Complementary Therapies in Medicine (2011) 19, 4753

available at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/ctim

Efcacy of Clinacanthus nutans extracts in patients

with herpes infection: Systematic review and
meta-analysis of randomised clinical trials
Chuenjid Kongkaew a, Nathorn Chaiyakunapruk a,b,c,d,

a
Faculty of Pharmaceutical Sciences, Naresuan Univerisity, Thailand
b
Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan
University, Phitsanulok, Thailand
c
School of Pharmacy, University of Wisconsin, Madison, USA
d
School of Population Health, University of Queensland, Australia
Available online 12 January 2011

KEYWORDS Summary
Clinacanthus nutans; Objective: To examine the efcacy of Clinacanthus nutans extracts in treatment of Herpes
Herpesvirus; genitalis and Herpes zoster from randomised clinical trials (RCTs).
Herpes genitalis; Methods: Bibliographic databases, including MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL,
Herpes zoster AMED, WHO trial registry, http://www.clinicaltrial.gov, Thai Index Medicus, and Index Medicus
Siriraj library, were searched from their inception dates to February 2010 without language
restrictions. Methodological quality of included trials was assessed using Jadads quality scale
and Cochranes risk of bias.
Results: Four RCTs (n = 286) met our inclusion criteria which include two studies on H. genitalis
and the other two on H. zoster; in these studies, a total of 151 patients were assigned to the
C. nutans group of H. genitalis trials, a pooled relative risk of C. nutans preparations against
placebo for a 3 day-full crusting was 6.62 (95% C.I. 3.8311.47) and of a 7-day complete healing
was 3.77 (95% C.I. 2.465.78). In H. zoster, the relative risk for a 3 day-full crusting was 3.21
(IQR 0.9710.58).
Conclusions: This meta-analysis and systematic review suggests some benecial effects of
C. nutans preparations on treatments of H. genitalis and H. zoster. However, more robustly
designed trials are needed to substantiate the benet of these plants, specically on their active
puried compounds, and their potencies and benets on treatment outcome of H. genitalis and
H. zoster.
2010 Elsevier Ltd. All rights reserved.

Corresponding author at: Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical

Sciences, Naresuan University, Phitsanulok-Nakornsawan Rd., Mueng, Phitsanulok 65000, Thailand. Tel.: +66 55 961826; fax: +66 55 963731.
E-mail addresses: nui@u.washington.edu, chaiyakunapr@wisc.edu (N. Chaiyakunapruk).

0965-2299/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctim.2010.12.003
48
Introduction
Herpes simplex virus (HSV) and Varicella-zoster virus (VZV)
belong to the family Herpesviridae. Both Herpes simplex
virus type 1 (HSV-1) and type 2 (HSV-2) can cause Herpes
genitalis. However, in most cases, HSV-2 had been deter-
mined to be the leading cause for H. genitalis, while VZV
was discovered to be majorly responsible for Herpes zoster.1
Worldwides prevalence of HSV-2 infections in the general
population ranged from 10% to 60%.2 In 2003, the total num-
ber of people aged 1549 years who were living with HSV-2
infection was estimated closed to 536 millions (16.2% of
the worlds population in this age range) and 23.6 million
(0.7%) newly infected cases.3 By this pattern, it exhibits that
a number of infected populations increases, seemingly, in
proportion with aging years. The classical clinical presenta-
tion is characterized by bilateral clusters of erythematous
papules and group of vesicles on the external genitalia,
usually appear 47 days after sexual exposure to HSV for
the rst time; developing within2 23 weeks, a majority of
patients (75%) manifest with newer lesions and the exist-
ing lesions progress to vesicles, pustules, and potentiate
ulcers prior to crustings and healings. Typical complications,
of untreated cases, could include aseptic meningitis, extra
genital lesions, and autonomic dysfunctioning and possibly
following urinary retentions.
Likewise, recent evidences show that there are a mil-
lion of new cases H. zoster occur each year, resulting in
50,00060,000 hospitalisations.4 H. zoster occurs at all
ages, but its incidence is highest (510 cases per 1000 per-
sons) among individuals aged over 60 years-old. The life
time risk for development of H. zoster was estimated to be
approximately 30% or about one in three adults. H. zoster
results in a rash with a unilateral dermatomal distribution,
which typically lasts for 710 days and fully heals within
24 weeks. Complications such as postherpetic neuralgia
may develop if the infection does not resolve after the acute
phase.
These diseases are of high prevalent among immuno-
compromised patients (e.g. those with Human Immunod-
eciency Virus (HIV), cancer, or those who are receiving
immunosuppressants). Given the increase in the num-
ber of immunocompromised patients (e.g. 33.4 million
people living with HIV5 and over 12 million people
diagnosed with cancer in 20086 ), these viral infec-
tions are of signicance public health concern by global
scale.
Clinacanthus nutans (Burm.f.) Lindau (Thai name: Phaya
Yo or Phaya Plong Thong), is a small shrub, native to trop-
ical Asia and belongs to the family Acantaceae.7 This plant
has been used as Thai traditional remedies for the treat-
ment of HSV infection, VZV lesions, skin rashes, insect or
snake bites. Extracts from leaves of C. nutans have been
reported to have antiviral activities against HSV-28 and VZV9
as well as analgesic and anti-inammatory activities.10 Neg-
ative results relating to the anti-HSV-2 activities of C. nutans
were also noted.11 It remains unclear whether C. nutans
extracts is efcacious for use in patients with HSV-2 or VZV
infection. This systematic review aims to determine the ef-
cacy of C. nutans extracts in the treatment of H. genitalis
and H. zoster using a meta-analysis technique.
C. Kongkaew, N. Chaiyakunapruk
Methods
Search strategy
Bibliographic databases (i.e. MEDLINE, EMBASE,
CINAHL, Cochrane CENTRAL, AMED, WHO trial registry,
http://www.clinicaltrial.gov, Thai Index Medicus, and
Thai Medical Index) were searched from the inception
dates. Reference sections of the included studies were also
checked. The keywords were C. nutans and Herpes or Her-
pesvirus. There were no language restrictions. Randomised
clinical trials which met the following inclusion criteria
were included in this study.
(1) Studies that compared C. nutans preparations to
placebo
(2) Studies in humans
The reference sections of all retrieved primary research
publications were manually searched for additional studies.
Data extraction and quality assessment
Data were extracted from each study by two independent
reviewers (CK, NC) using a standardized extraction form.
The extracted data included study settings, study size, for-
mulations, dosage and administration, and outcomes. If
there was any disagreement between reviewers, discus-
sions were held to reach of agreement. The methodological
quality of each trial was assessed using two assessment mea-
sures: Jadads quality scale12 and Cochranes risk of bias
assessment.13
Outcome measures
The outcome measures in used were 3 day-full crusting and
7 day-complete healing. The proportion of patients who
had full crusting within 3 days and those who had complete
healing within 7 days were calculated and compared using
relative risk.
Data analysis
The relative risks and 95% condence interval (C.I.) were
calculated using the DerSimonian and Laird method under
the random effect model.14 Heterogeneity between the
included trials was assessed using 2 and I2 tests to deter-
mine whether it would be appropriate to compute a
meta-analytic summary estimate. All statistical analyses
were performed using the STATA software v 10.0 (StataCorp.
College Station, TX).
Results
Search results
The bibliographic database and hand search yielded 12 stud-
ies. Eight studies were excluded because they were not
clinical trials.811,1518 These excluded studies were evalua-
Efcacy of Clinacanthus nutans extracts in patients with herpes infection
tion studies for the anti-HSV activity of C. nutans in in vitro
studies,811,16,17 a toxicological study of C. nutans,15 and the
anti-inammatory effects or inhibition of neutrophil respon-
siveness of C. nutans in an in vivo study.18 Four randomised
controlled clinical trials met the inclusion criteria.1922
Study and patient characteristics
A total of 151 patients were given preparations of C. nutans
cream, while 135 patients were assigned to control groups.
All included studies were undertaken in Thailand between
1992 and 1996. Two trials determined the efcacy of C.
nutans in patients with H. genitalis,20,21 while the other
two were related to those with H. zoster19,22 as shown in
Table 1. Demographic characteristics (i.e. age and gender)
were comparable between the C. nutans and placebo groups
in both studies.
Quality assessment of the included trials
In all of the included studies, patients were randomly
assigned. Distinguished types of randomisation: a block type
randomisation,19 allocation of patients alternately,21 and
sequential randomisation20 were followed. As far as the
methodology was concerned, only one study was a double-
blinded19 while, in the other two studies, methods were
likely to lead to bias.20,21 On all three studies, withdrawals
and dropouts were reported.19,21,22 The overall quality of one
study19 was rated as high (Jadad score of 3), while the study
of Sangkitporn et al.,22 Sangkitporn et al.,21 and Jayavasu
et al.20 were rated with JADAD score of 2, 1, and 0, respec-
tively. The risk of bias for the outcomes 3 day-full crusting
or 7 day-complete healing within all trials was considered
unclear. The risks of bias for the outcomes 3 day-full crust-
ing or 7 day-complete healing across the HSV-2 and VZV
trials were determined to be unclear.
Heterogeneity of the included studies
The included studies were classied into two types of her-
pesvirus: HSV-2,20,21 or VZV.19,22 Based on (2 and I2 for
heterogeneity test, there was no heterogeneity between tri-
als found in the HSV-2 subgroup for both 3 day-full crusting
((2 0.11, d.f. 1, p = 0.744; I2 0.00%) and 7 day-completed
healing ((2 0.02, d.f. 1, p = 0.889; I2 0.00%) when comparing
the C. nutans group with placebo. There was low hetero-
geneity between the HSV-2 trials for full crusting within 3
days ((2 1.99, d.f. 1, p = 0.159; I2 49.70%). Given high hetero-
geneity between studies within the VZV subgroup ((2 4.04,
d.f. 1, p = 0.044; I2 75.30%), calculation of a meta-analytic
summary estimation was considered inappropriate. Instead,
relative risk of the C. nutans group against placebo for 3
day-full crusting from the high quality study (Jadads score
of 3) will be presented.19
Efcacy of C. nutans cream on HSV-2
Signicant efcacies on C. nutans cream against HSV-2 for
3 day-full crusting and 7 day-complete healing.20,21 were ing in Charuwichitratana et al. than that in Sangkitporn
reported in two studies. Seventy-nine patients (95.18%)
49
treated with C. nutans cream developed full crusting within
3 days (n = 83) compared to 11 patients (14.28%) in the
placebo group (n = 77) and 71 patients (88.75%) in the acy-
clovir group (n = 80). The relative risk of C. nutans group
against the placebo group for full crusting within 3 days
was 6.62 (95% C.I. 3.8311.47). These results indicate that
C. nutans cream was signicantly better than the placebo
(p = 0.001), as seen in Table 2 and Fig. 1. The relative risk
of C. nutans group against the acyclovir group for 3 day-
full crusting was found to be 1.08 (95% C.I. 0.931.25). This
indicates that C. nutans cream demonstrates a comparable
effect to acyclovir (p = 0.136).
Sixty-nine patients (83.13%) treated with C. nutans
cream completely healed within 7 days (n = 83) compared to
17 patients (22.08%) in the placebo group (n = 77). The rela-
tive risk of the C. nutans group against the placebo group for
7 day-complete healing was 3.77 (95% C.I. 2.465.78). This
also indicates that C. nutans cream was signicantly better
than the placebo (p = 0.001), as seen in Table 2 and Fig. 2.
Efcacy of C. nutans cream on VZV
Eleven patients (27.50%) treated with C. nutans cream
developed 3 day-full crusting (n = 40), compared to three
patients (8.57%) in the placebo group (n = 35). The relative
risk of the C. nutans group against the placebo group for 3
day-full crusting was 3.21 (95% C.I. 0.9710.58).
Discussion
To our knowledge, this is the rst systematic review and
meta-analysis of randomised, controlled trials that exam-
ines the benets of C. nutans for the treatment of H.
genitalis and H. zoster. Our ndings demonstrate that
C. nutans cream is efcacious for the treatment of H.
genitalis. In vitro, potential compounds isolated from C.
nutans exhibit anti-HSV activity, including monoglycosyl
diglycerides,16 glycoglycerolipids,23 and three pure chloro-
phyll a and chlorophyll b related compounds, namely
132 -hydroxy-(132 -R)-phaeophytin b, 132 -hydroxy-(132 -S)-
phaeophytin a, and 132 -hydroxy-(132 -R)-phaeophytin a.17
The chlorophyll a and chlorophyll b related compounds
inactivate the virus before entry to the host cells by inter-
fering with the virion envelop structure or a mask viral
glycoprotein, which involved in host cell adsorption and
penetration.17
C. nutans cream is likely to be favourable for the
treatment of H. zoster. Given the observed heterogene-
ity between the VZV studies, we provided the relative
risk and their corresponding C.I. from a high quality study
rather than weight mean analytics. Efforts were made to
identify sources of heterogeneity according to the PRISMA
statement.24 The potential sources of heterogeneity include
frequency of the use of C. nutans cream, duration of the
diseases, lesion characteristics, outcome measures (e.g.
crusting), and formulations. Frequency of usage of C.
nutans cream was different: three times daily in Charuwi-
chitratana et al.19 versus ve times daily in Sangkitporn
et al.22 This may partly contribute to the faster crust-
et al.19,22 The difference in the duration of disease could
 50
Table 1 Characteristics of the included studies.

Authors Study Group No. of Male: Mean age (years) Duration of primary Mean reactivated rate Administration Pain score
setting patients Female infection before study (time per year) of products
(month) (times per
day)
D0h D3 D7

Genital herpes simplex

c
Jayavasu Thailand 5%C. nutansa 27 20:7 27.6 25.9 3.6 4 n/a n/a n/a
et al.20 1.5 (M) 28.0 1.5 (F) 3.9 (M) ns (F) 0.7 (M) ns (F)

Acyclovir 26 20:6 27.2 27.0 3.6 n/a n/a n/a

1.3 (M) 25.2 2.2 (F) 6.8 (M) ns (F) 0.7 (M) ns (F)

Placebob 24 20:4 29.4 30.3 3.2 n/a n/a n/a

1.5 (M) 31.5 9.5 (F) 6.9 (M) ns (F) 0.7 (M) ns (F)

c
Sangkitporn Thailand 5%C. nutans 56 30:26 27.8 25.5 3.6 4 n/a n/a n/a
et al.21 1.6 (M) 27.5 1.4 (F) 3.7 (M) 26.1 4.0 (F) 0.8 (M) 3.4 0.9 (F)

Acyclovir 54 28:26 27.4 26.5 3.7 n/a n/a n/a

1.4 (M) 27.6 1.6 (F) 4.0 (M) 25.8 4.1 (F) 0.6 (M) 3.6 0.6 (F)

Placebob 53 27:26 28.1 27.4 3.4 n/a n/a n/a

1.5 (M) 27.8 1.2 (F) 5.6 (M) 26.2 5.0 (F) 0.4 (M) 3.7 0.8 (F)

Herpes zoster
d,f
Sangkitporn Thailand 5%C. nutans 28 11:17 35.1 n/a n/a 5 3.0 1.2 0
et al.22 12.8 (B) (range 1760)

Placebob 23 10:13 34.8 n/a n/a 2.9 2.3 1.3

13.6 (B) (range 1760)

C. Kongkaew, N. Chaiyakunapruk
e
Charuwi- Thailand 5%C. nutans 40 20:20 43.5 (B) (range 1780) n/a n/a 3g 1.68 n/a n/a
chitratana
et al.19
Placebob 35 18:17 42.4 (B) (range 1770) n/a n/a 1.42 n/a n/a
a 5 g of ethanol extract of C. nutans at dilution 1:4800 or more in cream base 100 g.
b None stated the formulation of placebo cream.
c Conrmation of HSV infection using the immunouorescent assay (IFA) and neutralisation test (NT).
d Use IFA to conrm positive VZV infection.
e Use a linear visual analogue scale from 0 to 4 for none to very severe.
f Use the Chapman et al.25 pain scale of 05 from none to intense, incapacitating pain.
g Apply after wet compress with normal saline.
h Baseline pain score; n/a = not applicable.
Efcacy of Clinacanthus nutans extracts in patients with herpes infection 51

Table 2 Proportions of patients who had full crusting within 3 and completely healed within 7 days.

Author A 3 day-full crustinga A 7 day-complete healinga

C. nutans Acyclovir Placebo C. nutans Acyclovir Placebo

Jayavasu et al.20 26/27 (96.30%) 21/26 (80.77%) 3/24 (12.50%) 18/27 (66.67%) 26/26 (100.00%) 4/24 (16.67%)
Sangkitporn et al.21 53/56 (94.64%) 50/54 (92.59%) 8/53 (15.09%) 51/56 (91.07%) 54/54 (100.00%) 13/53 (24.53%)
Sangkitporn et al.22 25/28 (89.29%) n/a 0/23 (0.00%) 22/28 (78.57%) n/a 0/23 (0.00%)
Charuwichitratana et al.19 11/40 (27.50%) n/a 3/35 (8.57%) n/a n/a n/a
n/a = not applicable.
a All included studies did not state the descriptions of full crusting/complete healing.

Study %

ID RR (95% CI) Weight

Jayavasu (1992) 7.70 (2.67, 22.26) 26.77

Sangkitporn (1993) 6.27 (3.30, 11.91) 73.23

Overall (I-squared = 0.0%, p = 0.744) 6.63 (3.83, 11.47) 100.00

NOTE: Weights are from random effects analysis

.1 1 10
Favours C.Nutans Favours Control

Figure 1 Relative risks for 3 day-full crusting in treatment of Herpe genitalis.

Study %

ID RR (95% CI) Weight

Jayavasu (1992) 4.00 (1.57, 10.17) 20.86

Sangkitporn (1993) 3.71 (2.30, 6.00) 79.14

Overall (I-squared = 0.0%, p = 0.889) 3.77 (2.46, 5.78) 100.00

NOTE: Weights are from random effects analysis

.1 1 10
Favours C.Nutans Favours Control

Figure 2 Relative risks for 7 day-complete heals in treatment of Herpe genitalis.

52
affect treatment outcome; only patients treated within 48 h
were included in Sangkitporn et al., while only patients,
treated beyond 48 h, were included in Charuwichitratana
et al.19,22 This may indicate that the earlier the applica-
tion of C. nutans cream, the better of the treatment result
is expected, owing to the fact that C. nutans affects the
virus before entering host cells. However, lesion character-
istics in both trials were not clearly reported. Sangkitporn
et al. stated that patients with no more than one dermatome
were included into the trials, while Charuwichitratanas
et al. did not specically indicate the number of der-
matomes in the inclusion criteria.19,22 If Charuwichitratanas
et al. had included patients with more than one der-
matome, it would be likely that these patients had more
severe conditions than those with only one dermatome of
lesion,19 and as resulted, the treatment outcome would
have been expectedly less satisfactory. In addition, crust-
ing time is considered to be somewhat subjective as an
outcome measure, which is vulnerable to information bias.
Non-blinding trials may also contribute to this consider-
ably better full crusting outcome assessment in C. nutans
group in Sangkitporn et al. than that in Charuwichitratana
et al.19,22
Our meta-analysis was performed using a wide range
of well-accepted international bibliographic databases.
Thai medical databases were included to maximize the
likelihood of identication of all relevant clinical trials
on C. nutans conducted in tropical areas. In addition,
our study adheres to standard methodology of system-
atic review and meta-analysis as indicated by the PRISMA
statement.24
The ndings from this meta-analysis have important
implications for the use of C. nutans preparation in H. gen-
italis with HSV-2 infection. It is clear that the usage of C.
nutans cream results in better 3 day-full crusting and 7
day-complete healing outcomes when compares to placebo.
It postulates that C. nutans cream may have a synergis-
tic effect when used in combination with acyclovir; due
to their actions via different mechanisms: acyclovir inter-
feres with the viral DNA polymerase inside the infected
cells, while C. nutans extracts prevent HSV from enter-
ing the host cells. Although the mechanism of action of C.
nutans extract on VZV remains unclear, C. nutans prepa-
ration could be useful as one of potential alternatives in
treatment of H. zoster.9 In recent years, it has been possi-
ble to make C. nutans preparations from the puried active
compounds in order to increase potency of the products.17
In spite of rigorous reviews, clinical trials of such puri-
ed active compounds could not be identied at the time
of the search. It would be interesting to be included, in
future clinical trials, of the examined efcacy of prod-
ucts derived from the puried active compounds of C.
nutans.
Due to the small number of trials included in this meta-
analysis, some limitations exist. First, test of publication
bias cannot be performed. The effects revealed in our meta-
analysis might be inuenced by the small study effect.
Second, one of the included studies was not double-blind
which could result in an overestimate of positive out-
comes in the C. nutans group. The efcacy of C. nutans
cream in the treatment of H. genitalis could be overes-
timated due to non-blinding clinical trials, although there
C. Kongkaew, N. Chaiyakunapruk
was no heterogeneity between the studies. The results of
our study should therefore need to be interpreted with cau-
tion.
Conclusion
This meta-analysis suggests that C. nutans extract may be
benecial in the treatment of H. genitalis, as well as H.
zoster. Given its potential synergistic mechanism with acy-
clovir to HSV, C. nutans extract may be an attractive option
as an adjuvant therapy in the treatment of H. genitalis.
Likewise, this plant may be one of the potential options in
the treatment of H. zoster. Further well-controlled RCTs are
needed before this form of therapy can be generally recom-
mended, especially if the active puried compounds of C.
nutans provide more potent clinical benets.
Acknowledgements
We gratefully acknowledge the support of Bruce Hugman and
Chollapat Anthony Chaturongkul, M.D. in proofreading this
manuscript.
Appendix A. Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/
j.ctim.2010.12.003.
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