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TRANSCRIPT
저 시-비 리- 경 지 2.0 한민
는 아래 조건 르는 경 에 한하여 게
l 저 물 복제, 포, 전송, 전시, 공연 송할 수 습니다.
다 과 같 조건 라야 합니다:
l 하는, 저 물 나 포 경 , 저 물에 적 된 허락조건 명확하게 나타내어야 합니다.
l 저 터 허가를 면 러한 조건들 적 되지 않습니다.
저 에 른 리는 내 에 하여 향 지 않습니다.
것 허락규약(Legal Code) 해하 쉽게 약한 것 니다.
Disclaimer
저 시. 하는 원저 를 시하여야 합니다.
비 리. 하는 저 물 리 목적 할 수 없습니다.
경 지. 하는 저 물 개 , 형 또는 가공할 수 없습니다.
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VgR]fReV hYVeYVc eYVcV hVcV UidTcVaRnTiVd SVehVVn eYV ]ide oW
hieYUcRhn UcfXd Woc BocVR cVaoceVU in eYV KE :ondo]iUReVU Cided RnU
eYV RTefR] ]ide oW UcfXd hieYUcRhn in BocVR. JYV on]inV mVUiTinV ]iScRcj
oW BD=;I% hYiTY YRd To]]VTeVU dRWVej ]VeeVcd dinTV 2))1% hRd cVgiVhVU
Re Yeea3((UcfX.mWUd.Xo.kc(Yem](inUVi.[da.
). 5GtG GSGlysOs
JYV ToccV]Reion SVehVVn eYV nfmSVcd oW hieYUcRhn RnU
cVdeciTeVU UcfXd hRd bfRneiWiVU fdinX GVRcdonpd ToccV]Reion ToVWWiTiVne.
IaVRcmRnpd nonaRcRmVeciT ToccV]Reion mVeYoU hRd Raa]iVU eo VgR]fReV
eYV RddoTiReion SVehVVn eYV nfmSVc oW hieYUcRhn RnU cVdeciTeVU UcfXd
cVaoceVU eo eYV KE RnU eYV ,. YVR]eY RnU WinRnTiR] WRTeocd Wcom eYV
16
F<:; RnU eYV Moc]U 9Rnk. JYV ineVcTofnecj RXcVVmVne Woc eYV ]ided oW
hieYUcRhn UcfXd hRd RddVddVU fdinX =]Viddpd kRaaR. 8]] bfoeVU
acoSRSi]iej gR]fVd RcV eho&eRi]VU. IeReideiTR] RnR]jdid hRd aVcWocmVU Sj
eYV H IeReideiTR] GRTkRXV% gVcdion ,.1.2 P,2].
A6BDLCB
NuRHKW TL wOtNdWGwS GSd/TW WKstWOItKd dWuMs
JYVcV hVcV ,/2 UcfXd eYRe hVcV hieYUcRhn RnU 2-1 UcfXd eYRe
hVcV cVdeciTeVU (Sfe noe hieYUcRhn) in Re ]VRde 1 Tofnecj in eYV KE
:ondo]iUReVU Cided. JYV ogVcR]] nfmSVcd oW hieYUcRhn RnU cVdeciTeVU
UcfXd on R aVc&Tofnecj SRdid in eYV 2- TofneciVd hVcV 12.)2 l 1,.)0
RnU ..00 l 1./2% cVdaVTeigV]j (=iXfcV. 1&1). JYV ]ided R]do cVaoceVU eYV
UcfXd hieYUcRhn RnU cVdeciTeVU Sj eYV <fcoaVRn :ommiddion%
<fcoaVRn DVUiTinVd 8XVnTj (<D8)% RnU :ofnTi] oW <fcoaV4 eYVcV
hVcV ,% 0 RnU 1 hieYUcRhn UcfXd RnU /% -% RnU ) cVdeciTeVU UcfXd%
cVdaVTeigV]j% Woc eYVdV ocXRnikReiond. JYVcV hVcV R]do 20 RnU 2
ineVcnReionR]]j hieYUcRhn RnU cVdeciTeVU UcfXd% cVdaVTeigV]j. JYVcV hRd
R diXniWiTRne ToccV]Reion SVehVVn eYV nfmSVcd oW hieYUcRhn RnU
17
cVdeciTeVU UcfXd Woc eYV 2- TofneciVd (G 5 ).))1% c 6 ).11) (=iXfcV 1&2).
7OMuWK (-(. FOtNdWGwS GSd WKstWOItKd dWuMs wTWldwOdK. (2)
5OstWOHutOTS TS G UKW-ITuStWy HGsOs (RKGS GSd B5 dGtG) GSd (3)
ITWWKlGtOTS GIWTss 04 ITuStWOKs.
Withdrawn or restricted status
No.
of d
rugs
Withdrawn drugs Restricted drugs
05
1015
2025
30
18
7OMuWK (-). 5OstWOHutOTSs TL tNK SuRHKWs TL wOtNdWGwS GSd WKstWOItKd
dWuMs OS 33 O645 RKRHKWs GSd UGWtSKWs.
JYV WigV TofneciVd hieY eYV ]RcXVde nfmSVcd oW hieYUcRhn UcfXd
hVcV GVcmRnj% KI8% FmRn% =cRnTV% RnU KB% dYohinX /1% .2% -,% -2%
RnU -1 hieYUcRhn UcfXd% cVdaVTeigV]j. JYV WigV TofneciVd hieY eYV
]RcXVde nfmSVcd oW cVdeciTeVU UcfX hVcV GVcmRnj% KB% KI% =cRnTV% RnU
IeR]j% dYohinX .2% -2% ,1% 2/% RnU 2) cVdeciTeVU UcfXd% cVdaVTeigV]j
(=iXfcV 1&,).
●
●
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●
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●
●●
●
●
●
●●
●
●
0 10 20 30 40 50
010
2030
4050
6070
No. of withdrawn drugs
No.
of r
estri
cted
dru
gsr = 0.807P < 0.001
19
=iXfcV 1&,. ;ideciSfeiond oW eYV nfmSVcd oW hieYUcRhn RnU cVdeciTeVU
UcfXd in 2- KE TofneciVd
20
7OMuWK (-4. 5OstWOHutOTSs TL tNK SuRHKWs TL wOtNdWGwS GSd WKstWOItKd
dWuMs OS 33 O645 RKRHKWs GSd UGWtSKWs.
8monX eYV ,2 F<:; mVmSVcd RnU aRcenVcd% RWeVc ViT]fUinX /
TofneciVd ]RTkinX UcfX cVXf]Reion&cV]ReVU inWocmReion in eYV KE
:ondo]iUReVU Cided (i.V.% :kVTY HVafS]iT% <deoniR% CfiVmSofcX% Go]RnU%
I]ogRk HVafS]iT% RnU I]ogVniR)% ,, TofneciVd hVcV inT]fUVU Woc WfceYVc
RnR]jdid. JYV ogVcR]] nfmSVcd oW hieYUcRhn RnU cVdeciTeVU UcfXd on R
aVc&Tofnecj SRdid in eYVdV ,, TofneciVd hVcV 11.2. l 1..00 RnU 11 l
12.)/% cVdaVTeigV]j (=iXfcV 1&-).
5MFs GSd O645 NKGltN GSd KITSTROI dGtG
=igV F<:; YVR]eY&RnU&hV]WRcV inUiTReocdnG;G aVc TRaieR%
GermanyUnited States
FranceUnited Kingdom
ItalyNorwaySweden
JapanTurkeyBrazil
GreeceOECD avarage
AustriaDenmark
CanadaSpain
AustraliaIndia
New ZealandIreland
SwitzerlandChile
NetherlandsBelgiumFinland
IsraelKorea
PortugalIceland
South AfricaHungary
IndonesiaMexicoChina
No. of withdrawn drugs
0 10 20 30 40 50 60 70
Coun
tries
GermanyUnited Kingdom
United StatesFrance
ItalyJapan
New ZealandBelgium
ChileIreland
SwedenAustralia
AustriaOECD avarage
CanadaSpain
NetherlandsNorway
SwitzerlandDenmark
GreeceBrazilIsrael
FinlandHungary
IndiaKorea
TurkeyIndonesia
South AfricaChina
IcelandMexico
Portugal
No. of restricted drugs
0 10 20 30 40 50 60
Coun
tries
21
G;G aVc Yofc hockVU% YVR]eY ViaVnUiefcV aVc G;G% ofe&oW&aoTkVe
aRjmVne cReV% RnU V]UVc]j aoaf]Reion cReVnhVcV diXniWiTRne]j ToccV]ReVU
hieY eYV nfmSVcd oW hieYUcRhn RnU cVdeciTeVU UcfXd (G 5 ).).%
=iXfcVd 1&. RnU 1&/). JYV nfmSVc oW cVdeciTeVU UcfXd hRd R]do
diXniWiTRne]j ToccV]ReVU hieY eYV nfmSVc oW UcfX&cV]ReVU UVReYd aVc
1))%))) aVcdond (G 5 ).).% =iXfcV 1&.(=)). Ffe&oW&aoTkVe aRjmVne
cReV dYohVU R nVXReigV ToccV]Reion hieY eYV nfmSVcd oW hieYUcRhn RnU
cVdeciTeVU UcfXd% hYi]V eYV oeYVc inUiTReocd dYohVU aodieigV ToccV]Reiond.
EGlOdGtOTS TL NKGltN GSd KITSTROI LGItTWs LWTR tNK FTWld 3GSP
dGtG
Iii WRTeocd dYohVU diXniWiTRne ToccV]Reiond hieY eYV nfmSVcd oW
UcfXd hieYUcRhn RnU(oc cVdeciTeVU Woc VRTY oW eYV ,, F<:; TofneciVd3
G;G aVc TRaieR% G;G aVc Yofc hockVU% YVR]eY ViaVnUiefcV aVc G;G%
ofe&oW&aoTkVe aRjmVne cReV% V]UVc]j aoaf]Reion cReV% RnU cReV oW UcfX&
cV]ReVU UVReYd. JYVdV ToccV]Reiond hVcV Tcodd&gR]iUReVU Sj Uohn]oRUinX
RnU RnR]jkinX eYV mReTYVU UReR Wcom eYV Moc]U 9Rnk Woc 2)1). IinTV
eYV G;G aVc Yofc hockVU RnU eYV cReV oW UcfX&cV]ReVU UVReYd hVcV
22
RSdVne Wcom eYV Moc]U 9Rnk UReR% hV TomaRcVU on]j eYV G;G aVc
TRaieR% YVR]eY ViaVnUiefcV aVc G;G% ofe&oW&aoTkVe aRjmVne cReV% RnU
V]UVc]j aoaf]Reion cReV Wcom eYV Moc]U 9Rnk UReR hieY eYV nfmSVc oW
hieYUcRhn(cVdeciTeVU UcfXd Woc VRTY Tofnecj. 8d Woc eYV F<:; inUViVd%
eYV G;G aVc TRaieR% YVR]eY ViaVnUiefcV aVc G;G% RnU V]UVc]j
aoaf]Reion cReV dYohVU diXniWiTRne aodieigV ToccV]Reiond hieY eYV
nfmSVc oW hieYUcRhn UcfXd in eYV 2- KE TofneciVd (c 6 ).-2/% G 5
).))14 c 6 ).,1,% G 6 ).))24 RnU c 6 ).,,1% G 6 ).))14 cVdaVTeigV]j) RnU
eYV nfmSVc oW cVdeciTeVU UcfXd (c 6 ).-01% G 5 ).))14 c 6 ).--2% G 5
).))14 RnU c 6 ).-10% G 5 ).))1). JYV ofe&oW&aoTkVe aRjmVne cReV hRd
nVXReigV]j ToccV]ReVU hieY eYV nfmSVc oW hieYUcRhn (c 6 m).200% G 6
).))1) RnU cVdeciTeVU (c 6 m).,-2% G 6 ).))1) UcfXd in eYV 2- KE
TofneciVd.
PTTW GMWKKRKSt HKtwKKS tNK lOsts TL wOtNdWGwS dWuMs GIWTss
ITuStWOKs
;cfXd hieYUcRhn in onV Tofnecj mRj SV acVdTciSVU in oeYVcd.
Jo VgR]fReV eYV UVXcVV oW RXcVVmVne SVehVVn eYV ]ided oW UcfXd
23
hieYUcRhn Wcom UiWWVcVne TofneciVd% =]Viddpd kRaaR gR]fVd hVcV
mVRdfcVU Woc eYV WigV TofneciVd hieY eYV ]RcXVde nfmSVcd oW hieYUcRhn
UcfXd RTTocUinX eo eYV KE :ondo]iUReVU Cided (=iXfcV 1&0(8)) (kRaaR
6 m).11-% G 5 ).))1) RnU F<:; UReR (=iXfcV 1&0(9)) (kRaaR 6 m
).11/% G 5 ).))1) RnU eYVj dYohVU ]oh RXcVVmVned. JRS]V 1&1 ]ided eYV
hieYUcRhn UcfXd ineVcnReionR]]j RnU eYV WigV TofneciVd hieY eYV ]RcXVde
nfmSVcd oW ;DMd in eYV F<:;.
24
7OMuWK (-,. :occV]Reiond SVehVVn YVR]eY(VTonomiT inUiTReocd RnU eYV
●
●
●
●
●
●
●●
●
●
●
●
●
●
●
0 10000 20000 30000 40000 50000
010
2030
4050
6070
GDP per capita
No. o
f with
draw
n dr
ugs
IndonesiaChina
South Africa
Turkey
Mexico
Chile
HungaryPortugal
Greece
New Zealand
Spain
Israel
Italy
Korea
France
Japan
Finland
Denmark
Belgium
United Kingdom
Germany
Sweden
Iceland
CanadaAustriaAustraliaIreland
NetherlandsSwitzerland
United States
Norway
r = 0.46P < 0.01
●
●●
●
●
●
●
●
●
●
●
●
●
10 20 30 40 50 60 70
1020
3040
5060
70
GDP per hour worked
No. o
f with
draw
n dr
ugs
Mexico
Chile
Turkey
HungaryPortugal
Korea
Greece
New Zealand
Israel
Japan
Iceland
Italy
Spain
Finland
Switzerland
Canada
United Kingdom
Australia
Sweden
AustriaDenmark
Ireland
Germany
France
BelgiumNetherlands
United States
Norway
r = 0.5P = 0.007
●
●
●
●
●
●
●
●
●
●
●
●
0 10 20 30 40 50
1020
3040
5060
70
Out−of−pocket payment (% of total expenditure on health)
No. o
f with
draw
n dr
ugs
FranceUnited Kingdom
New Zealand
United States
Germany
DenmarkCanada
JapanTurkeySweden
Italy
Iceland
IrelandAustralia
Finland
Spain
Belgium
Israel
Switzerland
PortugalHungary
Greece
Chile
Korea
Mexico
r = − 0.59P < 0.001
●
●
●
●
●
●
●
●
●
●●
●
●
6 8 10 12 14 16 18
1020
3040
5060
70
Rate of health expenditure per GDP (%)
No. o
f with
draw
n dr
ugs
Turkey
Mexico
Chile
KoreaIsraelHungary
Australia
Finland
Ireland
Italy
United Kingdom
Sweden
Norway
Iceland
Greece
Spain
Japan
New Zealand
Portugal
Austria
Canada
Belgium
Denmark
Switzerland
France
Germany
Netherlands
United States
r = 0.53P = 0.004
●
●
●
●●
●
●
●
●
●
●
●
●
●
●
●
0 5 10 15 20 25
010
2030
4050
6070
Elderly population (%)
No. o
f with
draw
n dr
ugs
South Africa
India
MexicoIndonesia
Turkey
Brazil
China
Chile
IsraelKorea
Ireland
Iceland
United States
New ZealandCanadaAustralia
Norway
Netherlands
United Kingdom
Denmark
France
Hungary
Switzerland
Belgium
Finland
Spain
Portugal
Austria
Sweden
Greece
Germany
Italy
Japan
r = 0.4P < 0.05
25
nfmSVc oW UcfX hieYUcRhR]d Wcom eYV mRckVe in ,, F<:; TofneciVd.
(8) G;G aVc TRaieR% (9) G;G aVc Yofc hockVU% (:) ofe&oW&aoTkVe
aRjmVne cReV% (;) YVR]eY ViaVnUiefcV aVc G;G% RnU (<) V]UVc]j
aoaf]Reion cReV R]] ViYiSie diXniWiTRne ToccV]Reiond hieY eYV nfmSVc oW
UcfX hieYUcRhR]d (G5).).).
26
● ●
●
●
●
●
● ●
●
●
●
●
●
●
●
0 10000 20000 30000 40000 50000
010
2030
4050
GDP per capita
No.
of r
estri
cted
dru
gs
Indonesia
ChinaSouth Africa
Turkey
Mexico
Chile
Hungary
Portugal
Greece
New Zealand
Spain
Israel
Italy
Korea
France
Japan
Finland
Denmark
Belgium
United Kingdom
Germany
Sweden
Iceland
CanadaAustriaAustraliaIreland
NetherlandsSwitzerland
United States
Norway
r = 0.34P = 0.048
●
●
●
●
●
●
●
●
●●
●
●
●
10 20 30 40 50 60 70
010
2030
4050
GDP per hour worked
No.
of r
estri
cted
dru
gs
Mexico
Chile
TurkeyHungary
Portugal
Korea
Greece
New Zealand
Israel
Japan
Iceland
Italy
Spain
FinlandSwitzerland
Canada
United Kingdom
AustraliaSweden
Austria
Denmark
Ireland
Germany
France
Belgium
Netherlands
United States
Norway
r = 0.46P = 0.037
●
●
●
●
●
●
●
●
●
●
●
●
0 10 20 30 40 50
010
2030
4050
Out−of−pocket payment (% of total expenditure on health)
No. o
f res
trict
ed d
rugs
France
United Kingdom
New Zealand
United States
Germany
Denmark
Canada
Japan
Turkey
Sweden
Italy
Iceland
IrelandAustralia
Finland
Spain
Belgium
Israel
Switzerland
Portugal
Hungary
Greece
Chile
Korea
Mexico
r = 0.5P = 0.03
●
●● ●
●
●
●
● ●
●
●●
●
6 8 10 12 14 16 18
010
2030
4050
Rate of health expenditure per GDP (%)
No.
of r
estri
cted
dru
gs
Turkey
Mexico
Chile
Korea
Israel
Hungary
Australia
Finland
Ireland
Italy
United Kingdom
Sweden
Norway
Iceland
Greece
Spain
JapanNew Zealand
Portugal
AustriaCanada
Belgium
DenmarkSwitzerland
France
Germany
Netherlands
United States
r = −0.59P = 0.003
● ●
●
●
●
●●
●
● ●
●●
●
0 5 10 15 20 25
010
2030
4050
Elderly population (%)
No.
of r
estri
cted
dru
gs
Mexico
Turkey
Chile
IsraelKorea
Iceland
United States
New Zealand
CanadaAustralia
NorwayNetherlands
United Kingdom
Denmark
France
Hungary
Belgium
Finland
Spain
Portugal
AustriaSweden
Germany
ItalyJapan
r = 0.4P = 0.007
●●
●
●
●
●
●
●
●
●
●
●
0.0 0.5 1.0 1.5 2.0 2.5
010
2030
4050
Drug Use Death per 100000 population (%)
No.
of r
estri
cted
dru
gs
Chile
Hungary
Japan
KoreaTurkey
Spain
Mexico
Netherlands
New Zealand
Australia
Israel
Italy
Portugal
Belgium
Canada
Finland
Iceland
Sweden
France
Norway
United States
Denmark
Germany
United Kingdom
Austria
r = 0.53P = 0.014
27
7OMuWK (--. :occV]Reiond SVehVVn YVR]eY RnU VTonomiT inUiTReocd RnU
eYV nfmSVc oW UcfX mRckVe cVdeciTeiond in eYV mRckVe in ,, F<:;
TofneciVd. (8) G;G aVc TRaieR% (9) G;G aVc Yofc hockVU% (:) ofe&oW&
aoTkVe aRjmVne cReV% (;) YVR]eY ViaVnUiefcV aVc G;G% (<) V]UVc]j
aoaf]Reion cReV% RnU (=) UcfX&fdV UVReYd aVc 1))%))) aVcdond R]]
ViYiSie diXniWiTRne ToccV]Reiond hieY eYV nfmSVc oW UcfX cVdeciTeVU
(G5).).).
28
7OMuWK (-.. 8XcVVmVne oW eYV ]ide oW hieYUcRhn UcfXd in eYV WigV
TofneciVd hieY eYV ]RcXVde nfmSVcd oW hieYUcRhn RnU cVdeciTeVU UcfXd.
;ideciSfeiond oW eYV nfmSVcd oW eYV UcfXd eYRe RcV (8) hieYUcRhn Wcom
A"
B"
29
eYV eoa . oW 2- KE TofneciVd RnU (9) cVdeciTeVU in eYV eoa . oW ,,
F<:; TofneciVd.
4GsK study1 KTWKG
MV aVcWocmVU R TRdV defUj oW hieYUcRhn RnU cVdeciTeVU UcfXd
Woc onV Tofnecj% BocVR. BocVR hRd cRnkVU 2/eY (n 6 /) in UcfX
hieYUcRhR]d RnU 2,eY (n 6 2) in UcfX cVdeciTeiond RmonX eYV ,, F<:;
TofneciVd (=iXfcV 2&2). Jho oW eYV 20 ineVcnReionR]]j hieYUcRhn UcfXd
hVcV SVinX acVdTciSVU in BocVR Rd oW 2)11. FnV eYV eho% ]oaVcRmiUV%
hRd hieYUcRhn ineVcnReionR]]j on]j in eYV Wocm UVdiXnVU Woc fdV Sj
TYi]UcVn% RnU eYid Wocm hRd R]do cVdeciTeVU in BocVR. JYV oeYVc UcfX%
Racoeinin% id Rn RneiWiScino]jeiT mo]VTf]V fdVU eo acVgVne mR[oc S]VVUinX
UfcinX mR[oc dfcXVcj% RnU hRd hieYUcRhn hoc]UhiUV in 2))1% RnU
TieVU Rd oJYV mRnfWRTefcVc (9RjVc InT.) YRd SVVn RUgidVU eo dfdaVnU eYV
mRckVeinX oW eYid acoUfTep in eYV KE :ondo]iUReVU Cided. JYV KE
:ondo]iUReVU Cided cVaoce eYRe dii UcfXd YRgV SVVn hieYUcRhn
(RminoaYVnRkonV% SociT RTiU RnU SocReVd% UiWVnoiin% UiaYVnoij]ReV%
WfcRko]iUonV% RnU eYiociURkinV) RnU eYcVV UcfXd YRgV SVVn cVdeciTeVU
30
(RecoainV in TomSinReion% ]oaVcRmiUV% RnU decVaeomjTin) in BocVR. 8]]
oW eYVdV UcfXd RcV in eYV 1eY KE :ondo]iUReVU Cide afS]idYVU in 2)),
(ViTVae Woc eYiociURkinV% hYiTY hRd cVaoceVU in 2)).). Jo VgR]fReV eYV
aoddiSi]iej oW fnUVccVacVdVneReion oW eYV KE :ondo]iUReVU Cided Woc
UVTidiond oW UcfX hieYUcRhn Sj eYV BD=;I% hV TomaRcVU eYV ]ide oW
hieYUcRhn UcfXd To]]VTeVU Wcom eYV on]inV ]iScRcj oW BD=;I hieY eYV
KE :ondo]iUReVU Cided. In eoeR]% 11, dRWVej ]VeeVcd hcieeVn Wcom 8fXfde
2))1 eo DRcTY 2)1. hVcV cVgiVhVU. JYV dRWVej ]VeeVcd ]ideVU 1-
inXcVUiVne UcfXd eYRe hVcV SRnnVU(hieYUcRhn in BocVR. 9VWocV FTeoSVc
2))1% hYiTY TogVcd eYV dRmV aVcioU Rd eYV KE :ondo]iUReVU Cided% eYcVV
UcfXd hVcV cVaoceVU Rd SVinX hieYUcRhn3 nVWRkoUonV YjUcoTY]ociUV (in
2)),)% eYiociURkinV (in 2)).)% RnU Racoeinin (in 2))0). 8acoeinin cV&
VneVcVU eYV mRckVe in eYV dRmV jVRc% RnU do eYVcV hVcV RTefR]]j eho
UcfXd hieYUcRhn Wcom 8fXfde 2))1 eo FTeoSVc 2))1. In eYV KE
:ondo]iUReVU Cided% dii UcfXd hVcV cVaoceVU eo SV hieYUcRhn in BocVR3
RminoaYVnRkonV (in 1201)% SociT RTiU RnU SocReVd (in 120,)% UiWVnoiin
(in 1221)% UiaYVnoij]ReV (in 1221)% WfcRko]iUonV (in 1211)% RnU
eYiociURkinV (in 2)).). 8d R cVdf]e% eYV nVWRkoUonV hieYUcRhR] UVTidion
31
in 2)), hRd noe cVaoceVU eo eYV KE.
32
TabIe 1-1. TEe IFst LC TFtEdOaTK dOuDs FK tEe tLp 5 O312 cLuKtOFes EaSFKD EFDEest KumbeO LC TFtEdOaTK dOuDs aKd tEe IFst LC
FKteOKatFLKaIIy TFtEdOaTK dOuDs
1LuKtOy (9L. LC
TFtEdOaTK dOuDs)
2OuDs
5eOmaKy (K0,.) aIbumFK, aIcILCeKac, amFKLpEeKazLKe, amFKLOeU, aKaDestLKe acetate, aOFstLILcEFcacFd,
beKzaOLKe, betaetELUyIacetaKFIFde, bLOFc acFd aKd bLOates, bucetFK, buCLOmFK, caKOeKLKe,
caKtEaUaKtEFK, caOtFIaDe eUtOact, ceII pOepaOatFLKs, cEILOLCLOm, cEILOpEeKteOmFKe, cFaKFdaKLI,
cFKcELpEeK, cFsapOFde, cILCFbOate, cILCLOeU, daKtOLK, dFCemeOFKe, dFLKaeamuscFpuIa eUtOact,
etEyIeKe dFcEILOFde, CepOazLKe, DaKDIFLsFdes, DeOmaKdeO, DFKkDL bFILba, DIaCeKFKe, DIucLsamFKe
suICate, EeOpes sFmpIeU SaccFKes, FKdLpOLCeK, FsLUFcam, ketLcLKazLIe, 8-tOyptLpEaK, meDestOLI
33
acetate, mesKa, metEapyOFIeKe, mFbeCOadFI, muzLIFmFKe, KFtOeCazLIe, KLmFCeKsFKe, LmepOazLIe,
LODLteFK, LUeIadFK, LUypEeKFsatFKeacetate, pEeKacetFK, pEeKCLOmFK, pEeKyIpOLpaKLIamFKe,
pLIySFdLKe, pLtassFum caKOeKLate, pOactLILI, pyOOLIFzFdFKe, OubFaetFKctLOumOadFU, suICacaObamFde,
suICadFcOamFde, suICadFmFdFKe, suICaDuaKFdFKe, suICameOazFKe sLdFum, suICaKFIamFde, suICFsLmFdFKe,
suILctFdFI, tFeKFIFcacFd, tOFacetyI dFpEeKLIFsatFK, uOetEaKe, SFKcamFKe
=KFted States (K059) adKOLDeKs, amaOaKtE, amCetamFKe, amFKL DIutetEFmFde, amFKLpEeKazLKe, amFpOFILse,
apEOLdFsFac dOuDs, beKzyI peKFcFIFK sLdFum tLpFcaI pOepaOatFLKs, bFtEFLKLI, bOLmCeKac,
buKamFLdyI, caIamus, cEILOmadFKLKeacetate, cEILOLCLOm, cFsapOFde, cLbaIt KLK OadFLactFSe CLOms,
cycIaKdeIate, daIkLKsEFeId, daKtOLK, depLt medOLUypOLDesteOLKe acetate (dmpa), deUamCetamFKe,
dFEydOL stOeptLmycFK, dFmazLIe, epEedOa, etEyIKFtOFte spFOFt, EaILDeKatedsaIFcyIaKFIFdes,
34
EydOLmLOpELKe EydOLcEILOFde, FKteOCeOLK Damma 0b, FLdFKatedcaseFKstOLpEaKtEFK KeL baOFKe,
I.tOyptLpEaK, IaetOFIe, IeSacetyImetEadLI, IeSamCetamFKe, metamFzLIe sLdFum, metEapyOFIeKe,
metLCLIFKe, mFbeCOadFI, LUypEeKFsatFKeacetate, pemLIFKe, peODLIFde, peUFDaKaK, pEeKacetFK,
pEeKCLOmFK, pEeKyIpOLpaKLIamFKe, pFpamazFKe, pFtuFtaOy cELOFLKFcDLKadLtOLpFK FKGectabIe,
pOasteOLKe, NuFKFKesuICate, saODOamLstFm, sLmatOLpFK pFtuFtaOy deOFSed, suICatEFazLIe,
tecEKetFum99mtc CaKLIesLmab, teOCeKadFKe, tetOacycIFKe paedFatOFc, tEeKaIFdFKe, tFeKFIFcacFd,
uOetEaKe, SaIdecLUFb, SFKaOLI aKd SFDa
4OaKce (K04() acetyI saIFcyIFc acFd (paedFatOFc), aIpFdem, amFKeptFKe, amFKLpEeKazLKe, aOFstLILcEFc acFd,
beKzbOLmaOLKe, bFsmutE saIts, bLSFKe tFssue deOFSed medFcFKes, cameIIFa sFKeKsFs, cEILOampEeKFcLI,
cILmetacFK, cLumaOFKe syKtEetFc, dFtEFazaKFKeFLdFde, DeOmaKdeO, DIaCeKFKe, FKdaIpFKe,
35
FsaULKFKepELspEate, FsLUFcam, ketLcLKazLIe, Iead LUFde aKd Iead saIts, medFCLUamFKe, metamFzLIe
sLdFum, mLUFsyIyte, mucLpLIysaccEaOFde pLIysuICuOFc acFdesteO, muzLIFmFKe, KaCtFdOLCuOyI
paOeKteOaI CLOmuIatFLKs, KaKdOLILKedecaKLate FKGectabIe, LUeIadFK, LUypEeKFsatFKe acetate,
pEeKCLOmFK, pEeKLbaObFtaI, pEeKLIpEtEaIeFK, pIaceKtaI tFssue deOFSed medFcFKe, pLdLpEyIIumOesFK,
pLtassFumcEILOFde, pLtassFumKFtOate, pOLUFbaObaI, teOCeKadFKe, tEeKaIFdFKe, tFeKFIFcacFd,
tFIbOLNuFKLI, UeKazLFcacFd
=KFted 7FKDdLm
(K041)
aIbumFK, aIcILCeKac, amCepOamLKe EydOLcEILOFde, amFKLpEeKazLKe, aOFstLILcEFa,
bFcaIutamFde, bLOFc acFd aKd bLOates, cEILOmadFKLKeacetate, cEILOLCLOm, cFsapOFde, daIkLKsEFeId,
dFKLpOLstLKe, dOLpeOFdLI, CactLOSIII, CeKcILCeKac, CepOazLKe, CILseNuFKaK, DameILKFc acFd,
DOepaCILUacFK EydOLcEILOFde, FKdLpOLCeK, I-tOyptLpEaK, mepOLbamate, metEapyOFIeKe, metOLdFK-
36
Ep, mFbeCOadFI, KLmFCeKsFKe, KLscapFKe, LUypEeKbutazLKe, pEeKCLOmFK, pEeKteOmFKe,
pEeKyIepEOFKe, pOactLILI, pumactaKt, pyOOLIFzFdFKe, seOtFKdLIe, sLmatOLpFK(pFtuFtaOy-deOFSed),
tEeKaIFdFKe, tLIcapLKe, tOFazLIam, tOLDIFtazLKe, UFmeIaDatOaK
6taIFa (K0)() aIcILCeKac, amFKLpEeKazLKe, aOseKFc based cLmpLuKds, baObFtaI, beKzyI peKFcFIIFK sLdFum
tLpFcaI pOepaOatFLKs, cEILOmadFKLKeacetate, cEILOLCLOm, cFaKFdaKLI, cFKcELpEeK, cIFLNuFKLI (see
aIsL EaILDeKated EydOLUyNuFKLIFKe deOFSatFSes), dFeKestOLI, dFetEyIstFIbestOLI, dFEydOL
stOeptLmycFK, dFtEFazaKFKeFLdFde, EaILDeKated EydOLUyNuFKLIFKe deOFSatFSes, EeUestOLI, FKdLpOLCeK,
FpOLKFazFd, FsLUFcam, ILbeIFa, metEapyOFIeKe, LpFumFK aKtFtussFSe pOepaOatFLKs, pEeKacetFK,
pFpeOazFKe, pLdLpEyIIumOesFK, pLIyLUyetEyIated castLOLFI, suUFbuzLKe, tetOacycIFKe (paedFatOFc),
tOaKyIcypOLmFKe, tOFacetyIdFpEeKLIFsatFK, tOFazLIam, uOetEaKe
37
6KteOKatFLKaIIy
TFtEdOaTK dOuDs (K0(-)
beKLUapOLCeK, cEILOmezaKLKe, cFaKFdaKLI, dFIeSaILI, dLmpeOFdLKe (FKGectabIe),
CeKCIuOamFKe, DIaCeKFKe, FKdLpOLCeK, FsLUFcam, ILpeOamFde, Kebacumab, KLmFCeKsFKe,
pEeKLIpEtEaIeFK, pFOpOLCeK, pLIyLUyetEyIatedcastLOLFI, pOeKyIamFKe, OemLUFpOFde, suILctFdFI,
supOLCeK, temaCILUacFK, teOLdFIFKe, tLIOestat, SaccFKes (CLO mumps, measIes, aKd OubeIIa), zFmeIdFKe,
zLmepFOac, ceOFSastatFK, apOLtFKFK
38
/4S.USS4O7
I] ]cr PSab kn]elSRUS, bVS prSaSnb abcRg Wa bVS TWrab b]
c][prSVSnaWdSlg SdOlcObS Ul]POl RrcU eWbVRrOeOla OnR rSabrWcbW]na Wn
c][pOrWa]n eWbV ]TTWcWOl VSOlbV OnR Sc]n][Wc WnRWcOb]ra. IVS rSaclba
RS[]nabrObS bVOb c]cnbrWSa eWbV VWUVSr =:F OnR/]r VWUVSr VSOlbV
SfpSnRWbcrS pSr =:F eWbVRrOe []rS RrcUa. IVS nc[PSr ]T eWbVRrOen
RrcUa eOa abr]nUlg OnR p]aWbWdSlg c]rrSlObW]n eWbV =:F pSr cOpWbO,
=:F pSr V]cr e]rkSR, OnR VSOlbV SfpSnRWbcrS pSr =:F, OnR abr]nUlg
OnR nSUObWdSlg c]rrSlObSR eWbV bVS ]cb%]T%p]ckSb pOg[Snb rObS. Ib Wa
acUUSabSR bVOb bVS nc[PSr ]T RrcU eWbVRrOeOl/rSabrWcbW]n Wa rSlObWdSlg
l]e Wn c]cnbrWSa eWbV VWUV rSaWRSnb aSlT%pOg[Snba T]r VSOlbV cOrS OnR
l]e U]dSrn[Snb%c]dSrSR pOg[Snba. FVOr[OcScbWcOl apSnRWnU Wa O
[Oj]r c][p]nSnb ]T VSOlbV cOrS SfpSnRWbcrS O[]nU []rS RSdSl]pSR
c]cnbrWSa M33N, OnR bVS nc[PSr ]T eWbVRrOen RrcUa [Og PS caSR Oa On
WnRWcOb]r ]T V]e [ccV O c]cnbrg WndSaba Wn Wba VSOlbV cOrS agabS[.
Ib Wa eWRSlg kn]en bVOb =:F pSr cOpWbO Wa c]rrSlObSR eWbV [Oj]r
VSOlbV cOrS WnRWcOb]ra accV Oa lWTS SfpScbOncg OnR WnTOnb []rbOlWbg rObS
M33N. LS SfpScbSR bVOb RrcU rSUclObW]n, Wn bVS T]r[ ]T RrcU
39
eWbVRrOeOla OnR rSabrWcbW]na, e]clR Ola] PS WnTlcSncSR Pg SOcV
c]cnbrgla Sc]n][Wc WnRSf OnR bVWa eOa c]nTWr[SR Occ]rRWnU b] ]cr
abcRg. 8cb RWaSOaS []rbOlWbg OnR lWTS SfpScbOncg eSrS n]b aWUnWTWcOnblg
c]rrSlObSR eWbV bVS nc[PSr ]T RrcU eWbVRrOeOla. Ib Wa c]ndWncWnU
Sn]cUV, PScOcaS ]T bVS [Oj]r VSOlbV WnRWcOb]r, accV Oa lWTS SfpScbOncg
]r [Oj]r RWaSOaS []rbOlWbg, eSrS WnTlcSncSR [OWnlg WnTOnbWlS []rbOlWbg
rObS, WnTScbW]n c]nbr]l, OnR [Oj]r rWak TOcb]r c]nbr]l M3,N. IVS W[pOcb
]T Oppr]prWObS RrcU rSUclObW]n ]n bVS p]pclObW]n VSOlbV c]clR PS
[SOacrSR Pg ]bVSr apScWTWc WnRSfSa accV Oa nc[PSr ]T 7:Ga ]r RrcU%
rSlObSR []rbOlWbg.
JnSfpScbSRlg, bVS nc[PSr ]T RrcU%caS RSObVa pSr )((,(((
pSra]na eOa p]aWbWdSlg c]rrSlObSR eWbV bVS nc[PSr ]T rSabrWcbSR RrcUa
(<WUcrS )%.(<)). IVWa eOa cnSfpScbSR PScOcaS ]nS e]clR SfpScb b] aSS
a[OllSr RrcU%caS RSObV rObSa Wn O c]cnbrg eWbV O VWUVSr nc[PSr ]T
rSabrWcbSR RrcUa. Ib c]clR PS p]aaWPlS bVOb bVSrS eOa O
RSbScbW]n/rSp]rbWnU PWOa Wn bVOb bVS c]cnbrWSa bVOb acrdSg OnR rSp]rb
RrcU%rSlObSR RSObV []rS OcccrObSlg c]clR rSUclObS bVS ROnUSr]ca RrcUa
[]rS abrWcblg. 8ScOcaS bVS WllWcWb RrcU caS OnR RrcU%rSlObSR []rbOlWbg OrS
40
RWTTWcclb b] acrdSg SdSn Wn RSdSl]pSR c]cnbrWSa M3-N, bVS c]cnbrWSa eWbV
[]rS eSll%]rUOnWhSR RrcU acrdSWllOncS OnR rSUclObW]n agabS[ e]clR
n]b ]nlg VOdS []rS rSabrWcbSR RrcUa Pcb Ola] VWUVSr RrcU%rSlObSR RSObV
rObSa. >]eSdSr, Wb Wa VOrR b] c]nclcRS bVOb bVSrS e]clR PS accV PWOaSa
Wn rSp]rbSR RrcU%rSlObSR RSObV ]nlg Tr][ bVWa abcRg a] TcrbVSr
SdOlcObW]n Wa nSSRSR.
IVS RrcUa lWabSR Oa PSWnU eWbVRrOen eSrS VWUVlg dOrWOPlS SdSn
O[]nU bVS b]p TWdS c]cnbrWSa. IVWa TWnRWnU Wa c]naWabSnb eWbV prSdW]ca
rSp]rba ]T [Ong aWnUlS [OrkSb eWbVRrOeOla, eVSrS []ab ]T bVSaS
eWbVRrOeOla eSrS Wn ;cr]pSOn c]cnbrWSa M)0N. IVS RWTTSrSncS [Og PS
RcS b] RWTTSrSncSa Wn bVS RrcUa caSR Pg RWTTSrSnb c]cnbrWSa, bVS c]nbr]l
bVOb [Oj]r pVOr[OcScbWcOl c][pOnWSa VOdS ]dSr bVS prSacrWpbW]n RrcU
[OrkSb, bVS RrcUa nSelg SnbSrWnU bVS [OrkSb, OnR cclbcrOl OnR
WnabWbcbW]nOl abOnROrRa rSlObSR b] bVS prSacrWPWnU ]T RrcUa.
Ie] RrcUa bVOb eSrS eWbVRrOen prW]r b] 2((0 e]rlReWRS eSrS
abWll prSacrWPSR Wn 2()) Wn A]rSO. In cOaS ]T l]pSrO[WRS, bVS eWbVRrOeOl
OpplWSR ]nlg b] bVS agrcp T]r[ T]r caS Pg cVWlRrSn, OnR Wba caS Pg
cVWlRrSn eOa Ola] rSabrWcbSR Wn A]rSO. 7pr]bWnWn eOa eWbVRrOen Wn 2((0
41
RcS b] bVS WncrSOaWnU RSObV rObS O[]nU pObWSnba, Pcb , gSOra lObSr bVS
;cr]pSOn JnW]n rSOppr]dSR Wb RcS b] Wba STTScbWdSnSaa PSWnU c]naWRSrSR
b] ]dSrrWRS Wba VOr[Tcl STTScba. IVS A]rSO <]]R OnR :rcU
7R[WnWabrObW]n Oll]eSR bVWa RrcU T]r caS ]nlg Wn lW[WbSR cOaSa Occ]rRWnU
b] O aOTSbg lSbbSr pcPlWaVSR Wn 2((0 M3.N. :rcUa bVOb eSrS eWbVRrOen
Tr][ bVS JH [OrkSb RWR n]b OppSOr SWbVSr Wn bVS eWbVRrOen ]r bVS
prSacrWpbW]n RrcU lWab Wn A]rSO. H][S RrcUa eWbVRrOen Wn ;cr]pS eSrS
T]cnR b] PS n]b eWbVRrOen Tr][ bVS prSacrWpbW]n RrcU lWab Wn A]rSO. Ib
aSS[a bVOb bVS RrcUa eWbVRrOen Wn bVS JH [Og VOdS TOWlSR b] SnbSr bVS
A]rSOn pVOr[OcScbWcOl [OrkSb OnR bVOb bVSrS [Og PS a][S OcbV]rWbg%
lSdSl WnbSrOcbW]na Wn RrcU rSUclObW]n pr]cSaaSa. 7a WnRWcObSR Wn IOPlS ),
bVS 2/ WnbSrnObW]nOllg eWbVRrOen RrcUa rSprSaSnb ,.% ]T bVS -1 RrcUa
eWbVRrOen Pg bVS JH <]]R OnR :rcU 7R[WnWabrObW]n Occ]rRWnU b] bVS
JD 9]na]lWRObSR BWaba. IVSrST]rS, Wb Wa W[p]rbOnb T]r rSUclOb]rg
OcbV]rWbWSa b] Ul]POllg []nWb]r 7:Ga OnR rSUclOb]rg RScWaW]na T]r RrcUa
OnR b] SabOPlWaV bVSWr ]en RrcU acrdSWllOncS agabS[a OnR rSUclOb]rg
UcWRSlWnSa.
Ib [Og n]b PS nScSaaOrg T]r Ong pOrbWcclOr c]cnbrg b] eWbVRrOe
42
Oll RrcUa bVOb OrS eWbVRrOen Pg ]bVSr c]cnbrWSa. IVS RScWaW]n T]r O RrcU
eWbVRrOeOl Wa WnTlcSncSR Pg dOrW]ca TOcb]ra, WnclcRWnU a]cWOl, cclbcrOl,
Sc]n][Wc, OnR SbVWcOl WaacSa. 7 :CL Wa O rSaclb ]T c][plSf p]lWbWcOl,
a]cWOl, SbVWcOl, OnR Sc]n][Wc WaacSa Oa eSll Oa 7:Ga OnR RrcU
STTScbWdSnSaa. IVSrST]rS, eS [cab OacSrbOWn bVS rSUclOb]rg RScWaW]na Wn
]bVSr c]cnbrWSa aSnaWbWdSlg OnR Ob bVS aO[S bW[S WRSnbWTg bVS l]cOl
]cccrrSncS ]T aSdSrS 7:Ga Wn O bW[Slg [OnnSr. IVS rSUclOb]rg
RScWaW]n%[OkWnU Wn A]rSO VOa lOrUSlg rSTlScbSR RScWaW]na [ORS Wn lOrUS
c]cnbrWSa accV Oa bVS JH, JOpOn, OnR ;cr]pSOn c]cnbrWSa M3/N. 8ScOcaS
7:Ga RSpSnR ]n pObbSrna ]T RrcU caS bVOb RWTTSr PSbeSSn c]cnbrWSa, Wb Wa
nScSaaOrg b] SabOPlWaV O R][SabWc acrdSWllOncS agabS[ OnR Oppr]prWObS
rSUclOb]rg UcWRSlWnSa.
7n W[p]rbOnb lW[WbObW]n ]T bVS prSaSnb abcRg Wa bVOb bVS ]PaSrdSR
c]rrSlObW]na R] n]b nScSaaOrWlg WnRWcObS cOcaOlWbg. GSUclObW]n ]T O RrcU
Wnd]ldSa O dOrWSbg ]T TcncbW]na3 lWcSnaWnU, WnapScbW]n ]T [OncTOcbcrWnU
TOcWlWbWSa OnR RWabrWPcbW]n cVOnnSla, pr]Rccb OaaSaa[Snb OnR rSUWabrObW]n,
7:G []nWb]rWnU, qcOlWbg c]nbr]l, c]nbr]l ]T RrcU pr][]bW]n OnR
ORdSrbWaWnU, OnR c]nbr]l ]T clWnWcOl RrcU brWOla M30N. In bVWa abcRg,
43
c]cnbrWSa eWbV [Ong eWbVRrOen/rSabrWcbSR RrcUa bSnR b] PS eSll
RSdSl]pSR OnR VSncS Ola] VOdS lOrUS pVOr[OcScbWcOl WnRcabrWSa. IVS
nc[PSr ]T eWbVRrOen RrcUa Wa clSOrlg c]rrSlObSR eWbV bVS nc[PSr ]T
RrcUa [OrkSbSR ]r bVS ]dSrOll [OrkSb aWhS ]T bVS c]cnbrg. IVca, bVS
rSaclba ]T bVS prSaSnb abcRg ]n VSOlbV OnR Sc]n][Wc TOcb]ra c]clR VOdS
PSSn OTTScbSR Pg [Ong c]nT]cnRSra. >]eSdSr, Wb Wa VWUVlg lWkSlg bVOb bVS
nc[PSr ]T RrcUa eWbVRrOen/rSabrWcbSR Pg O rSUclOb]rg OcbV]rWbg cOn PS
O caSTcl WnRWcOb]r T]r O c]cnbrgla ]pbW[c[ lSdSl ]T Sc]n][Wc
WndSab[Snba Wn bVS VSOlbV cOrS agabS[ OTTScbWnU RrcU rSUclObW]n
pr]cSaaSa.
7n]bVSr lW[WbObW]n Wa bVOb bVS nc[PSr ]T W[p]rbSR RrcUa eOa
n]b c]cnbSR RcS b] O lOck ]T WnT]r[ObW]n. IT O c]cnbrg ]pSrObSa O al]e
OnR c]naSrdObWdS RrcU Oppr]dOl agabS[, bVS rObS ]T p]ab[OrkSb RrcU
eWbVRrOeOla [Og PS l]eSr. ;dOlcObW]n ]T bVS RWTTSrSnb RrcU Oppr]dOl
agabS[a eOa PSg]nR bVS ac]pS ]T bVS prSaSnb abcRg. 8ScOcaS RrcU
Oppr]dOl agabS[a VOdS Sd]ldSR ]dSr bW[S, bW[S%aSrWSa OnOlgaSa ]T
Oppr]dSR OnR POnnSR RrcUa T]r RWTTSrSnb c]cnbrWSa OrSO aV]clR PS
pSrT]r[SR Wn TcbcrS c][pOrObWdS abcRWSa.
44
IVS JD 9]na]lWRObSR BWaba ]T Fr]Rccba OrS n]b pSrTScb. H][S
W[p]rbOnb RObO OrS clSOrlg [WaaWnU, Oa SfS[plWTWSR Wn bVS cOaS abcRg ]T
A]rSO eVSrS ]nS ]T bVS be] eWbVRrOen RrcUa VOa n]b PSSn rSp]rbSR b]
bVS JD T]r 0 gSOra. DSdSrbVSlSaa, bVS lWaba OrS kn]en b] PS bVS []ab
c][prSVSnaWdS OnR OcbV]rWhSR OdOWlOPlS WnT]r[ObW]n a]crcSa. <WnOllg,
bVS clOW[a RObO T]r bVS eV]lS A]rSOn p]pclObW]n Tr][ bVS >SOlbV
InacrOncS GSdWSe 7USncg OrS rSlObSR b] prSacrWpbW]n RrcUa ]nlg, OnR
n]b ]dSr%bVS%c]cnbSr RrcUa.
In c]nclcaW]n, bVS nc[PSr ]T RrcU eWbVRrOeOla OnR rSabrWcbW]na
cOn PS caSR Oa On WnRWcOb]r ]T O c]cnbrgla lSdSl ]T WndSab[Snb Wn Wba
VSOlbV cOrS agabS[. IVS lWaba ]T eWbVRrOen OnR rSabrWcbSR RrcUa dOrg
[OrkSRlg PSbeSSn c]cnbrWSa, accV bVOb O RrcU eWbVRrOen Wn ]nS
c]cnbrg [Og PS prSacrWPSR Wn On]bVSr. ;dSn RrcUa eWbVRrOen
WnbSrnObW]nOllg Pg RrcU [OncTOcbcrSra OrS abWll PSWnU prSacrWPSR Wn a][S
c]cnbrWSa. LVWlS OcbV]rWbWSa cl]aSlg c]llOP]rObS eWbV SOcV ]bVSr, Wb aSS[a
bVOb bVSrS rS[OWna r]][ T]r W[pr]dS[Snba Wn bVS ccrrSnb RrcU
rSUclOb]rg agabS[a e]rlReWRS. DSe RrcUa eWll c]nbWnc]calg OppSOr
P]bV eWbV W[pr]dSR VSOlbV cOrS PSnSTWba OnR p]bSnbWOllg VOr[Tcl 7:Ga.
45
C]rS]dSr, nSe WnRWcObW]na T]r RrcUa eWll S[SrUS OnR bVS caOUS pObbSrna
eWll cVOnUS c]nabOnblg. <crbVSr W[pr]dS[Snba Ob P]bV bVS Ul]POl OnR
nObW]nOl lSdSla OrS rSqcWrSR Wn RrcU acrdSWllOncS agabS[a OnR rSUclOb]rg
c][[cnWcObW]n nSbe]rka.
46
.3-PTE: 2
2DLMmHc VaOHaAHlHtT aLC /ORF SaEDtT
47
47T:O/U.T4O7
IVS pSra]n%b]%pSra]n dOrWOPWlWbg Wn RrcU rSap]naS Wa O [Oj]r
cVOllSnUS T]r ccrrSnb clWnWcOl prOcbWcS, RrcU RSdSl]p[Snb, OnR RrcU
rSUclObW]n M2N. 7 RrcU eWbV pr]dSn clWnWcOl STTWcOcg Wn a][S pObWSnba
]TbSn TOWla b] e]rk Wn ]bVSra, ]r [Og SdSn cOcaS aSrW]ca aWRS STTScba,
WnclcRWnU RSObV M2j,N. IVS WncWRSncS ]T aSdSrS 7:Ga VOa PSSn
SabW[ObSR Ob ..2j../% Wn V]apWbOlWhSR pObWSnba, OnR []rS bVOn 2
[WllW]n 7:G cOaSa ]cccr OnncOllg Wn bVS JH7, WnclcRWnU )((,((( RSObVa
M,,-N. 7a O rSaclb, [Ong RrcUa cOcaWnU cnSfpScbSR aSdSrS 7:Ga OrS
SdSnbcOllg eWbVRrOen Tr][ bVS [OrkSb.
IVS W[pOcb OnR c]ab PcrRSn ]T pVOr[OcScbWcOl [OrkSb eWbVRrOeOla
OrS Sn]r[]ca. ET bVS -,0 nSe RrcUa Oppr]dSR PSbeSSn )1/- OnR )111
Wn bVS JH7, -. ()(.2%) rScSWdSR O nSe P]fSR%eOrnWnU ]r eSrS
SdSnbcOllg eWbVRrOen Tr][ bVS [OrkSb M.,/N. IeSnbg (3.0%) ]T bVS -20
nSe RrcUa Oppr]dSR PSbeSSn )11( OnR 2((1 Wn 9OnORO eSrS
eWbVRrOen T]r aOTSbg rSOa]na, OnR bVS pSrcSnbOUS ]T RrcU rS[]dOla
Tr][ bVS [OrkSb RWR n]b cVOnUS aWUnWTWcOnblg ]dSr bVOb pSrW]R,
WnRWcObWnU bVOb bVSrS eOa Ola] n] cVOnUS Wn bVS cOpOPWlWbg ]T bVS RrcU
48
rSdWSe agabS[ M0N. :SapWbS acPabOnbWOl prS[OrkSb STT]rba, WnclcRWnU dSrg
l]nU OnR c]ablg clWnWcOl brWOla, p]ab%[OrkSb RrcU eWbVRrOeOla OrS
USnSrOllg n]b prSdSnbOPlS Pg bVS ccrrSnblg OdOWlOPlS [SOna M31,,(N.
=Sn]bgpWc RWdSraWbg Wn bVS p]pclObW]n Wa lWkSlg b] cnRSrlWS pSra]n%
b]%pSra]n dOrWOPWlWbg Wn RrcU rSap]naSa. FVOr[Oc]USn][Wca pr]dWRSa
bVS WnT]r[ObW]n OP]cb bVS STTScb ]T USnSbWc dOrWObW]na ]n WnRWdWRcOl RrcU
rSap]naSa M,)N, eVWcV Wa pcb ]n bVS lOPSla ]T OP]cb )-( RrcUa Oppr]dSR
Pg bVS JnWbSR HbObSa <]]R OnR :rcU 7R[WnWabrObW]n (JH <:7) M,2N.
IVS Occc[clObW]n ]T USnSbWc RObO rSlObSR b] RrcU rSap]naS Wa O
aWUnWTWcOnb abSp b]eOrRa rSOlWhObW]n ]T bVS pSra]nOlWhSR [SRWcWnS
c]ncSpb. F]pclObW]n%POaSR USn][S%eWRS ]PaSrdObW]nOl rSaSOrcV accV
Oa =Sn][S%LWRS 7aa]cWObW]n HbcRWSa (=L7H) Wa ]nS ]T bVS []ab
p]eSrTcl b]]la T]r WndSabWUObWnU bVS rSlObW]naVWp PSbeSSn USn]bgpWc
dOrWOPWlWbg OnR RrcU rSap]naSa. >]eSdSr, bVS ccrrSnb p]pclObW]n%POaSR
Oppr]OcV Wn On OTTScbSR%dSraca%n]nOTTScbSR cOaS%c]nbr]l aSbbWnU Wa
WnVSrSnblg lW[WbSR PScOcaS bVS nc[PSra ]T USn]bgpSa, RrcUa, OnR bVSWr
Oaa]cWObW]na OrS b]] VWUV b] PS rSlWOPlg bSabSR Wn O T]rSaSSOPlS TcbcrS.
IVSrST]rS, []ab RrcUa OrS n]b SfO[WnSR Pg =L7H.
49
=Sn][S aSqcSncWnU bScVn]l]Ug VOa rSdSOlSR VcnRrSRa ]T USnSbWc
dOrWOnba bVOb OrS prSRWcbSR b] cOcaS l]aa ]T TcncbW]n (B]<) Wn pr]bSWn%
c]RWnU USnSa M,3N. IVS USnSa rSlObSR b] RrcU FA/F: VOdS [Ong B]<
dOrWOnba, eVWcV SfVWPWb aWUnWTWcOnb pSra]n%b]%pSra]n dOrWOPWlWbg Wn
RWabrWPcbW]n M,,N. IVS cnSfpScbSRlg lOrUS nc[PSr ]T RSlSbSrW]ca USnSbWc
dOrWOnba T]cnR Wn OppOrSnblg VSOlbVg acPjScba OnR bVSWr cnSdSn
RWabrWPcbW]n Ocr]aa WnRWdWRcOl USn][Sa [Og SfplOWn RScrSOaSR ]r
cncacOl acacSpbWPWlWbg b] cSrbOWn RrcUa Wn a[Oll acPp]pclObW]na. 9lWnWcOl
brWOla OrS USnSrOllg c]nRccbSR Wn Ur]cpa V][]USnS]ca Wn OUS, USnRSr,
OnR/]r SbVnWcWbg, OnR bVS rSaclba OrS bVSn SfbrOp]lObSR b] bVS USnSrOl
p]pclObW]n M,-N. >]eSdSr, bVSg [Og n]b PS OpplWcOPlS b] cSrbOWn a[Oll
acPp]pclObW]na, eVWcV [Og RS[]nabrObS cnSfpScbSR 7:Ga n]b
RSbScbSR RcrWnU pVOaS%III clWnWcOl brWOla, lSORWnU b] RrcU eWbVRrOeOl
Tr][ bVS pVOr[OcScbWcOl [OrkSb.
IVS )((( =Sn][Sa Fr]jScb pr]dWRSa cnPWOaSR RObO ]n USnSbWc
dOrWObW]n Wn 2,-(, pSra]nOl USn][Sa Tr][ rSprSaSnbObWdS p]pclObW]na
Snc][pOaaWnU 2. SbVnWc Ur]cpa M,.N. LS Vgp]bVSaWhSR bVOb bVS pSra]n%
b]%pSra]n dOrWOPWlWbg Wn bVS RWabrWPcbW]n ]T B]< dOrWOnba ]T FA/F: USnSa
50
Wn RWTTSrSnb SbVnWc Ur]cpa [Og rSdSOl acPp]pclObW]na prSRWap]aSR b]
aSdSrS 7:Ga, eVWcV [Og acPaSqcSnblg rSaclb Wn RrcU rS[]dOl Tr][ bVS
[OrkSb.
IVS TWnRWnUa ]T bVS prSaSnb abcRg acUUSab bVOb bVS pSra]n%b]%pSra]n
USnSbWc dOrWOPWlWbg Wa O abr]nU WnRSpSnRSnb prSRWcb]r ]T RrcU
eWbVRrOeOla T]r aOTSbg rSOa]na. In bVWa abcRg, eS pr]p]aS O [SbV]R b]
WRSnbWTg WnRWdWRcOla (]r acPp]pclObW]na) eWbV WncrSOaSR dclnSrOPWlWbg b]
aWRS STTScba ]T O apScWTWc RrcU OnR acUUSab n]dSl [SOacrSa b] SnacrS RrcU
aOTSbg POaSR ]n pSra]nOl USn][S aSqcSncS OnOlgaWa, eVWcV cOn W[pr]dS
RrcU RSdSl]p[Snb, caS, OnR rSUclObW]na.
6-TE:4-5 -7/ 6ET3O/S
/ORF SDlDctHML 1lMS
IVS :rcU8Onk RObOPOaS Wa O PW]WnT]r[ObWca rSa]crcS bVOb pr]dWRSa
RSbOWlSR RrcU WnT]r[ObW]n, WnclcRWnU cVS[WcOl abrccbcrS OnR
pVOr[Oc]l]UWcOl [ScVOnWa[, b]USbVSr eWbV RrcU bOrUSba, [SbOP]lWc
Snhg[Sa, cOrrWSra, OnR brOnap]rbSra M,/N. 7[]nU bVS /,/13 RrcUa Wn bVS
:rcU8Onk, -,(11 OnR ),(,) SnbWbWSa VOdS Ob lSOab ]nS ]r TWdS WRSnbWTWSR
51
FA/F: USnSa, rSapScbWdSlg (OccSaaSR HSpbS[PSr ,, 2()- Ob
Vbbp2//eee.RrcUPOnk.cO/). In bVS prSaSnb SdOlcObW]n abcRg, eS
OnOlghSR bVS ),(,) RrcUa eWbV TWdS ]r []rS FA/F: USnSa OnR 2,0(/
FA/F: USnSa kn]en b] PS Wnd]ldSR Wn RrcU rSap]naSa dWO )2,00/ RrcU%
USnS WnbSrOcbW]na (<WUcrS 2%)).
1HFROD 2-1. 1lMS CHaFOam ME CORF HLclRPHML NOMcDPP
6RltH-EtGLHc 2DLMmD /ata
LS R]enl]ORSR 2,-(, pcPlWclg OdOWlOPlS pSra]nOl USn][Sa Tr][ bVS
)((( =Sn][Sa Fr]jScb, eVWcV pr]dWRSa USn][Wc WnT]r[ObW]n ]n 2.
SbVnWc acPUr]cpa Tr][ ;cr]pS, ;Oab 7aWO, H]cbV 7aWO, 7TrWcO, OnR bVS
DrugBank (n = 7,793)
Excluding drugs without drug-gene relationship (n = 2,695)
1,041 Drugs
Excluding drugs with less than five known PK/PD genes (n =
4,058)
5,099 Drugs
52
7[SrWcOa M,0N (OccSaaSR HSpbS[PSr ,, 2()- Ob
Vbbp2//eee.)(((USn][Sa.]rU/).
SDlDctHML ME PODcaRtHMLaOT aLC 6aOIDt-SHtGCOaSL /ORFP
IVS RScWaW]n pr]cSaa ]T RrcU eWbVRrOeOla Wa VWUVlg c][plSf OnR Wa
WnTlcSncSR Pg p]lWbWcOl, c][[SrcWOl, SbVWcOl, OnR ]bVSr TOcb]ra. LS
pSrT]r[SR On Wn%RSpbV rSdWSe ]T rSa]crcSa b] crSObS O c][prSVSnaWdS
lWab ]T eWbVRrOen RrcUa2 ()) bVS 0bV, )(bV, )2bV, OnR ),bV IaacSa ]T bVS
k9]na]lWRObSR BWab ]T Fr]Rccba LV]aS 9]nac[pbW]n OnR/]r HOlS >OdS
8SSn 8OnnSR, LWbVRrOen, HSdSrSlg GSabrWcbSR, ]r D]b 7ppr]dSR Pg
=]dSrn[Snba2 FVOr[OcScbWcOlal pcPlWaVSR Pg bVS JnWbSR DObW]na (JD
9]na]lWRObSR BWaba) aWncS 2((3, M)2, 2,%2.N eVWcV OrS bVS []ab
c][prSVSnaWdS lWaba ]T eWbVRrOen OnR aSdSrSlg rSabrWcbSR RrcUa
pr]RccSR Pg Ob lSOab ]nS ]T 1, U]dSrn[Snba, (2) RScWaW]na b] eWbVRrOe
On OpplWcObW]n [ORS b] bVS ;C7 M,1N T]r O Vc[On [SRWcWnS Pg bVS
rSdWSe ]T bVS 9][[WbbSS T]r CSRWcWnOl Fr]Rccba T]r >c[On JaS
(9>CF) OnR (3) :rcU8Onk Onn]bObW]na T]r pVOr[OcScbWcOl [OrkSb
eWbVRrOeOla M,/N.
53
1HFROD 2-2. /ORFP SHtGCOaSL aLC NODcaRtHMLaOT EOMm tGD maOIDt
<]r bVS pcrp]aS ]T bVS prSaSnb abcRg, O RrcU eOa RSTWnSR Oa
eWbVRrOen WT Wb VOR PSSn rS[]dSR, POnnSR, ]r RWaOppr]dSR Pg Ob lSOab
]nS c]cnbrg T]r Ong rSOa]n. LS [OncOllg aSlScbSR 3-( RrcUa
eWbVRrOen Pg Ob lSOab ]nS c]cnbrg Occ]rRWnU b] bVS JD 9]na]lWRObSR
BWaba M)2, 2,%2.N, )/, RrcUa eWbVRrOen Tr][ JOncOrg 2((. b]
HSpbS[PSr 2()- Occ]rRWnU b] bVS ;C7 M,1N, OnR )0) eWbVRrOen RrcUa
Onn]bObSR Pg :rcU8Onk, M,/N rSapScbWdSlg. In ORRWbW]n, eS Ola] aSlScbSR
277
51
0 115
67
113
UN withdrawn drugs (n=350)
DrugBank withdrawn
drugs (n=181)
EMA withdrawn
drugs (n=121)
n=578
25 112123FDA PGx drugs
(n=148)
Beers criteria drugs
(n=137)
n=260
Withdrawn Drugs Precautionary Drugs
34544 226Precautionary drugs (n=260)
Withdrawn drugs (n=578)
n=804
54
prScOcbW]nOrg RrcUa Pg OpplgWnU bVS 8SSra crWbSrWO (n 5 )3/) M-(N OnR
JH <:7 pVOr[Oc]USn][Wc PW][OrkSr WnT]r[ObW]n Wn RrcU lOPSla (n 5
),0) M,2N (<WUcrS 2%2). IVS 8SSra crWbSrWO T]r F]bSnbWOllg InOppr]prWObS
CSRWcObW]n JaS Wn ElRSr 7Rclba VOdS PSSn WaacSR Wn 2((3 Pg bVS
7[SrWcOn =SrWObrWc H]cWSbg OnR OrS eWRSlg caSR Wn clWnWcOl cOrS b]
prSdSnb 7:Ga Wn bVS SlRSrlg p]pclObW]n.
IOPlS )%) aV]ea bVOb bVS RWabrWPcbW]n ]T eWbVRrOen ]r
prScOcbW]nOrg RrcUa Occ]rRWnU b] bVS TWlbSrWnU pr]cSaa ]T nc[PSr ]T
FA/F: USnSa rSlObSR b] RrcUa. <WUcrS 2%3 aV]ea bVOb O[]nU bVS ),(,)
aSlScbSR RrcUa eWbV Ob lSOab TWdS FA/F: USnSa, 201 eSrS clOaaWTWSR Oa
eWbVRrOen ]r prScOcbW]nOrg. 7[]nU bVS )-, eWbVRrOen RrcUa, ). OnR
)0 eSrS Ola] rSRcnROnblg clOaaWTWSR Oa prScOcbW]nOrg Occ]rRWnU b] bVS
8SSra crWbSrWO (n 5 1() OnR JH <:7 pVOr[Oc]USn][Wc PW][OrkSr
WnT]r[ObW]n (n 5 1.) (<WUcrS 2%3).
55
TaAlD 2-1. 7RmADO ME SHtGCOaSL aLC NODcaRtHMLaOT CORFP accMOCHLF
tM tGD EHltDOHLF AT tGD LRmADO ME FDLDP ODlatDC tM CORFP.
1HFROD 2-3. /ORF PDlDctHML ElMS aLC tGD CHPtOHARtHML ME SHtGCOaSL,
NODcaRtHMLaOT, aLC MtGDO CORFP
124
144
12
576117
Withdrawn (n=154)
Beers criteria(n=90)
Drugs labelled with FDA-approved
pharmacogenomic information (n=96)
Excluding drugs with poor PK/PD (n<5) information
DrugBank (n = 7,793)
Drugs with at least five known PK/PD genes
(n=1,041)
Other drugs(n = 752)
Withdrawn or Precautionary drugs(n = 289)
(The%1,041%study%drugs%have%2,807%PK/PD%genes%%connected%by%12,887%drug–gene%interac@ons.)
752
289
515Total Withdrawn or
Precautionary drugs, n=804
56
In b]bOl, ),(,) RrcUa Tr][ bVS :rcU8Onk eWbV Ob lSOab TWdS WRSnbWTWSR
USnSa Wnd]ldSR Wn RrcU pVOr[Oc]kWnSbWca (FA) OnR pVOr[Oc]RgnO[Wca
(F:) eSrS WnclcRSR Wn bVS abcRg. 7 c][prSVSnaWdS lWab ]T eWbVRrOen
RrcUa (n 5 )-,) eOa ]PbOWnSR Pg rSdWSeWnU bVrSS rSa]crcSa2 ()) bVS 0bV,
)(bV, )2bV, OnR ),bV IaacSa ]T bVS k9]na]lWRObSR BWab ]T Fr]Rccba LV]aS
9]nac[pbW]n OnR/]r HOlS >OdS 8SSn 8OnnSR, LWbVRrOen, HSdSrSlg
GSabrWcbSR, ]r D]b 7ppr]dSR Pg =]dSrn[Snba2 FVOr[OcScbWcOlal
pcPlWaVSR Pg bVS JnWbSR DObW]na3 (2) OpplWcObW]na T]r eWbVRrOeOl Tr][
;C73 OnR (3) bVS :rcU8Onk Onn]bObW]na T]r eWbVRrOeOla.
FrScOcbW]nOrg RrcUa (n 5 ).-) eSrS WRSnbWTWSR POaSR ]n bVS 8SSra
crWbSrWO OnR JH <:7 bOPlS ]T pVOr[Oc]USn][Wca PW][OrkSra. IVS
rS[OWnWnU /-2 RrcUa eSrS clOaaWTWSR Oa ]bVSr RrcUa.
/DlDtDOHMRPLDPP ScMODP EMO 2DLDP, VaOHaLtP, /ORFP, aLC
PMNRlatHMLP
7n WnRWdWRcOlla rSap]naS b] O RrcU Wa OTTScbSR Pg bVS USnSa Snc]RWnU
RrcU bOrUSba, rSlObSR [SbOP]lWc Snhg[Sa OnR RrcU brOnap]rbSra. Ib VOa
PSSn RS[]nabrObSR bVOb bVS W[pOcb ]T n]nagn]ng[]ca acPabWbcbW]na ]n
57
pr]bSWn abrccbcrS OnR TcncbW]n cOn PS rSlWOPlg prSRWcbSR Pg OpplgWnU
abrOWUVbT]reOrR S[pWrWcOl rclSa caWnU apScWTWc OlU]rWbV[a accV Oa HI<I
M-)N, F]lgFVSn%2 M-2N, CcbObW]n7aaSaa]r M-3N, 97:: M-,N, OnR
9]nRSl M--N.
LS caSR bVS HI<I OlU]rWbV[ M-)N b] c][pcbS bVS dOrWOnb
RSlSbSrW]canSaa ac]rS (K) T]r Oll n]nagn]ng[]ca c]RWnU dOrWOnba T]cnR
Wn bVS 2,0(/ FA/F: USnSa ]T bVS 2,(-, pSra]nOl USn][Sa aSlScbSR Tr][
bVS )((( =Sn][Sa Fr]jScb.
IVS USnS RSlSbSrW]canSaa ac]rS (=) eOa RSTWnSR Oa bVS US][SbrWc
[SOn ]T bVS K ac]rSa T]r Oll n]nagn]ng[]ca c]RWnU dOrWOnba ]T bVS
USnS (<WUcrS 2%,). HW[WlOrlg, bVS RrcU RSlSbSrW]canSaa ac]rS (:) eOa
RSTWnSR Oa bVS US][SbrWc [SOn ]T bVS = ac]rSa T]r Oll RrcU%rSlObSR
FA/F: USnSa (<WUcrS 2%,). IVS US][SbrWc [SOn eOa caSR b] WRSnbWTg
bVS cSnbrOl bSnRSncg Wn bVS cVOnUS ]T bVS OnOlghSR pOrO[SbSra. IVS K,
=, OnR : RSlSbSrW]canSaa ac]rSa rOnUS Tr][ ( b] )3 l]e K OnR = ac]rSa
WnRWcObS aSdSrSlg OlbSrSR abrccbcrS OnR/]r TcncbW]n ]T bVS c]rrSap]nRWnU
USnS, eVWlS l]e : dOlcS WnRWcObSa WncrSOaSR prSRWap]aWbW]n b] 7:Ga.
58
1HFROD 2-4. /DlDtDOHMRPLDPP ScMODP EMO 2DLDP, VaOHaLtP, /ORFP, aLC
PMNRlatHMLP
IVS dOrWOnb ac]rS, K Wa bVS HI<I ac]rS. IVS USnS RSlSbSrW]canSaa ac]rS,
= eOa cOlcclObSR Pg US][SbrWc [SOn ]T bVS K ac]rSa ]T bVS USnS OnR bVS
RrcU%eWaS RSlSbSrW]canSaa ac]rS, : eOa RSTWnSR Oa bVS US][SbrWc [SOn
]T bVS = ac]rSa T]r Oll RrcU%rSlObSR FA/F: USnSa. IVS RrcU%USnS
rSlObW]naVWpa c][S Tr][ :rcU8Onk RObOPOaS. IVS p]pclObW]n
RSlSbSrW]canSaa ac]rS, F ]r bVS OrSO cnRSr bVS ccrdS (7J9) T]r bVS
RWabrWPcbW]n ]T bVS : ac]rS T]r O RrcU k Wn O p]pclObW]n cOn PS
c][pcbSR Pg OdSrOUWnU pSra]nOlWhSR : ac]rSa ]T bVS eV]lS p]pclObW]n.
v1 v2
Ga=(V1%x%V2%x%V3)1/3
Dk=(Ga%x%Gb%x%Gc)1/3
v3 v4 v5 v6 v7 v8 v9 v10 v11 v12 v13
Genea Geneb Genec Gened
S4
S3
S2
S1
……
……
……
……
……
Gb=(V4%%x%V6)1/2 Gc=(V7%x%V8%x%V9%x%V10)1/4 Gd%=(V11%x%V13)1/2
Dj=(Gb%x%Gd%x%…)1/|G|
…… Gene$–wise$$Deleteriousness$$Score,$G
Drug$–wise$Deleteriousness$Score,$D
……
P:$Popula7on–wise$Deleteriousness$Score,$P$(=*AUC*of*D*distribu7on*in*a*popula7on*
=*average*of*Ds*in*a*popula7on)*
……
S1
S1
……
SN
Dk Dj S2
Popula7on
S3 SN
Dk%for%S1 Dj%for%S1 !! = !"#! =
1! !!
!
!!! !! = !"#! =
1! !!
!
!!!
59
<WUcrS 2%, (l]e pOnSla) aV]ea bVS RWabrWPcbW]na ]T bVS : ac]rSa T]r
SOcV RrcU (W.S., :k, :j, Sbc.) O[]nU bVS 2,(-, pSra]nOl USn][Sa. IVS
p]pclObW]n RSlSbSrW]canSaa ac]rS (F) ]r bVS OrSO cnRSr bVS ccrdS (7J9)
T]r bVS RWabrWPcbW]n ]T bVS : ac]rS T]r O RrcU k Wn O p]pclObW]n cOn PS
c][pcbSR Pg OdSrOUWnU pSra]nOlWhSR : ac]rSa ]T bVS eV]lS p]pclObW]n
(<WUcrS 2%,)2
!!"
#$$%
&== '
=
N
pkkk DN
AUCP1
1
LS c][pOrSR bVrSS bgpSa ]T [SOna, OrWbV[SbWc, US][SbrWc, OnR
VOr[]nWc [SOn. LWbV Oll bVrSaV]lR c][pOrWa]n, Tr][ b]bOl -(11 RrcUa
b] )(,) RrcUa VOdWnU rSlObSR USnSa []rS bVOn TWdS, eS T]cnR ]cb bVOb WT
bVS nc[PSr ]T USnSa rSlObSR b] RrcUa WncrSOaWnU, bVS bVrSS bgpSa ]T
[SOna aV]e aW[WlOr cSnbrOl bSnRSncg. (<WUcrS 2%-)
60
1HFROD 2-5. .MmNaOHPML ME tGODD tTNDP ME mDaLP
StatHPtHcal -LalTPHP
7DEK7 OnR p]ab%V]c IckSg OnOlgaWa eSrS caSR b] c][pOrS bVS
7J9a O[]nU bVS T]cr RrcU cObSU]rWSa2 eWbVRrOen, prScOcbW]nOrg Pg
8SSra crWbSrWO, prScOcbW]nOrg Pg <:7 pVOr[Oc]USn][Wca lOPSlWnU, OnR
]bVSr RrcUa. I] c]nbr]l bVS STTScb ]T nc[PSr ]T USnSa rSlObSR b] SOcV
RrcU, 7D9EK7 OnOlgaWa eOa Ola] OpplWSR b] c][pOrS bVS 7J9a O[]nU
, cObSU]rWSa. GSlObWdS TrSqcSncWSa ]T RrcU eWbVRrOeOla OnR prScOcbW]na
eSrS c][pcbSR Ocr]aa 7J9 ac]rS PWna T]r TcrbVSr OnOlgaWa. IVS
61
9]cVrOnS%7r[WbOUS IrSnR bSab eOa pSrT]r[SR Ocr]aa 7J9 ac]rS PWna
b] SabW[ObS bVS STTScb ]T bVS 7J9 ac]rSa ]n bVS TrSqcSncWSa ]T RrcU
eWbVRrOeOl OnR prScOcbW]n. 7ll F dOlcSa eSrS be] aWRSR, OnR
c]naWRSrSR abObWabWcOllg aWUnWTWcOncS Ob 4 (.(-. 7ll abObWabWcOl OnOlgaSa
eSrS c]nRccbSR caWnU bVS G abObWabWcOl pOckOUS (dSr. 3.()) M32N.
:ESU5TS
/ORF WHtGCOaSalP aLC PODcaRtHMLP
LS OnOlghSR ),(,) RrcUa eWbV Ob lSOab TWdS FA/F: USnSa aSlScbSR
Tr][ bVS :rcU8Onk). (<WUcrS 2%3). EdSrOll, )-, (),.0%) ]T bVS ),(,)
OnOlghSR RrcUa eSrS SdSnbcOllg eWbVRrOen Tr][ bVS [OrkSb Pg Ob lSOab
]nS c]cnbrg. 7[]nU bVS )3/ RrcUa Wn bVS 8SSra lWab OnR ),0 RrcUa eWbV
<:7 pVOr[Oc]USn][Wc lOPSla, 1( (.-./%) OnR 1. (.,.1%), rSapScbWdSlg,
eWbV Ob lSOab TWdS FA/F: USnSa eSrS Wn bVS lWab ]T bVS ),(,) abcRg RrcUa,
OnR 3( ()0.2%) ]T bVSaS prScOcbW]nOrg RrcUa eSrS Ola] eWbVRrOen Tr][
bVS [OrkSb Pg Ob lSOab ]nS c]cnbrg (<WUcrS 2%3).
62
TGD P ScMOD aLC /ORF WHtGCOaSalP/PODcaRtHMLP
1HFROD 2-6. .MmNaOHPML ME NMNRlatHML CDlDtDOHMRPLDPP PcMODP ADtSDDL
SHtGCOaSL, NODcaRtHMLaOT, aLC MtGDO CORFP
<WUcrS 2%. RS[]nabrObSa bVOb bVS eWbVRrOen RrcUa (7J9 5 (.--0 i
(.)/() Oa eSll Oa prScOcbW]nOrg RrcUa Wn bVS 8SSra lWab (7J9 5 (.-,1 i
(.)-3) OnR eWbV <:7 pVOr[Oc]USn][Wc lOPSla (7J9 5 (.-,2 i (.),-)
SfVWPWbSR aWUnWTWcOnblg l]eSr 7J9a c][pOrSR b] ]bVSr RrcUa (7J9 5
(..3- i (.)0/) Oa WnRWcObSR Pg 7DEK7 eWbV p]ab%V]c IckSg OnOlgaWa
(F 4 (.(()).
Popu
latio
n−wi
se d
elet
erio
usne
ss s
core
(AUC
)
Withdrawn Beers criteria FDA PGx Other
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
P <0.001P <0.001
P <0.001
63
IVS RrcUa eWbVRrOen Tr][ bVS [OrkSb (7J9 5 (.--0 i (.)/() OnR
prScOcbW]nOrg RrcUa Occ]rRWnU b] bVS 8SSra crWbSrWO (7J9 5 (.-,1 i
(.)-3) OnR <:7 pVO[Oc]USn][Wc WnT]r[ObW]n (7J9 5 (.-,2 i (.),-)
SfVWPWbSR aWUnWTWcOnblg l]eSr 7J9 dOlcSa bVOn ]bVSr RrcUa (7J9 5
(..3-i (.)0/3 F 4 (.((), ]nS%eOg 7DEK7 T]ll]eSR Pg p]ab%V]c
IckSg%bSaba). In c]nbrOab, bVS RWTTSrSncS O[]nU bVS bVrSS
eWbVRrOen/prScOcbW]nOrg RrcU Ur]cpa RWR n]b rSOcV abObWabWcOl
aWUnWTWcOncS (F 6 (.(-). 7J9, OrSO cnRSr bVS RrcU RSlSbSrW]canSaa ac]rS
ccrdS3 <:7 F=f, <:7%Oppr]dSR RrcUa eWbV pVOr[Oc]USn][Wc
WnT]r[ObW]n ]n RrcU lOPSla. <WUcrS 2%/ aV]eSR bVS nc[PSr ]T USnSa
Occ]rRWnU b] bVS bVrSS cObSU]rWSa ]T RrcUa.
64
1HFROD 2-7. .MmNaOHPML ME tGD LRmADO ME FDLDP ODlatDC tM CORFP
accMOCHLF tM tGD tGODD catDFMOHDP, SHtGCOaSL, NODcaRtHMLaOT, aLC MtGDO
CORFP
<WUcrS 2%0 aV]ea rSlObWdS TrSqcSncg VWab]UrO[a ]T bVS eWbVRrOen
RrcUa Occ]rRWnU b] bVS JD 9]na]lWRObSR BWaba M)2, 2,j2.N, ;C7 M,1N,
OnR :rcU8Onk M,/N. 8ScOcaS SOcV c]cnbrg VOa RWTTSrSnb p]lWcg
rSUOrRWnU bVS Oppr]dOl ]T pVOr[OcScbWcOl pr]Rccba, eS OnOlghSR bVSaS
rSa]crcSa aSpOrObSlg Oa eSll Oa Wn c][PWnObW]n. IVS rSaclba WnRWcObS bVOb
l]eSr 7J9 dOlcSa aWUnWTWcOnblg c]rrSlObSR eWbV VWUVSr rSlObWdS
65
TrSqcSncWSa ]T RrcU eWbVRrOeOla Tr][ bVS [OrkSb Wn SdSrg c]nTWUcrObW]n
(F 4 (.(-, 9]cVrOnS%7r[WbOUS IrSnR bSab3 IOPlS 2%2). IVS aO[S brSnR
eOa c]naWabSnblg ]PaSrdSR T]r prScOcbW]nOrg RrcUa Pg bVS 8SSra crWbSrWO
(F 5 (.((13 <WUcrS 2%1(7)) Oa eSll Oa Pg <:7 pVOr[Oc]USn][Wca
lOPSla (F 4 (.((), 9]cVrOnS%7r[WbOUS IrSnR bSab3 <WUcrS 2%1(8) OnR
IOPlS 2%)).
66
T-.le 2-2. Cochr-n-Armit-ge test 2or trend 2or drug withdr-w-ls -nd prec-utions.
AUC score .ins S0.1 S0.2 S0.3 S0.4 S0.5 S0.6 S0.7 S0., S0.- S1.0 :um. 9 T
No. o2 Withdr-wn Drugs
;oNal 1 4 7 13 30 34 3- 16 6 4 154 .010 <8 or 571 1 3 7 11 26 31 34 15 4 2 134 .00- <8 or 4ruC2anF 1 3 5 5 25 26 2, 12 5 3 113 .033 571 or 4ruC2anF. 1 4 3 11 16 14 26 , 5 3 -1 .007 <8 1 2 5 3 21 23 23 11 3 1 -3 .016 571 0 1 2 , 6 , 12 4 1 1 43 .066 4ruC2anF 1 3 1 3 10 6 14 4 4 2 4, .02,
No. o2 Prec-ution-ry
Drugs
2AArM crENArEa 0 1 6 7 16 25 25 6 3 1 -0 .00- 641
pDarmacoCAnomEcM
0 0 6 11 17 32 1- 7 3 1 -6 0.00
1
No. o2 Tot-l Study Drugs 5 14 34 6, 144 217 234 167 ,, 70 70
T9-PaluAM by 3ocDran-1rmENaCA NAMN Bor NrAnd. 1bbrAPEaNEonM. 1<3, 1rAa undAr NDA druC-wEMA dAlANArEouMnAMM-McorA
67
curPA; <8, NDA <nENAd 8aNEonM; 571, NDA 5uropAan 7AdEcEnAM 1CAncy; 641, NDA <nENAd :NaNAM 6ood and 4ruC
1dmEnEMNraNEon
68
EMA only withdrawn drugs, n=41UN only withdrawn drugs, n=63DrugBank only withdrawn drugs, n=20Withdrawn drugs at least two databases, n=30
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
dru
g w
ithdr
awal
05
1015
2025
30
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
EMA only withdrawn drugs, n=48UN only withdrawn drugs, n=43UN and EMA withdrawn drugs, n=2
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
dru
g w
ithdr
awal
05
1015
20
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
UN only withdrawn drugs, n=65DrugBank only withdrawn drugs, n=20UN and DrugBank withdrawn drugs, n=28
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
dru
g w
ithdr
awal
05
1015
20
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
EMA only withdrawn drugs, n=43DrugBank only withdrawn drugs, n=48
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
dru
g w
ithdr
awal
05
1015
2025
30
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
UN withdrawn drugs, n=93
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
dru
g w
ithdr
awal
05
1015
20
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
EMA withdrawn drugs, n=43
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
dru
g w
ithdr
awal
02
46
810
12
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
DrugBank withdrawn drugs, n=48
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
dru
g w
ithdr
awal
05
1015
20
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
A B C D
E F G
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Samples
Da
0 500 1000 1500 2000 2500
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
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Samples
Db
0 500 1000 1500 2000 2500
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
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Samples
Dc
0 500 1000 1500 2000 2500
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
69
FiguGe 2-8. FGeFueC9y :isIGi8uIiDC Df :Gug LiIh:GaLals a99DG:iCg ID
EDEulaIiDC :eleIeGiDusCess s9DGes
L[bWj_l[ fh[gk[dYo ef Zhk] m_jhZhWmWbi mWi ebjW_d[Z feh [WYh ef jh[
-, ;O= iYeh[ b_di ef [gkWb i_p[i* (;% ;bb jhh[[ h[iekhY[i7 (<wD% fW_h[Z
h[iekhY[i7 (?wA% _dZ_l_ZkWb h[iekhY[i6 OH (?%( ?G; (F%( WdZ
Dhk]<Wda (A%* Dhk]i m_jh bem[h ;O= lWbk[i m[h[ ceh[ fh[gk[djbo
m_jhZhWmd fhec jh[ cWha[j (i[[ NWbb[ -%* Nh[ jhh[[ _Yedi _d ; (bem[h
fWd[b% ihem Zhk] Z[b[j[h_ekid[ii iYeh[ Ykhl[i jof_YWb feh jh[
Yehh[ifedZ_d] ;O= iYeh[ b_di* Nh[ ihWZ[Z Wh[W h[fh[i[dj_d] -);O=
ihemi jh[ Z_ijWdY[ ef jh[ Zhk] fhec W y][d[j_YWbbo _Z[Wbz fhWhcWY[kj_YWb
_d j[hci ef ][dec[ i[gk[dY[ lWh_Wj_ed* ;O=( Wh[W kdZ[h jh[ Zhk]
Z[b[j[h_ekid[ii iYeh[ Ykhl[7 ?G;( ?khef[Wd G[Z_Y_d[i ;][dYo7 OH(
Od_j[Z HWj_edi*
Beers criteria drugs, n=90
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
pre
caut
iona
ry d
rugs
05
1015
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
FDA pharmacogenomic drugs, n=96
Population−wise deleteriousness score (AUC)
Rel
ative
freq
uenc
y of
pre
caut
iona
ry d
rugs
05
1015
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
A B
70
FiguGe 2-9. DisIGi8uIiDC Df GelaIive fGeFueC9y Df :Gug EGe9auIiDCs
a99DG:iCg ID EDEulaIiDC :eleIeGiDusCess s9DGes
L[bWj_l[ fh[gk[dY_[i ef Zhk] fh[YWkj_edi WYYehZ_d] je (;% OM FD;
fhWhcWYe][dec_Yi bWb[bi WdZ (<% jh[ <[[hi Yh_j[h_W m[h[ i_]d_f_YWdjbo
h_]h[h _d bem[h jhWd _d h_]h[h ;O= iYeh[ b_di (J 8 ,*,-( =eYhhWd)
;hc_jW][ Nh[dZ j[ij7 i[[ NWbb[ -%* ;O=( Wh[W kdZ[h jh[ Zhk]
Z[b[j[h_ekid[ii iYeh[ Ykhl[*
-eCDmi9 VaGia8iliIy aC: DGug SafeIy
Nh[ fh[i[dj ijkZo Z[cedijhWj[Z kd[nf[Yj[Zbo h_]h f[hied)je)
f[hied lWh_Wb_b_jo ef Z[b[j[h_eki lWh_Wdji Wced] Zhk])h[bWj[Z ][d[i* ;
Zhk] c_]hj Wi m[bb b[ y][d[j_YWbbo _Z[Wbz _f jh[ Zhk])h[bWj[Z ][d[i hWl[
de Z[b[j[h_eki lWh_Wdji WYheii jh[ [dj_h[ hkcWd fefkbWj_ed( mh_Yh _i
hWjh[h hWh[* <Wi[Z ed jh[ WdWboi_i ef Zhk])h[bWj[Z ][d[ lWh_Wb_b_jo _d jh[
fefkbWj_ed( m[ h[h[ fhefei[ jme ][dec_Y fWhWc[j[hi je Wii[ii Zhk]
iWf[jo( ;O= WdZ Pj( mh_Yh cWo fWY_b_jWj[ Zhk] Z[l[befc[dj( ki[( WdZ
h[]kbWj_ed( WdZ [l[djkWbbo fh[l[dj Zhk] m_jhZhWmWb*
71
F_]kh[ .)-, Z[cedijhWj[i jh[ Z_ijh_bkj_ed Ykhl[ ef jh[ D iYeh[i
Wced] .(1,0 _dZ_l_ZkWbi feh jhh[[ Zhk]i( Z_iefohWc_Z[( fheYW_dWc_Z[(
WdZ gk_d_Z_d[ b[bed]_d] je ;dj_Whhojhc_Yi( YbWii CW (=,-<;% WYYehZ_d]
je jh[ ;dWjec_YWb Nh[hWf[kj_Y =h[c_YWb (;N=% YbWii_f_YWj_ed ioij[c*
Nh[ ;O= feh Z_iefohWc_Z[ (t+u+v% _i bWh][h jhWd jhei[ feh
fheYW_dWc_Z[ (u+v% WdZ gk_d_Z_d[ (v% bkj icWbb[h jhWd jhWj ef W
y][d[j_YWbbo _Z[Wbz Zhk] (s+t+u+v%( mh_Yh cWo b[ [gkWb je -*,*
Nhki( s (eh -);O= ef gk_d_Z_d[% h[fh[i[dji jh[ Z_ijWdY[ ef
Z_iefohWc_Z[ fhec W y][d[j_YWbbo _Z[Wbz Zhk] _d j[hci ef ][dec[
i[gk[dY[ lWh_Wj_ed WdZ _i icWbb[h jhWd jhWj ef fheYW_dWc_Z[ (-)Tu+vU%
WdZ gk_d_Z_d[ (-)v% (F_]kh[ .)-,%( _dZ_YWj_d] jhWj Wced] jh[ .(1,0
_dZ_l_ZkWbi _d jh[ -,,, A[dec[i Jhej[Yj( jh[ ][d[i h[bWj[Z je JE+JD ef
Z_iefohWc_Z[ hWl[ b[ii Z[b[j[h_eki lWh_Wdji jhWd jhei[ ef fheYW_dWc_Z[
WdZ gk_d_Z_d[*
F_]kh[ .)-, Z[cedijhWj[i jhWj Wced] jh[ .(1,0 _dZ_l_ZkWbi( /1
(-*0"%( /,. (-.*-"%( WdZ -(3// (25*."% hWl[ _dYh[Wi[Z h_iai feh ;DLi
YWki[Z bo Z_iefohWc_Z[( fheYW_dWc_Z[( WdZ( gk_d_Z_d[ h[if[Yj_l[bo( _f
,*/ _i jh[ h_ia jhh[ihebZ feh jh[ D iYeh[ (P,*/%* Pj _i Z[f_d[Z Wi jh[
72
fhefehj_ed ef f[efb[ ][d[j_YWbbo lkbd[hWbb[ feh ;DLi ef W Y[hjW_d Zhk](
mhe hWl[ D iYeh[i bem[h jhWd jh[ h_ia jhh[ihebZ( j* Nh[ Z_ijh_bkj_edi ef
P,*/ WdZ P,*3 feh jh[ jhh[[ Zhk]i Wh[ ihemd _d F_]kh[ .)-,*
FiguGe 2-10. 2GDEDse: measuGes Df :Gug safeIy ID EGeveCI EGe9auIiDCs
aC: :Gug LiIh:GaLals fGDm Ihe maGkeI
(;% Dhk] Z[b[j[h_ekid[ii iYeh[i feh jhh[[ Zhk]i( Z_iefohWc_Z[
(]h[[d%( fheYW_dWc_Z[ (bbk[%( WdZ gk_d_Z_d[ (h[Z% m_jh jh[ iWc[ ;N=
YeZ[ (=,-<; feh ;dj_Whhojhc_Yi YbWii CW% m[h[ Yecfkj[Z feh .(,10
][dec[i ef jh[ -,,, A[dec[i Jhej[Yj WdZ iehj[Z _d jh[ WiY[dZ_d]
V0.3 = 35 (1.4%)
V0.7 = 564 (22.5%) V0.3 = 302 (12.1%)
V0.7 = 2283 (91.2%)
V0.3 = 1733 (69.2%) V0.7 = 2498 (99.8%)
A
C
α
β
γ
δ
B
Disopyramide, Procainamide, Quinidine,
DisopyramideProcainamideQuinidine
α
β
γ
δ
73
ehZ[h* (<% Nh[ ;O= WdZ -);O= lWbk[i h[fh[i[dj fefkbWj_ed
Z[b[j[h_ekid[ii WdZ ][dec_Y lWh_Wb_b_jo ef Zhk])h[bWj[Z ][d[i(
h[if[Yj_l[bo* (=% Qh[d jh[ h_ia jhh[ihebZ _i i[j Wj ,*/( jh[d /1 (-*0"%(
/,. (-.*-"%( WdZ -(3// (25*."% Wced] jh[ .(1,0 _dZ_l_ZkWbi YWd b[
YbWii_f_[Z Wi ][d[j_YWbbo lkbd[hWbb[ je i_Z[ [ff[Yji ef Z_iefohWc_Z[(
fheYW_dWc_Z[( WdZ( gk_d_Z_d[ h[if[Yj_l[bo (P,*/%* ;bbh[l_Wj_edi6 ;O=(
Wh[W kdZ[h jh[ Zhk] Z[b[j[h_ekid[ii iYeh[ Ykhl[7 ;N=( ;dWjec_YWb
Nh[hWf[kj_Y =h[c_YWb =bWii_f_YWj_ed Moij[c*
D.SCUSS.10
Cd jh_i ijkZo( m[ hWl[ Z[cedijhWj[Z jhWj jh[ f[hied)je)f[hied
][dec[ lWh_Wb_b_jo _i W ijhed] _dZ[f[dZ[dj fhe]deij_Y fWYjeh ef Zhk]
m_jhZhWmWb fhec jh[ fhWhcWY[kj_YWb cWha[j( mh_Yh hWi bed] b[[d
Yedi_Z[h[Z kdfh[Z_YjWbb[* Q[ fhefei[ del[b c[Wikh[i ef Zhk] iWf[jo
Wii[iic[dj bWi[Z ed f[hiedWb ][dec[ i[gk[dY[ WdWboi_i( mh_Yh mekbZ
_cfhel[ Zhk] Z[l[befc[dj( ki[( WdZ h[]kbWj_ed* Nh[ fhefei[Z c[jheZ
YWd b[ h[WZ_bo Wffb_[Z je _Z[dj_fo _dZ_l_ZkWbi m_jh _dYh[Wi[Z ][d[j_Y
74
lkbd[hWb_b_jo je WZl[hi[ i_Z[ [ff[Yji ef W if[Y_f_Y Zhk]* Jhoi_Y_Wdi YWd
ki[ jh_i c[jheZ Wi W jeeb je ikffehj Yb_d_YWb Z[Y_i_edi WdZ fh[l[dj
kd_dj[dZ[Z Zhk] h[WYj_edi* Nh[ fhefei[Z ][dec_Y c[Wikh[i YWd b[
ki[Z feh [ff_Y_[dj iYh[[d_d] ef YWdZ_ZWj[ fhWhcWY[kj_YWbi( Z[l[befc[dj
ef iWf[h Zhk]i( ][dec[)bWi[Z fhWhcWYel_]_bWdY[( WdZ h[]kbWj_ed ef
Zhk] iWf[jo*
=h_j_Yi hWl[ Wh]k[Z jhWj W Yb_d_YWb jh_Wb _dlebl_d] Wbekj .(,,,q/(,,,
fWhj_Y_fWdji YWddej h[b_Wbbo Z[j[Yj hWh[ ;DLi m_jh Wd _dY_Z[dY[ ef b[ii
jhWd - f[h -,(,,, T12U* ;bjhek]h _dYh[Wi_d] jh[ dkcb[h ef jh_Wb
fWhj_Y_fWdji _i dej _cfhWYj_YWb( _j cWo ij_bb b[ _dWZ[gkWj[ je WZZh[ii jh[
Yecfb[n_jo ef f[hiedWb ][dec[ i[gk[dY[ lWh_Wj_edi T13U* Nh[ Ykhh[dj
Wff[Yj[Z)l[hiki)kdWff[Yj[Z YWi[)Yedjheb WffheWYh ki[Z _d
fhWhcWYe][dec_Yi h[i[WhYh T14U YWddej fhel_Z[ Yecfh[h[di_l[
WdWboi_i ef ckbj_fb[ Yecfb[n WiieY_Wj_edi b[jm[[d dkc[heki ][dejof[i
WdZ Zhk]i* Cd YedjhWij( jh[ fhefei[Z Wb _d_j_e c[jheZ _i iYWbWbb[ je
_dYh[Wi_d] dkcb[hi ef ][dejof[i WdZ Zhk]i WdZ h[b_[i edbo ed
_dj[]hWj[Z fkbb_Y h[iekhY[i6 f[hiedWb ][dec[ i[gk[dY[ ZWjWbWi[i
75
Yel[h_d] Z_ff[h[dj [jhd_Y ]hekfi( Zhk] JE+JD _dfehcWj_ed( WdZ jh[
h[YehZi ef m_jhZhWmd WdZ+eh fh[YWkj_edWho Zhk]i*
Geh[ _cfehjWdjbo( fkjkh[ Yb_d_YWb jh_Wb Z[i_]d cWo b[ b[d[f_j[Z bo
_dYehfehWj_d] [jhd_Y_jo)h[bWj[Z ZWjW h[]WhZ_d] ][dec[ i[gk[dY[
lWh_Wb_b_jo( mh_Yh YWd Wff[Yj Zhk] iWf[jo* Feh [nWcfb[( mh[d W ikb)
fefkbWj_ed eh [jhd_Y ]hekf _i el[hh[fh[i[dj[Z kdZ[h jh[ h_ia jhh[ihebZ
(Pj% feh W jh_Wb Zhk]( h[Yhk_j_d] ceh[ ikbj[Yji fhec Wdejh[h ikb]hekf
][d[j_YWbbo lkbd[hWbb[ feh Zhk] i_Z[ [ff[Yji cWo b[WZ je W ceh[ hWj_edWb
jh_Wb Z[i_]d( kbj_cWj[bo _cfhel_d] Zhk] iWf[jo* Fkhjh[hceh[( je h[b_Wbbo
Z[j[Yj ;DLi b[feh[ cWha[j_d]( Zhk]i m_jh bem ;O= lWbk[i (_*[*( bWh][
][dec_Y Z_ijWdY[ fhec W y][d[j_YWbbo _Z[Wbz Zhk]% ihekbZ b[ j[ij[Z _d
bWh][h fefkbWj_ed jhWd Zhk]i m_jh h_]h ;O= lWbk[i*
=ecfkjWj_ed ef jh[ D iYeh[i YedZkYj[Z _d jh[ fh[i[dj ijkZo _i
ikbj[Yj je iec[ b_c_jWj_edi( fWhj_Wbbo Zk[ je jh[ _cf[hf[Yj ademb[Z][
Wbekj Zhk] JE+JD WdZ jh[ [ff[Yji ef dediodedoceki YeZ_d] lWh_Wdji
ed fhej[_d ijhkYjkh[ WdZ fkdYj_ed T1-)11U* ;dejh[h b_c_jWj_ed _i
_dikff_Y_[dj fkbb_Y h[iekhY[i fhel_Z_d] jh[ _dfehcWj_ed ed f[hiedWb
][dec[ i[gk[dY[i ef Z_ff[h[dj [jhd_Y ]hekfi WdZ ijWdZWhZ_p[Z h[fehji
76
ef m_jhZhWmd WdZ fh[YWkj_edWho Zhk]i* Fkhjh[h [nfWdi_ed ef jh[i[
Yh_j_YWb h[iekhY[i mekbZ mWhhWdj jh[ _cfhel[c[dj ef Zhk] iWf[jo
ijhWj[]_[i*
OdfehjkdWj[bo( m[ fekdZ jhWj cWdo Zhk]i [b_]_bb[ feh _dYbki_ed _d
ekh ijkZo bWYa[Z JE+JD _dfehcWj_ed* A_l[d jh[ ikbijWdj_Wb [ff[Yj ef
][dec_Y lWh_Wb_b_jo ed Zhk] h[ifedi[i( ceh[ WYYkhWj[ WdZ
Yecfh[h[di_l[ JE+JD ZWjW ihekbZ b[ WlW_bWbb[ feh fkjkh[ Zhk]
Z[l[befc[dj( ki[( WdZ h[]kbWj_ed* Geh[el[h( dedYeZ_d] h[]_edi ef jh[
hkcWd ][dec[ YedjW_d kf je 44" ef m[Wabo fh[dejof[)WiieY_Wj[Z
lWh_Wdji _Z[dj_f_[Z bo jh[ AQ;M T15U WdZ ?H=ID? (?H=oYbef[Z_W If
DH; ?b[c[dji% T2,U* Nh[ _dj[]hWj_ed ef jh[ YeZ_d] WdZ dedYeZ_d] ][d[
_dfehcWj_ed cWo fkhjh[h _cfhel[ jh[ fh[i[dj iYeh_d] ioij[c*
77
C10CLUS.10
Nh[ ijhed] Yehh[bWj_ed b[jm[[d jh[ fefkbWj_ed Z[b[j[h_ekid[ii iYeh[
(eh ;O=% WdZ fhWhcWY[kj_YWb cWha[j m_jhZhWmWb hWj[ mWi Yedi_ij[djbo
ebi[hl[Z _d Z_ff[h[dj ZWjWbWi[i WdZ b_iji ef Zhk] m_jhZhWmWbi WdZ
fh[YWkj_edi( _dYbkZ_d] OH =edieb_ZWj[Z F_iji( Dhk]<Wda( ?khef[Wd
G[Z_Y_d[i ;][dYo( <[[hi ]k_Z[b_d[i( WdZ OM FD;* Id[ _dj[h[ij_d]
bofheZkYj ef jh[ fh[i[dj ijkZo _i jhWj jh[ fhefei[Z c[jheZ cWo h[iYk[
d[Y[iiWho Zhk]i jhWj hWl[ Wbh[WZo b[[d m_jhZhWmd fhec jh[ cWha[j feh
iWf[jo h[Wiedi( Wbjhek]h _j ihekbZ b[ Z[f[hh[Z kdj_b jh[ ][d[j_Y YWki[ ef
;DLi _d W lkbd[hWbb[ ikbfefkbWj_ed _i Yb[Whbo _Z[dj_f_[Z WdZ
Yehh[ifedZ_d] Z_W]deij_Y j[ij_d] fheY[Zkh[i Z[l[bef[Z*
78
REFERE0CES
-* Iib[h Q* Nh[ Jh_dY_fb[i WdZ JhWYj_Y[ ef G[Z_Y_d[* H[m Reha6
;ffb[jed7 -45.*
.* GW K( Fk ;R* JhWhcWYe][d[j_Yi( fhWhcWYe][dec_Yi( WdZ
_dZ_l_ZkWb_p[Z c[Z_Y_d[* JhWhcWYebe]_YWb L[l* .,--72/(.%60/3)15*
/* Qoiemia_ DE( MmWhjp F* ;Zl[hi[ Zhk] [l[dj ikhl[_bbWdY[ WdZ Zhk]
m_jhZhWmWbi _d jh[ Od_j[Z MjWj[i( -525).,,.6 jh[ _cfehjWdY[ ef
h[fehj_d] ikif[Yj[Z h[WYj_edi* ;hYh Cdj[hd G[Z* .,,17-21(-.%6-/2/)5*
0* FWpWhek D( Jec[hWdp <B( =eh[o JH* CdY_Z[dY[ ef WZl[hi[ Zhk]
h[WYj_edi _d heif_jWb_p[Z fWj_[dji6 W c[jW)WdWboi_i ef fheif[Yj_l[
ijkZ_[i* D;G;* -5547.35(-1%6-.,,)1*
1* Q_ba_died AL* Dhk] c[jWbeb_ic WdZ lWh_Wb_b_jo Wced] fWj_[dji _d
Zhk] h[ifedi[* H[m ?d]b D G[Z* .,,17/1.(.-%6..--).-*
2* FWii[h E?( ;bb[d JD( QeebhWdZb[h MD( B_cc[bij[_d DO( Qebf[ MG(
<eh DB* N_c_d] ef d[m bbWYa ben mWhd_d]i WdZ m_jhZhWmWbi feh
fh[iYh_fj_ed c[Z_YWj_edi* D;G;* .,,.7.43(-3%6..-1).,*
3* H_dWd <( Q[hjh[_c[h ;C* Q_jhZhWm_d] Dhk]i _d jh[ OM P[hiki Ijh[h
=ekdjh_[i* Cdel JhWhc* .,-.7/(/%6-)-.*
79
4* F[nYh_d D* Bem iWf[ Wh[ d[m Zhk]i: GWha[j m_jhZhWmWb ef Zhk]i
Wffhel[Z _d =WdWZW b[jm[[d -55, WdZ .,,5* If[d G[Z_Y_d[*
.,-074(-%6-0)5*
5* Fh_[ZcWd G;( QeeZYeYa D( Fkcfa_d GG( Mhkh[d D?( BWii ;?(
Nhecfied FD* Nh[ iWf[jo ef d[mbo Wffhel[Z c[Z_Y_d[i6 Ze h[Y[dj
cWha[j h[celWbi c[Wd jh[h[ _i W fhebb[c: D;G; -5557.4-6-3.4)/0*
-,* <Waa[ IG( GWdeYYh_W G( Z[ ;bWje F( EW_j_d EC( FWiW]dW F* Dhk]
iWf[jo Z_iYedj_dkWj_edi _d jh[ Od_j[Z E_d]Zec( jh[ Od_j[Z MjWj[i( WdZ
MfW_d fhec -530 jhhek]h -55/6 W h[]kbWjeho f[hif[Yj_l[* =b_d
JhWhcWYeb Nh[h -5517146-,4)-3*
--* D_[ff[ J;( ?bhWh_c M( GWhj_d LG( Dkd_ J* F[iiedi fhec jh[
m_jhZhWmWb ef hef[Yen_b* <GD .,,07/.56423)4*
-.* O*H* D[fWhjc[dj ef ?Yedec_Y WdZ MeY_Wb ;ffW_hi* =edieb_ZWj[Z F_ij
ef JheZkYji Qhei[ =edikcfj_ed WdZ+eh MWb[ BWl[ <[[d <Wdd[Z(
Q_jhZhWmd( M[l[h[bo L[ijh_Yj[Z eh dej ;ffhel[Z bo Ael[hdc[dji6
JhWhcWY[kj_YWbi ?_]hjh Ciik[* H[m Reha6 Od_j[Z HWj_edi Jkbb_YWj_ed7
.,,/*
-/* SWd][h OG* JhWhcWYe][d[j_Yi ) YhWbb[d][i WdZ effehjkd_j_[i
80
Wh[WZ* Fhedj_[hi _d fhWhcWYebe]o .,-,( -6--.*-0* GWb_[fWWhZ( GWhY(
[j Wb* JhWhcWYe][d[j_Yi _d jh[ [lWbkWj_ed ef d[m Zhk]i6 W ckbj_h[]_edWb
h[]kbWjeho f[hif[Yj_l[* HWj L[l Dhk] D_iY -.*. (.,-/%6 -,/)--1*
-1* IdWafeoW CD( B[d[]hWd =D( ;hedied DE* D[bWoi _d jh[ feij)
cWha[j_d] m_jhZhWmWb ef Zhk]i je mh_Yh Z[Wjhi hWl[ b[[d Wjjh_bkj[Z6 W
ioij[cWj_Y _dl[ij_]Wj_ed WdZ WdWboi_i* <G= G[Z .,-17-/6.2*
-2* Ahebh_Wb CG( LWjakcWh MP* GWdW][c[dj ef jhWb_Zec_Z[ jen_Y_jo* D
Mkffehj IdYeb .,,/7-6-50).,1*
-3* D_[ff[ J;( ?bhWh_c M( GWhj_d LG( Dkd_ J* F[iiedi fhec jh[
m_jhZhWmWb ef hef[Yen_b* <GD .,,07/.56423)4*
-4* Fkd] G( Nhehdjed ;( Gob[Ya E( Qk DB( BehdbkYab[ E( Gkd_p ?*
?lWbkWj_ed ef jh[ YhWhWYj[h_ij_Yi ef iWf[jo m_jhZhWmWb ef fh[iYh_fj_ed
Zhk]i fhec mehbZm_Z[ fhWhcWY[kj_YWb cWha[ji)-52, je -555&* Dhk]
Cdf D .,,-7/16.5/)/-3*
-5* H_dWd <( Q[hjh[_c[h ;C* Q_jhZhWm_d] Zhk]i _d jh[ OM l[hiki ejh[h
Yekdjh_[i* Od_l[hi_jo ef G_dd[iejW( =ebb[][ ef JhWhcWYo* L[jh_[l[Z
fhec jh[ Od_l[hi_jo ef G_dd[iejW D_]_jWb =edi[hlWdYo(
hjjf6++fkhb*kcd*[Zk+-/3---* .,-.*T;YY[ii[Z ed 5( Dkd[( .,-0U
81
.,* GWakYh LQ( Mh_ L* =ecfWh_ied ef Zhk] WffhelWbi _d [khef[
l[hiki jh[ Od_j[Z MjWj[i6 ;d WdWboi_i ef Z_iYh[fWdY_[i b[jm[[d Zhk]
fheZkYji h[l_[m[Z bo ?G; WdZ FD;* Nh[h Cddel L[]kb MY_
.,-07046/2.)2*
.-* ;bhWhWc D( DWl_i =* ; YecfWhWj_l[ WdWboi_i ef Zhk] iWf[jo
m_jhZhWmWbi _d jh[ OE WdZ jh[ OM (-53-)-55.%6 _cfb_YWj_edi feh
Ykhh[dj h[]kbWjeho jh_da_d] WdZ feb_Yo* MeY MY_ G[Z .,,172-644-)5.*
..* =ebecW JG( MYhk[c_[ GD( Nh_f_h A( A_d_ L( B[h_d]i L(
B_ff_ib[o) =en D( GWppW]b_W A( A_Wgk_dje =( =ehhWe A( J[Z[hi[d F*
=ecb_d_d] [b[Yjhed_Y h[WbjhYWh[ ZWjWbWi[i _d ?khef[ je Wbbem feh
bWh][)iYWb[ Zhk] iWf[jo ced_jeh_d]6 jh[ ?O ;DL Jhej[Yj*
JhWhcWYe[f_Z[c_eb Dhk] MWf .,--7.,6-)--*
./* <[hhcWd L?( <[dd[h DM( <hemd DM( GY=b[bbWd G( QeeZYeYa D(
JbWjj L* D[l[bef_d] jh[ M[dj_d[b Moij[cxW dWj_edWb h[iekhY[ feh
[l_Z[dY[ Z[l[befc[dj* H?DG .,--7/206054)5*
.0* OH( =edieb_ZWj[Z F_ij ef JheZkYji Qhei[ =edikcfj_ed WdZ+eh
MWb[ BWl[ <[[d <Wdd[Z( Q_jhZhWmd( M[l[h[bo L[ijh_Yj[Z eh dej
;ffhel[Z bo Ael[hdc[dji6 JhWhcWY[kj_YWbi* (D[fWhjc[dj ef
82
?Yedec_Yi WdZ MeY_Wb ;ffW_hi( .,,0%*
.1* OH( =edieb_ZWj[Z F_ij ef JheZkYji Qhei[ =edikcfj_ed WdZ+eh
MWb[ BWl[ <[[d <Wdd[Z( Q_jhZhWmd( M[l[h[bo L[ijh_Yj[Z eh dej
;ffhel[Z bo Ael[hdc[dji6 JhWhcWY[kj_YWbi* (D[fWhjc[dj ef
?Yedec_Yi WdZ MeY_Wb ;ffW_hi( .,,1%*
.2* OH( =edieb_ZWj[Z F_ij ef JheZkYji Qhei[ =edikcfj_ed WdZ+eh
MWb[ BWl[ <[[d <Wdd[Z( Q_jhZhWmd( M[l[h[bo L[ijh_Yj[Z eh dej
;ffhel[Z bo Ael[hdc[dji6 JhWhcWY[kj_YWbi* (D[fWhjc[dj ef
?Yedec_Yi WdZ MeY_Wb ;ffW_hi( .,,5%*
.3* I?=D* I?=D MjWj_ij_Yi* ;lW_bWbb[ Wj hjjf6++mmm*e[YZ)
_b_bhWho*eh]+ijWj_ij_Yi TWYY[ii[Z ed - D[Y[cb[h .,-0U*
.4* QehbZ <Wda* QehbZ D[l[befc[dj CdZ_YWjehi .,-,* ;lW_bWbb[ Wj
hjjf6++ZWjW*mehbZbWda*eh]+_dZ_YWjeh TWYY[ii[Z ed -1 F[bkbWho .,-1U*
.5* MB HWc( RM E_c( RM Dk* ; ijkZo ef Yecfei_j[ _dZ[n ed h[Wbjh
WdZ m[bfWh[* Eeh[W Cdij_jkj[ feh B[Wbjh WdZ MeY_Wb ;ffW_hi6 M[ekb 7.,-.*
/,* ED F_c( MG F_c( EB M[e* ;dWboi_i ef jh[ I?=D B[Wbjh DWjW
.,-.* L[i[WhYh Cdij_jkj[ feh B[WbjhYWh[ Jeb_Yo6 M[ekb7 .,-/*
/-* E_c F( E_c D;( E_c M* ; ]k_Z[ feh jh[ kj_b_pWj_ed ef B[Wbjh
83
CdikhWdY[ L[l_[m WdZ ;ii[iic[dj M[hl_Y[ HWj_edWb JWj_[dj MWcfb[i*
?f_Z[c_eb B[Wbjh .,-07/26[.,-0,,4*
/.* N[Wc L=* L6 ; bWd]kW][ WdZ [dl_hedc[dj feh ijWj_ij_YWb
Yecfkj_d]* P_[ddW( ;kijh_W* .,-.*
//* I?=D* F_f[ [nf[YjWdYo Wj b_hjh WdZ ADJ f[h YWf_jW( .,-- (eh
d[Wh[ij o[Wh%* B[Wbjh Wj W AbWdY[* I?=D Jkbb_ih_d]( JWh_i7 .,-/*
/0* RWd] M( EhWd] R)B( BWhf[h M( DWl[o Mc_jh A( F[ed D;( FodYh D*
OdZ[hijWdZ_d] jh[ LWf_Z CdYh[Wi[ _d F_f[ ?nf[YjWdYo _d Mekjh Eeh[W*
;c D Jkb B[Wbjh .,-,7-,,6452)5,/*
/1* BWbb Q( DehWd =( D[][dhWhZj F( Mh[fWhZ D* Cbb_Y_j If_Wj[ ;bki[*
Cd6 DWc_ied DN( <h[cWd DA( G[WihWc ;L( ;bb[od[ A( =bW[ied G(
?lWdi D<( [j Wb*( [Z_jehi* D_i[Wi[ =edjheb Jh_eh_j_[i _d D[l[bef_d]
=ekdjh_[i* .dZ [Z* QWih_d]jed D=7 .,,2*
/2* Eeh[W FeeZ WdZ Dhk] ;Zc_d_ijhWj_ed( D[Wh B[WbjhYWh[ Jhef[ii_edWb
F[jj[h (;fhej_d_d%** .,,4*
hjjf6++Zhk]*cfZi*]e*ah+hjcb+Whj_Yb[F_da<eZo*jif:fVc[dkCZ9,2,.&fVi
kbVc[dkCZ9,2,.,-&fVde9---
/3* =he_ D( =he_ G( Ee ;* =khh[dj ijWjki ef fhWhcWY[kj_YWb iWf[jo
84
cWdW][c[dj _d Eeh[W* D Eeh[Wd G[Z ;iieY .,-.71164.3)/0*
/4* LWjWdWm_j_jhWi_d M( QedZ[cW][]d[hk ?* "?ff[Yj_l[ Zhk] h[]kbWj_ed*"
; ckbj_Yekdjho ijkZo* A[d[lW( Mm_jp[hbWdZ6 QehbZ B[Wbjh
Ih]Wd_pWj_ed .,,.*
/5* MhWh LL* =Wd fhWhcWYe][d[j_Yi h[bf h[iYk[ Zhk]i m_jhZhWmd fhec
jh[ cWha[j: JhWhcWYe][dec_Yi* .,,273(2%6445)5,4*
Ze_6-,*..-3+-02..0-2*3*2*445*
0,* DW]]kcWbb_ DMP( GWhj_d CA* ;h[ JhWhcWY[kj_YWb GWha[j
Q_jhZhWmWbi Jh[l[djWbb[: ; Jh[b_c_dWho ;dWboi_i* Dhk] Cdf D*
.,-.702(2%6250)3,,*
0-* QWd] F( GYF[eZ BF( Q[_dih_bbekc LG* A[dec_Yi WdZ Zhk]
h[ifedi[* H[m ?d]b D G[Z* .,--7/20(-.%6--00w1/*
0.* FD;* NWbb[ ef fhWhcWYe][dec_Y b_ecWha[hi _d Zhk] bWb[b_d]*
hjjf6++mmm*fZW*]el+Dhk]i+MY_[dY[L[i[WhYh+L[i[WhYh;h[Wi+JhWhcWYe
][d[j_Yi+kYc,4//34*hjc( ;YY[ii[Z M[fj[cb[h 4( .,-1*
0/* GWY;hjhkh DA( <WbWikbhWcWd_Wd M( FhWda_ih ;( BkWd] H( Gehh_i
D( QWbj[h E [j Wb* ; ioij[cWj_Y ikhl[o ef beii)ef)fkdYj_ed lWh_Wdji _d
hkcWd fhej[_d)YeZ_d] ][d[i* MY_[dY[* .,-.7//1(2,3,%64./)4*
85
00* LeZ[d DG( A[eh][ Dh ;F* Nh[ ][d[j_Y bWi_i ef lWh_Wb_b_jo _d Zhk]
h[ifedi[i* HWj L[l Dhk] D_iYel* .,,.7-(-%6/3)00*
01* B[_Wj ;( Aheii =J( Ehkchebp BG* L[fh[i[djWj_ed ef jh[ [bZ[hbo(
mec[d( WdZ c_deh_j_[i _d h[Whj fW_bkh[ Yb_d_YWb jh_Wbi* ;hYh Cdj[hd G[Z*
.,,.7-2.(-1%*
02* -,,, A[dec[i Jhej[Yj =ediehj_kc( ;b[YWi_i AL( ;kjed ;( [j Wb*
;d _dj[]hWj[Z cWf ef ][d[j_Y lWh_Wj_ed fhec -(,5. hkcWd ][dec[i*
HWjkh[* .,-.705-(30..%612)21*
03* Q_ihWhj DM( Eden =( Ake ;=( [j Wb* Dhk]<Wda6 W Yecfh[h[di_l[
h[iekhY[ feh _d i_b_Ye Zhk] Z_iYel[ho WdZ [nfbehWj_ed* HkYb[_Y ;Y_Zi
L[i* .,,27/0(DWjWbWi[ _iik[%6D224)23.*
04* -,,, A[dec[i Jhej[Yj =ediehj_kc( ;b[YWi_i AL( ;kjed ;( [j Wb*
;d _dj[]hWj[Z cWf ef ][d[j_Y lWh_Wj_ed fhec -(,5. hkcWd ][dec[i*
HWjkh[* .,-.705-(30..%612)21*
05* ?khef[Wd G[Z_Y_d[i ;][dYo6 ?G;+G<+255./+.,-,);ddkWb
h[fehj ef jh[ ?khef[Wd G[Z_Y_d[i ;][dYo .,,5*
hjjf6++mmm*[cW*[khefW*[k+ZeYi+[dVA<+ZeYkc[djVb_bhWho+;ddkWbVh[
fehj+.,-,+,1+Q=1,,,5,3-.*fZf( ;YY[ii[Z M[fj[cb[h -4( .,-1*
86
1,* <o jh[ ;c[h_YWd A[h_Wjh_Yi MeY_[jo <[[hi =h_j[h_W OfZWj[ ?nf[hj J*
;c[h_YWd A[h_Wjh_Yi MeY_[jo .,-1 OfZWj[Z <[[hi =h_j[h_W feh Jej[dj_Wbbo
CdWffhefh_Wj[ G[Z_YWj_ed Oi[ _d IbZ[h ;Zkbji* D ;c A[h_Wjh MeY* .,-1*
1-* EkcWh J( B[d_aeff M( H] J=* Jh[Z_Yj_d] jh[ [ff[Yji ef YeZ_d] ded)
iodedoceki lWh_Wdji ed fhej[_d fkdYj_ed ki_d] jh[ MCFN Wb]eh_jhc* HWj
JhejeY* .,,570(3%6-,3/)4-*
1.* LWc[diao P( <eha J( MkdoW[l M* BkcWd ded)iodedoceki MHJi6
i[hl[h WdZ ikhl[o* HkYb[_Y ;Y_Zi L[i* .,,.7/,(-3%6/450)5,,*
1/* L[lW <( ;dj_f_d R( MWdZ[h =* D[j[hc_dWdji ef fhej[_d fkdYj_ed
h[l[Wb[Z bo Yecb_dWjeh_Wb [djhefo efj_c_pWj_ed* A[dec[ <_eb*
.,,374(--%6L./.*
10* E_hYh[h G( Q_jj[d DG( DW_d J( [j Wb( ; ][d[hWb fhWc[meha feh
[ij_cWj_d] jh[ h[bWj_l[ fWjhe][d_Y_jo ef hkcWd ][d[j_Y lWh_Wdji* HWj
A[d[j* .,-0 GWh702(/%6/-,)/-1*
11* Aedp b[p)J h[p ;( F f[p)<_]Wi H* Ccfhel_d] jh[ Wii[iic[dj ef jh[
ekjYec[ ef dediodedoceki MHPi m_jh W Yedi[diki Z[b[j[h_ekid[ii
iYeh[( =edZ[b* ;c D Bkc A[d[j* .,--744(0%600,)5*
12* Mjhec <F* Bem jh[ OM Zhk] iWf[jo ioij[c ihekbZ b[ YhWd][Z*
87
D;G;* .,,27.51(-3%6.,3.)1*
13* <[hb_d D;( AbWii[h M=( ?bb[db[h] MM* ;Zl[hi[ [l[dj Z[j[Yj_ed _d
Zhk] Z[l[befc[dj6 h[Yecc[dZWj_edi WdZ ebb_]Wj_edi b[oedZ fhWi[ /*
;c D Jkbb_Y B[Wbjh* .,,4( 54(4%6-/22)-/3-*
14* ;b[hd[jho D( QeeZYeYa D( F[iae F* JhWhcWYebe]_YWb c[YhWd_ic)
bWi[Z Zhk] iWf[jo Wii[iic[dj WdZ fh[Z_Yj_ed* =b_d JhWhcWYeb Nh[h*
.,--745(2%635/)3*
15* MYhWkb G;( <eob[ ;J( EkdZWj[ ;( <Wjpe]bek M( MdoZ[h G* F_da_d]
Z_i[Wi[ WiieY_Wj_edi m_jh h[]kbWjeho _dfehcWj_ed _d jh[ hkcWd ][dec[*
A[dec[ L[i* .,-.7..(5%6-304)15*
2,* =ediehj_kc ?J* Nh[ ?H=ID? (?H=oYbef[Z_W ef DH; [b[c[dji%
fhej[Yj* MY_[dY[* .,,07/,2(1252%62/2)0,*
88
PS 초록
VR6 많은 환자에서 임상적인 효용을 입증 받은 약이라 할지라도 종종
다른 환자들에서 –료에 실패하거나 사망을 포함한 심각한 γ작용을
일으— 수 있다* 이러한 약물 반응의 개인차는 임상 현장( 약물 개발 단계와
의약품 규제 단계 모두에서 주요 해결 과제이다* α 연구는 약물 안전성에
중요한 결정 요인인 국가별 약물 규제관련 요인을 δ석해보고( 개인
유전체 염기서열 변이 δ석을 ’해 인구 집단의 약물 유전학적 안전성이
실제 약물의 위험성을 예측할 수 있는지 확인하고자 하였다*
방U: 우선 거시적으로 국가별 약물 안전성 평가 및 그에 따른 규제의
차이를 나타내는 지표로서 국가별 퇴출 및 제한 약물의 수를 OH
보고서에서 리뷰하여 조사하였다* 또한 이러한 약물 규제와 연관된 국가별
경제( 사회( 보건( 복지 및 건강 지표들을 알아보기 위해 QehbZ <Wda 와
I?=D 지표 조사를 이용하였다* 다른 한편으로( 개인 유전체 변이의
변이성의 정도가 인구 집단 약물 안전성에 반영되는지 확인하기 위해
.1,0 명의 건강한 개인으로 이루어진 -,,, A[dec[i Jhej[Yj 로γ터 개인
유전체 데이터를 δ석하여 약물의 약동학 및 약력학에 영향을 미–는 모든
단백질 손상 변이의 총합을 δ석하였다* 그리고 각 약물마다 약물 유전
89
안전성 점수를 산출하여 이를 위험 약물 리스트 (퇴출 혹은 사용 주의 약물%
와 비교하여 위험한 약물군과 그렇지 않은 약물군 사이에 인구집단 약물
유전 안전성 점수가 어떻게 다른지 확인하였다* 이때 사용된 위험 약물
리스트는 퇴출)OH 보고서( ?G;( Dhk]<Wda 에서 퇴출 약물로 표시한
경우 혹은 사용 주의) <[[hi Yh_j[h_W 혹은 OM FD; fhWhcWYe][dec_Yi
라벨 약물이었다* 연구에 포함된 전체 약물은 Dhk]<Wda
데이터베이스로γ터 약물 관련 약동학+약력학 유전자가 최소 1 개 이상
연결되어 있는 약물 -,0- 개였다*
NO: 국가별 약물 규제에 관해 가장 포±적인 정보를 제공하는 OH
=edieb_ZWj[Z b_ij ef fheZkYj 를 ’해 -51, 년γ터 .,-, 년까지 기간 동안(
50 개 나라로γ터 한번이라도 퇴출된 /2. 개 약물과 .04 개의 제한 약물을
확인하였다* 국가별 퇴출 약물과 제한 약물 수의 평균은 각각 -.*,. r
-/*,3 ( 1*33 r 4*25 (c[Wd r MD%였다* 국가별 사용 규제 (퇴출 및 제한%
약물의 수는 ADJ( ADJ f[h YWf_jW( ADJ f[h hekh meha[Z( B[Wbjh
[nf[dZ_jkh[ f[h ADJ( [bZ[hbo fefkbWj_ed hWj[ 와 유의하게 양의
상관관계를 보였고( ekj)ef)feYa[j fWoc[dj 와는 유의하게 음의
상관관계를 보였다* 또한 약물 제한 수의 경우 약물 γ작용으로 인한
사망률과 유의한 양의 상관관계를 보였다*
90
한편 집단 유전체 δ석을 ’해 구한 약물 유전학적 안전성 점수는 퇴출+
제한 약물 모두에서 유의하게 (J 8,*,,-% 낮았다* 약물 손상 점수가 낮아질
수록( 즉 약물 관련 손상 변이가 많을 수록( 퇴출 약물 혹은 <[[hi Yh_j[h_W
나 FD; 약물 유전학 데이터베이스에 속한 약물의 비율이 유의하게
증가하였다* (J 8,*,1% 이러한 경향은 나눠서 ?G;( OH( Dhk]<Wda 의
데이터베이스의 약물 리스트를 개별적으로 δ석하거나 혹은 조합해서
δ석해도 모두 같은 경향을 보였다* NR: 국가별로 규제 대상 약물 수와
프로파일은 매우 다양했지만( 규제 약물의 수와 ADJ 등 경제지표 및 국가
의료비 지출이 비례하고 개인 의료비 지출 수준과 반비례함을 β 때(
적절한 약물 규제는 국가 의료시스‘의 수준을 반영한다고 β 수 있다*
또한 인구집단 유전 변이 δ석을 ’해 위험 약물 및 시장 퇴출 약물을 예측
할 수 있었다* 각 개인과 민족의 약물 관련 유전자의 손상 프로파일의
변동성을 ~안할 때( 우리는 이를 이용해 모든 사람들의 위한 위험한
약물의 조합을 추정할 수 있다* 특정 약물의 경우 사람 사이 변이가 적은
동시에 거의 모든 사람에게 위험한 것으로 나타난 약물도 있었다* JE+JD
유전자와 약물의 상관관계가 좀 더 밝혀지고 누적된다면( 이 예측 모델은
더욱 정확해질 것이다* 약물 γ작용의 개인 차이와 인종간 차이를
91
고려했을 때 국가별 약물 γ작용 ~시시스‘의 활성화와 약물 γ작용 및
규제 정보의 교류가 더욱 활발해져야 할 것이다*
)))))))))))))))))))))))))))))))))))))
주요어 6 약물 γ작용( 유전 변이( 유전자( 약물 유전학( 위험 약물 퇴출(
약물 퇴출과 철수( 국가별 사회경제적요인평가
학 번 6 .,-/)/--34