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The use of Phyllanthus niruri L. as an immunomodulator for the treatment of infectious diseases in clinical settings

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Abstract

Phyllanthus niruri L. (Euphorbiaceae) (P. niruri) has traditionally been used in many tropical countries to treat various ailments, such as kidney stones, chronic liver diseases, diabetes and viral infections. The versatile ethnomedicinal usage of the herb is tightly associated with its multiple pharmacological properties such as immunomodulator, anti-viral, antibacterial, diuretic, anti-hyperglycemia and hepatoprotector. The scope of this review is limited only to the clinical evidences demonstrating benefits of the plant P. niruri with its immunomodulatory properties, for the treatment of various infectious diseases. These evidences are expected to provide the plant a more significant place in the current clinical settings, particularly in the management of infectious diseases. P. niruri as an immunomodulator has scientifically been studied and evaluated in various clinical trials for the treatment of chronic hepatitis B, pulmonary tuberculosis, vaginitis, as well as varicella-zoster infection. In such diseases, the effective immune system is crucial to the treatment success and eradication of the pathogens. In those clinical studies, P. niruri has been proven for its capacity to modulate and activate the immune system. In fact, there are numerous in vitro and animal studies reporting potential benefits of the immunomodulatory properties of P. niruri, and numbers of randomized controlled clinical studies have been published to date. In the light of the scarcity of research to discover new, more effective and safe anti-infection chemical entities, that is also complicated with the growing threat from the new generations of drug resistant-pathogens, the utilization of nature-derived immunomodulatory agents, either alone or combined with the currently available antibiotics or antivirals, is undoubtedly promising and of clinical importance. Most of the studies on P. niruri warrant its potential benefits in various infectious diseases, and are expected to grant the herb an important place in the management of such diseases in the formal clinical practice.
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Infectious disease research https://doi.org/10.12980/apjtd.7.2017D6-287 ©2017 by the Asian Pacific Journal of Tropical Disease. All rights reserved.
The use of Phyllanthus niruri L. as an immunomodulator for the treatment of infectious diseases in
clinical settings
Raymond Rubianto Tjandrawinata1,2*, Liana Wijaya Susanto2, Dwi Nofiarny2
1Dexa Laboratories of Biomolecular Sciences, Dexa Medica Group, Jl. Industri Selatan V, Block PP No. 7, Kawasan Industri Jababeka II, Cikarang 17550,
Indonesia
2Clinical Research Unit, Dexa Medica Group, Titan Center, 5th Floor, Jl. Boulevard Bintaro, Block B7/B1, No. 5, Bintaro Jaya Sector 7, Tangerang 15224,
Indonesia
Asian Pac J Trop Dis 2017; 7(3): 132-140
Asian Pacific Journal of Tropical Disease
journal homepage: http://www.apjtcm.com
*Corresponding author: Raymond Rubianto Tjandrawinata, Dexa Laboratories of
Biomolecular Sciences, Dexa Medica Group, Cikarang 17550, Indonesia.
Tel: +62 21 89841901
Fax: +62 21 89841905
E-mail: raymond@dexa-medica.com
The journal implements double-blind peer review practiced by specially invited
international editorial board members.
1. Introduction
Plants stand as an infinite and important natural resource for
drug development, novel chemotypes, pharmacophores, and other
valuable bioactive agents, for a multitude of therapeutic indications.
Many of the nature-derived compounds have been directly utilized
as drug entities; while many others can also serve as chemical
models for the design, synthesis or semi-synthesis of novel drug
molecules. A tremendous number of natural compounds are
currently in various stages of clinical development, highlighting
the significance and persisting viability of the nature-derived
products as sources of new drug candidates[1-8]. This paper reviews
Phyllanthus niruri L. (P. niruri), one herb species among the
gigantic number of medicinal plants that have widely been studied
worldwide.
P. niruri (Euphorbiaceae) is a worldwide distributed tropical plant
acclaimed for its versatile ethnomedicinal uses[9,10]. It features
multiple pharmacological properties such as an immunomodulator,
anti-viral, antibacterial, diuretic, anti-hyperglycemia and
hepatoprotector[10,11]. Therefore, it is not surprising that P. niruri
ARTICLE INFO ABSTRACT
Phyllanthus niruri L. (Euphorbiaceae) (P. niruri) has traditionally been used in many tropical
countries to treat various ailments, such as kidney stones, chronic liver diseases, diabetes
and viral infections. The versatile ethnomedicinal usage of the herb is tightly associated with
its multiple pharmacological properties such as immunomodulator, anti-viral, antibacterial,
diuretic, anti-hyperglycemia and hepatoprotector. The scope of this review is limited only to
the clinical evidences demonstrating benefits of the plant P. niruri with its immunomodulatory
properties, for the treatment of various infectious diseases. These evidences are expected
to provide the plant a more significant place in the current clinical settings, particularly in
the management of infectious diseases. P. niruri as an immunomodulator has scientifically
been studied and evaluated in various clinical trials for the treatment of chronic hepatitis B,
pulmonary tuberculosis, vaginitis, as well as varicella-zoster infection. In such diseases, the
effective immune system is crucial to the treatment success and eradication of the pathogens.
In those clinical studies, P. niruri has been proven for its capacity to modulate and activate
the immune system. In fact, there are numerous in vitro and animal studies reporting potential
benefits of the immunomodulatory properties of P. niruri, and numbers of randomized
controlled clinical studies have been published to date. In the light of the scarcity of research to
discover new, more effective and safe anti-infection chemical entities, that is also complicated
with the growing threat from the new generations of drug resistant-pathogens, the utilization
of nature-derived immunomodulatory agents, either alone or combined with the currently
available antibiotics or antivirals, is undoubtedly promising and of clinical importance. Most
of the studies on P. niruri warrant its potential benefits in various infectious diseases, and are
expected to grant the herb an important place in the management of such diseases in the formal
clinical practice.
Article history:
Received 25 Aug 2016
Received in revised form 27 Sep, 2nd
revised form 24 Nov, 3rd revised form
8 Dec 2016
Accepted 16 Dec 2016
Available online 16 Jan 2017
Keywords:
Clinical trials
Herbal medicines
Immunomodulator
Infectious diseases
Phyllanthus niruri
Raymond Rubianto Tjandrawinata et al./Asian Pac J Trop Dis 2017; 7(3): 132-140 133
has traditionally been used in many tropical countries to treat various
ailments, such as kidney stones, chronic liver diseases, diabetes, and
viral infections[12]. This plant is popularly known as stonebreaker,
gale of the wind or seed-under-leaf. The other names of the herbal
plant in assorted languages are chanca piedra (Spanish), quebra-
pedra (Portuguese), keezha nelli (Tamil), keezhar nelli (Malayalam),
turi hutan and meniran hijau (Indonesian)[11,13].
P. niruri is a 2-feet-height weed and has small leaves that grow
in an alternate arrangement in 2 rows. The leaves are membranous
and unusually thin and glaucous under its surface, elliptical in shape
and have a narrow base with 2 stipules. The plant bears herbaceous
branches and the light green bark is velvety. The plant’s monoecious
flowers are small and grow in pairs with the pale green color that is
often flushed with red color tone. The fruits are tiny with the shape
of depressed and globose capsule and contain endospermic and
trigonous seeds[14]. Usually the entire plant of P. niruri is used in
medicinal preparations by herbalists since the active phytochemicals,
such as flavonoids, alkaloids, terpenoids, lignans, polyphenols,
tannins, coumarins and saponins, have been identified from various
parts of the plant[15,16]. Extracts of this herb have been proven to
have therapeutic effects in many clinical studies, which will also be
presented in this review.
The scope of this review includes clinical evidences demonstrating
the benefits of the plant P. niruri with its immunomodulatory
properties, for the treatment of various infectious diseases. These
evidences are expected to provide the plant a more significant place
in the current clinical settings, particularly in the management of
infectious diseases.
P. niruri has scientifically been studied and evaluated in various
clinical trials on infectious diseases, such as chronic hepatitis
B[17,18], pulmonary tuberculosis (TB)[19-22], vaginitis[23], as well as
varicella-zoster infection[24]. In such diseases, the effective immune
system is crucial to the treatment success and eradication of the
pathogens. P. niruri has been studied for its capacity to modulate and
activate the immune system, a pharmacological feature that is partly
contributing to the ethnomedicinal applications of the plant extracts
in the management of infectious diseases[25,26].
Ma’at demonstrated that P. niruri extract enhanced the activity and
functions of immune system components, such as marked stimulation
of natural killer (NK) cell cytotoxicity, tumor necrosis factor (TNF)-α
secretion by T-helper 1 subset, and decreased interleukin (IL)-10
secretion by T-helper 2 subset. Therefore, P. niruri modulates both
humoral and cellular immunity[25]. In line with such findings, Nworu
et al. in their study reported that the aqueous extract of P. niruri was
a potent murine lymphocytes mitogen, inducing marked increases in
the expression of surface activation maker (CD69) and proliferation
of B and T lymphocytes. The P. niruri extract-stimulated naïve
splenocytes cultures also increased the production of interferon
(IFN)-γ and IL-4 in a concentration-dependent manner. Phagocytosis,
lysosomal enzymes activity, and TNF-α released by the murine bone
marrow-derived macrophages were significantly augmented by
pre-treatment with the extract. In addition, nitric oxide released by
macrophages was also modulated by the extract[26]. The capacity of
P. niruri extract as an immunomodulator has warranted numerous
clinical studies of the extract for the treatment of infectious diseases.
Besides, a study by Liu et al.[27,28] and Mohan et al.[29] also
quantitatively determined the antiviral activity of these herbs in well-
defined in vitro systems.
2. Chronic hepatitis B
Chronic hepatitis B infection is confirmed by the presence of
any of the viral antigens, including the hepatitis B virus surface
antigen (HbsAg), hepatitis B e antigen (HBeAg), or hepatitis B virus
(HBV) DNA at detectable levels in the blood, and the absence of
antibodies to the virus core antigen (anti-HBc immunoglobulin M).
The presence of the viral antigens should be found at two sequential
tests performed at least 6 months apart. Such a chronic infection is
attributable to the inadequate response of virus-specific T-cells, under
which the exhausted T-cells show poor cytotoxic capacity, impaired
cytokine production and prolonged expression of multiple inhibitory
receptors[30-32]. In chronic hepatitis B, the level of virus replication,
liver disease activity, and humoral responses can be markedly
different between patients. Liver inflammation can be present or
absent in chronic hepatitis B patients, regardless of the level of HBV
replication. The profile of virus-specific CD8 (cytotoxic)-T cell
response along the infection progress highly varies between patients
and is associated with the level of HBV DNA replication rather than
the liver disease activity[33].
The treatment of chronic hepatitis B is mainly aimed to suppress
HBV DNA replication leading to the regression of hepatic necro-
inflammation and prevention of fibrosis progression, cirrhosis and
its complications including hepatocellular carcinoma that at the end
will improve survival[34]. Response to treatment is indicated by the
reduction of serum HBV DNA load reflecting the suppression of HBV
replication, then followed by diminished hepatic necroinflammation,
fibrosis stabilization or even regression; the risk of reactivation
still persists, however. If HBV DNA load can sufficiently be
maintained under the subclinical threshold level and there is an
effective immune response to clear the infected hepatocytes, the
seroconversion of HBeAg may occur; thus the risk of reactivation is
low. Further, if HBV replication is completely interrupted, reflected
as the undetectable level of serum HBV DNA by sensitive assays,
with stable HBeAg seroconversion, the HBsAg can no longer be
detected (with or without HBsAg seroconversion), indicating the
complete cessation of hepatic necroinflammation, thus no risk of
reactivation[35].
To date, IFN-α or pegylated IFN-α, and long-term therapy with
nucleos(t)ide analogues are the primary treatment strategies for
chronic hepatitis B. IFNs exert antiviral, antiproliferative, and
immunomodulatory activities. Nucleos(t)ide analogues, such as
lamivudine, adefovir, entecavir and tenofovir directly inhibit HBV
DNA polymerase, thus suppressing viral replication[36,37]. To date,
pegylated IFN treatment given concomitantly with a nucleos(t)ide
analogue antiviral is disappointing due to its short-term efficacy.
However, long-term efficacy needs to be assessed using different
schedules of combination (e.g. sequentially)[33,36]. Further,
necleos(t)ide analogue antivirals have to be indefinitely administered
in the majority of patients as they cannot sustain their efficacy after
discontinuation of therapy. Patients with chronic infections who then
Raymond Rubianto Tjandrawinata et al./Asian Pac J Trop Dis 2017; 7(3): 132-140
134
withdraw their therapy before HBsAg loss or seroconversion are
at high risk to relapse due to the prevailing HBV DNA (cccDNA) in
the infected cells[35]. In general, the successful treatment rate of the
standard agents at 1-year treatment is only around 20%, 48%–78%,
21%–93%, in terms of HBeAg seroconversion, normalization of
serum A LT levels, and undetectable HBV DNA level, respectively[38].
Further, IFN use is limited due to its highly expensive cost and
intolerable adverse effects. Long-term use of the current antivirals
is also hindered due to the emergence of drug resistance[34,37].
The overall limitations of those currently available therapies for
chronic HBV infection underline the need for more cost-effective
and safer alternative therapies. Considering the immunological
aspect, particularly the T cells, play a critical role in the pathogenesis
of chronic HBV infection, combining the conventional antiviral
therapies with safer and more affordable immunomodulatory agents
able to stimulate and restore the antiviral T cell response directly and
specifically may be an attractive alternative and rational strategy for
treating chronic HBV infection[30,33,35].
As a folk medicine, the plants of P. niruri have long been
used to treat chronic liver disease, including chronic hepatitis
B infection[39,40]. Clinical studies of P. niruri for treatment of
chronic hepatitis B carrier were started by Thyagarajan et al.[18].
In the 1990s, a major reorganization of the Phyllanthus genus was
conducted, which classified Phyllanthus amarus as a variant of P.
niruri[11,41]. Thyagarajan had also extracted three therapeutically
active substances of the plant that showed activity against the
hepatitis B surface antigen, improved the body’s immune system,
and protected the liver. The inability of the immune system to
eliminate hepatitis B viruses from the liver cells keeps the body at
the “carrier state” of hepatitis B infection. A study by Thyagarajan
et al.[18], involved 37 patients chronically infected with HBV who
were given a daily dose of P. niruri 600 mg extract for 30 days.
Two weeks after the end of the treatment, 59% of the patients lost
the HBsAg. Furthermore, after a 9-month follow-up, none of the
cases showed any symptoms of HBsAg reappearance. The authors
postulated that P. niruri might inhibit DNA replication of the virus,
thus suppressing the proliferation. In another study involving 60
chronically HBV infected patients, Thyagarajan et al. reported that
treatment of 200 mg of P. niruri herbs powder three times a day
for 30 days resulted in seroconversion of HBsAg (59% vs. 4%, in
Phyllanthus and placebo groups, respectively) within 15–20 days
after the end of treatment and the HBsAg were still negative after 90
days of evaluation. In summary, this descriptive preliminary study
concluded that P. niruri extract at a dose of 2 times 100 mg daily for
12 weeks has not yet demonstrated its benefits in terms of HBeAg
clearance and ALT normalization[17].
Twenty-two randomized trials on Phyllanthus sp., with a total
sample size of 1 947 chronic hepatitis B patients were analyzed in
a systematic review by Liu et al.[39]. The review included five and
seventeen clinical trials with high- and low-quality methodology,
respectively. The pooled analyses showed that the chance to reach
serum HBsAg clearance was significantly higher with Phyllanthus
species treatment compared to placebo or no intervention, with a
relative risk (RR) of 5.64 [95% confidence interval (CI) 1.85–17.21;
P = 0.002]. Further, Phyllanthus demonstrated no significant
difference with IFN treatment in the clearance of serum HBsAg,
HBeAg and HBV DNA . Combination treatment of Phyllanthus
and IFN, however, provided a significantly better chance for the
clearance of serum HBeAg (RR 1.56; 90% CI 1.06–2.32; P =
0.03) and HBV DNA (RR 1.52; 90% CI 1.05–2.21; P = 0.03) than
IFN alone. No serious adverse event was observed. The review
concluded that Phyllanthus species may possess an antiviral property
against the chronic HBV infection that protects liver function. The
evidence is not robust, however, particularly due to the generally low
methodological quality and non-standardized extracts of the herb
used in those trials. Adequately large trials are still necessary.
A Cochrane systematic review by Xia et al.[40] reported that
based on fifteen randomized trials with a total of 1 284 chronic
hepatitis B patients, the addition of Phyllanthus sp. treatment to an
antiviral agent like IFN-α, lamivudine, adefovir dipivoxil, thymosin,
vidarabine, or conventional treatment, significantly reduced serum
HBV DNA (RR 0.69; 95% CI 0.52–0.91, P = 0.008; I2 = 71%),
serum HBeAg (RR 0.70; 95% CI 0.60– 0.81, P < 0.001; I2 = 68%),
and induced HBeAg seroconversion (RR 0.77; 95% CI 0.63–0.92,
P = 0.005; I2 = 78%) compared to the respective antiviral alone.
However, the report also noted that the heterogeneity among those
trials and high risk of bias were substantial. The trial sequential
analysis did not support the result regarding serum HBV DNA.
Mortality and hepatitis B-related morbidity, quality of life, or liver
histology were not reported by any of the trials. No intolerable or
serious adverse events due to Phyllanthus treatment were reported.
Larger clinical trials with low risk of bias are needed to confirm such
findings.
A randomized controlled study was also conducted by Lesmana et
al.[42] involving forty patients with HBeAg-positive chronic hepatitis
B, elevated serum glutamate-pyruvate transaminase levels, age of
18–75 years old, and naïve to treatments with either lamivudine or
IFN. Trial medication was P. niruri extract 50 mg capsules or the
placebo, given three times on top of vitamin B supplementation.
Means of HBV DNA baseline level in Phyllanthus and placebo
groups were (8.40 ± 0.64) and (7.69 ± 1.30) log10 copies/mL,
respectively. After 12 weeks of treatment, 65% (11 of 17) patients
in the Phyllanthus group showed twice as much decrease in serum
HBV DNA level [by (1.22 ± 1.86) log10 copies/mL] as shown by
similar percentage of patients (13 of 20) in the placebo group (0.69
± 0.80 log10 copies/mL). The remaining 35% (6 of 17) of patients
in the Phyllanthus group showed their serum HBV DNA slightly
increased [by only (0.08 ± 0.05) log10 copies/mL], while 35% (7
of 20) of patients in the placebo group increased by (0.41 ± 0.50)
log10 copies/mL. Phyllanthus extract was found to be well tolerated,
with an incidence of adverse events similar to that for placebo.
The commonest adverse events were headache, fatigue, cold,
hyperurinaria and loss of appetite. Of them, only hyperurinaria and
loss of appetite were possibly related to Phyllanthus treatment. The
proportion of patient in the Phyllanthus group experienced HBeAg
clearance was slightly higher than that of the placebo (41% vs. 35%).
However, this study did not measure the anti-HBe antibodies, thus
the rate of HBe-seroconversion could not be confirmed in this study.
Those currently available clinical studies showed that P. niruri
extract was capable to suppress the serum levels of HBV DNA. It
Raymond Rubianto Tjandrawinata et al./Asian Pac J Trop Dis 2017; 7(3): 132-140 135
is likely that the herb exerts such favourable effect through both
immunomodulatory and direct antiviral activity, which is yet to
be proven in a further larger study. The direct antiviral activity of
P. niruri might occur through the inhibition of polymerase DNA
enzyme activity during the growth phase of hepatitis B virus[27-
29]. On the other hand, P. niruri also exerts its immunomodulatory
activity against the HBV infection through several ways. P. niruri-
induced NK cell cytotoxicity increases the number of infected
hepatocytes (host cells) that can be lysed. Enhanced TNF-α secretion
by P. niruri-induced T-helper 1 subset also increases the major
histocompatibility complex-class I molecule expression with virus
peptide of hepatitis B, resulting in optimized specific-cytotoxic
activity of T lymphocytes (CD8). In addition, decreased secretion
of IL-10 by T-helper 2 subset diminishes suppression on monocyte/
macrophage activity, either as phagocyte cells or antigen presenting
cell. Therefore, hepatitis B viruses released to circulation or extra
cellular milieu due to infected hepatocyte lysis by NK cells or
cytotoxic T cells will then be eradicated whether by the complement
system or by the phagocytic activity of monocytes/macrophages
through the classical pathway[43]. Stimulation of T cell response by
Phyllanthus, which is plausibly associated with either HBV DNA
load or suppression, will induce HBV antigen seroconversion that
ultimately leads to recovery from the disease. Patients’ immune
responses determine the successful immunomodulatory therapy with
P. niruri extract. Recent evidence showed that the prone of being
high or low responders is closely dependent on the human leucocyte
antigen-type of the patients[43]. Thus, a combination of an antiviral
agent and P. niruri extract as an immunomodulator may be a rational
and synergistic therapy for an effective management of chronic
hepatitis B infection. Further clinical studies with more robust
methodology are needed to explore this possibility. Whether both
agents should be given sequentially or simultaneously is another
important thing which needs further investigation. An increased dose
of Phyllanthus extract and extension of the treatment period up to at
least 6 months is also interesting to be explored.
3. Pulmonary TB
The host cellular immune response plays a critical role to eradicate
the intracellular pathogens, such as Mycobacterium tuberculosis (M.
tuberculosis), the culprit of pulmonary TB in humans. T-lymphocytes
together with their secreted cytokines that activate macrophage
phagocytosis may contribute to the pathology of the disease and are
fundamental for effective control of the disease progression[44,45].
IFN-γ, one among various cytokines secreted by the T-lymphocytes,
seems to be responsible for augmenting the microbicidal activity of
the phagocytes, thus controlling mycobacterial infection[46]. IFN-γ
is biologically involved in the activation of macrophages and natural
immunity, promotion of antigen-presenting cells, and development
of T-helper phenotype and humoral immunity[47]. Defects in IFN-γ
secretion due to depressed Th1 responses are prevalent in TB
patients[48]. On the contrary, gradually improved immunity status
of TB patients that appears as an elevated IFN-γ level is critically
required to protect the body from and to combat M. tuberculosis.
A TB therapy that is capable to stimulate IFN-γ secretion is a main
factor that determines the success of TB therapy.
The stimulation of IFN-γ secretion by treatment with P. niruri
extract was demonstrated in two prospective, randomized, double-
blind and placebo-controlled clinical studies on TB patients[19,21].
In those studies, P. niruri extract 50 mg three times daily or
the matching placebo was given concomitantly with the WHO-
standardized TB regimens[49]. In one study involving 40 active TB
patients, a significant elevation of plasma IFN-γ level (+7.65 pg/
mL from the mean baseline level of 5.24 pg/mL) was found after 2
months of concomitant treatment with Phyllanthus[21]. Aligned with
that finding, another separate study involving 67 active pulmonary
TB patients also reported a moderate IFN-γ elevation in those who
received a 6-month concomitant Phyllanthus treatment[19]. In that
study, the elevated cytokine level observed after 2 months of therapy
with Phyllanthus extract was even maintained up to 6 months, albeit
not significant due to the small statistical power. In subjects of the
placebo group (i.e. those with the standard TB regimens alone),
IFN-γ was slightly elevated after 2 months of treatment (+0.41 pg/
mL from the mean baseline level of 7.73 pg/mL). However, in those
subjects, IFN-γ level was then declining along the way from 2 to 6
months of the TB-therapeutic course[19].
Other than IFN-γ, P. niruri treatment on TB patients was also found
to be associated with the elevated secretion of TNF-α[19]. A slight
decrease of TNF-α level was observed earlier during the course, and
then followed by its elevation for the last 4 months of therapy. Such
an elevation indicated a favorable response of the body immune
system against the growth of mycobacterial pathogens[19]. In active
pulmonary TB patients, the levels of IFN-γ and TNF-α were found
to be lower than those of healthy subjects[48]. In the process of
mycobacterial infection control, the role of TNF-α seems to be more
primordial. The cytokine is mainly secreted by monocytes, activated
macrophages, T-lymphocytes, and dendritic cells, and acts in synergy
with IFN-γ, upon various kinds of cells, to induce the production
of reactive nitrogen intermediates and mediate the tuberculostatic
function of macrophages[50,51]. TNF-α stimulates the immune
cell migration to the infection site, contributing to the granuloma
formation capable of controlling the disease progression.Induction
of apoptosis is also associated with the control of M. tuberculosis
by TNF-α. The IFN-γ and TNF-α locally produced by leucocytes
critically contribute to the differentiation and activation of the
recruited peripheral monocytes to devour the mycobacteria[44,52,53].
During M. tuberculosis infection, IL-10, an anti-inflammatory
cytokine also known as human cytokine synthesis inhibitory factor,
is produced and released primarily by macrophages and cytotoxic
T-cells (CD8+), inhibiting the actions of NK cells against the
pathogens[54]. In a randomized, double-blind, and placebo-controlled
study, Amin[19] reported that P. niruri extract treatment in addition to
the standard TB regimens suppressed human IL-10 secretion in 39
active pulmonary TB patients with moderate or severe radiological
lesions and positive sputum acid-fast bacilli test. After 2 months of
therapy, the IL-10 increased by 25% from the baseline level in group
receiving standard TB regimens alone, compared to a suppression of
50% from the baseline in group receiving both P. niruri extract and
the standard TB regimens. IL-10 suppression by P. niruri facilitated
the inflammatory response required to eradicate the microbes. Such a
Raymond Rubianto Tjandrawinata et al./Asian Pac J Trop Dis 2017; 7(3): 132-140
136
response also indicated a restored immunity of TB patients receiving
P. niruri extract on top of the standard TB regimens.
Unlike IFN-γ and TNF-α, IL-10 primarily serves as an inhibitory
cytokine; and therefore it plays an important role to regulate the
balance between the inflammatory and immunopathological
responses. In brief, it has an immunoregulatory function[55].
Active pulmonary TB patients particularly the anergic patients,
demonstrated markedly elevated IL-10 level, both in serum and
bronchoalveolar lavage fluid, suggesting that M. tuberculosis
stimulates IL-10 production that in turn disrupts an effective immune
response[48,56]. The higher the capacity of IL-10 production is, the
greater the risk for developing the disease[57,58]. IL-10 was also
found to downregulate M. tuberculosis-induced Th1 responses,
thus inhibiting the synthesis of IFN-γ[56]. Therefore, the inhibition
of IL-10 by P. niruri reverses the suppression on macrophages and
T-lymphocytes observed in patients suffering from TB, indicating
the restoration of the protective T-cell response.
IL-10 also possesses the capacity to directly inhibit the responses
of CD4+ T lymphocyte[56]. Therefore, IL-10 suppression by P. niruri
treatment also implies the optimization of CD4+ T lymphocyte
activity as demonstrated in a randomized controlled clinical study
by Raveinal[22]. Parallel with favorable effects of P. niruri on IFN-γ,
TNF-α and IL-10, the study, which involved 40 TB patients with
comparable baseline immunological status, reported that the addition
of P. niruri 50 mg extract given three times daily to the standard TB
therapy markedly elevated peripheral CD4+ count [from the baseline
value of (45.55 ± 6.07) mm3 to (56.25 ± 5.95) mm3, P < 0.01] and
CD4+/CD8+ ratio [from the baseline value of (1.39 ± 0.22) mm3 to
(1.71 ± 0.21) mm3, P < 0.01]. Such increases were also significantly
greater (P = 0.010) than those of group receiving the standard TB
therapy alone[22]. Unlike the finding in P. niruri group, the increaseof
CD4+ count in that group [from the baseline of (42.70 ± 5.97) mm3
to (47.15 ± 5.69) mm3, P < 0.05] was not accompanied by a sizeable
increase in CD4+/CD8+ ratio [from 1.36 ± 0.25 to 1.41 ± 0.20, P >
0.05]. The level of CD8+ was not significantly affected by treatment
in both groups[22].
Recent studies reported that a increased peripheral CD8+
lymphocytes and reduced CD4+/CD8+ ratio were observed in severe
or advanced TB patients compared to those with less severe disease
or healthy subjects[59-61]. In clinical practice, the ratio of CD4+/CD8+
has been used as a conventional indicator to evaluate the immunity
of TB patients[60]. The increasein CD4+ count and CD4+/CD8+ ratio,
which were reported by Raveinal after one month of treatment with
P. niruri, indicated the presence of early immunity recovery of the
TB patients[22].
The immunological findings found in clinical studies on
Phyllanthus treatment were well correlated to those observed in
preclinical studies. Further, those studies also reported that the
enhancement in immunological parameters seen with Phyllanthus,
as indicated by the improved balance of various cytokines, was
also translated into positive clinical and radiological outcomes[19-
22]. The addition of P. niruri extract to the TB standard therapy also
speeded up the conversion of sputum acid-fast bacilli, which was
found to occur within just 1 week after treatment initiation. Such
an early sputum acid-fast bacilli conversion was observed in higher
proportion of patients receiving Phyllanthus treatment (52.9%) than
that of placebo (39.4%)[19]. The difference between groups was not
statistically significant due to the small sample size of the study. Yet,
the finding provided a favorable clinical consequence, particularly
for the community around which the patients lived. An earlier
sputum conversion will reduce the risk of TB transmission among
the community. The finding of this study suggests that TB treatment
with Phyllanthus supplementation may potentially lower the risk of
TB transmission.
The consistent immunological improvement reported in those
clinical studies was aligned with the immunomodulatory activities
of P. niruri demonstrated in many preclinical studies[62-64]. The herb
promises a great potency to earn position in the management of TB
therapy where it may act in synergy with the standard treatment of
TB to achieve more optimized and successful outcomes.
The utilization of immunotherapy for TB infection is emergent,
particularly because the current long-term use of antibiotic therapy
for treating the disease has increased the emergence of antibiotic-
resistant strains of the pathogens. In fact, the multiple and severe
multiple drug resistant (MDR and XDR) forms of TB have become
a serious global threat worldwide. A combination of antibiotics and
immunomodulator agents could be the key of therapy, to minimize
generation of drug resistant bacteria, shorten the duration of
treatment, and lower the incidence of reinfection and reactivation[65-
67].
4. Varicella-zoster infection
Varicella or chicken pox, a highly contagious infection, is known
as a benign disease in childhood. However, in adults, varicella
infections usually manifest more severely and adult patients are
at risk of developing complications. Varicella-zoster, which is
classified as herpes virus, is the causal pathogen of chicken pox as
well as herpes zoster infection or shingles[68]. In immunocompetent
patients, recovery from varicella infection critically depends on
the effective body immune system. Therefore, it is advisable to use
immunostimulating agents rather than antivirals to manage varicella
infection in immunocompetent patients.
A randomized controlled study to examine clinical benefits of P.
niruri extract in paediatric patients with varicella-zoster infection
was conducted by Sarisetyaningtyas et al.[24], in a hundred children
of 2–14 years old who were diagnosed to have uncomplicated
varicella infection. In the study, the eligible subjects received either
P. niruri extract at a dose of 25 mg/5 mL syrup three times daily or
the matching placebo in a randomized, double-blind fashion. The
study evaluated the course of recovery from varicella infection that is
clinically characterized by disappearance of fever and new papules,
followed by the crust formation in most parts of the body. The
number of visible papules and crusts throughout the 4-day treatment
was also measured quantitatively to indicate the clinical efficacy of
the treatment.
The study reported that the clinical improvement of the
Phyllanthus-treated patients was not significantly different with that
of the placebo-control group. After two treatment days, fever had no
longer persisted in all patients, suggesting that P. niruri had a neutral
Raymond Rubianto Tjandrawinata et al./Asian Pac J Trop Dis 2017; 7(3): 132-140 137
effect on fever. After four treatment days, more than 50% of the
crusty lesions had been aborted in a greater proportion of subject (P
= 0.053) in Phyllanthus-treated group (43.1%) than in the placebo-
control group (30.0%). The statistical number needed to treat was
considerably low, i.e. 7.6, which means that we need to treat only
8 varicella-infected patients, to gain one patient with a complete
recovery within 4 days after treatment initiation. Further, the study
also reported that after 3 days of treatment, the crusts formation was
found in more subjects of Phyllanthus-treated group than of control
group. According to the clinical point of view, the result suggested
that P. niruri extract was beneficial to shorten the time to recovery
from varicella infection, particularly by accelerating crust formation,
which was immediately followed by their disappearance indicating
disease relief. The appearance of lots of crusts during the healing
process is a clinically important indication that the infection is no
longer contagious[24].
In the study, no subjects in both groups were inflicted with
secondary skin infections or other central nervous system
complications[24]. The finding was expected because such
complications are rarely found in most immunocompetent patients
with varicella infection[69].
The study provided a preliminary clinical evidence of P. niruri’s
potential benefit to shorten the whole morphological course of skin
lesions observed in varicella disease. Larger clinical studies are
still necessaryto further explore whether such a potential benefit
was merely associated with the immunomodulatory activity of the
plant or it possesses a direct antiviral activity. To date, there are no
available data studying the herbs’ direct antiviral effect on varicella-
zoster virus.
5. Vaginal candidiasis
Vaginitis is the most predominant gynecological condition
worldwide, with vaginal candidiasis (vulvovaginitis candidiasis),
which is caused by Candida albicans, comprising up to a quarter
of the diagnosis[70]. In fact, 75% of women experience vaginal
candidiasis at least once during their lifetime[71]. Insufficiency of
IFN-γ due to T-lymphocyte dysfunction was a predisposing factor to
the recurrent vaginal candidiasis[72]. Promoting the host’s specific
immune response to candida is critical for the healing process of
candidal infections[73]. Since the effectiveness and safety of currently
available anti-fungal agents are limited, it is reasonable to apply
a combination therapy of the anti-fungal and immunotherapy in
dealing with candidiasis, particularly for the recurrent or refractory
cases[74,75].
The efficacy of P. niruri in vaginal candidiasis based on its
immunomodulatory property was clinically examined by Pramayanti
et al.[23]. Under a double-blind fashion, thirty married female
patients with vaginal candidiasis were randomly allocated to receive
oral ketoconazole 200 mg given twice daily for 5 days, and either
P. niruri 100 mg extract or its matching placebo given three times
daily for 7 days. Follow-up and evaluation were continued up to 3
months after the treatment was ended. After 7 days of treatment,
then a 1 and 3 month follow-up, IFN-γ levels in vaginal secretes
of patients without P. niruri treatment were found lower [(100.76
± 28.54) pg/mL, (96.26 ± 28.39) pg/mL and (91.35 ± 30.37) pg/
mL, respectively] than that of baseline [(105.11 ± 28.67) pg/mL].
It is obvious that their IFN-γ levels dropped even lower than that of
baseline at 1 and 3 months of follow-up. On the contrary, in patients
receiving P. niruri, the IFN-γ levels after 7 days of treatment, and
1 to 3 months of follow-up [(138.00 ± 34.67) pg/mL, (159.10 ±
58.76) pg/mL and (128.48 ± 24.92) pg/mL, respectively] were all
significantly higher than that of baseline [(120.14 ± 44.51) pg/mL],
and significantly higher than those of patients without P. niruri
treatment (P = 0.004, P < 0.001, P < 0.001, at 7 days of treatment, 1
and 3 months of follow-up, respectively)[23]. Elevation of IFN-γ level
indicates an augmented activity of the T-helper 1 cellular immune
response, with concurrent suppression of IL-4 and IL-10 secretion
by Th2 subsets, and activation of the macrophages necessary for
candida eradication from the vaginal tissues[72,76].
The study also reported that along with the elevation of IFN-γ in P.
niruri group, a noticeably higher level of IL-12 in the vaginal secrets
was observed after 7 days of treatment, and one to three months
afterwards [(118.23 ± 109.15) pg/mL, (128.31 ± 112.76) pg/mL,
(97.80 ± 81.60) pg/mL, respectively] than those of baseline [(71.68
± 68.71) pg/mL]. There were no significant changes of IL-12 level
observed in placebo group [(60.10 ± 25.20) pg/mL, (60.13 ± 28.04)
pg/mL, (67.88 ± 23.95) pg/mL, (55.47 ± 20.44) pg/mL, at baseline,
7 days of treatment, one and 3 months of follow-up, respectively].
In specific cellular immunity, IL-12 is notably associated with the
stimulation of IFN-γ production by NK and T cells as well as the
augmentation of NK cell cytotoxicity[77].
Consistent with the immunological improvement, a high recovery
rate (73.33%) was observed in patients receiving P. niruri at 7 days
of treatment, also followed by a low recurrence rate after one and
three months of follow-up period (18.2% and 45.5%, respectively).
Those rates were all found much lower in patients without P. niruri
treatment (26.67%, 50.00% and 100.00%, respectively)[23]. Finally,
despite the necessity of more adequately powered clinical studies, the
findings of the study have excitingly indicated the clinical benefits
of chemo-immunotherapy in the management of vaginal candidiasis.
Such an approach has been shown to accelerate the recovery as well
as reduce the recurrence of the disease[78].
6. Tonsillopharyngitis
The immunomodulatory activity of P. niruri has also been
studied in patients with acute tonsillopharyngitis. In a randomized,
placebo-controlled study, P. niruri extract was given in a combined
preparation with Nigella sativa (N. sativa) extract, which is known
to possess an anti-inflammatory property[79,80]. One hundred and
ninety-six enrolled patients were randomly allocated to receive
either the active capsules containing a combination of P. niruri 50
mg extract and N. sativa 360 mg extract, or the matching placebo,
under a double-blind fashion. The capsules were to be taken three
times daily orally, for 7 days. The combined extracts greatly
alleviated sore throat symptoms indicated by the visual analogue
scale reduction in swallowing pain and swallowing difficulty within
6 h after administration. The reductions in Phyllanthus-Nigella
treated group (29.29 ± 19.46 or 58.71% from baseline; and 33.81
Raymond Rubianto Tjandrawinata et al./Asian Pac J Trop Dis 2017; 7(3): 132-140
138
± 18.56 or 62.06% from baseline, respectively) were greater (P =
0.008 and P = 0.001, respectively) than that of the placebo (22.72 ±
19.08 or 46.44% from baseline, and 26.40 ± 20.36, or 48.10% from
baseline, respectively). Treatment with Phyllanthus-Nigella extract
also provided a complete relief of the sore-throat in a significantly
greater proportion of patients than the placebo did (60.0% versus
38.4%, P = 0.022)[79]. In the study, Phyllanthus-Nigella extract was
efficacious in relieving the symptoms of acute tonsillopharyngitis
with any baseline severity ranging from mild to severe. Yet, it
showed a greater relief in those with moderate to severe baseline
symptoms. This study alludes that P. niruri has a potential to be used
in combination with other herbs to provide a synergistic effectiveness
in the treatment of acute infections in clinical practice.
The anti-nociceptive property of P. niruri[81] altogether with
the antibacterial activity of P. niruriN. sativa combination might
contribute to the effectiveness of the treatment with the combined
extracts[82]. An in vitro study demonstrated that various pathogenic
bacteria, including Streptococcus pneumoniae, one of the most
common causes of bacterial tonsillopharyingitis, were sensitive to
the combined P. niruriN. sativa extract. The antibacterial potency
of the P. niruriN. sativa extract was much greater than that of either
extract alone, suggesting that both extracts given in combination
deliver a synergistic antibacterial effect[82-85]. The clinical benefit
of the combination of P. niruriN. sativa for the treatment of acute
tonsillopharyngitis as confirmed through this study may contribute to
minimizing the irrational and excessive use of antibiotics in such an
infection, which is mostly viral in origin, thus in turn, the incidence
of antibiotic-resistance will hopefully be reduced.
7. Conclusions
Altogether, all of the studies depicted P. niruri’s clinical efficacy as
an immunomodulator through the activation and augmentation of the
cellular immune system. Specifically, P. niruri activates neutrophils,
macrophages or monocytes, and T and B lymphocytes. Activated
phagocytic process by the neutrophils suggests an acceleration of the
active eradication process, particularly of the extracellular pathogens,
such as invading viruses, microbes, or fungi and their removal from
our bodies. On the other side, the enhanced phagocytic profile of
monocytes and macrophages by P. niruri induces the lysis of the
intracellular pathogen-infected cells, rendering them being exposed
to other immune components in the extracellular compartments.
Further, the modulation of cytokine secretion by P. niruri treatment,
as observed in various clinical studies, such as stimulation to
IFN-γ, TNF-α, IL-4, IL-6, IL-12, and suppression to IL-10, strongly
indicates that P. niruri influences our body’s defense reaction
involving cellular immune system against foreign pathogens.
It is also critical to note that in all of the studies published over the
past two decades, no signs of toxicity or serious adverse reactions
of P. niruri have been reported. The plant-derived extracts were
proven to be practically safe in any of the human and animal
studies, both for acute or chronic use[9,86,87]. Therefore, P. niruri is
currently gaining popularity in many countries as an effective and
safe herbal remedy for various infectious diseases. However, the use
of the herb extract in formal practices is still low. In fact, there are
numerous in vitro and animal studies reporting potential benefits of
the immunomodulatory properties of the species, and numbers of
randomized controlled clinical studies have been published to date.
In the light of the scarcity of research to discover new, more effective
and safe anti-infection chemical entities, complicated with the
growing threat from the new generations of drug resistant-pathogens,
the utilization of nature-derived immunomodulatory agents, either
alone or combined with the currently available antibiotics or
antivirals, is undoubtedly promising and of clinical importance. Most
of the studies on P. niruri warrant its potential benefits in various
infectious diseases, and are expected to grant the herb an important
place in the management of such diseases in the formal clinical
practice.
Conflict of interest statement
We declare that we have no conflict of interest.
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... As far as the immunomodulatory property of these plants is concerned, P. niruri has scientifically been studied and evaluated in various clinical trials on infectious diseases, such as chronic hepatitis B [5,17], pulmonary tuberculosis (TB) [10,11,18,19], vaginitis [20], as well as varicella-zoster infection [21]. In such diseases, the effective immune system is crucial for the treatment and successful eradication of pathogens [19,22]. ...
... As far as the immunomodulatory property of these plants is concerned, P. niruri has scientifically been studied and evaluated in various clinical trials on infectious diseases, such as chronic hepatitis B [5,17], pulmonary tuberculosis (TB) [10,11,18,19], vaginitis [20], as well as varicella-zoster infection [21]. In such diseases, the effective immune system is crucial for the treatment and successful eradication of pathogens [19,22]. Ma'at (1996) reported the enhancement in activity and functioning of the immune system by P. niruri extract through stimulation of natural killer (NK) cell cytotoxicity, secretion of tumor necrosis factor (TNF-α), and decreased interleukin (IL-10) secretions. ...
... Ma'at (1996) reported the enhancement in activity and functioning of the immune system by P. niruri extract through stimulation of natural killer (NK) cell cytotoxicity, secretion of tumor necrosis factor (TNF-α), and decreased interleukin (IL-10) secretions. Thus, P. niruri modulates both humoral and cellular immunity [19]. In Mycobacterium tuberculosis infection, IFN-γ is biologically involved in the activation of macrophages. ...
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Objective: This study aims to assess the immunomodulatory potential of an Ayurvedic formulation, Nirocil syrup, in Wistar rats. Methods: The experiments were conducted on Wistar rats with prior approval from the Institutional Animal Ethics Committee. Nirocil syrup was administered for 6 weeks to experimental animals. Parameters such as hemagglutination titer, histopathology of immunological organs, complete blood count, differential leukocyte count, and immunological paw edema were recorded and compared with controlled (untreated) and becozinc treated groups. Results: Nirocil treated group significantly enhanced the antibody titer in comparison to the control group. The results are supported by the increase in blood lymphocyte count and antigenic stimulation in immunological organs (spleen). Nirocil syrup enhanced antibody formation and suppressed the immunological edema in experimental animals. Conclusions: The study concludes that the Ayurvedic formulation Nirocil syrup has immunopotentiating activity.
... Kesimpulan, panelis lebih menyukai teh dengan metode penyeduhan TBF berdasarkan atribut warna, aroma dan rasa serta memiliki aktivitas antioksidan yang tinggi. Kata Kunci: Antioksidan, metode seduh, teh meniran Pendahuluan Meniran (Phyllanthus niruri Linn.) merupakan tanaman herbal tropis yang telah banyak dilaporkan dalam penggunaan etnomedisinalnya seperti imunomodulator, anti-virus, anti bakteri, diuretik, anti-hiperglikemik dan hepatoprotektor (Tjandrawinata et al., 2017). Analisis kandungan fitokimia pada meniran memberikan respon positif terhadap senyawa fenolik, tanin, flavonoid, saponin, triterpenoid, seteroid, dan alkaloid yang memberikan aktivitas antioksidan pada ekstrak meniran . ...
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Meniran is an herbal plant that has many health benefits. Meniran tea contains phytochemicals like teas in general such as saponins, phenolics, flavonoids, and tannins. This study aims to determine the effect of the meniran leaf tea brewing method on the preference value and content of an antioxidant activity. This research was a laboratory experiment with a completely randomized design (CRD). Meniran tea was brewed using the Decoction Brew (DB), Cold Brew (CB), and True Brew (TB) methods with filter and non-filter treatments. The organoleptic test in this study used 30 untrained panelists. Organoleptic test data collection consisting of color, aroma, and taste attributes were assessed using a 9-scale hedonic scale questionnaire. Organoleptic data that had been collected was then tested for normality using Kolmogorov Smirnov, if normally distributed, continued with ANOVA statistical test and then Duncan's further test with 99% CI. Organoleptic test results in the form of attributes of color (p= 0,000), aroma (p= 0,003), and taste (p= 0,000) of panelists preferred tea with the TBF brewing method. Based on the antioxidant activity content of selected meniran tea (TBF) around 2,33 – 2,81 mg/mL. In conclusion, the panelists prefer tea with the TBF brewing method based on the attributes of color, aroma, and taste as well as high antioxidant activity.
... The application of flavonoids is extensive, namely, to treat bacterial infections and viral infections. Research shows that meniran functions to inhibit DNA polymerase from viruses inhibit reverse transcriptase enzymes from retroviruses, as antibacterial, antifungal, antidiarrheal, and other gastrointestinal diseases (Tjandrawinata, 2017). In addition to flavonoids, meniran also has filatin and hepofilatin, which are the main components that are efficacious in protecting the liver from toxic substances, both in the form of parasites, drugs, viruses, and bacteria (Hutomo, 2018). ...
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Indonesia is abundant in natural substances with immunomodulatory and tonic qualities that can help maintain immunity and keep the body healthy in the face of the COVID-19 pandemic. This paper Analysing herbal plants that are effective in terms of safety and actual efficacy in increasing the endurance and fitness of Indonesians in the face of the Covid 19 Pandemic becomes the first step in pioneering efforts to create national drug independence and sovereignty in the context of national health sector resilience. This study suggests that herbal plants such as Papaya (Carica papaya), Turmeric/Curcumin (Curcuma domestica), Meniran (Phyllanthus niruri), Brotowali (Tinospora crispa), and Ginger (Zingiber officinale Rosc.) which have immunomodulatory and tonic properties, as well as data on the potential for increasing endurance and body wellness by enhancing immune response, to raise awareness of the nation's ability and potential natural resources in supporting national drug independence, resilience, and sovereignty. Therefore, the usage of immunomodulator herbal medications is thought to have an activity to boost the immune system and protect the body from COVID-19 and preparedness for the next pandemic. However, these findings should be confirmed through additional scientific research or clinical trials.
... It is identified in Amazon rainforest and other tropical areas, including South East Asia, Southern India, and China. P. niruri L. has been extensively reported in traditional and folk medication systems such as Ayurveda and Siddha to treat various diseases including diabetes mellitus, jaundice, asthma, joint pain, immunomodulator, loss of appetite, constipation, injuries, as antimicrobial, conjunctivitis, gonorrheal diseases of males and females, inflammatory diseases, skin itching, kidney stones or failures, and urogenital disease [4][5][6][7][8][9][10][11][12][13][14][15][16]. Curative properties of P. niruri are due to the presence of polyphenols, include classes of chromones, coumarins, lignans, stilbenes, xanthones, and flavonoid [17][18][19]. ...
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Objective: The objective of this study is to evaluate the neurological, behavioral, and autonomic changes of Phyllanthus niruri in Swiss albino mice using Irwin’s method. Methods: A total of 24 mice was divided into four groups of six each (3-male, 3-female in each group). Aqueous extract of P. niruri was prepared. Based on body weight aqueous extract was given to the mice by orally through gavage tube (Group I – 300 mg/kg, Group II – 600 mg/kg, Group III – 900 mg/kg, and Group IV – 1200 mg/kg). Neuropharmacological profile is studied for each mice using Irwin’s observational test, the mice were observed for 4 h after oral administration for various behavioral, neurological, and autonomic changes at 0, 1, 2, 3, 4 h. Results: P. niruri showed negligible actions at 300 mg/kg and 600 mg/kg body weight. At 900 mg/kg and 1200 mg/kg P. niruri showed certain behavioral and neuronal changes. P. niruri increased alertness, stereotypy, restlessness, irritability/aggressiveness in behavioral profile indicating that the drug is a CNS stimulant. Furthermore, it showed mild tremors in neurological profile indicating CNS excitation. Conclusion: Aqueous extract of P. niruri at 900 mg/kg and 1200 mg/kg showed changes in behavioral profile, neurological profile, showing it as CNS stimulant properties. Since it is an observational study further research should be done to explore CNS stimulant properties in various in vivo studies.
... P. niruri has medicinal effects on conditions such as dysentery, influenza, vaginitis, tumors, diabetes, diuretics, jaundice, kidney stones, dyspepsia, anti-hepatoxic, anti-hepatitis B, and antihyperglycemic. P. niruri also has antiviral activity against the human immunodeficiency virus [13]. P. niruri extract showed significant anti-tumor activity. ...
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Traditional medicine is an ingredient or a recipe for components in the form of plant ingredients, animal ingredients, mineral substances, galenic preparations, or mixtures of these ingredients that have been used for treatment from generation to generation and can be applied by the prevailing norms in society. Traditional medicinal herbs can be an option for health maintenance, disease prevention, and health care and strengthening a person's immune system. With low prices and easy-to-find raw materials, traditional medicinal ingredients can be made and consumed at home. This review aims to provide information that native Indonesian herbs act as traditional medicines and also have potential as immunomodulators. The way to get this information is by searching through Google Scholar. The results show that many native Indonesian herbs act as natural immunomodulators. Therefore, it can be concluded that native Indonesian herbs can be developed into phytopharmaca as immunomodulators.
... A review about the use and phytochemistry of this species was conducted by Zunino et al. (2003), Tewari et al. (2017), and Kaur et al. (2017). The clinical evidence demonstrating the beneficial properties of P. niruri as immunomodulatory for the treatment of various infectious diseases were reviewed by Tjandrawinata et al. (2017). The anti-hyperglycemic and antioxidant potential effect was demonstrated by Kumar et al. (2019) this species is used in infusion as abortive, or to treat urinary calculus, diabetes, loss of appetite, and cholecystitis (Magalhães et al. 2019). ...
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Immunomodulators are being used to revive immune imbalance which helps in preventing and healing many diseases. Phyllanthus niruri (P. niruri) which is commonly called as stone breaker is widely distributed in tropical areas and known for its various ethnomedicinal and pharmacological effects. P. niruri is intensively being studied for its immunomodulating effects because of its wide-ranging uses in treating diseases related to immune system in indigenous medicine by scientifically studying and evaluating it in various clinical trials for the treatment of Pulmonary Tuberculosis, chronic Hepatitis- B, Varicella-Zoster and Vaginitis infection. In such diseases, effective immune system is essential for curing the disease and elimination of the pathogens. It has proved for its ability to modulate and activate the immune system through clinical studies.
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Meniran (Phyllanthus niruri Linn.) is a medicinal plant that can reduce obesity status, hypoglycemic, hypotensive, and have antioxidant activity. Meniran has been long used as a medicinal plant, but its utilization in a form of water infusion is still rare. This research is a continuation study which aims to identify the biomolecules that have antioxidant activity in water infusion of meniran. The making of water infusion of meniran requires drying process, which can be done by room temperature drying and sun drying. Phenol and fl avonoid compounds in meniran are assumed to have antioxidant activity. Both compounds are easily oxidized and isomerized due to sun exposure. It is assumed that the drying method will aff ect the presence of phenol and fl avonoid compounds and its antioxidant activity. The study began with the process of sun drying and room temperature without direct sun exposure. Then the extraction process used water soxhlet by soxhlet extraction method. The extract was then tested qualitatively using the DPPH IC50 method. The results of the qualitative analysis with meniran color visualization are positive containing fl avonoids and phenols. The results of quantitative analysis of meniran which are dried by sun drying; fl avonoids 0.90% w/w and 1.65% w/w phenols, in samples stored at room temperature: 2.00% w/w fl avonoids and phenol 56.16% w/w. The antioxidant activity of IC50-DPHH in extract concentrations (2, 4, 6, 8, 10, 15, 20 ppm) of dried meniran at room temperature 18.48 ppm, sun drying cannot be determined.
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Background Clinical benefits of antiviral treatment in childrenexperience varicella without complications, remains controversial.Phyllanthus niruri Linn extract as a natural medicine is used toincrease cellular and humoral immunity.Objective To determine the efficacy and safety of Phyllanthusniruri Linn extract in the treatment of varicella in children comparedto placebo.Methods This was a double-blind randomized controlled trial onchildren ages 2-14 years who experienced varicella without com-plications. Subjects were randomly assigned to receive eitherPhyllanthus niruri Linn extract syrup (5 mg/5ml, 3 times daily) orplacebo. Efficacy was measured by calculating the number of pap-ules and crusts after taking the extract for 4 days of administration.A five-day monitoring sheet to record daily follow up and adverseeffects of the subjects were given to their parents.Results Efficacy of Phyllanthus niruri Linn measurement basedon no more new papules occurred at the five-day monitor was de-tected in 46 subject (51.1%) of the Phyllantus niruri Linn groupcompared to the placebo group (P=0.723). Meanwhile, the differ-ence of efficacy based on time of crusts disappear in Phyllanthusniruri Linn and placebo group were 22 subjects (43.1%) and 15subject (30.0%), respectively (P=0.053). This finding proved haveclinical benefit (NNT=7.6).Conclusion There was no significant difference between the ef-ficacy of Phyllanthus niruri Linn and placebo in terms of the pre-vention appearing new papules and crusts. However, clinicallyPhyllanthus niruri Linn accelerates appearing and aborting crustcompared to placebo
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Background: Identification of effective treatments in hepatitis B virus (HBV) infection remains a controversial topic. Although the currently approved drugs for HBV control the disease's progression and also limit associated outcomes, these drugs may not fully eradicate HBV infection. In addition to better managing patients with chronic hepatitis B (CHB) infection, the induction of seroclearance by these drugs has been a commonly discussed topic in recent years. Objectives: In this study, we focused on treating CHB infection via the manipulation of T cells' responses to identify possible approaches to cure CHB. Materials and methods: All studies relevant to the role of cellular and humoral responses in HBV infection (especially regulatory cells) were investigated via a systematic search of different databases, including PubMed, Scopus, and Google Scholar. Considering extracted data and also our unpublished data regarding the association between regulatory cytokines and CHB, we introduced a novel approach for the induction of seroclearance. Results: Considering the increased levels of regulatory cytokines and also regulatory T cells (Tregs) during CHB, it seems that these cells are deeply involved in CHB infection. The inhibition of regulatory T cells may reverse the dysfunction of effector T cells in patients with CHB infection. In order to inhibit Tregs' responses, different types of approaches could be employed to restore the impaired function of effector T cells. The blockade of IL-10, IL-35, CTLA-4, PD-1, and TIM-3 were discussed throughout this study. Regardless of the efficacy of these methods, CHB patients may experience serious liver injuries due to the cytotoxic action of CD8+ T cells. Antiviral therapy and a decrease in HBV DNA to undetectable levels could also significantly reduce the risk of the hepatitis B flare. Conclusions: The inhibition of Tregs is a novel therapeutic approach to cure chronically HBV infected patients. However, further studies are needed to investigate the safety and efficacy of this approach.
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T-cells play an important role in immunity but when these cells are overexposed to specific antigens, their function may decline. This state is usually referred to as exhaustion and the T-cells show reduced proliferation and functions such as cytokine release. T-cell exhaustion has been observed in several cancers as well as in chronic infections such as tuberculosis (TB). In chronic Mycobacterium tuberculosis (Mtb) infection, T-cells may express the exhaustion phenotype and show a progressive loss of secretion of IL-2, IFN-γ and TNF-α. In some cancers and chronic infection models, blocking the exhaustion phenotype can be achieved with the so-called checkpoint inhibitors. This results in tumor control and more effective immunity. However, in the case of TB, the T-cell exhaustion results are quite ambiguous. Hence, there is a need to investigate and explain the contribution of checkpoint at a molecular level to the outcome of events in chronic TB. Such information could help to guide the success of new therapies against chronic TB. This review highlights the mechanism through which T-cells undergo exhaustion and the approaches that can avert such events. This will help to design immunotherapies that can reinvigorate T-cell potency to protect patients from TB.
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Background: Methicillin resistance is a serious health concern since it has spread among Staphylococcus aureus and coagulase-negative Staphylococci (CoNS) that are frequent community and nosocomial pathogens worldwide. Methicillin-resistant strains are often resistant to other classes of antibiotics, making their treatment difficult. Nigella sativa oil is known to be active against Gram-positive cocci, yet its in vitro cytotoxicity is rarely investigated, is a proper and powerful candidate for treatment of methicillin-resistant isolates. Objectives: The aim of this study is to evaluate the in vitro antibacterial activity and cytotoxicity effect of N. sativa oil. Materials and methods: The minimal inhibitory concentrations (MICs) of N. sativa oil were determined by broth microdilution method against four different American Type Culture Collection strains, 45 clinical isolates of methicillin-resistant S. aureus (MRSA), and 77 methicillin-resistant CoNS (MRCoNS). The effects of different dilutions (0.25 μg/mL, 0.5 μg/mL, and 1 μg/mL) of N. sativa oil on the proliferation of gingival fibroblasts were evaluated. Results: The MIC values of N. sativa oil against clinical isolates of Staphylococci were between <0.25 μg/mL and 1.0 μg/mL. Compared to the control group, there was no cytotoxic effect on the proliferation of the gingival fibroblasts. Conclusion: In the present study, the oil of N. sativa was very active against MRSA and MRCoNS and had no in vitro cytotoxicity at relevant concentrations. These findings emphasize that there is a requirement for further clinical trials on N. sativa oil for "safe" medical management of infections caused by methicillin-resistant Staphylococci. Summary: The minimal inhibitory concentration (MIC) values of Nigella sativa oil against Staphylococcus aureus American Type Culture Collection (ATCC) 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 standard strains were 0.5 μg/mL, 2 μg/mL, 64 μg/mL, and 64 μg/mL, respectivelyThe N. sativa oil showed an excellent antibacterial activity against clinical isolates of methicillin-resistant S. aureus and methicillin-resistant coagulase-negative Staphylococci with very low MIC range of <0.25-1.0 µg/mLThe N. sativa oil exhibited no cytotoxic effect on the proliferation of the gingival fibroblasts. Abbreviation used: ATCC: American Type Culture Collection; CLSI: Clinical and Laboratory Standards Institute; CoNS: Coagulase-negative Staphylococci; DMEM: Dulbecco's modified Eagle's medium; DMSO: Dimethyl sulfoxide; FBS: Fetal bovine serum; HGF: Human gingival fibroblast; MIC: Minimal inhibitory concentration; MRCoNS: Methicillin-resistant CoNS; MRSA: Methicillin-resistant S. aureus.
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Although being an utterly frequent, non-mortal, yet distressing disease, and despite good knowledge of the pathogenesis and the availability of specific and safe treatment, vulvovaginal Candida (VVC) infection remains one of the most enigmatic problems for both physicians and patients. Good treatment requires a proper diagnosis. Too many caregivers (and patients treating themselves) react too simple-minded on the symptoms of VVC and treat VVC where they see it on the vulva. In this opinion paper, we plea for a thorough examination of women with VVC, especially in those women who suffer from recurrent disease since a long time, sometimes decades, which necessitates intensive examination of the vaginal flora, as this is invariably the reservoir for relapses and recurrent vulvitis. Examination of such complicated cases requires experienced clinical judgement, expertise bedside phase contrast microscopy of fresh vaginal fluid, classical cultures on Sabouroud medium and, if still unresolved, repetitive cultures taken by the patient herself at moments of symptoms, and/or nuclear acid amplification techniques to detect Candida genes in the vaginal fluid. Even if only vulvitis is evident, thorough expert examination of vaginal fluid is obligatory to diagnose VVC.
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IntroductionPhyllanthus niruri is a traditional shrub of the genus Phyllanthaceae with long-standing Ayurvedic, Chinese and Malay ethnomedical records. Preliminary studies from cell and animal model have provided valuable scientific evidence for its use. AimThis review aims to summarize selected scientific evidence on the pharmacological properties of P.niruri over the past 35years while identifying potential areas of further development of this herb as an economical adjunct. Methods The review covers literature pertaining to the evidence base therapeutic potential of P.niruri spanning from 1980 to 2015 available on PubMed. ResultsEvidence suggests that the extracts of P.niruri possess hepatoprotective, antiviral, antibacterial, hypolipidaemic, hypoglycaemic, analgesic, anti-inflammatory, cardioprotective, anti-urolithiatic and antihyperuricaemic properties due its novel bioactive compounds. Conclusion Scientific evidence suggests that there is strong pharmacological potential in developing P.niruri as a drug to be used in liver disorders and in antiviral therapy. Despites this, large-scale heterogeneity in study protocol and unstandardized reporting standards limit the ability for valuable comparison and may mask the ability to replicate these studies. Thus interpretation of findings should be performed with caution and further studies should be performed in line with best practices. More cheminformatics, toxicological and mechanistic studies would aid the progress to clinical trial studies.