Phytomedicine 9: 38, 2002

Urban & Fischer Verlag

http://www.urbanfischer.de/journals/phytomed

Phytomedicine

Recent findings of green tea extract AR25 (Exolise) and

its activity for the treatment of obesity
P. Chantre1 and D. Lairon2
1
2

Laboratoires Arkopharma, Carros, France

Unit 476 INSERM (Institut National de la Sant et de la Recherche Mdicale), Marseille France

Summary
The green tea extract AR25 is an 80% ethanolic dry extract standardized at 25% catechins expressed as epigallocatechin gallate (EGCG). In vitro, green tea extract AR25 exerts a direct inhibition of gastric and pancreatic lipases and a stimulation of thermogenesis. In an open study, the effects of extract AR25 were evaluated in moderately obese patients. After 3 months, body weight
was decreased by 4.6% and waist circumference by 4.48%. These results suggest the green tea extract AR25 to be a natural product for the treatment of obesity, which exerts its activity by several
ways: inhibition of lipases and stimulation of thermogenesis.
Key words: green tea extract, gastric and pancreatic lipase, thermogenesis, obesity, catechins

j Introduction

j Pharmacological approach for the

treatment of obesity

Obesity is caused by chronic imbalance between energy intake and energy expenditure. It is defined in terms
of body mass index (BMI), which is calculated as body
weight/square of height (kg/m2). A goal BMI for both
genders aged 1934 years is between 19 and 25 kg/m2,
slightly increasing with age (Cerulli et al. 1998; Leonhardt et al. 1999).
Primary obesity may be caused by genetic predisposition, environmental factors, metabolic and endocrine
abnormalities, or combinations of these factors. Obesity is secondary to a positive energy balance where energy intake exceeds energy expenditure (Cerulli et al.
1998; Leonhardt et al. 1999).
Weight reduction can be achieved by decreasing energy intake and increasing energy expenditure. Compliance of classical weight loss programs as low-fat
diets, behavioral modification and exercise often fail to
achieve long-term maintenance of weight loss. Due to
the low success rates, the development of drugs to control weight are currently under investigation (Cerulli et
al. 1998; Ludvik 1998; Leonhardt et al. 1999).

The regulation of weight and appetite control is a complex interrelationship between several neurologic and
hormonal mechanisms. Discrete areas of the hypothalamus act as regulatory centers for obesity where energy homeostasis is regulated through food intake
(hunger and satiety), energy expenditure, and the secretion of hormones that regulate the use and storage of
substrates (Cerulli et al. 1998; Leonhardt et al. 1999).
Serotonin, histamine, dopamine and associated receptor activities appear to be closely interlinked with
the regulation of satiety. Therefore the activity of these
receptors provides possible mechanisms for pharmacological interventions in the management of obesity by
reducing energy intake or increasing energy expenditure (EE). The modern pharmacological approach concentrates on drugs to interfere with monoamine neurotransmitter effects (e.g. sibutramine) and act as appetite
suppressants, drugs which increase thermogenesis (e.g.
3-adrenoreceptor agonists), decrease fat absorption by
inhibiting the pancreatic lipase (orlistat), or drugs
0944-7113/02/09/01-003 $ 15.00/0

P. Chantre and D. Lairon

which act on brain peptides (Cerulli et al. 1998; Ludvik

1998; Leonhardt et al. 1999).
Energy expenditure is controlled by the resting
metabolic rate (RMR), physical activity and dietary
thermogenesis. In the past emphasis has shifted towards a systematic research for drugs which mimic the
activity of the sympathetic nervous system. Evidence
suggested an important role of the sympathetic nervous
system activity via its heat-producing neurotransmitter
noradrenaline (NA) in energy balance regulation
(Landsberg 1986, Dulloo and Miller 1987, Peterson
et al. 1988); diminished sympathetic nervous system
activity may contribute to the diminished EE leading to
obesity (Spraul et al. 1993).
Considerable interest is also on natural substances
with potential thermogenic properties which interfere
with the sympathoadrenal system (Dulloo 1998). Caffeine is effective in potentiating thermogenesis induced
by drugs (Dulloo 1993). In rat brown adipose tissue
(BAT) the effect of low doses of caffeine on thermogenesis is entirely dependent on an intact sympathetic innervation. It potentiates the effect of sympathetically
released NA on thermogenesis primarily by inhibiting
phosphodiesterase enzyme activities rather than antagonizing adenosine receptors (Dulloo et al. 1992).
The level of NA at the synaptic junction and its interaction with adrenoceptors is also negatively modulated
by its enzymatic degradation by catechol-O-methyltransferase (COMT), thereby providing an additional
target for pharmacological interference by prolonging
the effect of NA and so increasing cAMP level and
thermogenesis. Tea polyphenols have been shown to
inhibit this NA-degrading COMT, notably some of the
class of catechins which are found in high quantities in
tea prior to its fermentation (Borchardt and Huber
1975; Rhodes 1996).
Other polyphenolic compounds like tannins and
tannic acids had been reported to exert an influence
on lipid metabolism (Kimura et al. 1984; Wrisez and
Lambert 2001). In particular, tannic acid supplementation decreased both basal and isoproterenol-stimulated
lipolysis significantly whereas cyclic AMP production
as well as adenyl cyclase activity increased significantly.
Tea one of the most ancient and, next to water, the
most widely consumed beverage in the world is made
from the leaves of Camellia sinensis L. species of the
Theaceae family. The leaves are processed as green,
oolong or black tea. Green tea is the non-oxidized/nonfermented product and contains high quantities of several polyphenolic components such as epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin
gallate (EGCG).
Green tea, by containing high quantities of pharmacologically active compounds (catechin and caffeine),

might act at different steps of NA modulatory pathways

and by this way exert a thermogenic and so an antiobesity action. However, green tea, like any active
principle, needs to be used at the right composition and
the right posology to exert a pharmacologicaly significant effect. As an example, a recent paper (Martinet et
al. 1999) demonstrated that 12 plant preparations (including green tea) had no effect on energy expenditure
nor respiratory quotient (RQ). On the other hand, a
standardized extract of green tea was developed and
tested in various experimental and clinical designs to
have thermogenic and anti-lipase activity.

j HPLC fingerprint analysis

of green tea extract AR25
The green tea extract AR25 is an 80% ethanolic dry
extract standardized at 25% catechins expressed as
epigallocatechin gallate (EGCG).The percentage content of caffeine is 510%. The medicinal product
EXOLISE is a capsule containing 375 mg of green
tea extract AR25.
Extraction and HPLC analysis: green tea extract
AR25 (0.2 g) was extracted with methanol (80 ml)
under ultrasonication for 5 min. After filtration, the
filtrate was adjusted to a volume of 50 ml in a volumetric flask and 5 ml of this solution was diluted to 25 ml
with the same solvent. HPLC analyses were performed
on a Nucleosil 5 m C18 column (250 4.6 mn) with a
gradient of acetonitrile (pump A) : water (+ 2%
CH3COOH) (pump B) : 05 min, 5% A in B (isocratie);
510 min, 510% A in B (linear gradient); 1017 min,
1015% A in B (linear gradient); 1730 min, 1518%
A in B (linear gradient); 3035 min, 18% A in B (isocratic); 3540 min, 185% A in B (linear gradient). The
flow rate was 1 ml/min ; detection was carried out at
278 nm. The injected volume of the sample was 10 l.
The HPLC profile of green tea extract AR25 is shown
in Fig. 1. Epigallocatechin gallate (5) with caffeine (3)
dominate the chromatogram with epicatechin gallate
(7) assuming of secondary importance. These constituents are accompanied by three other catechins [epigallocatechin (2), epicatechin (4) and gallocatechin gallate (6)] and another methylxanthine [thobromine (1)].

j Pharmacological and clinical

properties of green tea extract AR25
Inhibition of triglycerides lipolysis

Alimentary fat digestion starts in the stomach where

gastric lipase hydrolyzes 10 to 30% of dietary triglycerides under acidic conditions. In the small intestine

Recent findings of green tea extract AR25 (Exolise)

Fig. 1. HPLC separation of the

catechins and methylxanthines of
green tea extract AR25. Peak identification: (1) theobromine; (2)
epigallocatechin; (3) caffeine; (4)
epicatechin; (5) epigallocatechin
gallate; (6) gallocatechin gallate;
(7) epicatechin gallate

lipolysis is completed by pancreatic lipase acting with

colipase as cofactor and absorption of lipolytic products starts.
In vitro data showed a reduced gastric and intestinal
fat digestion by green tea extract AR25 mediated by direct inhibition of lipases as well as a reduction of lipid
emulsification process. The effects both on gastric and
pancreatic lipase activities were studied in a biochemical assay (Juhel et al. 2000).
In a first step, tributyrin, a short-chain triglyceride,
was used as substrate. Gastric lipase was totally inhibited by 40 mg AR25/g tributyrin and pancreatic lipase
inhibition was maximum (78.8 0.7%) with 80 mg
AR25/g tributyrin (Fig. 2). Triolein, a long-chain triglyceride, was inhibited by 96.8 0.4% at AR25
60 mg/g triolein; pancreatic lipase activity was reduced
to 66.50 0.92% at the same concentration. Incubation
of AR25 with an excess of digestive lipases, mimicking
physiologic conditions, resulted in a strong decrease in
gastric lipolysis but only a slight reduction of pancreatic lipase activity (Juhel et al. 2000).
To mimic in vivo conditions, triolein emulsion was
successively incubated with an excess of gastric lipase
in acidic medium and an excess of pancreatic lipase
and colipase in duodenal conditions. The amount of released fatty acids was markedly and significantly low-

ered (11.7 5.2% of control) by 60 mg AR 25/g triolein

during gastric lipolysis. The inhibitory effect of AR25
on pancreatic lipolysis appeared to be delayed compared with the result obtained in excess of substrate
and was observed at 60 minutes (i.e., 30 minutes after
the pancreatic lipase and colipase additions). Over all,
lipolysis catalyzed by the action of both gastric and
pancreatic lipases on triolein was significantly reduced
by 37.1 0.6%. Furthermore, AR25 strongly reduced
the lipid emulsification process in gastric medium by
more than 90% and completely prevented lipid emulsification in duodenal medium, thus reducing the lipid/
water interface area and enzyme access (Juhel et al.
2000).
Stimulation of thermogenesis

Dulloo has recently investigated in an in vitro system

whether an extract of green tea, by virtue of its high
content of both caffeine and catechin, could be an
effective promoter of thermogenesis. These in vitro
results can be summarized as follow :
1) The green tea extract was found to be more effective than were equivalent amounts of caffeine in
stimulating peripheral tissue thermogenesis (Dulloo
et al. 2000).

P. Chantre and D. Lairon

Fig. 2. Effect of increasing amounts

of AR25 (mg/g tributyrin) on (A)
gastric lipase and (B) pancreatic lipase activities. Tributyrin hydrolysis in gastric or duodenal operating
conditions was measured using a
pH-stat Titrator.

2) The difference between the green tea extract and

equimolar caffeine was much more marked under
conditions of increased norepinephrine release because the synergistic interaction between the green
tea extract and epinephrine on tissue thermogenesis
was much more pronounced than that of caffeine or
ephedrine (Dulloo et al. 2000).
On the basis of these in vitro data, a human study
was carried out (Dulloo et al. 1999).
On 3 separate occasions, 10 healthy men were randomly assigned among 3 treatments : green tea extract
(50 mg caffeine and 90 mg epigallocatechin gallate),
caffeine (50 mg) and placebo, which they ingested at
breakfast, lunch and dinner.
Relative to placebo, treatment with the green tea extract resulted in a significant increase in 24 h energy expenditure (EE) (4%; p < 0.01) (Table 1) and a significant
decrease in 24 h respiratory quotient (p < 0.001) without
any change in urinary nitrogen. Treatment with caffeine
in amounts equivalent to those found in the green tea extract had no effect on EE and respiratory quotient.
Table 1. Energy expenditure (EE) during diurnal, nocturnal,
and total 24-h periods1.
Placebo

Caffeine

Green tea

p2

KJ
Diurnal EE
6463 386 6547 383 6754 3523 <0.01
Nocturnal EE 3075 149 3053 148 3112 140 NS
Total 24-h EE 9538 521 9599 518 9867 4883,4 <0.01
x SEM; n = 10
For differences across treatments (ANOVA)
3
Significantly different from placebo, P < 0.05 (post hoc
pairwise comparison with Tukeys test)
4
Significantly different from caffeine, p < 0.05 (post hoc
pairwise comparison with Tukets test)
1
2

Stimulation of thermogenesis by the green tea extract was not accompagnied by an increase in heart
rate. In this respect, the green tea extract is distinct
from sympathomimetic drugs, whose use as antiobesity thermogenic agents is limited by their adverse cardiovascular effects and are particularly inappropriate
for obese individuals with hypertension and other cardiovascular complications.
Results of a first open study with AR25 for the
treatment of obesity

Administration of green tea extract stimulated thermogenesis and fat oxidation and this extract has the potential to influence body weight and body composition via
changes in both energy expenditure and substrate utilization.
Patients and methods:
The present investigation was conducted in France
from June 1999 to December 1999 as a multicenter
open study performed by 5 endocrinologists.
Enrolled patients were 18 years of age or older, with
a body mass index of between 25 and 32 kg/m2. The
Ethics Commitee of Marseille approved the study and
all patients gave written informed consent.
The main exclusion criteria were : history of any serious systemic disease, including diabetes; significant
cardiac, renal, hepatic or endocrine disorders, pregnancy or lactation. Patients were excluded if they had
taken drugs capable of influencing body weight within
the previous month.
Each subject received 2 times/d (i.e. 2 capsules
morning, 2 capsules midday) a green tea extract
AR25; ingestion of 4 capsules containing AR25 provided a daily total of 375 mg catechins, of which
270 mg was epigallocatechin gallate.

Recent findings of green tea extract AR25 (Exolise)

Assessments:
The initial screening visit included a medical history
taking physical examination, body weight evaluation.
Body weight, the primary efficacy measure, was evaluated every 4 weeks until week 12. Waist circumference
was also measured at each visit. Secondary outcome
measures included total cholesterol, low density
lipoprotein, high density lipoprotein and very low density lipoprotein cholesterol. Sitting blood pressure and
heart rate were measured at each clinic visit. All adverse events were documented and their severity and
apparent relationship to drug administration recorded
by the investigator at each visit.
Table 2. Baseline charactistics of patients.
Characteristic

Exolise

Sex
Male
Female

7
63

(10%)
(90%)

Age (years)*

44.7

(2069)

Anthropometry*
Weight (kg)
Body mass index (kg/m2)
Waist circumference (cm)

75.99 (59103)
28.9 (2532)
92.41 (69138)

Table 3. Evolution of weight.

Baseline (C1)

Week 4

Week 8

Week 12

70
75.99
8.85

68
74.64
8.93

63
73.97
9.02

66
72.49
8.97

Table 4. Evolution of waist circumference.

Number
Mean
stdt

Results:
A total of 70 patients 20 to 69 years of age were monitored. Demographic data are listed in Table 2. During
the course of the study, there was observed a continuing decrease of body weight as well as waist circumference (Table 3 and 4). At the end of the study, mean
body weight was decreased by 4.60% and waist circumference by 4.48%. No significant differences in
plasma cholesterol were observed after 3 months of
treatment.
No significant differences in blood pressure were observed during the 3 months of treatment (Table 5).
Overall, AR25 extract was well tolerated by the subjects. 5 adverse events were reported: abdominal pain
(2), diarrhea (2) and increase of transaminases (1).
Investigators and patients were requested to express
their overall opinion about the safety of the investigated
drug. AR25 extract was found to be well or very well
tolerated by 94% of subjects and 96% of investigators.

j Discussion

* Mean (range)

Number
Mean
stdt

Baseline (C1)

Week 4

Week 8

Week 12

70
92.41
11.72

68
90.6
10.86

63
89.98
10.91

66
88.27
10.8

Both increase in thermogenesis and inhibition of lipase

activities are two important pharmacological approaches for the treatment of obesity. Interestingly, all of the
above reported experimental and clinical studies
strongly suggest the tested green tea extract AR25 to be
a natural substance for the treatment of obesity, which
exerts its activity by several ways. In vitro green tea extract AR25 was shown to exert a
direct inhibition of gastric and pancreatic lipases,
stimulation of thermogenesis, possibly mediated by a
reduction in enzymatic degradation of NA and prolongation of action of sympathetically released NA.
In human studies there was observed a
significant increase of energy expenditure,
lowering of body weight, and
good tolerance.
Even under respect of the open uncontrolled design of
the study, the reduction of body weight by 4.6% in only 3
months of treatment is noticeable. This is underlined by
clinical findings with modern chemically defined sub-

Table 5. Evolution of blood pressure.

Number
Mean stdt

SBP (mmg Hg)

Baseline
Week 4
Week 8
Week 12

DBP (mm Hg)

----------
Baseline
Week 4
Week 8
Week 12

70
128.31
13.09

70
76.24
8.84

68
129.16
12.3

SBP Systolic blood pressure

DBP Diastolic blood pressure

63
127.70
12.53

66
127.65
12.41

68
75.26
8.23

63
74.05
8.36

66
76.15
8.95

P. Chantre and D. Lairon

stances. In a study in strong obese patients (medium BMI

of about 35 kg/m2) the dose-related effects of sibutramine (130 mg daily) on body weight loss were evaluated for 24 months. After 3 months, mean percent change
in weight was about 1% for placebo and about 3 up to
7.5% for sibutramine. The dose of sibutramine, which
was nearest to that effect of AR25 (4.6%), was in the
range of 5 to 10 mg of sibutramine (Bray et al. 1999).
Orlistat, administered by 120 mg t.i.d. for 1 year to patients with an BMI of about 36 kg/m2 together with a
hypocaloric diet lowered body weight by 10.2% as compared to placebo (6.1%). The study started with a placebo-run-in phase of 4 weeks. After 3 months of treatment
body weight reduction was about 2% under placebo and
5% for verum (Sjstrm et al. 1998). However, these
two studies where performed as controlled clinical studies and therefore exceed the significance and reliability
of a study in open design.
Stimulation of thermogenesis and fat oxidation by
the green tea extract AR25 was not accompanied by an
increase in heart rate. In this respect, the green tea extract is distinct from sympathomimetic drugs, whose
use as antiobesity thermogenic agents is limited by
their adverse cardiovascular effects and, hence, are particularly inappropriate for obese individuals with hypertension and other cardiovascular complications
(Dulloo et al. 1999).
Further studies are necessary to evaluate and document the observed weight-reducing action of green tea
extract AR25, especially in patients with a much
stronger obesity. However, since this extract is an
herbal medicinal product with a low risk potential, it
might be a suitable pharmacological approach in patients with moderate obesity and support their activities
to lower body weight.

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j Address
Dr. P. Chantre, Arkopharma Laboratories, B.P. 28, F - 06511
Carros Cedex, France.
Tel: ++33-493-29 11 28; Fax: ++33-493-29 11 62;
E-mail: r-d@arkopharma.com