Phytomedicine 18 (2011) 402–407

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Phytomedicine
journal homepage: www.elsevier.de/phymed

Short communication

Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa

Korth in mice model of depression
N. Farah Idayu a , M. Taufik Hidayat a,b,∗ , M.A.M. Moklas a , F. Sharida a ,
A.R. Nurul Raudzah a , A.R. Shamima a , Evhy Apryani a
a
Human Anatomy Laboratory, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia
b
Laboratory of Physical Performance and Skills Analysis, Sports Academy, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia

a r t i c l e i n f o a b s t r a c t

Keywords: Mitragyna speciosa Korth. leaves have been used for decades as a traditional medicine to treat diarrhea,
Mitragyna speciosa diabetes and to improve blood circulation by natives of Malaysia, Thailand and other regions of Southeast
Mitragynine Asia. Mitragynine is the major active alkaloid in the plant. To date, the role of mitragynine in psychological
Immobility time
disorders such as depression is not scientifically evaluated. Hence, the present investigation evaluates the
Forced swimming test
antidepressant effect of mitragynine in the mouse forced swim test (FST) and tail suspension test (TST),
Tail suspension test
Antidepressant-like activity two models predictive of antidepressant activity and the effect of mitragynine towards neuroendocrine
HPA axis system of hypothalamic-pituitary-adrenal (HPA) axis by measuring the corticosterone concentration of
Corticosterone mice exposed to FST and TST. An open-field test (OFT) was used to detect any association of immobility
in the FST and TST with changes in motor activity of mice treated with mitragynine. In the present
study, mitragynine at dose of 10 mg/kg and 30 mg/kg i.p. injected significantly reduced the immobility
time of mice in both FST and TST without any significant effect on locomotor activity in OFT. Moreover,
mitragynine significantly reduced the released of corticosterone in mice exposed to FST and TST at dose
of 10 mg/kg and 30 mg/kg. Overall, the present study clearly demonstrated that mitragynine exerts an
antidepressant effect in animal behavioral model of depression (FST and TST) and the effect appears to
be mediated by an interaction with neuroendocrine HPA axis systems.
© 2010 Elsevier GmbH. All rights reserved.

Introduction 2009). Therefore, other mechanism should be considered, as they

Mental disorder particularly major depression causes a signifi-
cant burden on health worldwide. The main symptom of depression
is characterized by a pervasive low mood, feeling of helplessness,
loss of interest and loss of pleasure in most of the usual activities
(Bhutani et al. 2009). Stressful environment, adverse life-event and
lack of supporting relationship are some of the causal factor that
contributes to development of depression in human.
Interactions between monoamine neurotransmitters system
including 5-hydroxytryptamine (5-HT), noradrenaline (NA) and
dopamine (DA) in the brain along with their specific reuptake
and receptor protein has gain so much interest in the spectrum
of antidepressant studies (Yi et al. 2008). As far, antidepressant
drugs available in the market claimed to be effective in treatment of
depression. However, the main significant drawbacks of that syn-
thetic antidepressant are due to their high incidence of dangerous
side effects and inadequate for number of individuals (Binfaré et al.
∗ Corresponding author. Tel.: +603 89472356.
E-mail address: taufik@medic.upm.edu.my (M. Taufik Hidayat).
might provide potential effective target with higher efficacy for
treatment of depression, and perhaps with fewer drawbacks.
The hypothalamic-pituitary-adrenal (HPA) axis in the neu-
roendocrine system is one of the complicated neurobiological
mechanisms which play important roles as similar as monoamine
neurotransmitters system in the new antidepressant development.
Dysfunction or hyperactivity of HPA axis system provides signifi-
cant indicator of depression together in the response to stressors
reflected by overproduction of glucocorticoid hormones mainly
corticosterone in rodent and cortisol in human (Xu et al. 2008).
Hence, the normalization of the HPA axis system as another prime
mechanism of antidepressant actions appears to be one of the spe-
cial interest.
Recently, more herbal medicine has being used as alternative
therapy for depression (Kessler et al. 2001). Due to its natural
constituent and availability, natural herbs which obtained from
natural sources are believed to provide less untoward effect profiles
and provide greater effectiveness as compared to synthetic drug
available over the market. Mitragyna speciosa Korth. is a tropical
plant endemic to Southeast Asia particularly in northern peninsula
of Malaysia, central and southern part of Thailand, and Indone-

0944-7113/$ – see front matter © 2010 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2010.08.011
 N. Farah Idayu et al. / Phytomedicine 18 (2011) 402–407
Fig. 1. Chemical structure of mitragynine.
sia (Jansen and Prast 1988; Mossadeq et al. 2009). It is popularly
known by local as ‘ketum’ in Malaysia and ‘kratom’ in Thailand. The
plant was classified under the coffee family of Rubiaceae. Mitrag-
yna speciosa leaves have been used by natives for its opium-like
effect and cocaine-like stimulant ability as anti-fatigue, anti-pain
and as tonic to increase endurances or performances of work under
hot sunlight (Reanmongkol et al. 2007). It is traditionally used
by villagers as an alternative treatment for fever, malaria, cough,
hypertension, diarrhea, to prolong sexual intercourse as well as
substitution for treatment of opiate addiction such as morphine
(Chan et al. 2005; Assanangkornchai et al. 2004).
Mitragyna speciosa contains abundant of indole alkaloids
(Matsumoto et al. 2008). Mitragynine (Fig. 1) was found to be
the primary active alkaloid compound of the entire plant which
might hold the key for the effects of Mitragyna speciosa (Takayama
2004). It has a molecule formula of 9-methoxy-corynantheidine
(C23 H30 N2 O4 ) with the molecular weight of 398.50 (Chee et al.
2008). Previously, in two different studies, alkaloid extract and
aqueous extract of Mitragyna speciosa has been shown to have
antidepressant-like effects in mouse models of behavioral despair
tests (Kumarnsit et al. 2007a, 2007b). However, antidepressant
mechanism of the plant in both studies is not clearly demon-
strated. In consideration of previous findings, mitragynine could be
a beneficial option in prevention and treatment for stress-induced
disorder such as depression.
In the present study, we evaluated the antidepressant-like effect
of mitragynine using two classical behavioral models of antide-
pressants screening known as forced swimming test (FST) and
tail suspension test (TST) together with open-field test (OFT). In
accordance to the tests, the effect of mitragynine on serum cor-
ticosterone concentrations (an index of HPA axis status) was also
simultaneously investigated in the present study.
Materials and methods
Preparation of mitragynine from Mitragyna speciosa leaves
The fresh leaves of Mitragyna speciosa Korth. were collected from
its natural sources around Peninsula Malaysia particularly in Perlis
and Kedah. The plant was authenticated by botanist from Depart-
ment of Botany, Faculty of Forestry, Universiti Putra Malaysia
(UPM), Serdang, Malaysia, based on their microscopic and macro-
scopic characteristics. A voucher specimen (ATS 001) was deposited
in the Herbarium of the Department of Botany, Faculty of Forestry,
Universiti Putra Malaysia (UPM), Serdang, Malaysia. Mitragynine
was purified from the fresh leaves of Mitragyna speciosa Korth
according to the method described by previous study (Houghton
and Ikram 1986; Ponglux et al. 1994; Reanmongkol et al. 2007).
403
The fresh leaves of Mitragyna speciosa (1 kg) were dried at
45–50 ◦ C, powdered and macerated with absolute methanol for
72 hours. The extracts were mixed, filtered and evaporated using
rotary evaporator (Eyela N-1000, Tokyo Rikakikai CO., LTD., Tokyo,
Japan) to yield 14.5% (w/w) of crude methanol extract. The
methanol extract was dissolved in 10% acetic acid solution, well
shaken, left to stand for 24 hours and filtered to give acidic fil-
trate. The acidic filtrate was washed with petroleum ether, made
into alkaline (pH 9) with 25% ammonia solution and extracted with
chloroform. The combined chloroform extracts were washed with
distilled water, dried over anhydrous sodium sulphate and evap-
orated to yield 0.73% (w/w) of crude alkaloid extract. The major
alkaloid was isolated by silica gel column chromatography elut-
ing with diethyl ether was identified as mitragynine with standard
spectroscopic methods (1 H NMR, 13 C NMR). Over all, the yield of
mitragynine was approximately 0.087% (w/w) of the fresh leaves
weight.
Reagent and chemicals
Mitragynine was dissolved in 20% (v/v) Tween-80 (poly-
oxyethylene sorbitan monooleate, Sigma–Aldrich Co.). Fluoxetine
hydrochloride, amitriptyline hydrochloride and amphetamine
hydrochloride were purchased from Sigma Chemical Co. (USA) and
were used as reference drugs. All drugs were dissolved in physio-
logical saline (NaCl 0.9%). All other reagents used in the study were
of analytical grade.
Animals
Male mice from the ICR strain purchased from Northern RK
Supplier, Sri Kembangan, Selangor, weighing 25–35 g were used.
Animals were placed at Animal house, Faculty of Medicine and
Health Sciences, Universiti Putra Malaysia Serdang, Selangor,
Malaysia, housed 8 per cage under a normal 12-h/12-h light/dark
schedule with the lights on at 07:00 a.m and had free access to water
and food pellets. They were allowed at least 7 days to adapt to the
laboratory prior to the administration. Experiments were carried
out between 9:00 a.m. and 3:00 p.m. All studies were conducted in
accordance with Animal Care Committee, Faculty of Medicines and
Health Sciences, Universiti Putra Malaysia, Serdang. The minimum
number of animals and duration of observations required to obtain
consistent data were employed. All efforts were made to minimize
animal suffering and to reduce the number of animal used.
Drugs administration
The animals were randomly assigned into control and six
experimental groups (8 mice per group) as follows: vehicle-
treated; mitragynine 5 mg/kg; mitragynine 10 mg/kg; mitragy-
nine 30 mg/kg; fluoxetine 20 mg/kg; amitriptyline 10 mg/kg and
amphetamine (1 mg/kg). Mitragynine and all drugs were intraperi-
toneally (i.p.) administered once. Mitragynine was dissolved in 20%
Tween-80 and diluted to the desired concentration on the day
of testing while fluoxetine, amitriptyline and amphetamine were
dissolved in normal saline (0.9% NaCl). Vehicle and mitragynine
were injected i.p., 30 min before testing. Fluoxetine was admin-
istered i.p., 60 min before testing, amitriptyline was administered
i.p., 30 min before testing and amphetamine was administered i.p.,
15 min before undertaking the test.
Forced swimming test (FST)
The test was conducted according to the reported methodology
originally described by Porsolt with minor modification (Porsolt
et al. 1977). Briefly, mice were individually forced to swim in an
404 N. Farah Idayu et al. / Phytomedicine 18 (2011) 402–407

open cylindrical container (diameter 14 cm, height 20 cm), with a
depth of 15 cm of water at 25 ± 1 ◦ C. The immobility time, defined
as the absence of escape-oriented behaviors, such as swimming,
was scored during 6 min with the help of stop-watch, as described
previously by (Eckeli et al. 2000; Zomkowsi et al. 2004; Kaster et
al. 2007). Each mouse was judge to be immobile when it ceased
struggling and remained floating motionless in the water, making
only those movements necessary to keep its head above water. The
parameter obtained was the number of seconds spent immobile.
The water in the containers was changed after each trial.
Tail suspension test (TST)
The total duration of immobility induced by tail suspension
test was measured according to the method described by Steru
et al. (1985). Mice both acoustically and visually isolated were
suspended 50 cm above the floor by adhesive tape placed approx-
imately 1 cm from the tip of the tail. The total immobility period
was scored manually during 6 minutes test session with the help of
stop-watch. Immobility was defined as the absence of any limb or
body movements, except for those caused by respiration or when
they hung passively and completely motionless. The parameter
obtained was the number of seconds spent immobile. Parameter
used was the number of seconds spent immobile.
the manufacturer’s instructions. The sensitivity of the assay was
<1.631 nmol/l. Intra-assay and inter-assay coefficients of variations
were less than 4.09% and 6.36% respectively. Data were expressed
as nmol/l.
Statistical analysis
Data were expressed as the mean ± standard error of mean
(S.E.M.). Comparisons between experimental and control groups
were performed by one-way analysis of variance (ANOVA) followed
by Tukey’s HSD test when appropriate. P < 0.05 was considered sig-
nificant.
Results
Effects of mitragynine on immobility time of FST
After 30 minutes of treatment, mitragynine significantly
reduced (P < 0.05) the duration of immobility time at 10 mg/kg and
30 mg/kg respectively as compared to control. Antidepressant drug
of selective serotonin reuptake inhibitor, fluoxetine at 20 mg/kg
and tricyclic antidepressant drug amitriptyline at 10 mg/kg that
used as positive control, administered by i.p. route caused signifi-
cant reduction (P < 0.05) in the immobility time of mice forced swim
test (FST) as compared with control (Fig. 2).

Open-field test (OFT) Effects of mitragynine on immobility time of TST

In order to rule out any unspecific locomotor effect of mitragy-
nine on antidepressant-like effect of these compounds, mice were
administered with the same regimen as in the FST or TST. Their
locomotor activities (crossing activity) were evaluated in the open-
field paradigm. Before each test, animals were kept in the test
room at least 1 hour before the open-field test (OFT) for habit-
uation. The ambulatory behavior was assessed in open-field test
described by Rodrigues et al. (1996) and Peng et al. (2007) with
slight modifications. The main apparatus consisted of square arena
(50 cm × 50 cm × 40 cm) high with grey surface covering every wall.
The floor of the arena was divided equally into twenty-five squares
(10 cm × 10 cm) marked by black lines. All animals were used only
once in this test. These animals were different from those used
in the FST and TST. Each mouse was placed individually into the
center of the arena and allowed to explore freely. The number
of squares crossed with all paws (crossing) were observed and
counted in 60 minutes. During the test session, the locomotor or
crossing activity of mice was recorded and saved using video cam-
era for permanent record (Moklas et al. 2008). The square arena
was cleaned with a solution of 10% alcohol between tests and dried
after occupancy by each mouse in order to hide animal clues and
to prevent each mouse from being influenced by the odors present
in the urine and feces of the previous mouse.
Mitragynine at 10 mg/kg and 30 mg/kg significantly reduced
(P < 0.05) immobility time of mice in tail suspension test (TST) as
compared to the control (vehicle). The clinically effective antide-
pressant fluoxetine at 20 mg/kg and amitriptyline at 10 mg/kg that
used as positive control produced a marked significant reduction
(P < 0.05) in the duration of immobility time as compared with con-
trol (Fig. 3).
Effects of mitragnine on locomotor activity of OFT
Treatment with mitragynine at 10 mg/kg and mitragynine at
30 mg/kg which significantly reduced duration of immobility time
in FST and TST produced no significant difference in number of
crossing activity of mice in OFT. The clinically effective antidepres-
sant fluoxetine at 20 mg/kg and amitriptyline at 10 mg/kg which
significantly reduced the duration of immobility time of mice FST
and TST produced no significant difference in number of crossing

Corticosterone assay

Blood from each mouse was withdrawn immediately after

exposure to force swim test (FST) and tail suspension test (TST)
respectively. In order to avoid fluctuations on hormone levels due
to circadian rhythm, mice were bled at 12:00 p.m. to 13:00 p.m. on
the day of sacrifice. Blood was collected through cardiac puncture
and sampled into plain tubes and was kept in room tempera-
ture. It was centrifuged at 3000 rpm for 10 minutes to separate
the serum and red blood cells. The serum was kept frozen at
−20 ◦ C freezer and stored it until assayed was performed. Serum
corticosterone concentrations were determined using a commer- Fig. 2. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine
cially available enzyme immunoassay kits (corticosterone ELISA, (20 mg/kg) and amitriptyline (10 mg/kg) on immobility time in the mouse forced
IBL International GMBH, Hamburgh Germany) used for the quanti- swim test (FST). Mitragynine was intraperitoneally (i.p.) administered 30 minutes
before FST. Each column represents the mean ± S.E.M. of immobility period (s) of 8
tative determinants of corticosterone in serum or plasma following
animals in each group (n = 8). *P < 0.05 compared to control.
 N. Farah Idayu et al. / Phytomedicine 18 (2011) 402–407
Fig. 3. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine
(20 mg/kg) and amitriptyline (10 mg/kg) on immobility time in the mouse tail sus-
pension test (TST). Mitragynine intraperitoneally (i.p.) administered 30 minutes
before the test. Each column represents the mean ± S.E.M. of immobility period (s)
of 8 animals in each group (n = 8). *P < 0.05 compared control.
activity as compared to control. However, psychostimulant drug,
amphetamine hydrochloride at 1 mg/kg which served as refer-
ence drug in open-field test (OFT) significantly increased (P < 0.05)
the number of crossing activity of mice as compared with control
(Fig. 4).
Effects of mitragynine on serum corticosterone levels in mice
exposed to FST
Swim stress procedure evoked a significant increased (P < 0.05)
in serum corticosterone levels of control mice as compared
to other treatment. Mitragynine elicited a significant reduction
(P < 0.05) in increased serum corticosterone levels induced by
forced swim test (FST). Mitragynine treatment of 5 mg/kg, 10 mg/kg
and 30 mg/kg significantly reduced (P < 0.05) the serum corticos-
terone levels in mice as compared with control. Amitriptyline at
10 mg/kg and fluoxetine at 20 mg/kg decreased the serum cor-
Fig. 4. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine
(20 mg/kg), amitriptyline (10 mg/kg) and amphetamine (1 mg/kg) on number of
crossings in open-field test (OFT) in 60 min. Mitragynine was intraperitoneally (i.p.)
administered 30 minutes before OFT. Each column represents the mean ± S.E.M of
number of crossing (s) of 8 animals in each group (n = 8). *P < 0.05 compared to
control.
405
Fig. 5. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine
(20 mg/kg), amitriptyline (10 mg/kg) on serum corticosterone levels in the mice
exposed to forced swim test (FST). Each column represents the mean ± S.E.M. of
serum corticosterone concentration (nmol/l) of 8 animals in each group (n = 8).
*P < 0.05 compared to control.
ticosterone levels (P < 0.05) significantly as compared to control
(Fig. 5).
Effects of mitragynine on serum corticosterone levels in mice
exposed to TST
A significant increased (P < 0.05) in serum corticosterone con-
centrations were observed in mice exposed to TST of control
vehicle-treated mice. Mitragynine at 10 mg/kg and 30 mg/kg sig-
nificantly reduced (P < 0.05) the serum corticosterone levels in
mice as compared with control. Treatment of mice with fluoxetine
at 20 mg/kg and amitriptyline at 10 mg/kg significantly reduced
(P < 0.05) the serum corticosterone in TST as compared with control
(Fig. 6).
Discussion
Behavioral studies have been shown to play an important part
in the evaluation and development of antidepressant drugs (Xu
et al. 2008). Forced swimming test (FST) and tail suspension test
(TST) are among behavioral models that widely and routinely used
for screening new antidepressant compound (Cryan et al. 2005).
In the present study, statistically significant results were obtained
in FST with treatment of mitragynine at 10 mg/kg and 30 mg/kg
(33% and 48% reduction respectively). Positive control antidepres-
sant drugs fluoxetine and amitriptyline produced significant result
Fig. 6. Effects of mitragynine (5 mg/kg, 10 mg/kg and 30 mg/kg), fluoxetine
(20 mg/kg), amitriptyline (10 mg/kg) on serum corticosterone levels in the mice
exposed to tail suspension test (TST). Each column represents the mean ± S.E.M.
of serum corticosterone concentration (nmol/l) of 8 animals in each group (n = 8).
*P < 0.05 compared to control.
406 N. Farah Idayu et al. / Phytomedicine 18 (2011) 402–407
on immobility time (57% and 76% reduction respectively) similar
with previous study (Reneric and Lucki 1998). The highest dose of
mitragynine shows comparable effect as fluoxetine and amitripty-
line in terms of its antidepressant actions revealing mitragynine
might share some pharmacological mechanisms with established
antidepressant drugs in this investigation.
Similar outcome were obtained in TST as mitragynine extract
at doses 10 mg/kg and 30 mg/kg significantly reduced the immo-
bility time (47% and 58% reduction respectively). Fluoxetine at
10 mg/kg and amitriptyline at 20 mg/kg decreased the immobility
time (75% and 76% reduction respectively). These results indicate
that mitragynine extract has a dose-dependent antidepressant-
like effect that is comparable to established antidepressant drugs.
Hence, the antidepressant action of mitragynine could possibly
through one of the mechanisms precipitated by established antide-
pressant agents that manage to be detected in TST.
Agents that able to enhance locomotor activity in OFT including
stimulants, convulsants and anticholinergic tend to produce a false
positive result in FST and TST (Bourin et al. 2001; Butterweck et al.
2003). In fact, hyperkinesia also causes false positive effect in FST
and TST by shortening the immobility time in both tests (Takahashi
et al. 2008). Therefore, OFT was used to exclude these false effects
that could be associated with hyperkinesia (Kwon et al. 2009). The
main difference between antidepressants and psycho-stimulant is
that antidepressants would not cause general increased in motor
activity (Borsini and Meli 1988). As a classical stimulant agent,
amphetamine produces effects via elevation of mood and energy
(hyperactivity) (Rothman and Baumann 2003). Mitragynine seems
unable to produce acute toxicity or psycho-stimulant side effect
related with hyperkinesia in the brain. In addition, the finding sug-
gested that reduction of immobility time elicited by mitragynine
in FST as well as in TST was specifically arises via its antidepres-
sant mechanism. This outcome is similar with previous study which
reported alkaloid and methanol extract of Mitragyna speciosa leaves
produced no significance effect over locomotor activity and on
pentobarbital-induced sleep in mice (Reanmongkol et al. 2007).
Forced swimming in FST induced alterations in the HPA axis,
thereby increase the cortisol level of mice (Shalam et al. 2007).
Reduction of HPA axis hyperactivity by antidepressants is crucial in
defining its therapeutic effects. In the present study, we observed
that mitragynine significantly reduced the corticosterone concen-
tration in mice exposed to FST and TST, in a way similar to previous
outcomes obtained using different antidepressant compounds (Yi
et al. 2007). Indeed, the present study shows mitragynine reduced
the corticosterone level of mice similar to classical antidepressant
drugs, amitriptyline and fluoxetine. These results are somewhat
similar to clinical studies that revealed amitriptyline caused signif-
icant decreased of salivary cortisol in depressed patient (Deuschle
et al. 2003) while fluoxetine produced the initial recovery of HPA
axis in depression (Inder et al. 2001).
Previous study also demonstrated that antinociceptive effect of
mitragynine is mediated through descending noradrenergic and
serotonergic systems receptors suggesting that mitragynine might
be able to stimulate the release of endogenous noradrenaline
(NA) and serotonin (5-HT) from nerve terminals of descending
monoaminergic neuron (Matsumoto et al. 1996). In fact, numerous
studies have reported that most classical antidepressants produce
antinociceptive actions (Casas et al. 1995; Rodrigues-Filho and
Takahashi 1999). Taken together those findings, we suggest that
the antidepressant-like action of mitragynine might be through the
restoration of monoamine neurotransmitter levels including sero-
tonin, noradrenaline and dopamine in mice. However, based on
our behavioral approach, we could not make definitive conclusions
on the detailed mechanism of mitragynine on monoamine levels.
Thus, further studies should be taken to confirm this particular
issue.
In conclusion, our results obviously show that administration of
mitragynine is able to produce an antidepressant-like effect in FST
and TST, which not due to effect of psycho-stimulant or hyperkine-
sia. Besides, we provide convincing evidence that the effect is due to
interaction with neuroendocrine HPA axis systems. Taken together,
our findings are somewhat in accordance with clinical results, fur-
ther suggesting that mitragynine may exert a role in the modulation
of depression and has psychotherapeutic value in management of
depression disorder. However, some consideration should be tak-
ing into account that FST and TST is not the only model of depression
by which the results obtained using this model should be consid-
ered and interpreted with caution due to some differences among
experimental animals and clinical studies in human. Hence, further
investigations are necessary to evaluate the effect of mitragynine in
other animal’s behavioral model including relevant antidepressant
doses of mitragynine on its safety and efficacy level.
Acknowledgements
This study was supported by Fundamental Research Grants
Scheme, Universiti Putra Malaysia, UPM Serdang, Selangor,
Malaysia.
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