1

DAFTAR ISI Halaman Cover Daftar Isi .. BAB I PENDAHU UAN 1.1 atar Bela"an# .. 1.! T%&%an ........................................................................................................ BAB II TIN'AUAN PUSTA(A ...................................................................... !.1 *a#al 'ant%n# (on#estif.............................................................................. !.1.1 Definisi ..................................................................................................... !.1.! Etiolo#i ..................................................................................................... !.1.$ ,anifestasi (linis .................................................................................. !.1.) Patofisiolo#i ............................................................................................. !.1.+ Pemeri"saan Pen%n&an# ........................................................................ !.! Rosi#lita/one .............................................................................................. !.!.1 Des"ri0si .................................................................................................. !.!.! Dosis ......................................................................................................... !.!.$ In1i"asi .................................................................................................... !.!.) Farma"o1inami" .................................................................................... !.!.+ Farma"o"ineti" ...................................................................................... !.!.- Efe" Sam0in# .......................................................................................... 01 0! 0$ 0$ 0) 0) 0) + . 11 11 1! 1$ 1$ 1) 1+ 1-

!.!.2 Intera"si .................................................................................................. BAB III PE,BAHASAN .. BAB I4 (ESI,PU AN . BAB 4 DAFTAR PUSTA(A ..

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BAB 1 PENDAHU UAN

2.1.1

Definisi CHF a1ala5 s%at% "e#a#alan &ant%n# 1alam memom0a 1ara5 %nt%"

memen%5i "e6%t%5an t%6%5 7P%rna8an '%na1i9 1.3!:. (e#a#alan &ant%n# "on#estif a1ala5 s%at% "e#a#alan 0emom0aan 71i mana ;ar1ia; o%t0%t ti1a" men;%"%0i "e6%t%5an meta6oli" t%6%5:9 5al ini m%n#"in ter&a1i se6a#ai a"i6at a"5ir 1ari #an##%an &ant%n#9 0em6%l%5 1ara5 ata% "a0asitas o"si#en <an# ter6a8a 1alam 1ara5 <an# men#a"i6at"an &ant%n# ti1a" 1a0at men;%"%0i "e6%t%5an o"si#en 0a1a 6er6a#ai or#an 7Ni %5 *e1e =asmin9 1..$:. *a#al &ant%n# "on#estif 7CHF: a1ala5 "ea1aan 0atofisiolo#is 6er%0a "elainan f%n#si &ant%n#9 se5in##a &ant%n# ti1a" mam0% memom0a 1ara5 %nt%" memen%5i "e6%t%5an meta6olisme &arin#an ata% "emam0%ann<a 5an<a a1a "ala% 1isertai 0enin##ian vol%me 1iastoli" se;ara a6normal. Penamaan #a#al &ant%n# "on#estif <an# serin# 1i#%na"an "ala% ter&a1i #a#al &ant%n# sisi "iri 1an sisi "anan 7,ans&oer9 !001:. *a#al &ant%n# "on#estif a1ala5 "eti1a"mam0%an &ant%n# %nt%" memom0a 1ara5 1alam &%mla5 <an# ;%"%0 %nt%" memen%5i "e6%t%5an &arin#an ter5a1a0 o"si#en 1an n%trien. 7Diane C. Ba%#5man 1an 'o Ann C. Ho;"le<9 !000:

S%at% "ea1aan 6era"i6at

0atofisiolo#i

a1an<a "elainan

f%n#si &ant%n#

&ant%n# #a#al memom0a"an 1ara5 %nt%" memen%5i "e6%t%5an

meta6olisme &arin#an 1an ata% "emam0%ann<a 5an<a a1a "ala% 1isertai 0enin##ian te"anan 0en#isian ventri"el "iri 7Bra%n18al1:. *a#al &ant%n# "on#estif a1ala5 "eti1a"mam0%an &ant%n# %nt%" memom0a 1ara5 <an# a1e"%at %nt%" memen%5i "e6%t%5an &arin#an a"an o"si#en 1an n%trisi 7Smelt/er > Bare9 !001:9 ?aren > Stea1 1alam So1eman91..1:9 Renar1i9 1..!:. 2.1.2 Etiologi ,e"anisme <an# men1asari ter&a1in<a #a#al &ant%n# "on#estif meli0%ti #an##%an "emam0%an "ontera"tilitas &ant%n#9 <an# men<e6a6"an ;%ra5 &ant%n# le6i5 ren1a5 1ari ;%ra5 &ant%n# normal. Teta0i 0a1a #a#al &ant%n# 1en#an masala5 <an# %tama ter&a1i a1ala5 "er%sa"an sera6%t otot &ant%n#9 vol%me se"%n;%0 6er"%ran# 1an ;%ra5 &ant%n# normal masi5 1a0at 1i0erta5an"an. 4ol%me se"%n;%0 a1ala5 &%mla5 1ara5 <an# 1i0om0a 0a1a setia0 "ontera"si ter#ant%n# 0a1a ti#a fa"tor <ait% @ 1. Preloa1 a1ala5 &%mla5 1ara5 <an# men#isi &ant%n# 6er6an1in# lan#s%n# 1en#an te"anan <an# 1itim6%l"an ole5 0an&an#n<a re#an#an sera6%t otot &ant%n#. !. (ontera"tillitas men#a;% 0a1a 0er%6a5an "e"%atan "ontera"si <an# ter&a1i 0a1a tin#"at sel 1an 6er5%6%n#an 1en#an 0er%6a5an 0an&an# sera6%t &ant%n# 1an "a1ar "alsi%m

$. Afterloa1 men#a;% 0a1a 6esarn<a te"anan venteri"el <an# 5ar%s 1i5asil"an %nt%" memom0a 1ara5 mela8an 0er6e1aan te"anan <an# 1itim6%l"an ole5 te"anan arteriol. Pa1a #a#al &ant%n#9 &i"a sala5 sat% ata% le6i5 fa"tor ini ter#an##%9 ma"a ;%ra5 &ant%n# 6er"%ran# 7Br%nner an1 S%11art5 !00!:. *a#al &ant%n# "on#estif &%#a 1a0at 1ise6a6"an ole5 @ (elainan otot &ant%n# @ *a#al &ant%n# serin# ter&a1i 0a1a 0en1erita "elainan otot &ant%n#9 1ise6a6"an men%r%nn<a "ontra"tilitas &ant%n#. (on1isi <an# men1asari 0en<e6a6 "elainan f%n#si otot men;a"%0 aterios"lerosis "oroner9 5i0rtensi arterial9 1an 0en<a"it 1e#eneratif ata% inflamasi. 1. Ateros"lerosis "oroner ,en#a"i6at"an 1isf%n#si mio"ar1i%m "arena ter#an##%n<a aliran 1ara5 "e otot &ant%n#. Ter&a1i 5i0o"sia 1an asi1osis 7a"i6at 0en%m0%"an asam la"tat:. Infar" mio"ar1i%m 7"ematian sel &ant%n#: 6iasan<a men1a5%l%i ter&a1in<a #a#al &ant%n#. Pera1an#an 1an 0en<a"it mio"ar1i%m 1e#eneratif9 6er5%6%n#an 1en#an #a#al &ant%n# "arena "on1isi <an# se;ara lan#s%n# mer%sa" sera6%t &ant%n#9 men<e6a6"an "ontra"tilitaas men%r%n. !. Hi0ertensi sistemi" ata% 0%lmonal 70enin#"atan afterloa1: ,enin#"at"an 6e6an "er&a &ant%n# 1an 0a1a #ilirann<a mn#a"i6at"an

5i0ertrofi sera6%t otot &ant%n#. $. Pera1an#an 1an 0en<a"it m<o;ar1i%m 1e#enerative Ber5%6%n#an 1en#an #a#al &ant%n# "arena "on1isi ini se;ara lan#s%n# mer%sa" sera6%t &ant%n#9 men<e6a6"an "ontra"tilitas men%r%n. ). Pen<a"it &ant%n# lain

*a#al &ant%n# 1a0at ter&a1i se6a#ai a"i6at 0en<a"it &ant%n# <an# se6enarn<a9 <an# sse;ara lan#s%n# mem0en#ar%5i &ant%n#. ,e"anisme 6iasan<a terli6at men;a"%0 #an##%an aliran 1ara5 <an# mas%" &ant%n# 7stenosis "at%0 semil%ner:9 "eti1a"mam0%an &ant%n# %nt%" men#isi 1ara5 7tam0ona1e9 0eri"ar1i%m9 0eri"ar1itif "onstri"tif9 ata% stenosis A4:9 0enin#"atan men1a1a" afteer loa1. +. Fa"tor sistemi" Ter1a0at se&%mla5 6esar fa"tor <an# 6er0eran 1alam 0er"em6an#an 1an 6eratn<a #a#al &ant%n#. ,enin#"atn<a la&% meta6olism 7misal @ 1emam9 tiroto"si"osis :9 5i0o"sia 1an anemia 0erl%"an 0enin#"atan ;%ra5 &ant%n# %nt%" memen%5i "e6%t%5an o"si#en sistemi". Hi0o"sia 1an anemia &%#a 1a0at men%r%n"an s%0lai o"si#en "e &ant%n#. Asi1osis res0iratori" ata% meta6oli" 1an a6normalita ele"troni" 1a0at men%r%n"an "ontra"tilitas &ant%n#. Grade gagal jantung menurut New york Heart Associaion ter6a#i men&a1i ) "elainan f%n#sional9 <ait% @ 1. Tim6%l #e&ala sesa" 0a1a a"tifitas fisi" 6erat 2. Tim6%l #e&ala sesa" 0a1a a"tifitas fisi" se1an# 3. Tim6%l #e&ala sesa" 0a1a a"tifitas rin#an 4. Tim6%l #e&ala sesa" 0a1a a"tifitas san#at rin#anA istira5at 2.1.3 Manifestasi Klinis ,en%r%t Arif mas&oer !001 *e&ala <an# m%n;%l ses%ai 1en#an #e&ala &ant%n# "iri 1ii"%ti #a#al &ant%n# "anan 1a0at ter&a1in<a 1i 1a1a "arana 0enin#"atan "e6%t%5an o"si#en. Pa1a 0emeri"saan fisi" 1item%"an tan1a B tan1a #e&ala #a#al &ant%n# "on#estif 6iasan<a ter1a0at 6%n<i 1era0 1an 6isin# a"i6at re#%r#itasi mitral.

Tan1a 1ominan ,enin#"atn<a vol%me intravas"%ler. (on#estif &arin#an a"i6at te"anan arteri 1an vena menin#"at a"i6at 0en%r%nan ;%ra5 &ant%n#. ,anifestasi "on#esti 1a0at 6er6e1a ventri"el mana <an# ter&a1i . 1. Gagal jantung kiri : (on#esti 0ar% menon&ol 0a1a #a#al ventri"el "iri "arena ventri"el "iri ta" mam0% memom0a 1ara5 <an# 1atan# 1ari 0ar%. ,anifestasi "linis <an# ter&a1i <ait% @ a. Dis0n% Ter&a1i a"i6at 0enim6%nan ;airan 1alam alveoli 1an men##an##% ter#ant%n# 0a1a "e#a#alan

0ert%"aran #as. Da0at ter&a1i orto0n%. Be6era0a 0asien 1a0at men#alami orto0n% 0a1a malam 5ari <an# 1inama"an Paro"simal No"t%rnal Dis0nea 7 PND:. 6. Bat%" ;. C5e<nes sto"es 1. Crt5o0nea e. (o#estif vena 0%lmonalis f. ,%1a5 lela5 Ter&a1i "arena ;%ra5 &ant%n# <an# "%ran# <an# men#5am6at &arin#an 1ari sir"%lasi normal 1an o"si#en serta men%r%nn<a 0em6%an#an sisa 5asil "ata6olisme9 &%#a ter&a1i "arena 0ernafasan 1an 6at%". #. (e#elisa5an 1an "e;emasan menin#"atn<a ener#i <an# 1i#%na"an %nt%" 6ernafas 1an insomnia <an# ter&a1i "arena 1istress

Ter&a1i a"i6at

#an##%an o"si#enasi

&arin#an9 stress a"i6at "esa"itan

6ernafas 1an 0en#eta5%an 6a58a &ant%n# ti1a" 6erf%n#si 1en#an 6ai". 2. Gagal jantung kanan: a. (on#estif &arin#an 0erifer 1an viseral. 6. E1ema e"strimitas 6a8a5 7e1ema 1e0en1en:9 6iasan<a e1ema 0ittin#9 0enam6a5an 6erat 6a1an. ;. He0atome#ali 1an n<eri te"an 0a1a "%a1ran "anan atas a61omen ter&a1i a"i6at 0em6esaran vena 1i 5e0ar. 1. AnoreDia 1an m%al9 ter&a1i a"i6at 0em6esaran vena 1an statis vena 1alam ron##a a61omen. e. No"t%ria f. (elema5an #. Na%sea 5. As;ites i. Tan1aEtan1a 0en<a"it "roni"

2.1.4 Patofisiologi (elainan intrinsi; 0a1a "ontra"tilitas mio"ar1i%m <an# "5as 0a1a #a#al &ant%n# is"emi"9 men##an##% "emam0%an 0en#oson#an ventri"el <an# efe"tif. (ontra"tilitas ventri"el "iri <an# men%r%n men#%ran#i ;%ra5 se"%n;%09 1an menin#"at"an vol%me resi1% ventri"el. Den#an menin#"atn<a ED4 7vol%me a"5ir 1iastoli; ventri"el:9 ma"a ter&a1i 0%la 0en#in#"atan

te"anan a"5ir 1iastoli; ventri"el "iri 7 4EDP:. Dera&at 0enin#"atan te"anan ter#ant%n# 1ari "elent%ran ventri"el. Den#an menin#"atn<a 4EDP9 ma"a ter&a1i 0%la 0enin#"atan te"anan atri%m "iri 7 AP: "arena atri%m 1an ventri"el 6er5%6%n#an lan#s%n# selama 1iastole. Penin#"atan AP 1iter%s"an "e 6ela"an# "e 1alam an<aman vas;%lar 0ar%E0ar%9 menin#"at"an te"anan "a0iler 1an vena 0ar%E0ar%. 'i"a te"anan 5i1rostati" 1ari an<aman "a0iler 0ar%E0ar% mele6i5i te"anan on"oti" vas;%lar9 ma"a a"an ter&a1i trans%1asi ;airan "e 1alam intertisial. 'i"a "e;e0atan trans%1asi ;airan mele6i5i "e;e0atan 1rainase limfati"9 ma"a a"an ter&a1i e1ema intertisial. Penin#"atan te"anan le6i5 lan&%t 1a0at men#a"i6at"an ;airan merem6es "e 1alam alveoli 1an ter&a1ila5 e1ema 0ar%E0ar%. Te"anan arteria 0ar%E0ar% 1a0at menin#"at se6a#ai res0on ter5a1a0 0enin#"atan "ronis te"anan vena 0ar%. Hi0ertensi 0%lmonar< menin#"at"an ta5anan ter5a1a0 e&e"si ventri"el "anan. Serentetan "e&a1ian se0erti <an# ter&a1i 0a1a &ant%n# "iri9 &%#a a"an ter&a1i 0a1a &ant%n# "anan9 1i mana a"5irn<a a"an ter&a1i "on#esti sistemi" 1an e1ema. Per"em6an#an 1ari "on#esti sistemi" ata% 0ar%E0ar% 1an e1ema 1a0at 1ie"saser6asi ole5 re#%r#itasi f%n#sional 1ari "at%0E"at%0 tri"%s0i1alis ata% mitralis 6er#antian. Re#%r#itasi f%n#sional 1a0at 1ise6a6"an ole5 1ilatasi 1ari ann%l%s "at%0 atrioventri"%laris9 ata% 0er%6a5anE0er%6a5an 0a1a orientasi otot 0a0ilaris 1an "or1a ten1inae <an# ter&a1i se"%n1er a"i6at 1ilatasi r%an# 7smelt/er !001:. Patofisiologi Gagal Jantung Kanan Gangguan fungsi pompa ventrikel

Curah jantung kanan menurun dan tekanan akhir systole ventrikel meningkat

Bendungan Sistemik

Bendungan pada vena-vena sistemik tekanan vena kava meningkat

!am"atan arus "alik vena

Patofisiologi Gagal Jantung Kiri Bendungan Sistemik

#liran darah ke atrium dan ventrikel kiri menurun atau terjadi gangguan fungsi pompa

Curah jantung kiri menurun dan tekanan akhir diastole ventrikel kiri meningkat

Bendungan vena pulmonalis

11

$dema paru %& Gangguan system pernapasan

Gagal jantung kogestif 7Co#estive Healt5 Fail%re A CHF: FG Ga ungan gagal jantung kanan dan kiri. 2.1.5 Pemeriksaan Penunjang

1. Foto toraD 1a0at men#%n#"a0"an a1an<a 0em6esaran &ant%n#9 oe1ema ata% ef%si 0le%ra <an# mene#as"an 1ia#nosa CHF. !. E(* 1a0at men#%n#"a0"an a1an<a ta;5i;ar1i9 5i0ertrofi 6ili" &ant%n# 1an is"emi 7&i"a 1ise6a6"an A,I:9 E"o"ar1io#ram $. Pemeri"saan a6 meli0%ti @ Ele"trolit ser%m <an# men#%n#"a0"an "a1ar natri%m <an# ren1a5 se5in##a 5asil 5emo1el%si 1ara5 1ari a1an<a "ele6i5an retensi air9 (9 Na9 Cl9 Ure%m9 #%la 1ara5.

2.2. ROSI !I"#$O%E !.!.1 Des"ri0si Nama Da#an# @

Di Ameri"a Seri"at9 o6at ini 1i0asar"an ole5 0er%sa5aan farmasi *laDoSmit5(line se6a#ai o6at t%n##al 7avan1ia: 1an se6a#ai o6at 1en#an metformin 7avan1amet: ata% 1en#an #lime0iri1e 7Avan1ar<l:. Pen&%alan ta5%nan men;a0ai 0%n;a"n<a 0a1a se"itar H !.+6n 0a1a ta5%n !00-9 teta0i men%r%n setela5 la0oran efe" sam0in#. Paten o6at ini 6era"5ir 0a1a ta5%n !01!.73:

!.!.! Dosis Rosi#lita/one 1iin1i"asi"an se6a#ai monotera0i <an# 1isertai 1en#an 1iet 1an lati5an fisi" %nt%" menin#"at"an "ontrol "a1ar #%la 1alam 1ara5 0a1a 0asien 1en#an 1ia6etes melit%s ti0e !. Rosi#lita/one &%# 1iin1i"asi"an se6a#ai "om6inasi 1en#an

metformin 1an s%lfon<l%ria 1imana 1iet 1an lati5an fisi" #a#al 1ila"%"an. A0a6ila 0asien tela5 men1a0at metformin ata% s%lfon<l%ria9 0em6erian Rosi#lita/one 1a0at 1i6eri"an 1alam re#imen 1osis tertent%. Pen##%naan "om6inasi 1en#an ins%lin tela5 1ila"%"an 8ala%0%n ti1a" mer%0a"an in1i"asi <an# 1iterima. Cle5 "arena a#ent ini 6e"er&a a0a6ila ter1a0at en1o#eno%s ins%lin9 ma"a ti1a" 1ian&%r"an 0en##%naan 0a1a 1ia6etes melit%s ti0e 1 ata%0%n 0a1a Dia6etes (etoasi1osis7D(A:. Se0erti t5ia/oli1ine1ion lain9 Rosi#lita/one 1a0at men<e6a6"an 0enin#"atan ov%lasi se5in##a 0asien 8anita 0erl% 1iinformasi"an risi"o ter&a1in<a "e5amilan a0a6ila "ontase0si ti1a" 1ila"%"an. Rosi#lita/one maleat memili"i "asifi"asi o6at "ate#ori C 0a1a "e5amilan. C6at ini ti1a" memili"i efe" 0a1a im0lantasi em6r<o 0a1a a8al "e5amilan saat 1i%&i 0a1a men;it9 nam%n 0en##%naan 0a1a masa "e5amilan lan&%t 1a0at men<e6a6"an "ematian &anin 1an ter5am6atn<a 0ert%m6%5an 0a1a 0er;o6aan ter5a1a0 "elin;i 1an men;it. Terato#enisitas ti1a" 1i1a0at"an 0a1a 0er;o6aan $m#A"# 0a1a ti"%s 1an 100m#A"# 0a1a "elin;i9 nam%n 0enelitian ini ti1a" a1e"%at se5in##a Rosi#lita/one ti1a" 1ian&%r"an %nt%" 1i6eri"an 1alam "e5amilan "e;%ali 5asiln<a le6i5 1i%tama"an 1i6an1in# 1en#an risi"o 0a1a fet%s. Selain it%9 6er1asar"an fa"ta 6a58a "a1ar #%la a6normal 0a1a "e5amilan serin# 1i"ait"an 1en#an "on#enital anomali serta neonatal mort6i1it< 1an mortalit<. Be6era0a 0a"ar men#an&%r"an ins%lin monot5era0< se6a#ai 0ili5an 1alam "e5amilan %nt%" men#ontrol "a1ar #%la 1ara5. Rosi#lita/one maleat 1i Ameri"a Seri"at terse1ia 1alam se1iaan filmE;oate1 ta6let se#i lima !m#7&am6on:9 )m#7oran<e:9 1an 3m#7mera5E;o"lat:. Pasien monotera0i ma%0%n "om6inasi 1en#an s%lfonl<%ria 1an metformin 1im%lai 1en#an 1osis )m#A5ari. SIn#le 1ose ma%0%n 1osis ter6a#i 1a0at 1i6eri"an. A0a6ila setela5 3E 1! min##% "a1ar #l%"osa 0%asa masi5 ti1a" ter"ontrol9 1a0at 1ila"%"an 0enin#"atan 1osis 3m#A5ari 6ai" monotera0i ma%0%n "om6inasi 1en#an metformin. Pen##%naan "om6inasi 1en#an s%lfon<l%ria 1en#an 1osis le6i5 1ari )m#A5ari ti1a" 1ian%r"an

13

se5in##a 0ro1%sen men<aran"an %nt%" me#%ran#i 1osis s%lfon<l%ria a0a6ila ter&a1i 5i0o#li"emi 0a1a 0asien. Pem6erian Rosi#lita/one ter5a1a0 0asien 1en#an #an##%an f%n#si #in&al ti1a" 0erl% 1ila"%"an. A0a6ila mela"%"an 0er#antian &enis o6at anti 1ia6etes 7CAD: lain men&a1i Rosi#lita/one9 tera0i 0erl% 1ila"%"an 6er1asar"an "e6%t%5an 0asien. Diet 1an lati5an fisi" se6ai"n<a men&a1i "%n;i %tama 1alam tera0i. Ti1a" a1a 6%"ti "linis n<ata men#enai e"%ivalensi 1osis antara #olon#an o6at t5ia/oli1ine1iones.7.:

!.!.$ In1i"asi C6at ini 1i#%na"an %nt%" D, ti0e ! <an# ti1a" mem6eri res0ons 1en#an 1iet 1an lati5an fisi"9 se6a#ai monotera0i ata% 1itam6a5"an 0a1a mere"a <an# ti1a" mem6eri res0ons 0a1a o6at 5i0o#li"emi" lain 7s%lfonil %rea9 metformin: ata% ins%lin.
710:

!.!.) Farma"o1inami" Tia/oli1ine1ion mer%0a"an a#onist 0oten 1an sele"tif PPARI9 men#a"tif"an PPARI mem6ent%" PPARIERJR 1an ter6ent%"la5 a1i0ose PPARI men#%ran#i "el%arn<a asam lema"men%&% "e otot9 "arenan<a1a0at men#%ran#i resistensi ins%lin. Pen1a0at lain9 a"tivasi5ormon a1i0osit< 1an a1i0o"in9 <an# nam0a"n<aa1ala5 a1i0one"tin. Sen<a8a ini 1a0at menin#"at"an sensitivitas ins%lin melal%i 0enin#"atan A,P"inase <an# meran#san# trans0ort #l%"osa "esel 1an menin#"at"an o"si1asi asam lema". 'a1i a#ar o6at 1a0at 6e"er&a 5ar%s terse1ia ins%lin. Selain it% #lita/on&%#a men%r%n"an 0ro1%"si #l%"osa 5e0ar9 men%r%n"an asam lema" 6e6as 1i 0lasma 1an remo1elin# &arin#an a1i0ose Rosi#lita/on 1a0at men%r%n"an H6A1; 7190E19+: 1an 6er"e;en1er%n#an menin#"at"an HD 9 se1an# efe"n<a 0a1a tri#liseri1 1an D 6ervariasi.710:

!.!.+ Farma"o"ineti" Rosi#lita/one memili"i 6ioavaila6ilitas 0er oral <an# a6sol%te9 <ait% ..K. (a1ar 0%n;a" 0lasma ter;a0ai 1alam 8a"t% 1 &am setela5 0em6erian. (a1ar 0lasma ma"sim%m 1an "a1ar 0lasma 1i 6a8a5 area "%rva 7AUC: menin#"at se;ara 0ro0orsional 0.!E!0m#. Efe" ter5a1a0 ma"anan tela5 1iteliti 1alam se6%a5 st%1i 1en#an 1! s%"arela8an se5at <an# 1i6eri !m# 1osis t%n##al Rosi#lita/one setela5 1iet tin##i lema". Rosi#lita/one ti1a" 1i0en#ar%5i ole5 ma"anan9 8ala%0%n "e;e0atani a6sor6si le6i5 lam6at 1an "onsentrasi 0%n;a" 0lasma le6i5 ren1a5. Rosi#lita/one memili"i i"atan ter5a1a0 0rotein ...3K9 ter%tama ter5a1a0 al6%min. Rerata vol%me oral 1istri6%si a1ala5 129. Dalam t%6%59 Rosi#lita/one !C3 1imeta6olisme ole5 ! &al%r %tama9 NE1emetilasi 1an 5i1ro"silasi9 <an# 1ii"%ti en#an "on&%#asi 1en#an s%lfat 1an asam #l%"oronat. C<to;5rome P)+0 7C=P: isoen/im meme#an# 0eran %tama 1alam meta6olisme. Hasil meta6olit9 1alam 6ent%" s%lfat 1an #l%"oroni1ase le6i5 ti1a" 0otent 1ari0a1a s%6stansi %tama 1an ti1a" mem6eri"an "ontri6%si ter5a1a0 farma"o"ineti" o6at. E"s"resi meta6olit ter%tama 1i %rin 7-)K: 1an sisan<a melal%i feses 7!$K:. Rosi#lita/one memili"i 8a"t% 0ar%5 7T1A!: $E) &am. Fa"tor #eneti; 7ras: 1an mero"o" ti1a" memili"i efe" si#nifi"an ter5a1a0 efe" farma"o"ineti" Rosi#lita/one. CmaD 1an AUC 1i0er"ira"an $3K 1an $-K ata% le6i5 ren1a5. 6a#aimana0%n9 0a1a area "linis <an# le6i5 l%as9 0er6e1aan farma"o"ineti" ini ti1a"la5 0entin#9 se0erti terli5at 0a1a le6i5 1ari 1000 1ata 0asien 1en#an 1ia6etes ti0e ! men#in1i"asi"an 6a58a ti1a" a1a efe" <an# si#nifi"an 1ari farma"o"ineti" o6at rosi#lita/one. Pa1a 0asien 1en#an #an##%an f%n#si #in&al rin#an sam0ai se1an#9 farma"o"ineti" rosi#lita/one ti1a" 6er%6a5 0a1a 0en##%naan 1osis 3m# A 5ari. 0a1a 0asien 1en#an #a#al #in&al 6erat9 rata rata fra"s o6at ta" 6eri"at menin#"at 5in##a $3K 1i6an1in#"an 1en#an #r%0 <an# normal9 1an ini m%n#"in 1a0at menim6%l"an

15

"onsentrasi total <an# le6i5 ren1a5 0a1a 0asien 1en#an #a#al #in&al <an# 6erat. ;maD 1an AUC ti1a" 1i0en#ar%5i ole5 5emo1ial<sis. Pa1a st%1i 1osis t%n##al9 o0en trial eval%ate1 farma"o"ineti" 1ari rosi#lita/one !D)m# 0a1a 12 0asien <an# se5at 1an 13 0asien 1en#an #an##%an 5e0ar "ronis nai" $)K CmaD men%r%n !1K9 AUC 1an CmaD 1ari o6at <an# ta" 6eri"atan menin#"at 5in##a 133K 1an 20K9 masin# masin#9 1an 8a"t% 0ar%5 meman&an# 5in##a !&am 0a1a 0asien 1en#an #an##%an "ronis 5e0ar 1i6an1in#"an 1en#an ;ontrol <an# normal. Dian&%r"an %nt%" men#etes f%n#si 5ati se6el%m 1an selama 0en#o6atan9 nam%n ti1a" a1a 0en#at%ran 1osis <an# s0esifi".7.:

!.!.- Efe" Sam0in# Dalam st%1i Rosi#lita/one <an# 1i6eri"an 6ai" t%n##al ata%0%n "om6inasi 1en#an metformin ata% s%lfon<l%rea ter5a1a0 )+.3 0asien 1en#an Dia6etes ,elit%s ti0e ! 0a1a 0er;o6aan "linis 1en#an sam0el )-00 0asien9 1item%"an efe" sam0in# antara lain @ ISPA 7...K:9 ;e1era72.-K:9 1an sa"it "e0ala 7+..K:. Infe"si 1an sa"it "e0ala &%#a 1item%"an 1alam 0em6erian o6at #olon#an t5ia/oli1ine1ion lainn<a. Risi"o 5i0o#li"emi 1en#an monotera0i Rosi#lita/one ren1a5 70.-K: 9 a"an teta0i 0asien <an# 1itera0i "om6inasi 1en#an s%lfon<l%rea 1an ins%lin m%n#"in 1a0at menin#"at"an "e&a1ian 5i0o#li"emi se5in##a 0em6erian 1osis o6at "om6inasi 0erl% 1i0ertim6an#"an. T5ia/oli1ine1ione 1a0at men<e6a6"an retensi ;airan <an# 1a0at "e#a8atan 1an men<e6a6"an #a#al &ant%n#. Cle5 "arena it%9 0ro1%sen Rosi#lita/one mere"omen1asi 0asien 1en#an risi"o 1an tan1aEtan1a #a#al &ant%n# %nt%" ti1a" men##%na"an Rosi#lita/one a0a6ila ter&a1i 0er%6a5an ;ar1ia; stat%s. ?ala%0%n Pa1a 0er;o6aan ter5a1a0 ti"%s ;o6a 1en#an T5ia/oli1ine1ion 1osis tin##i 1a0at ter&a1i ;ar1ia; 5<0ertrofi9 nam%n 0a1a 0em6erian Rosi#lita/one ti1a" men%n&%"an a1an<a 0er%6a5an str%"t%r ma%0%n f%n#si &ant%n#.

Efe" sam0in# lain a1ala5 e1ema rin#an 5in##a se1an#9 1imana 0asien <an# 1itera0i 1en#an Rosi#lita/one memili"i risi"o e1ema 7)93K: le6i5 tin##i 1i6an1in# 0asien <an# 1ira8at 1en#an 0la;e6o. Fre"%ensi ini men&a1i le6i5 tin##i a0a6ila 1i"om6inasi 1en#an ins%lin 71)92K: a0a6ila 1i6an1in#"an 1en#an monotera0i ins%lin. Dalam s%at% st%1i9 1o%6le6lin1E0la;e6o ;ontrolle1 trial9 0enin#"atan rataErata vol%me 0lasma a1ala5 7193 mlA"#: 0a1a 0em6erian 3m#A5ari. Dalam st%1i9 1i1a0at"an ! oran# 0asien9 sala5 seoran# 0asien men#alami sesa" nafas 1an ef%si 0le%ra 0a1a 0en##%naan 3m#A5ari 1an 0asein lain men#alami e1ema rin#an 0a1a 0en##%naan 3m#A5ari 1an saat o6at 1i5enti"an9 0asien terse6%t 0%li5. Rosi#lita/one 1i"ait"an 1en#an 0en%r%nan rin#an 5emo#lo6in 71 #A1l: 1an 5emato"rit 7$.$K:9 nam%n ti1a" a1a 6%"ti <an# men#%at"an 6a58a 5al ini mem0en#ar%5i er<t5ro0oiesis ata% mer%sa" sel 1ara5 mera5. Anemia 1ila0or"an 0a1a 1..K 0asien 1an 0a1a 0en##%naan "om6inasi tin#"at ter&a1in<a anemia le6i5 tin##i 1ari0a1a monotera0i. Pen##%naan Rosi#lita/one9 se0erti t5ia/oli1ine1ion lain9 6er5%6%n#an 1en#an 0enam6a5an 6erat 6a1an <an# 6el%m &elas 0en<e6a6n<a a0a"a5 m%n#"in m%ltifa"torial ata%0%n 6er5%6%n#an 1en#an retensi ;airan 1an 0enim6%nan lema". Dalam st%1i 0em6erian Rosi#lita/one )m# ! "aliA5ari ter&a1i 0enin#"atan si#nifi"an 0a1a 1aera5 lema" s%6%"tan 1an lema" 0a1a 5ati9 nam%n ti1a" ter&a1i 0enin#"atan lema" intraa61omen. Pen##%naan Rosi#lita/one &%#a 0erna5 1i"ait"an 1en#an 5e0atoto"sisitas 1en#an 1item%"ann< seoran# 8anita +3 ta5%n 1en#an 1ia6etes lama9 ter&a1i 0enin#"atan en/im 5ati 1an men#alami i"ter%s setela5 $ min##% 1itera0i )m#A5ari 1an "em6ali normal setela5 ) min##% tera0i 1i5enti"an. Se6%at "as%s lain 1imana 8anita )2 ta5%n 1en#an 1ia6etes9 5i0ertensi9 5er0es /ooster9 1e0resi9 1an 1ia6etes #astro0aresis <an# men#alami 0enin#"atan al"ali fosfatase + "ali 6atas normal setela5 men##%na"an )m#A5ari selama + 6%lan. Setela5 tera0i 1i5enti"an9 tin#"at fosfatase "em6ali normal 1alam ! min##%.

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Cle5 "arena it%9 0en##%naan Rosi#lita/one 0erl% 1ila"%"an monitorin# se;ara 5atiE5ati 0a1a 0asien 1en#an 0enin#"atan en/im 5ati 1an a0a6ila menin#"at tin##i9 0en##%naan Rosi#lita/one 5ar%s 1i5enti"an. Pen##%naan Rosi#lita/one 1alam st%1i9 &%#a 1item%"an ter&a1i 0er%6a5an 0rofil li0i1. Pa1a st%1i !- min##% monotera0i Rosi#lita/one ter&a1i 0enin#"atan "enai"an lo8E1ensit< li0o0rotein 7 D 9 1)E1.K: 1an 5i#5E1ensit< li0o0rotein 7HD 9 11E1)K:. Dalam st%1i +! min##% 1o%6le 6lin1 0en##%naan rosi#lita/one ) 1an 3m#A5ari 1an #l<6%ri1eE;ontrolle1 trial9 1i"ait"an 1en#an 0enin#"atan D rataErata 1!K 1an HD 1.K. Penin#"atan D ter&a1i ter%tama 0a1a 1E! 6%lan 0ertama9 se1an#"an HD menin#"at se;ara linier. Per%6a5an Tri#liseri1 7T*: %m%mn<a ti1a" 1i1a0at"an 0er6e1aan 1en#an 0lase6o. Pen%r%an asam lema" 6e6as se6esar !!K 0a1a 0en##%naan Rosi#lita/one9 se1an#"an +K 0a1a 0en##%naan #l<6%ri1e 0a1a min##% "e +!.7.:

!.!.2 Intera"si Cle5 "arena Rosi#lita/one ter%tama 1imeta6olisme ole5 C=P!C39 se6enarn<a memili"i ten1ensi ren1a5 1alam intera"si antar o6at. ?ala%0%n isoen/im ti1a" mer%0a"an sala5 sat% r%te %tama 1alam meta6olisme o6at9 nam%n 6e6era0a s%6strat o6at C=P!C3 se0erti vera0amil. St%1i farma"o"ineti" <an# men#eval%asi 0otensial intera"sio6at 1en#an Rosi#lita/one men%n&%"an ti1a" a1a intera"si antar o6at anti 1ia6etes 7CAD9 #l<6%ri1e9 a;ar6ose9 metformin:9 s%6strate of C=P$A) 7nife1i0ine9 oral ;ontra;e0tives:9 1i#oDin9 8arfarin9 ma%0%n raniti1ine.7.: ;erivastatin9 0a;litaDel9 /o0i;lone9 1an enantiomers 1ari

BAB III PE,BAHASAN

*an##%an "ar1iovas"%lar mer%0a"an "om0li"asi <an# 0alin# %m%m 1item%i 1alam 0asien 1en#an 1ia6etes mellit%s ti0e ! 7D,:. H%6%n#an ini m%n#"in m%ltifa"torial 1an m%n#"in &%#a meli6at"an9 "5%s%s mes"i0%n ti1a" &elas9 1ia6etes ;ar1iom<o0at5<. Pasien 1en#an #a#al &ant%n# 1isertai 1en#an D, memili"i 6er"%ran# ;%ra5 &ant%n# 1i6an1in#"an 1en#an 0asien tan0a D,. T5ia/oli1ine1iones 7TLD: a1ala5 a#onis 1ari Pero"sisom 0roliferatorE1ia"tif"an rese0tor #amma 7PPARM: 1an memili"i efe" men#%nt%n#"an 1alam "ontrol #l%"osa 1ara5 1an 0arameter "ar1iovas"%lar9 teta0i "emam0%an o6at %nt%" men#in1%"si retensi 0lasma 5ar%s 1i6a8a "e 0ertim6an#an 1alam rese0 mere"a %nt%" 0asien 1en#an D, 6erisi"o tin##i "ar1iovas"%lar 0en<a"it. ,e"anisme mole"%l retensi ;airan ole5 TLDs 6el%m se0en%5n<a 1i&elas"an. B%"ti <an# terse1ia men%n&%""an "em%n#"inan 0eran sal%ran natri%m e0itel 7ENaC: 1alam men<e6a6"an efe" sam0in# 1ari TLDs. Penelitian e0i1emiolo#i tela5 men%n&%""an 6a58a se"itar 10K 0asien 1en#an 1ia6etes ti0e ! mellit%s 7D,: men#alami #a#al &ant%n# a"i6at men#ons%msi rosi#lita/on. Tin#"at 0revalensi a1ala5 !E) "ali le6i5 tin##i 1ari0a1a 1i 0asien tan0a D, 71E$: Selan&%tn<a. se"itar !+K 1ari 0asien 1alam st%1i #a#al &ant%n# men1erita D,9 7!: sementara 5an<a se"itar 09+K 1ari 0o0%lasi %m%m men1erita 1ari "e1%a 0en<a"it. 7$: Pasien 1en#an #a#al &ant%n# 1isertai 1en#an D, memili"i &ant%n# 6er"%ran# o%t0%t 1i6an1in#"an 1en#an 0asien tan0a D,. Para a#en anti1ia6eti" oral 1ise6%t t5ia/oli1ine1iones 7TLDs9 ata% #lita/ones:9 ter1iri 1ari rosi#lita/ones 7RS*: 1an 0io#lita/ones9 a1ala5 a#onis 1ari Pero"sisom 0roliferatorE1ia"tif"an rese0tor #amma 7PPARM: tin1a"an <an# menin#"at"an sensitivitas ins%lin. 7): Dalam Selain men%r%n"an tin#"at #l%"osa 1ara59 TLDs &%#a men%n&%""an efe" men#%nt%n#"an 0a1a "ar1iovas"%lar 0arameter9 se0erti tin#"at li0i19 13) t5ia/oli1ine1ione 1an "ar1iovas"%lar te"anan 1ara59 6iomar"er 0era1an#an9 en1otel f%n#si9 1an stat%s fi6rinoliti". 7+: Efe" <an# men#%nt%n#"an 1ari TLDs 0a1a #l%"osa 1ara5 1an fa"tor

19

risi"o "ar1iovas"%lar tela5 men#a"i6at"an e"stensif men##%na"an o6at ini 0a1a ti0e ! 0asien 1ia6etes <an# 6erisi"o tin##i 0en<a"it "ar1iovas"%lar. ,e"anisme m%n;%ln<a e1ema 0a1a 0en##%na TLDs <ait% "eti"a 1i#%na"an se6a#ai monotera0i9 "e&a1ian 0e1al e1ema 6er"isar antara $K sam0ai +K %nt%" masin#Emasin# TLDs. (e&a1ian le6i5 6esar saat o6at 1i#%na"an 1alam "om6inasi 1en#an a#en 0en%r%n #l%"osa lainn<a. Dalam %&i ;o6a ter"ontrol 0lase6o AS9 e1ema ter&a1i 0a1a )93K 1ari s%6<e" 0a1a 0io#lita/one monotera0i9 1i6an1in#"an 19!K 0a1a 0lase6o. (eti"a 0io#lita/one 1i"om6inasi"an 1en#an s%lfonil%rea9 e1ema ter;atat 0a1a 29+K 0asien 1i6an1in#"an 1en#an !91K 0a1a s%lfonil%rea sa&a. E1ema terli5at 0a1a -90K 0asien 0a1a "om6inasi 0io#lita/one A metformin 1i6an1in#"an !9+K 0a1a metformin sa&a. Dalam %&i ;o6a 1o%6leE6lin1 1en#an rosi#lita/one9 "e&a1ian e1ema a1ala5 )93K 0a1a "elom0o" rosi#lita/one 1i6an1in#"an 1en#an 19$K 0a1a 0lase6o. (eti"a 1i"om6inasi"an 1en#an metformin ata% s%lfonil%rea9 e1ema 1iamati 0a1a $K sam0ai )K 0asien 1i6an1in#"an 1en#an 191K men&a1i !9!K 1i "e1%a o6at 0em6an1in# sa&a. Data ini men%n&%""an 6a58a e1ema a1ala5 efe" sam0in# 1ari masin#Emasin# o6at TLD "e ser%0a 1era&at9 6ai" 6ila 1i#%na"an se6a#ai monotera0i ata% 6ila 1i"om6inasi"an 1en#an a#en oral 1ia6etes lainn<a. E1ema le6i5 %m%m "eti"a TLD 1i#%na"an 1alam tera0i "om6inasi. Pra"tisi <an# 0alin# m%n#"in %nt%" meli5at e1ema se6a#ai "onse"%ensi 1ari tera0i TLD "eti"a sala5 sat% 1ari TLDs 1i#%na"an 1alam "om6inasi 1en#an ins%lin. ,isaln<a9 rosi#lita/one ) ata% 3 m# 0er 5ari 1alam "om6inasi 1en#an ins%lin 1i"ait"an 1en#an 1$91K 1an 1-9!K "e&a1ian e1ema9 masin#Emasin#9 1i6an1in#"an 1en#an )92K 0a1a mere"a <an# mema"ai ins%lin sa&a. Pio#lita/one 0a1a 1+ m# ata% $0 m# se5ari 1alam "om6inasi 1en#an ins%lin men#5asil"an #a6%n#an 1+9$K "e&a1ian e1ema9 1i6an1in#"an 1en#an 290K %nt%" ins%lin sa&a. Cle5 "arena it%9 "e&a1ian e1ema le6i5 tin##i 6ila sala5 sat% 1ari TLDs 1i"om6inasi"an 1en#an ins%lin 1i6an1in#"an 1en#an a#en 5i0o#li"emi" oral lainn<a. Hal ini &%#a 5ar%s 1i;atat9 6a#aimana0%n9 6a58a e1ema ter&a1i le6i5 serin# 1en#an monotera0i ins%lin 1i6an1in#"an 1en#an s%lfonil%rea ata% metformin "eti"a sala5 1irese0"an sen1iri ata%

1alam "om6inasi. Pasien 1ia6etes ti0e ! 0a1a ins%lin 6iasan<a memili"i 1ia6etes selama 6erta5%nEta5%n 1an 1en#an 1emi"ian ;en1er%n# le6i5 t%a 1an memili"i 0revalensi <an# le6i5 6esar 1ari 5i0ertensi9 5i0ertrofi ventri"el "iri9 1an ri8a<at 0en<a"it arteriEsem%a "on1isi "oroner le6i5 m%n#"in %nt%" 1i5%6%n#"an 1en#an e1ema. ,eman#9 1i antara 1-- 0asien 1ia6etes <an# 1ira8at 1en#an TLD <an# memili"i 6an<a" "on1isi "omor6i1itas 1an 1i0anta% 1i 4eterans Affairs Clini; le6i5 1ari 1) 6%lan9 e1ema 1i"em6an#"an 0a1a 1391K. A/otemia 1asar9 CHF se6el%mn<a9 1an 0en<a"it arteri "oroner <an# %m%m 1alam "elom0o" ini. Prevalensi CHF latar 6ela"an# 0a1a 0asien <an# 1io6ati 1en#an ins%lin sen1iri 1a0at men&a1i le6i5 tin##i 1i6an1in#"an 0asien <an# ti1a" menerima ins%lin 7!9+K 1alam 6e6era0a %&i ;o6a rosi#lita/one:9 se5in##a 6er"ontri6%si %nt%" insi1en <an# le6i5 tin##i 1ari e1ema "eti"a TLD 1itam6a5"an "e ins%lin 1i6an1in#"an 1en#an a#en 0en%r%n #l%"osa lainn<a. ,es"i0%n TLDs 6el%m 1i6an1in#"an sat% sama lain 0a1a 1osis eN%i0otent9 "e&a1ian e1ema a1ala5 ser%0a "eti"a "e1%a o6at it% 1i"om6inasi"an 1en#an o6at 5i0o#li"emi" lainn<a 1alam &an#"a 0en1e"9 st%1i "linis non a;a". Pen<e6a6 retensi ;airan 1an e1ema 0erifer 1en#an men##%na"an TLD ti1a" se0en%5n<a 1i0a5ami 1an ;en1er%n# m%ltifa"torial. Penin#"atan vol%me 0lasma <an# 6er5%6%n#an 1en#an TLDs tela5 1i"%ti0 1an m%n#"in 5asil 1ari 0en%r%nan e"sresi natri%m 1an 0enin#"atan retensi natri%m 1an air #ratis. TLDs 1a0at 6erintera"si se;ara siner#is 1en#an ins%lin men<e6a6"an vaso1ilatasi arteri9 men<e6a6"an rea6sor0si natri%m 1en#an selan&%tn<a menin#"at"an vol%me e"strasel%ler9 1an 1en#an 1emi"ian men#a"i6at"an 0e1al e1ema. Penin#"atan a"tivitas sistem saraf sim0ati"9 1i%6a5 trans0ortasi ion interstitial9 0er%6a5an 1alam 0ermea6ilitas en1otel9 1an Pero"sisom 0roliferatorEa;tivate1 re;e0torEIE1ime1iasi e"s0resi vas"%lar fa"tor 0ert%m6%5an 0ermea6ilitas mer%0a"an me"anisme lain <an# m%n#"in %nt%" e1ema 1en#an a#en ini. Pa1a %&i "linis men##%na"an TLD9 CHF ti1a" serin# 1item%i. Insi1en CHF a1ala5 O1K %nt%" rosi#lita/one monotera0i ata% "eti"a rosi#lita/one 1itam6a5"an "e s%lfonil%rea ata% metformin9 1an miri0 1en#an <an# 1iamati selama 0en#o6atan

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1en#an 0lase6o. (eti"a rosi#lita/one 0a1a ) ata% 3 m# A 1 1itam6a5"an "e tera0i ins%lin9 Nam%n9 CHF menin#"at men&a1i !K 1an $K 1ari 0o0%lasi 0enelitian9 masin#Emasin#9 1i6an1in#"an 1en#an 1K 0a1a "elom0o" <an# 1io6ati 1en#an ins%lin sa&a. Pentin# %nt%" 1i;atat 6a58a s%1a5 a1a se6el%mn<a mi"rovas"%ler 1an "omor6i1itas "ar1iovas"%ler a1ala5 le6i5 %m%m 0a1a mere"a %&i "linis 1i mana rosi#lita/one tela5 1itam6a5"an "e tera0i ins%lin 1i6an1in#"an 0a1a mere"a %&i ;o6a 1i mana rosi#lita/one <an# 6ai" 1i#%na"an sen1iri 1an 1i6an1in#"an 1en#an 0lase6o ata% 1i"om6inasi"an 1en#an metformin ata% s%lfonil%rea. Para 0asien <an# men#em6an#"an CHF on rosi#lita/one 1itam6a5 ins%lin &%#a le6i5 t%a 1an men1erita 1ia6etes 1ari 1%rasi <an# le6i5 lama. Data 0a1a 0io#lita/one <an# a#a" miri0. Dalam %&i ;o6a ter"ontrol 0lase6o9 ! 1ari 1.1 0asien 7191K: menerima 1+ m# 0io#lita/one 1itam6a5 ins%lin 1an ! 1ari 133 7191K: 0asien <an# menerima 0io#lita/one 7$0 m#: 1itam6a5 ins%lin 1i"em6an#"an CHF9 1i6an1in#"an 1en#an ti1a" a1a 132 0asien <an# menerima ins%lin sa&a. Sem%a ) 1ari 0asien memili"i 0en<a"it arteri "oroner <an# men1asarin<a. Pen#ar%5 rosi#lita/one 0a1a res0on ventri"el "iri is"emia tela5 1inilai 1alam mo1el is"emiaEre0erf%si 0a1a 5e8an 0er;o6aan. (eti"a rosi#lita/one 1i6eri"an se#era se6el%m e0iso1e is"emia9 0em%li5an 0en%5 f%n#si ventri"el "iri setela5 re0erf%si a1ala5 le6i5 ;e0at 1i6an1in#"an 1en#an 5e8an "ontrol. Se6%a5 0enelitian ter6ar% &%#a men%n&%""an 6a58a 0io#lita/one 1itin#"at"an remo1elin# ventri"el "iri 1an f%n#si sistoli" se6a#ian 1inormalisasi 0a1a ti"%s setela5 e"stensif f%n#si mio"ar1 anterior. Efe" "ar1io0rote"tif TLDs in1e0en1en #l%"osa men%r%n"an 1an m%n#"in "arena antio"si1an9 antiinflamasi9 ata% sifat #l%;ometa6oli; o6at. Cle5 "arena it%9 a1ala5 m%n#"in 6a58a TLDs m%n#"in memili"i efe" lan#s%n# 0a1a otot &ant%n# <an# men;e#a5 #a#al &ant%n# 1alam 0en#at%ran is"emia a"%t.

BAB I4 (ESI,PU AN 1. Rosi#lita/on 1a0at men#a"i6at"an #an##%an f%n#si &ant%n# <ait% #a#al &ant%n# "on#estif !. Pen#atasan ESC 1a0at 1itan##%lan#i 1en#an 1i%reti"9 ACEI9 ARB9 PE 6lo;"er9 1an 1i#o"sin. $. ,onitorin# <an# 1a0at 1ila"%"an 1en#an 0emeri"asaan a1an<a e1ema 1i&ant%n# 1ann 0emeri"saan en%n&an# lainn<a.

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DAFTAR PUSTA(A

1. Nissen Steven E. !002. Effe;t of Rosi#lita/one on t5e Ris" of ,<o;ar1ial

Infar;tion an1 Deat5 from Car1iovas;%lar Ca%ses

!. S5a5a6 Al8i. !003. ,en#a0a Dia6etes ,elit%s ,enin#"at"an Risi"o

Ter&a1in<a Pen<a"it (ar1iovas"%ler.

$. Rosen Cliffor1 '. !002. T5e Rosi#lita/one Stor< B esson from an FDA

A1visor< Committee ,eetin#. Availa6le from@ 5tt0@AA;ontent.ne&m.or#A;#iA;ontentAf%llA$+.A11A10.! Q;ite1 on@ 1. ,aret !010 1-@ !+R
). T&o"ro0ra8iro A9 Hen1romartono9 S%t&a5&o et al. Pe1oman Dia#nosis 1an

Tera0i. Airlan##a Universit< Press .!003@ 3+E.+

+. (aram H 'o5n9 (at/%n# *Bertram. Farma"olo#i Dasar 1an (lini".E*C.

1..3 @ --$E-31
-. ?erner Am< . !003. A Revie8 of Rosi#lita/one in T<0e ! Dia6etes

,ellit%s.
2. S<arif Amir. !002. Farma"olo#i 1an Tera0i E1isi +. 8. Home P5ili0 D. !002. Rosi#lita/one Eval%ate1 for Car1iovas;%lar C%t;omes

B An Interim Anal<sis. Availa6le from@

5tt0@AA;ontent.ne&m.or#A;#iA;ontentAs5ortA$+2A1A!3 Q;ite1 on@ 13 ,aret !010 1)@!0R