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Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2012, Article ID 520198, 15 pagesdoi:10.1155/2012/520198
Review Article
Traditional Oriental Herbal Medicine for Children andAdolescents with ADHD: A Systematic Review
Yuk Wo Wong, Deog-gon Kim, and Jin-yong Lee
Department of Pediatrics, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu,Seoul 130-702, Republic of Korea
Correspondence should be addressed to Yuk Wo Wong, mon.y.w.wong@gmail.com
Received 23 July 2012; Revised 27 September 2012; Accepted 14 October 2012
Academic Editor: Jorg Melzer
Copyright © 2012 Yuk Wo Wong et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. To evaluate the efficacy of traditional Oriental herbal medicines (TOHM) for children and adolescents with ADHD.Methods. Randomized clinical trials published from January 1, 1990, to December 31, 2010, in English, Chinese, Japanese, orKorean language which evaluated the use of TOHM on ADHD subjects of 18 years old or below, diagnosed based on DSM-IV, weresearched from MEDLINE, EMBASE, PsyINFO, Cochrane Library, and 10 other databases. Results. Twelve studies involving 1189subjects met the inclusion criteria. In general, the included studies claimed that TOHM has similar efficacy to methylphenidateand at the same time has fewer side effects compared to methylphenidate. Some studies also suggested that the effect of TOHMsustained better than methylphenidate. However, solid conclusions could not be drawn because the included studies were not ofhigh quality. Risk of bias issues such as randomization, allocation, concealment and blinding were not addressed in most of thestudies, and the risk of publication bias could not be ruled out. Conclusion. Currently, there is not strong evidence to say thatTOHM is effective in treating the core symptoms of ADHD.
1. Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a behav-ioral disorder of which patients display persistent pattern ofinattention and hyperactivity/impulsivity or a combinationof the two at an abnormal level that their social, academic, oroccupational functioning is impaired [1]. While the etiologyof ADHD is not clearly known, studies have suggested thatthe abnormality of the frontal network and dysregulationof catecholamines are the underlying pathophysiology [2].Frontal lobes are involved in decision making to convertimpulse to action, attention, and concentration, and theyare primarily activated by the catecholamines, dopamine,and norepinephrine [3]. When frontal lobes are not fullyactivated, or when there are changes in the levels of dopamineand norepinephrine, the symptoms of hyperactivity andinattention are likely.
When making a diagnosis of ADHD, clinicians shoulddetermine that the diagnostic criteria have been met byassessing information obtained from primarily parents,guardians, and teachers [4]. For adolescents, information
from at least two teachers and other sources should beassessed because adolescents usually have multiple teachersand parents have little direct contact to observe theirstrengths and problems [4, 5]. Instruments such as theRevised Conners’ Parent Rating Scale and Revised Conners’Teacher Rating Scale are useful for screening and assessingbehavioral problems, and also helpful for assessing treatmenteffectiveness [6, 7].
Behavioral therapy and pharmacotherapy are two kindsof treatments commonly used in ADHD. Recommenda-tion of treatment for ADHD varies depending on thepatient’s age. While evidence-based behavioral therapy isrecommended as the first line of treatment for preschool-aged children (4-5 years of age), school-aged children (6–11 years of age) and adolescents (12–18 years of age) arerecommended a combination of medication and behavioraltherapy [4].
Stimulants are reported to be highly effective for mostchildren in reducing the core symptoms of ADHD and thusare used as first line medication for ADHD patients [2, 4].They are structurally similar to endogenous catecholamines
2 Evidence-Based Complementary and Alternative Medicine
and are thought to work by enhancing dopaminergic andnoradrenergic neurotransmission [2, 8].
Methylphenidate (Ritalin) is the most commonly usedstimulant for the treatment of ADHD [2, 9]. Around 70%of ADHD patients who receive stimulant treatment are givenmethylphenidate [10]. It is shown to be effective, at least inshort term, on improving the core symptoms of ADHD suchas attention, distractibility, and impulsivity (effect size 0.75–0.84, mean 0.78). Methylphenidate has observable effectson improving social and classroom behavior (effect size0.63–0.85, mean 0.8) [9]. Pemoline (Cylert) is a stimulantthat is longer acting than methylphenidate, but due to itspotential for hepatotoxicity, it is regarded as a third linetreatment [2]. In some cases, nonstimulants are also used inthe treatment of ADHD such as the norepinephrine specificreuptake inhibitors atomoxetine, and antidepressants suchas Imipramine, Phenelzine, and Bupropion [2, 11] but havebeen found to have significant differences in terms of efficacycompared to stimulants [8].
While stimulants are effective for many children withADHD, they may cause side effects, with the most commonones being decreased appetite, insomnia, and headache(Cohen’s d 0.67, 0.40, and 0.33 resp.) [12]. Other side effectssuch as motor tics, abdominal pain, irritability, nausea,and fatigue are also reported [9]. Therefore, many parentsof ADHD children try to search for more natural andsafe treatment options [13, 14], which has resulted in agrowing interest in complementary and alternative therapies(CAM), such as herbal remedies, dietary supplements,dietary modification, neurofeedback, homeopathic therapy,and chiropactic, in treatment of ADHD. Several surveysconducted on the use of CAM in ADHD showed over 50%of ADHD sufferers have used CAM [13, 15].
Herbal medicine is a treatment measure used in tra-ditional Oriental medicine. Although herb usually refersto materials from plant sources, in respect of traditionalOriental medicine, herbal materials can be originated fromplants, animals, or minerals. In this review, traditionalOriental herbal medicine (TOHM) is defined as medicinemade by materials used under traditional Oriental medicaltheory. Herbal materials that are not documented in theKorean Pharmacopoeia, the Japanese Pharmacopoeia, Phar-macopoeia of the People’s Republic of China, Zhong HuaBen Cao, and Zhong Yao Da Ci Dian (Chinese Medical GreatDictionary) are considered outside the context of TOHM.TOHM should be taken orally and studies employing otherroute of administration, such as intravenous or transdermal,are excluded from this review.
Even though ADHD was not described in literatureof traditional Oriental medicine, in traditional Orientalmedical theory, ADHD is related to congenital deficiency orinsufficient postnatal nourishment that leads to imbalancesin the body. It is suggested that the disorder is related to theheart, the liver, the spleen, and the kidneys [16]. TOHM isbelieved to work by adjusting the inner imbalances of ADHDpatients and thereby relieving the symptoms.
A study on ADHD using an animal model of spon-taneous hypertensive rat treated with an Oriental herbaldecoction comprised of Caulis Polygoni Multiflori (stem
of Polygonum multiflorum Thunb.), Radix RehmanniaePreparata (processed Rehmannia root), Carapax et Plas-trum Testudinis (Carapace and plastron of Chinemys reevsii(Gray)), Os Draconis (fossilized bones), Radix Polygalae(Polygala root), and Rhizoma Acori Tatarinowii (GrassleafSweetflag Rhizome) showed that the decoction increasedthe amount of dopamine at the frontal cortex and corpusstriatum [17], suggesting that its possible mechanism inADHD is to increase dopamine level and thereby enhancecatecholaminergic neurotransmission.
This review aims to evaluate the efficacy of TOHM as atreatment for ADHD in patients under the age of 18. TOHMis natural and often perceived to have fewer side effects thanconventional ADHD pharmacotherapy. Various research andclinical studies have been conducted on TOHM’s efficacy onADHD, but very few articles review the evidence of efficacyof the treatment. A systematic review on complementarymedicines for ADHD suggested that a Chinese herbalmedicine may be effective for ADHD [18] however in thereview only one study about Chinese herbal medicine wasincluded and analyzed. Further compilation and analysis ofcurrently available data about TOHM on ADHD may help tounderstand the true effect of the treatment on the disorders,and provide insight into the direction of future research.
2. Methods
2.1. Database Searching. English, Chinese, Korean andJapanese articles on randomized clinical trials (RCTs) ofOriental herbal treatment on ADHD published betweenJanuary 1, 1990, and December 31, 2010, were searchedfrom various databases. The details of search terms usedin different databases are presented in the appendix. Thefollowing databases were searched:
(1) Cochrane Library,
(2) EMBASE,
(3) MEDLINE,
(4) AMED,
(5) CINAHL Plus,
(6) PsyINFO,
(7) SinoMed–CBM—Chinese Database,
(8) China Journal Net—Chinese Database,
(9) WanFang Data—Chinese Database,
(10) Oriental Medicine Advanced Searching IntegratedSystem (OASIS)—Korean Database,
(11) Scholarly and Academic Information Navigator(CiNii)—Japanese Database,
(12) Database of Grants-in-Aid for Scientific Research(KAKEN)—Japanese Database,
(13) Japanese Institutional Repositories Online(JAIRO)—Japanese Database,
(14) Academic Research Database Repository (NII-DBR)—Japanese Database.
Evidence-Based Complementary and Alternative Medicine 3
2.2. Reference List. Other than searching from databases, thereference lists of the included studies were referred to in orderto identify more potential articles.
2.3. Criteria for Considering Studies for This Review
2.3.1. Type of Studies. Randomized clinical trials of TOHM.The efficacy of TOHM treatment should be compared toeither a placebo or a conventional medication used fortreating ADHD. If there was a baseline treatment, it had to bethe same in both the treatment and control groups. Studiesonly comparing different TOHM formulae, or comparingTOHM with other traditional Oriental treatment such asacupuncture were excluded. Studies without indicating “ran-domized” were considered not randomized and excluded.
2.3.2. Type of Participants. Subjects under the age of 18 whowere diagnosed with ADHD based on DSM-IV.
2.3.3. Type of Interventions. Traditional Oriental herbalmedicine must be used. Herbs that are not documented inthe Korean Pharmacopoeia, the Japanese Pharmacopoeia,Pharmacopoeia of the People’s Republic of China, ZhonghuaBencao, and Zhongyao Dacidian were not considered. Othertreatment measures of Oriental medicines such as acupunc-ture and moxibustion were excluded.
2.3.4. Types of Outcome Measures. The core symptoms ofADHD (hyperactivity, impulsivity, and inattention) wereconsidered in this review. Core symptoms should be assessedby at least one of the following tools: Revised Conners’ ParentRating Scale, Revised Conners’ Teacher Rating Scale, Con-ners’ Hyperactivity Index, Conners’ Abbreviated SymptomsQuestionnaire, Conners’ Global Index for Parents, and/orConners’ Global Index for Teachers.
2.4. Risk of Bias Assessment of Included Studies. The risk ofbias of all the included studies was assessed according toCochrane Handbook for Systematic Reviews of Inventionversion 5.1.0.
3. Results
The search came up with 1240 results, and 12 studies [16, 19–29] involving 1189 subjects were included in this review (seeFigure 1 for included studies selection).
All of the studies included in this review were conductedin China as single-centre trials. Five results in Japanese andeighteen results in Korean were identified. Only one Japanesearticle was about a clinical trial; however the trial was not arandomized trial and was therefore not selected.
Among the twelve included studies, none included theinformation on how sample size was derived and whetherthe study was statistically powered. The length of studyranged from 4 weeks to 24 weeks. Six studies had follow-up observation on subjects, ranging from 2 weeks to12 months after finishing treatment, to evaluate whetherthe intervention sustained effectiveness after treatment is
stopped while the other six studies did not report iffollow-up observations were conducted. Ten of the includedstudies reported homogeneity of baseline characteristics, butonly seven [20, 22, 24, 26–29] showed relevant descriptivestatistical data. Two studies [16, 19] did not report if baselinecharacteristics of subjects were homogenous. Only one ofthe studies [27] specified the subtype of ADHD subjectsincluded in the study. Characteristics of included studies aresummarized in Table 1.
3.1. Assessment of Risk of Bias. In general, the risk of bias inthe included articles is unclear. Very limited information wasrevealed in the studies to enable the reviewers to tell if theincluded studies were at risk of bias.
Only one of the included studies [16] described how ran-domization was done, but the study used two randomizationmethods where part of the subjects were randomized usinga random number table while part were allocated to thetreatment or control groups by their patient record numbers.The allocation concealment issue was not addressed in any ofthe included studies.
The blinding method was also not addressed in mostof the studies, and only two of the included studies [22,26] claimed to be a double-blind trial. Li et al. (1999)described the blinding method, which was to include aplacebo resembling methylphenidate in the treatment groupand a placebo that looked like the corresponding TOHM inthe control group. Wang et al. (2003) did not describe howblinding was done.
Most of the studies indicated no missing data. However,Ma et al. (2007) [25] did not specify the initial numberof subjects so it could not be determined if there was anyparticipant drop-out. Ma et al. (2007) [16] reported sevendrop-outs but no explanations were provided, and it wasunclear whether the drop-outs were from the treatmentgroup or the control group. In another study [23], threesubjects were excluded and there were five drop-outs, but thereasons were not sufficiently provided. Among those eightsubjects, it is only known that four of the drop-outs werereported to have terminated the study due to adverse effectof methylphenidate. Those three studies were considered tohave unknown risk of bias on incomplete outcome data.
Study protocols were not available for any of the includedstudies, therefore it could not be discerned whether all pre-specified outcomes were reported. Lai and Li (2006) [21] didnot report the baseline score before treatment and score aftertreatment. Xu (2005) [27] did not report the baseline scoreof rating. The two studies were considered to have high riskof reporting bias.
The risk of bias graph and summary are presented inFigures 2 and 3, respectively.
3.2. Diagnosis and Assessment of the Disorder. Although allincluded studies specified the diagnostic criteria and methodto assess treatment effect, only one study [16] specifiedwho completed the rating questionnaire or did the ratingassessment. None of the studies addressed under whichsetting the assessment was done. Also, the language of
4 Evidence-Based Complementary and Alternative Medicine
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Evidence-Based Complementary and Alternative Medicine 5
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prov
emen
tin
stu
dyin
g,eff
ecti
ven
ess
sust
ain
saf
ter
stop
pin
gm
edic
atio
nfo
r6
mon
ths,
Ch
ines
em
edic
ine
ther
apeu
tic
inde
x≥9
0%:
trea
tmen
t/co
ntr
ol:6
/2(i
i)Sh
owin
geff
ecti
ven
ess—
obvi
ous
alle
viat
ion
ofco
resy
mpt
oms,
Con
ner
sin
dex
decr
ease≤8
0%an
d>
50%
,im
prov
emen
tin
stu
dyin
g,C
hin
ese
med
icin
eth
erap
euti
cin
dex<
90%
and≥6
0%:t
reat
men
t/co
ntr
ol:2
0/18
(iii)
Show
ing
impr
ovem
ent—
impr
ovem
ent
ofco
resy
mpt
oms,
Con
ner
sin
dex
decr
ease≤5
0%an
d>
30%
,im
prov
emen
tin
stu
dyin
gbu
tn
otst
able
,Ch
ines
em
edic
ine
ther
apeu
tic
inde
x<
60%
and≥1
0%:
trea
tmen
t/co
ntr
ol:2
6/22
(iv)
Ineff
ecti
ve—
no
impr
ovem
ent
orw
orse
nin
gin
core
sym
ptom
san
dst
udy
ing,
Con
ner
sin
dex
decr
ease≤3
0%,
Ch
ines
em
edic
ine
ther
apeu
tic
inde
x<
10%
:tr
eatm
ent/
con
trol
:6/6
6 Evidence-Based Complementary and Alternative Medicine
Ta
ble
1:C
onti
nu
ed.
Stu
dyM
eth
odPa
rtic
ipan
tsIn
terv
enti
onO
utc
omes
Lin
etal
.200
7[2
4]R
ando
miz
edC
ontr
olTr
ial
Trea
tmen
tgro
upN
um
ber:
40,m
ale/
fem
ale:
32/8
Age
ran
ge:6
.5–1
3,m
ean
8.7±
2.7
Con
trol
grou
p1
(Rit
alin
)N
um
ber:
40,m
ale/
fem
ale:
31/9
Age
ran
ge:7
–12,
mea
n8.
5±
2.5
Con
trol
grou
p2
(tre
atm
ent
+R
ital
in)
Nu
mbe
r:40
,mal
e/fe
mal
e:32
/8A
gera
nge
:7–1
1,m
ean
8.2±
2.1
Cou
ntr
y:C
hin
aD
iagn
osti
ccr
iter
ia:D
SM-I
VB
asel
ine
char
acte
rist
ic:H
omog
enei
tyfo
rge
nde
r,ag
e,an
dco
urs
eof
dise
ase
Trea
tmen
tgro
upN
ings
hen
oral
liqu
id30
–60
mL
per
day
for
12w
eeks
Con
trol
grou
p1
Rit
alin
5m
g–40
mg
per
day
for
12w
eeks
Con
trol
grou
p2
Nin
gsh
enor
alliq
uid
30–6
0m
Lpl
us
Rit
alin
5m
g–40
mg
per
day
for
12w
eeks
Th
est
udy
defi
ned
trea
tmen
teff
ect
asfo
llow
s:(i
)N
ear
reco
very
—di
sapp
eara
nce
ofco
resy
mpt
oms,
Con
ner
sin
dex
decr
ease
>80
%,o
bvio
us
impr
ovem
ent
inst
udy
ing:
trea
tmen
t/co
ntr
ol1/
con
trol
2:4/
3/7
(ii)
Show
ing
effec
tive
nes
s—ob
viou
sal
levi
atio
nof
core
sym
ptom
s,C
onn
ers
inde
xde
crea
se≤8
0%an
d>
50%
,im
prov
emen
tin
stu
dyin
g:tr
eatm
ent/
con
trol
1/co
ntr
ol2:
7/7/
10(i
ii)Sh
owin
gim
prov
emen
t—im
prov
emen
tof
core
sym
ptom
s,C
onn
ers
inde
xde
crea
se≤5
0%an
d>
30%
,im
prov
emen
tin
stu
dyin
gbu
tn
otst
able
:tr
eatm
ent/
con
trol
1/co
ntr
ol2:
16/1
9/17
(iv)
Ineff
ecti
ve—
no
impr
ovem
ent
orw
orse
nin
gin
core
sym
ptom
san
dst
udy
ing,
Con
ner
sin
dex
decr
ease≤3
0%:
trea
tmen
t/co
ntr
ol1/
con
trol
2:13
/11/
6
Ass
essm
ent
ofC
onn
ers
inde
x12
wee
ksaf
ter
stop
pin
gm
edic
atio
nre
port
edth
atth
ere
was
sign
ifica
nt
drop
ineff
ecti
ven
ess
inR
ital
inco
ntr
olgr
oup
but
not
intr
eatm
ent
grou
pan
dco
mbi
ned
trea
tmen
tgr
oup.
Ma
2007
[16]
Ran
dom
ized
Con
trol
Tria
l
Trea
tmen
tgro
upN
um
ber:
22,m
ale/
fem
ale:
15/7
Con
trol
grou
pN
um
ber:
20,m
ale/
fem
ale:
20/1
6
Age
ran
ge:6
–13
Cou
ntr
y:C
hin
aD
iagn
osti
ccr
iter
ia:D
SM-I
VB
asel
ine
char
acte
rist
ic:n
otde
scri
bed
Th
ere
wer
eor
igin
ally
49su
bjec
tsin
the
stu
dyan
d7
case
sw
ere
attr
ited
,bu
tth
ere
was
no
indi
cati
onof
wh
eth
erth
eybe
lon
ged
totr
eatm
ent
grou
pan
dco
ntr
olgr
oup.
Rea
son
sfo
rat
trit
ion
wer
eal
son
otsu
ffici
entl
ypr
esen
ted
Trea
tmen
tgro
upD
uod
ongt
ing
deco
ctio
n15
0m
Lea
chti
me
for
age
4–7,
200
mL
each
tim
efo
rag
e8–
12,
twic
ea
day
for
28da
ys,a
nd
brea
kfo
r2
days
(1tr
eatm
ent
cycl
e)be
fore
star
tin
gan
oth
ertr
eatm
ent
cycl
e,fo
r2
cycl
es+
beh
avio
ral
ther
apy
Con
trol
grou
pR
ital
in0.
45m
g/kg
for
28da
ysan
dbr
eak
for
2da
ys(1
trea
tmen
tcy
cle)
befo
rest
arti
ng
anot
her
trea
tmen
tcy
cle,
for
2cy
cles
+be
hav
iora
lth
erap
y
Th
est
udy
defi
ned
trea
tmen
teff
ect
asfo
llow
s:(i
)Sh
owin
geff
ecti
ven
ess—
hype
ract
ivit
y,an
din
atte
nti
onal
levi
ated
by2/
3:tr
eatm
ent/
con
trol
:7/6
(ii)
Show
ing
impr
ovem
ent—
obvi
ous
sym
ptom
atic
impr
ovem
ent,
hype
ract
ivit
yan
din
atte
nti
onal
levi
ated
by1/
2:tr
eatm
ent/
con
trol
:11/
10(i
ii)
Ineff
ecti
ve—
no
sym
ptom
atic
relie
faft
er2
trea
tmen
tcy
cles
trea
tmen
t/co
ntr
ol:4
/4
Evidence-Based Complementary and Alternative Medicine 7
Ta
ble
1:C
onti
nu
ed.
Stu
dyM
eth
odPa
rtic
ipan
tsIn
terv
enti
onO
utc
omes
Ma
etal
.200
7[2
5]R
ando
miz
edC
ontr
olTr
ial
Trea
tmen
tgr
oup/
con
trol
grou
p-C
hin
ese
med
icin
e/co
ntr
olgr
oup-
Rit
alin
:55/
53/5
1
Cou
ntr
y:C
hin
aD
iagn
osti
ccr
iter
ia:D
SM-I
VB
asel
ine
char
acte
rist
ic:h
omog
enei
tyfo
rag
e,ge
nde
r,an
dco
urs
eof
dise
ase
Att
riti
oncr
iter
iaw
asm
enti
oned
but
ther
ew
asn
oin
dica
tion
ifan
ysu
bjec
tw
asat
trit
edbe
cau
sein
itia
lnu
mbe
rof
subj
ects
ran
dom
ized
was
not
stat
ed
Trea
tmen
tgro
upY
Izh
inin
gsh
engr
anu
les
10g
each
tim
efo
rag
e6–
10,1
5g
each
tim
efo
rag
e11
–18,
twic
ea
day
for
24w
eeks
Con
trol
grou
p1-
Chi
nese
med
icin
eJi
ngn
ing
oral
liqu
id10
mL
each
tim
e,tw
ice
ada
y,5
days
per
wee
kfo
r24
wee
ks
Con
trol
grou
p2-
Rit
alin
Rit
alin
5m
gea
chti
me
for
age
6–8,
and
10m
gea
chti
me
for
age
9–18
,tw
ice
ada
y,5
days
per
wee
kfo
r24
wee
ks
Th
est
udy
defi
ned
trea
tmen
teff
ect
asfo
llow
s:(i
)R
ecov
ery—
disa
ppea
ran
ceof
core
sym
ptom
s,C
onn
ers
inde
xde
crea
se>
80%
,obv
iou
sim
prov
emen
tin
stu
dyin
gan
dso
cial
fun
ctio
n,C
hin
ese
med
icin
eth
erap
euti
cin
dex
≥90%
:tre
atm
ent/
con
trol
1/co
ntr
ol2:
6/3/
3(i
i)Sh
owin
geff
ecti
ven
ess—
obvi
ous
alle
viat
ion
ofco
resy
mpt
oms,
Con
ner
sin
dex
decr
ease≤8
0%an
d>
50%
,im
prov
emen
tin
stu
dyin
gan
dso
cial
fun
ctio
n,C
hin
ese
med
icin
eth
erap
euti
cin
dex<
90%
and≥6
0%:
trea
tmen
t/co
ntr
ol1/
con
trol
2:29
/18/
19(i
ii)Sh
owin
gim
prov
emen
t—im
prov
emen
tof
core
sym
ptom
s,C
onn
ers
inde
xde
crea
se≤5
0%an
d>
30%
,im
prov
emen
tin
stu
dyin
gbu
tn
otst
able
,Ch
ines
em
edic
ine
ther
apeu
tic
inde
x<
60%
and≥1
0%:
trea
tmen
t/co
ntr
ol1/
con
trol
2:15
/27/
22(i
v)In
effec
tive
—n
oim
prov
emen
tor
wor
sen
ing
inco
resy
mpt
oms
and
stu
dyin
g,C
onn
ers
inde
xde
crea
se≤3
0%,
Ch
ines
em
edic
ine
ther
apeu
tic
inde
x<
10%
:tr
eatm
ent/
con
trol
1/co
ntr
ol2:
5/5/
7
Wan
gan
dSh
i20
03[2
6]R
ando
miz
edC
ontr
olTr
ial
Trea
tmen
tgro
upN
um
ber:
58,m
ale/
fem
ale:
49/9
Age
ran
ge:m
ean
9.3±
2.9
Con
trol
grou
pN
um
ber:
50,m
ale/
fem
ale:
42/8
Age
ran
ge:m
ean
9.5±
3.2
Cou
ntr
y:C
hin
aD
iagn
osti
ccr
iter
ia:D
SM-I
Van
dC
onn
ers
inde
x>
1.5
Bas
elin
ech
arac
teri
stic
:hom
ogen
eity
for
age,
gen
der,
cou
rse
ofdi
seas
e,an
dIQ
Trea
tmen
tgro
upJi
ngn
ing
oral
liqu
id10
mL
each
tim
e,tw
ice
ada
yfo
r4
wee
ks
Con
trol
grou
pR
ital
in10
mg
inth
em
orn
ing
and
5m
gat
nig
ht
for
4w
eeks
Th
est
udy
defi
ned
trea
tmen
teff
ect
asfo
llow
s:(i
)Sh
owin
geff
ecti
ven
ess—
disa
ppea
ran
ceof
sym
ptom
s,ob
viou
sim
prov
emen
tin
soci
alfu
nct
ion
and
stu
dyin
g,C
onn
ers
inde
x<
1.2:
trea
tmen
t/co
ntr
ol:2
7/23
(ii)
Show
ing
impr
ovem
ent—
impr
ovem
ent
ofsy
mpt
oms,
impr
ovem
ent
inso
cial
fun
ctio
nan
dst
udy
ing
but
impr
ovem
ent
not
stab
le,d
ecre
ase
inC
onn
ers
inde
xbu
tst
ill>
1.5:
trea
tmen
t/co
ntr
ol:2
6/22
(iii
)In
effec
tive
—n
oim
prov
emen
tor
wor
sen
ing
insy
mpt
oms,
Con
ner
sin
dex
and
stu
dyin
g:tr
eatm
ent/
con
trol
:5/5
No
side
effec
tsob
serv
edin
trea
tmen
tgr
oup
but
10su
bjec
tsin
con
trol
grou
pre
port
edn
ause
aan
dlo
ssin
appe
tite
,2su
bjec
tsre
port
eddi
zzin
ess,
and
1su
bjec
tre
port
edsl
eepl
essn
ess.
8 Evidence-Based Complementary and Alternative Medicine
Ta
ble
1:C
onti
nu
ed.
Stu
dyM
eth
odPa
rtic
ipan
tsIn
terv
enti
onO
utc
omes
Xu
2005
[27]
Ran
dom
ized
Con
trol
Tria
l
Trea
tmen
tgro
upN
um
ber:
100,
mal
e/fe
mal
e:87
/13
Age
ran
ge:m
ean
9.3±
2.4
Con
trol
grou
pN
um
ber:
50,m
ale/
fem
ale:
43/7
Age
ran
ge:m
ean
9.1±
2.3
Cou
ntr
y:C
hin
aD
iagn
osti
ccr
iter
ia:D
SM-I
Vcr
iter
iaof
com
bin
edty
pe
AD
HD
Bas
elin
ech
arac
teri
stic
:hom
ogen
eity
for
age,
gen
der,
cou
rse
ofdi
seas
e,an
dIQ
Trea
tmen
tgro
upJi
ngn
ingz
hid
ong
gran
ule
s1
g/kg
/day
,m
axim
um
50g,
for
12w
eeks
Con
trol
grou
pR
ital
in0.
3m
g/kg
/day
,in
crea
sedo
sage
grad
ual
lyto
max
imu
m0.
6m
g/kg
/day
,for
12w
eeks
Th
est
udy
defi
ned
trea
tmen
teff
ect
asfo
llow
s:(i
)Sh
owin
geff
ecti
ven
ess—
decr
ease
inC
onn
ers
inde
xby
≥66%
:tre
atm
ent/
con
trol
:56/
26(i
i)Sh
owin
gim
prov
emen
t—de
crea
sein
Con
ner
sin
dex
≥33%
and<
66%
:tre
atm
ent/
con
trol
:22/
14(i
ii)
Ineff
ecti
ve—
decr
ease
inC
onn
ers
inde
x<
33%
:tr
eatm
ent/
con
trol
:22/
10
Th
ere
was
alm
ost
no
side
effec
tre
port
edin
trea
tmen
tgr
oup
but
subj
ects
inco
ntr
olgr
oup
repo
rted
mor
eob
viou
san
dpe
rsis
ten
tsi
deeff
ects
.Ass
essm
ent
ofC
onn
ers
inde
x4
wee
ksaf
ter
stop
pin
gm
edic
atio
nre
port
edth
atth
ere
was
sign
ifica
nt
drop
ineff
ecti
ven
ess
inco
ntr
olgr
oup
but
not
intr
eatm
ent
grou
p.
L.Ya
ng
and
J.Ya
ng
2005
[28]
Ran
dom
ized
Con
trol
Tria
l
Trea
tmen
tgro
upN
um
ber:
48,m
ale/
fem
ale:
40/8
Age
ran
ge:6
–12
(mea
n8.
3)
Con
trol
grou
pN
um
ber:
38,m
ale/
fem
ale:
31/7
Age
ran
ge:6
.5–1
3(m
ean
8.6)
Cou
ntr
y:C
hin
aD
iagn
osti
ccr
iter
ia:D
SM-I
VB
asel
ine
char
acte
rist
ic:H
omog
enei
tyfo
rge
nde
r,ag
e,co
urs
eof
dise
ase,
and
coex
isti
ng
sym
ptom
s
Trea
tmen
tgro
upY
izh
inin
gsh
enor
alliq
uid
2×
10m
L,3
tim
esa
day
for
3m
onth
s+
beh
avio
ralt
her
apy
Con
trol
grou
pR
ital
in10
mg,
once
per
day
for
3m
onth
s,n
om
edic
atio
ndu
rin
gw
eeke
nd
and
hol
iday
+be
hav
iora
lth
erap
y
Th
est
udy
defi
ned
trea
tmen
teff
ect
asfo
llow
s:(i
)R
ecov
ery—
disa
ppea
ran
ceof
core
sym
ptom
s,C
onn
ers
inde
xde
crea
se>
80%
,obv
iou
sim
prov
emen
tin
stu
dyin
g,eff
ecti
ven
ess
sust
ain
saf
ter
stop
pin
gm
edic
atio
nfo
r6
mon
ths:
trea
tmen
t/co
ntr
ol:6
/2(i
i)Sh
owin
geff
ecti
ven
ess—
obvi
ous
alle
viat
ion
ofco
resy
mpt
oms,
Con
ner
sin
dex
decr
ease
>50
%,i
mpr
ovem
ent
inst
udy
ing:
trea
tmen
t/co
ntr
ol:1
6/15
(iii)
Show
ing
impr
ovem
ent—
impr
ovem
ent
ofco
resy
mpt
oms,
Con
ner
sin
dex
decr
ease
>30
%,i
mpr
ovem
ent
inst
udy
ing
but
not
stab
le:t
reat
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Evidence-Based Complementary and Alternative Medicine 9
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10 Evidence-Based Complementary and Alternative Medicine
Record identified through
database searching
N = 1235
Additional record identified
through other sources
N = 5
After duplicates removed
N = 790
Record screened
N = 790
Full text articles assessed
for eligibility
N = 124
Studies included in
qualitative synthesis
N = 12
666 records excluded
Reasons:
• Irrelevant topic
• Review/case report
• Animal study
112 records excluded
Reasons:
• Not controlled or randomized trial
• Improper control group
• Improper diagnostic/
assessment criteria
• Combined other treatments/different
baseline treatment
Figure 1: Selection of studies flowchart.
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias
0 25 50 75 100
(%)
Low risk of biasUnclear risk of biasHigh risk of bias
Figure 2: Risk of bias graph of the included studies.
Evidence-Based Complementary and Alternative Medicine 11
Cheng et al. 2006
Kong et al. 2007
L. Yang and J.Yang 2005
Lai and Chen 1999
Lai and Li 2006
Li et al. 2004
Lin et al. 2007
Ma et al. 2007
Ma 2007
Wang and Shi 2003
Xu et al. 2005
Yu and Wang 2005
? ? ?? ?? ?
?? ? ?? ? ?
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? ? ?? ? ?+
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dom
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ias)
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Figure 3: Risk of bias summary of the included studies.−: high riskof bias, +: low risk of bias, ?: unknown risk of bias.
assessment tools was not specified. It was not clear if theassessment tools were validated in cases where they weretranslated into another language.
3.3. Treatment Effectiveness. The herbal formulae used inthe included twelve studies varied, and dosage forms ofdecoction, granules, oral liquids, pill, and so forth were used.Nine studies [16, 19–22, 25, 27–29] provided the ingredientsof the formulae, but among them five [22, 25, 27–29] didnot specify the amount of each herb used in the formula,and therefore there was very little information on drug toextract ratio. Three studies [23, 24, 26] did not provide theformula at all. None of the studies mentioned how the herbalmedicines used were standardized. The details of the herbalingredients used in the included studies, their dosage form,and daily dose are presented in Table 2.
Among the twelve studies, there were ten 2-arm studies[16, 19–23, 26–29] that compared the effectiveness ofTOHM to methylphenidate, and one 3-arm study [24] whichincluded a TOHM treatment group, a TOHM control group,and methylphenidate control group. These studies claimedthat TOHM had no significant difference on effectivenesscompared to methylphenidate. However, seven of them[16, 21, 22, 26–29] did not conduct statistical analyses todemonstrate whether there was significant efficacy comparedto the baseline.
The remaining one of the twelve included studies [24]evaluated the net effect of TOHM by having a combinedtreatment group of TOHM and methylphenidate, and amethylphenidate control group. The study reported thatTOHM and methylphenidate worked better in combinationthan methylphenidate alone, with statistically significantdifferences when comparing the rate of effectiveness of thetwo groups.
3.4. Follow-Up Observation on Effectiveness. Among theincluded studies, six had follow-up observations to evaluatethe sustainability of treatment effect of core symptom afterstopping medication, while the other six studies did notspecify if follow-up observation was done. The follow-upperiod varied from 2 weeks to 12 months after stopping thetreatment. For the six studies with follow-up observation,five [20, 23, 24, 27, 28] compared the treatment effect ofTOHM and methylphenidate after stopping medication andall reported the effect of TOHM sustained better comparedto methylphenidate. The remaining one [25] only followedup on the effect of the TOHM treatment group.
3.5. Safety and Side Effects. In general, TOHM was claimedto have fewer side effects than methylphenidate. Eight ofthe included studies [19–24, 27, 28] discussed side effects.In general, more cases of side effect were reported in themethylphenidate control group than the TOHM treatmentgroup. Two studies [26, 28] reported no cases of sideeffect in the TOHM treatment group. Cheng et al. (2006)reported that among the side effect cases in their study, drymouth, sweating, nausea, weight loss, loss of appetite, andheadache were significantly fewer in the TOHM treatmentgroup compared to the methylphenidate control group(P < 0.05) [19]. Lai and Li (2006) reported that casesof loss of appetite and drowsiness were significantly fewer(P < 0.05) [21]. Lin et al. (2007) reported that casesof sleeplessness, dizziness/headache, sweating, dry mouth,nausea, loss of appetite, weight loss, and constipation weresignificantly fewer in the treatment group than the controlgroup (P < 0.01) [24]. Xu (2005) compared the averagescore of Treatment Emergent Symptoms Scale (TESS) in thetreatment group and the control group, and reported that theaverage score was significantly higher in the control group(P < 0.01) [27]. Four other studies [19, 20, 22, 26] alsoclaimed to have used TESS to evaluate side effects but scoreswere not reported.
Three studies [16, 25, 28] performed liver function tests,renal function tests, and/or ECGs on subjects after treatment
12 Evidence-Based Complementary and Alternative Medicine
Table 2: Details of the herbal treatments used in the included studies.
Cheng et al. 2006[19]
Ingredients and amount: Radix Rehmanniae Preparata 6 g, Carapax et Plastrum Testudinis 5 g, Cervi CornuDegelatinatum 5 g, Rhizoma Acori Tatarinowii 10 g, Radix Polygalae 10 g, Radix et Rhizoma Salviae Miltiorrhizae10 g, Fructus Schisandrae Chinensis 5 gDosage form: Decoction. The above amount of ingredients are boiled with water to yield 90 mL of decoction.Daily dose: 90 mLStandardization: not known
Kong et al. 2007[20]
Ingredients and amount: Fructus Lycii 9 g, Flos Chrysanthemi 9 g, Radix Rehmanniae Preparata 24 g, Fructus Corni12 g, Rhizoma Dioscoreae 12 g, Rhizoma Alismatis 9 g, Cortex Moutan 9 g, Poria 9 gDosage form: Pills. It was not clear how many pills were made out of the above amount of herbs.Daily dose: 9 pillsDrug to extract ratio: not knownStandardization: not known
Lai and Li 2006[21]
Ingredients and amount: Os Draconis 20 g, Carapax et Plastrum Testudinis 10 g, Radix Polygalae 5 g, Rhizoma AcoriTatarinowii 10 g, Fructus Tritici Levis 20 g, Radix Ophiopogonis 10 g, Caulis Polygoni Multiflori 15 g, RadixCodonopsis 15 g, Poria 15 g, Radix Rehmanniae Preparata 15 g, Fructus Schisandrae Chinensis 4 g, Radix et RhizomaGlycyrrhizae 4 g. Depending on the symptoms of different patients, other herbs might be added but the amount wasnot specified.Dosage form: Decoction. 150 mL of decoction was made from the above ingredients.Daily dose: 150 mLStandardization: not known
Li and Chen 1999[22]
Ingredients and amount: Fructus Lycii, Radix Rehmanniae Preparata, Fructus Schisandrae Chinensis, Radix etRhizoma Ginseng, Poria, Radix et Rhizoma Glycyrrhizae. Amount was not specified.Dosage form: GranulesDaily dose: 3 g or 6 g depending on the age of subjectDrug to extract ratio: not knownStandardization: not known
Li et al. 2004 [23]
Ingredients and amount: not knownDosage form: GranulesDaily dose: 2 doses or 4 doses depending on the age of subject. Amount of granules contained in 1 dose was notspecified.Drug to extract ratio: not knownStandardization: not known
Lin et al. 2007 [24]
Ingredients and amount: not knownDosage form: oral liquidDaily dose: 30–60 mLDrug to extract ratio: not knownStandardization: not known
Ma 2007 [16]
Ingredients and amount: Flos Magnoliae 10 g, Radix Paeoniae Alba (parched) 30 g, Rhizoma Gastrodiae 8 g, RadixIsatidis 15 g, Radix Scrophulariae 15 g, Massa Medicata Fermentata 6 g, Fructus Crataegi 6 gDosage form: Decoction. The amount of decoction yielded from the above ingredients was not specified.Daily dose: 150 mL or 200 mL depending on the age of subjectDrug to extract ratio: not knownStandardization: not known
Ma et al. 2007 [25]
Ingredients and amount: Homonis Placenta, Radix Rehmanniae Preparata, Rhizoma Acori Tatarinowii, RadixPolygalae, Rhizoma Alismatis, Rhizoma Coptidis, and so forth. Amount was not specified.Dosage form: GranulesDaily dose: 20 g or 30 g depending on the age of subjectDrug to extract ratio: not knownStandardization: not known
Wang and Shi 2003[26]
Ingredients and amount: not knownDosage form: Oral liquidDaily dose: 20 mLDrug to extract ratio: not knownStandardization: not known
Xu 2005 [27]
Ingredients and amount: Radix Bupleuri, Radix Peoniae Alba, Ramulus cum Uncis Uncariae, Os Draconis,Margaritifera Concha, Radix Pseudostellariae, Fructus Alpiniae Oxyphyllae, Radix Polygalae, Rhizoma AcoriTatarinowii, Fructus Schisandrae Chinensis, Poria, Radix et Rhizoma Glycyrrhizae Preparata. Amount was notspecified.Dosage form: Granules. 1 g of granules is equivalent to 5 g of herbs.Daily dose: up to 50 g depending on the body weight of subjectStandardization: not known
Evidence-Based Complementary and Alternative Medicine 13
Table 2: Continued.
L. Yang and J. Yang2005 [28]
Ingredients and amount: Radix Rehmanniae Preparata, Radix Astragali, Radix Peoniae Alba, Os Draconis, RadixPolygalae, Rhizoma Acori Tatarinowii, Fructus Schisandrae Chinensis, Rhizoma Atractylodis Macrocephalae.Amount not specified.Dosage form: Oral liquidDaily dose: 60 mLStandardization: not known
Yu and Wang 2005[29]
Ingredients and amount: Rhizoma Coptidis, Pericarpium Citri Reticulatae, Rhizoma Pinelliae Preparatum, Poria,Rhizoma Atractylodis Macrocephalae, Radix Peoniae Alba, Ramulus cum Uncis Uncariae, Flos Chrysanthemi, RadixPolygalae, Fructus Alpiniae Oxyphyllae, Fructus Corni. Amount was not specified. Other herbs might be addeddepending on the symptoms of individual subject but the exact ingredients and amount were not given.Dosage form: DecoctionDaily dose: 1 dose. The amount of 1 dose was not specified.Drug to extract ratio: not knownStandardization: not known
and results showed that subjects had no impairment onliver function, renal function, and/or cardiac function aftertreatment with TOHM and methylphenidate, suggestingthat both TOHM and methylphenidate do not cause anysignificant safety concern on treatment of ADHD, at least inthe short term.
4. Discussion
This review included twelve studies, and though findings ofthis review suggested that the herbal preparations coveredunder the term TOHM may be effective in treating thecore symptoms of ADHD; the overall evidence is not strongenough to draw solid conclusions, because in general theclinical trials were not of high quality and the herbalpreparations far too different. Additionally, it cannot be ruledout that there is possibility of publication bias.
The included studies that discussed side effect issues allsuggested that TOHM had fewer side effects compared tomethylphenidate. However, such result should be interpretedwith caution, because first of all it was not clear whetherthe side effect cases, both in the TOHM group and themethylphenidate group, were investigated to find out ifthey were related to the intervention. Secondly, it wasnot addressed in most studies whether blinding was done.As mentioned, since TOHM is indigenous to the studypopulation, and is often perceived as natural with fewer sideeffects, if measures are not properly done to blind subjectsfrom knowing what treatment they are getting, it may causebias in reporting side effects.
In the future, should more clinical trials on ADHD usingTOHM as treatment be conducted, clinical investigatorsshould consider to address the issues discussed below inorder to improve the robustness of data.
In the diagnosis of ADHD and assessment of treatmentefficacy, tools such as rating scales are often used. In orderto make precise assessment, information should be obtainedfrom different parties including parents, guardians, andteachers under different settings, such as home and school[4]. However, among the included studies, eleven of them didnot specify who completed the questionnaires for assessmentor under which setting the assessment was done. It was
difficult to tell whether sufficient information was obtainedto facilitate an accurate assessment of the treatment effect.Also, since the studies were done in Chinese population, itwas possible the questionnaires used were in Chinese, but noinformation was available to tell whether the questionnaires,in case written in another language, were validated or not.Investigators did not indicate whether the tool of assessmenthas been modified to suit the study purpose as well. Suchinformation should be described in the study methods.
Among the included studies, the herbal medicines them-selves varied. Some of the studies did not tell what herbswere used, some did not specify the amount of herbs used,and the treatment dosage was not clear in some studies.Also, the treatment period varied for each study. Due tosuch heterogeneity, it is not possible to deduce from the datawhich herbal formulae or ingredients may be effective forADHD, nor to conclude that TOHM is effective for ADHDin children and adolescents. Although it is inevitable thatdifferent studies may use different herbs and have differenttreatment periods, the materials used and the amount shouldbe stated clearly in the publication of clinical trial results. Asvarious herbal treatments are used in different clinical studiesthe results even of the positive studies cannot be compared.Clinical investigators may have to consider repeating a studywith the same herbal treatment, or to conduct a clinical trialin multiple sites.
Due to the complex nature of herbs, how the consistencyof herbal treatment is maintained throughout a clinicalstudy is often an issue to consider. Most of the studiesincluded in this review used the herbal treatment substancesin form of decoctions or other preparations such as granulesor oral liquid prepared by the clinical sites. It was notaddressed how the consistency of treatment substances waskept throughout the studies, or how the treatment substanceswere standardized to ensure quality. In addition, in threeof the studies [16, 21, 29], prescriptions given to subjectsvaried according to their symptoms. Although one of thecharacteristics of traditional Oriental medicine is tailor-made treatment according to the patient’s condition, ina clinical study setting, this may introduce confoundingvariables. Investigators should make an effort to ensure theherbal treatment used in a study is of consistent quality
14 Evidence-Based Complementary and Alternative Medicine
throughout the study period. One of the possible ways toaddress this problem is to use herbal medicines prepared byqualified pharmaceutical manufacturers, and the treatmentpreparation should also be standardized.
4.1. Strength of This Review . In this review, the reviewersperformed a thorough search in various databases. Otherthan major databases that have information of articlespublished mostly in English, additional Chinese, Korean,and Japanese databases were searched to identify potentialstudies. Articles written in English, Chinese, Korean, andJapanese languages were screened in order to include as manysuitable studies in the review as possible.
4.2. Limitation of This Review. Due to limited resources,the reviewers could only seek published studies. For a robustreview, nonpublished data should also be sought. Also, thereviewers were not able to contact the authors of includedstudies for clarification and further information on theirstudies.
Even though the reviewers did a thorough search ofpublished studies, the included studies were all conducted onChinese population. Little could be told about the effect ofTOHM on ADHD on populations of other countries .
5. Conclusion
This review included twelve studies on different herbalpreparations from TOHM as a treatment for children andadolescents with ADHD. Findings suggest that some of themmay have similar efficacy to methylphenidate, but solidconclusions could not be drawn due to quality problems ofthe clinical trials. In conclusion, currently there is no strongevidence to suggest that TOHM is effective in treating thecore symptoms of ADHD. More studies with low risk of biasand using the same herbal preparation are required beforefurther conclusions can be drawn.
Appendix
Search Terms Used in Different Databases
Cochrane Library, EMBASE, MEDLINE, AMED, CINAHLPlus, PsyINFO. ADHD (or attention-deficit/hyperactivitydisorder or hyperkinetic disorder or minimal brain dysfunc-tion) and alternative medicine (or complementary medicineor Chinese medicine or kampo or Korean medicine orOriental medicine or phytotherapy or herbal).
SinoMed (CBM), China Journal Net, WanFang Data—
Chinese Databases
(1) ADHD and Chinese medicine (in Chinese).
(2) Attention-deficit/hyperactivity disorder (in Chinese)and Chinese medicine (in Chinese).
(3) Hyperactivity (in Chinese) and Chinese medicine (inChinese).
(4) Minimal brain dysfunction (in Chinese) and Chinesemedicine (in Chinese).
(5) Hyperkinetic disorder (in Chinese) and Chinesemedicine (in Chinese).
Oriental Medicine Advanced Searching Integrated System
(OASIS)—Korean Database
(1) ADHD.
(2) Attention-deficit/hyperactivity disorder (in Korean).
Scholarly and Academic Information Navigator (CiNii),
Database of Grants-in-Aid for Scientific Research (KAKEN),
Japanese Institutional Repositories Online (JAIRO), Aca-
demic Research Database Repository (NII-DBR)—Japanese
Databases
(1) ADHD and Kampo (in Japanese).
(2) Attention-deficit/hyperactivity disorder (in Japanese)and Kampo (in Japanese).
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014
Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Parkinson’s Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com