2007; 8: S22-30.
40.Zhang Q, Kohara K, Qui HY, et al. Comparative effects of three sites of renin-angiotensin blockade on the regression of left ven- tricular hypertrophy in spontaneously hypertensive rats. Am J Ther 1997; 4: 199-202.
41.Mento PF, Maita ME, Murphy WR, et al. Comparison of an- giotensin converting enzyme and renin inhibition in rats fol- lowing myocardial infarction. J Cardiovasc Pharmacol 1993; 21:
791-6.
42.Pilz B, Shagdarsuren E, Wellner M, et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double- transgenic rats. Hypertension 2005; 46: 569-76.
43.Fisher ND, Allan D, Kifor I, et al. Responses to converting en- zyme and renin inhibition: role of angiotensin II in humans.
Hypertension 1994; 23: 44-51.
44.van Paassen P, de Zeeuw D, Navis G, et al. Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function.
Nephrol Dial Transplant 2000; 15: 637-43.
45.Tallant EA, Ferrario CM, Gallagher PE. Angiotensin-(1-7) in- hibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol 2005; 289: H1560-6.
46.Benter IF, Yousif MH, Cojocel C, et al. Angiotensin-(1-7) pre- vents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 2007; 292: H666-72.
47.Santos RA, Castro CH, Gava E, et al. Impairment of in vitro and in vivo heart function in angiotensin-(1-7) receptor MAS knock- out mice. Hypertension 2006; 47: 996-1002.
New Class of Antihypertensive Drug - Renin Inhibitors
Meng-Hsiu Wu, Jing-Ren Jeng, Ji-Hung Wang, and Chi-Mo Lin
The renin-angiotensin system (RAS) is important in regulation of blood pressure, electrolyte balance and vascular growth. Suppression of the RAS, through angiotensin converting enzyme inhibitor (ACEI) or angiotensin AT1-receptor blocker (ARB), is a proven effective therapeutic approach to the treatment of hypertension, heart failure and renal disorders. Renin, is the first step of the RAS, has long been recognized as the preferred target for RAS blockade. Intensive efforts have been devoted to the development of potent renin inhibitors over past twenty years. Aliskiren is the first in a new class of agents known as oral renin inhibitors and is approved for the treatment of high blood pressure as monotherapy or in combination with other antihypertensive medications. The effectiveness of aliskiren in lowering blood pressure was demonstrated in clinical trials, which included patients with mild to moderate hypertension. Given the success of ACE inhibitors and angiotensin receptor blockers in re- ducing morbidity and mortality amongst patients with hypertension, diabetes mellitus, cardiac failure, nephropa- thy and atherosclerosis, renin inhibitors may have the potential to be beneficial in the same disease states. In the long term, obviously, large studies comparing renin inhibition with the other blockers of the RAS will be needed.
( J Intern Med Taiwan 2008; 19: 277 -288 )
Division of Cardiology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital
