704 138
sibutramine orlistat rimonabant
( Anti-obesity agents ) Sibutramine
Orlistat Rimonabant
1 2 1 5
1980 1986 1996 12.4% 14.8%
15.6% 10.1% 11.1% 12.9%
1 9 9 3 - 1 9 9 6
10.5% 2000-2001 15.9%
13.7% 10.7%1
2 2-4
5
( metabolic syndrome )
B M I
B M I
27kg/m2 BMI <27
24kg/m2 6
P r a d e r - W i l l i
Albright hereditary osteodystrophy Fragile X
arcuate nu-
cleus neuropep-
tide Y ( NPY ) agouti-related peptide ( AgRP ) proopiomelanocortin ( POMC ) cocaine-and amphetamine-regulated transcript ( CART )
7
Cannabinoid system
( r e c e p t o r s ) cannabinoid receptor 1 ( CB1 ) cannabinoid re- ceptor 2 ( CB2) CB1
CB2
cannabinoid system 8
CB1
9 CB1 blockage
CB1 blockage
( ) (
)
10
( leptin )
( leptin receptor )
POMC -melanocyte-sti-
mulating hormone ( -MSH ) -MSH menalocortin-4 ( MC4-R )
P O M C MC4-R
11 - 1 3
( leptin resistance ) 14
adiponectin resistin interleukin 6 ( IL-6 ) tumor necrosis fac- tor-alpha ( TNF- ) visfatin
Ghrelin
g h r e l i n N P Y A g R P
15
ghrelin
1 6 , 1 7
18
ghrelin
c h o l e c y s t o k i n i n glucagon-like peptide 1 ( GLP-1 ) pancreatic polypeptide amylin peptide YY
Sibutramine ( Reductil® ®) Sibutramine
serotonin norepinephrine ( SNRI )
7 1 0 4 7
24 24
1.2%
sibutramine 1 mg 2.7% 5 mg
3.9% 10 mg 6.1% 15 mg
7 . 4 % 2 0 m g 8 . 8 % 3 0 m g
9 . 4 % 4
2 4 1 9
1 2
1.4±0.5kg sibutramine 5mg
2.4±0.5kg sibutramine 10 mg 5.1±0.5kg sibutramine 15 mg
4 . 9 ± 0 . 5 k g2 0 s i b u -
tramine
2 1
2 9
s i b u t r a m i n e 1 0 2 0
mg/day sibutramine 3
l 2 . 7 8 k g 4 . 4 5
kg22
sibutramine 15 mg
12.1±9.8kg
sibutramine 5.0±7.4kg
6.7±7.9kg
23
Sibutramine 2
1 5
mg sibutramine 2
1 2 s i b u t r a -
mine 0.3 mmol/l
1.4 mmol/l ( p=0.04 )
sibutramine 0.3% 0.0%
( p<0.05 ) 1.0% sibu-
t r a m i n e 3 3 % 5 %
( p < 0 . 0 5 ) 5 %
sibutramine 19% 0%
( fat mass ) sibutramine 1.0% 0.0%( p<0.05 ) 1.8kg 0.2kg ( p<0.001 ) 24 Sibutramine
5 mg- 30 mg
10 mg 15 mg
10 mg 5 mg
10 mg-15 mg 3-6
4 mmHg 1%
25
sibutramine
Orlistat ( Xenical® ®) Orlistat
26
1 5 7 4 3
orli- stat 120 mg Orlistat
10.2% ( 10.3kg ) 6.1% ( 6.2kg )
o r l i s t a t
orlistat 76%
84%
orlistat 0.9kg
2.5kg27 orlistat
orlistat
2.6% 10.4%28 orlistat
2
orlistat 6.2±0.45%
4.3±0.49% 5%
orlistat
49% 23%29
( XENDOS )
BMI 30
orlistat 2
9.0% orlistat 6 . 2 % o r l i s t a t
37.3% 3.0
kg orlistat 5.8kg ( p<0.001 ) 30 Orlistat
79% orlistat 59%
( )
( ) 31
A D E beta-
orlistat
b e t a - 8 , 1 0 , 1 2
Orlistat 120 mg
orlistat
A D E 2
Rimonabant ( Acomplia®)
Rimonabant cannabinoid receptor 1 ( CB1) blockage
( RIO-Europe ) 32 B M I 3 0 k g / m2 B M I 2 7 k g / m2
rimonabant 5 mg 20 mg
3.4kg ( p=0.002 )
6.6kg ( p<0.001 ) rimonabant 20mg
5% 10%
H D L triglyceride
( 12.9% ) ( 7.2% ) ( 8.7% )
( R I O - North America )33 RIO-Europe
rimonabant 20 mg 6.3kg 1.6kg ( p<0.01 ) HDL triglyceride
rimonabant 20 mg
rimonabant 20 mg
( 11.2% )
(RIO-Lipid ) 34
rimonabant 5 mg 20 mg
4.2kg ( p<0.001 ) 8.6kg ( p<0.001 ) rimonabant 20mg
triglyceride leptin HDL
adiponectin LDL
LDL CRP
rimonabant
( 12.7% ) ( 10.4% ) ( 9.5% ) ( 8.7% ) ( 7.2% ) ( 6.4% )
rimonabant
rimonabant
35,36
FDA
Exenatide ( Byetta® ) glucagon-like peptide
1 ( GLP-1 ) 2005
37-39
ghrelin
40 ghrelin ( receptor
antagonist ) ghrelin R-
NA ( anti-sense mRNA ) ghrelin
41-43
ghrelin ghre-
lin
Ciliary neurotrophic factor ( CNTF )
CNTF CNTF
CNTF
( re- combinant human variant ) CNTF ( rhvCNTF )
44
Pramlintide ( Symlin® ) amylin 2005
1 2
45-48
3 adrenergic receptor agonist
49 L-796568 ( 3 adrenergic r e c e p t o r a g o n i s t )
50, 51
3 adrenergic receptor agonist
Melanocortin melanocyte-stimulating hor- mone/adrenocorticotropin4–10 ( MSH/ACTH4–10 )
melanocortin-4 receptor ( MC4-R ) agonist MC4-R
52
53 54
Histamine H3 receptor ( H3R )
H 3 R
55 H3R antago-
nist 56
Neuropeptide Y ( NPY )
NPY Y1 receptor ( NPY Y1R )
57 NPY
Y1R antagonist
58
PPAR
f i b r a t e P PA R
agonist PPAR agonist
5 9 , 6 0
PPAR agonist 61
PPAR agonist TZD
PPAR antagonist
PPAR antagonist
62,63
PPAR
topiramate zonisamide bupro-
pion fluoxetine sertraline dia-
zoxide aromatase inhibitor D
s i b u -
tramine orlistat rimonabant
64
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Anti-Obesity Agents An Update
Hao-Chang Hung, Horng-Yih Ou, Shu-Hwa Hsiao1, and Ta-Jen Wu
As the development of civilization, worldwide prevalence rates of obesity are rising and become a big so- cial problem. Obesity-related disorders such as hypertension, hyperlipidemia, diabetes mellitus, cardiovascular disease, arthritis, gallstone and even cancer had been emerging to be heavy burden for individual, family and so- ciety. Prevention and treatment of obesity are essential for the prevention of these associated disorders. The treatment of obesity will be initiated from non-pharmacological therapy. Pharmacological therapy has recently much well developed. Pharmacotherapy may have synergistic effect on the weight reduction of non-pharmaco- logical interventions. The anti-obesity agents including sibutramine, orlistat, and rimonabant were approved by FDA. The evidence-based studies show that these agents have the effects on improving lipid profile and insulin resistance in addition to weight reduction. However, long-term studies with morbidity and mortality as clinical end- point are also expected. Many additional anti-obesity agents, some of which seem promising, are currently on developing. ( J Intern Med Taiwan 2006; 17: 155-162 )
Department of Internal Medicine and 1Department of Pharmacy , National Cheng Kung University Hospital, Tainan, Taiwan, R.O.C.
