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Effects of standardized Phyllantus Niruri extract on changes in immunological parameters: correlation between pre-clinical and clinical studies.

Authors:
DEXA MEDIA No. 3, Vol. 18, Juli - September 2005
Changes in Immunological Parameters
by Standardized Phyllanthus niruri Extract
in the Pre-Clinical and Clinical Studies
Raymond R Tjandrawinata*,
Suprapto Ma'at**, Dwi Noarny*
* Department of Medical Affairs
Dexa Medica Group, Jakarta
** Lab./Installation of Clinical Pathology
Faculty of Medicine University of Airlangga/
Dr. Soetomo District General Hospital, Surabaya
Abstract. One of traditional herbs used as medicine in many countries for various
uses is the herb Phyllanthus niruri L. Many pre-clinical studies have explored
its activities on the immune system. Further pre-clinical studies were done to
determine its safety and immunomodulating characteristics on mice and rats.
The results of these studies suggested that Phyllanthus niruri L extract is able
to modulate the immune system, via proliferation and activation of T- and B-
lymphocytes, secretion of specific cytokines such Interferon-gamma, Tumor
Necrosis Factor-alpha, and several interleukins, activation of the complement
system, activation of phagocytic cells such as macrophages and monocytes, as
well as increase of cytotoxic cells such as the Natural Killer cells. Finally, clinical
studies were designed to search its immunomodulating effects in patients on
various clinical conditions. Similar results from pre-clinical and clinical studies
were found on the immunological parameters, suggesting that Phyllanthus niruri
L extract can work as an immunomodulator, providing the benefits when used as
an adjunct therapy for infectious diseases.
Key words: Phyllanthus niruri L, standardized extract, immunomodulator
Introduction
The herb Phyllanthus niruri L, known as Meniran in some of
Indonesian area, is recognized and used in many countries for
over 2,000 years. There are many applications of this herb in the
use of the traditional setting of many cultures. These include jaundice,
gonorrhea, urinary tract infection, stomachache, toothache, anti-pyretic,
kidney stone and disease, diuretic, frequent menstruation, diabetes, as well
as dysentery.1,2
There are, at least, two kinds of meniran that easily found and used as
traditional medicine. One plant has a pale green stem Phyllanthus niruri,
while the other is characterized by its reddish stems Phyllanthus urinaria.2,3
In many countries, the name Phyllanthus niruri is also used to identify
the different species of genus Phyllanthus. In Middle and South America,
plant that recognized as P. niruri is actually a P. amarus. In Africa and Asia,
P. niruri name is used interchangeably to refer to P. amarus, P. debilis, P.
fraternus, or P. rotundifolius. In the Indian traditional medicines, Phyllanthus
urinaria is often used to refer to other types otherwise known as P. niruri,
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DEXA MEDIA No. 3, Vol. 18, Juli - September 2005
P. amarus, P. debilis and P. fraternus. In Indonesia, P. niruri and
P. urinaria have been used interchangeably to indicate the
same herb, having the same local name, meniran and used
for the same purpose to treat diseases.4 Thyagarajan has since
successfully isolated three active substances from P. amarus,
which have activities against replication of hepatitis B virus,
improve immune system, and protect the liver.5
We found previously that a specific Phyllanthus niruri
extract (subsequently abbreviated as PNE) could enhance
activities and function of immune system component, both
humoral and cellular immunity.6 This paper explains the
evidence that PNE can increase immunological parameters,
and that there is a tight correlation between the results
seen in the animal studies and the various clinical studies
performed in patients having different diseases.
Materials and Methods
Specific PNE used in our studies have been subjected to
various standardized herbal processes from growing, harvesting,
post-harvest process, and manufacturing process as have
been laid out by various Indonesian government regulations.
Based on Rules of Ministry of Health of Republic of Indonesia
no. 760/Menkes/PER/IX/1992 regarding Phytopharmaca
and Guidelines of Good Traditional Medicines Clinical
Practices, there are 4 steps to prove the efficacy, safety and
quality standard of traditional medicines to be used in formal
health services. Extracts that have followed these steps can
be then classified as phytopharmaca. Briefly, the four phases
involve: Phase-1, pre-clinical study for safety and efficacy
determination. Safety evidence determines by toxicities
tests and efficacy evidence determines by pharmacodynamic
studies; Phase-2, simple standardization of those traditional
medicines, Phase-3, pharmaceutical standardization to ensure
identities and produce standardize medicines, and Phase-4,
clinical studies on healthy volunteers or patients.7,8 PNE used
in our studies have been carefully formulated and produced
under a current GMP-certified plant in the form of Stimuno®
capsule and syrup.
Standardization of the Specific PNE: Production Process,
Raw Material and Finish Goods
Phyllanthus niruri were planted in an area in Banyuwangi,
East Java, Indonesia, adhering to the principles of Good
Agricultural Practice (GAP), were subsequently processed
and cultivated in a dedicated area in the Tradimun plant in
Gresik, East Java, Indonesia. PNE was obtained by maceration
with alcohol. It is a dark brown powder having a bitter taste
and a specific aroma. Considering that there are various
types of Phyllanthus and preparation process to produce the
extract, standardization plays important roles toward the
quality of herbal pharmaceutical products. Standardization
is a pivotal step to ensure reproducible result starting from
herbs determination, cultivation, extraction process, major
substances determination, and also dosage forms preparation.
In this regards, the efficacy and safety of extract are directly
influenced by the standardization of extract, followed by
further processing.
Standardization was done for some physical and chemical
characteristics according to the internationally-accepted
Swiss Pharmacopoeia. For example water contents should
be very minimal, while the total flavonoid contents should
be maintained to certain amounts compared to the total
flavonoids. The processing also makes sure that general
characteristics for herbal extracts such as loss on ignition,
residual pesticide, microbe and heavy metal contamination,
and other harmful materials have been singled out during
th e s ubseq u ent pro c esses . B iolog i cal/I m munolo g ical
Standardization were measured by increasing of T-lymphocyte
proliferation index and increase of IgM level, while various
cytokine measurements have been described previously.6
Because of these standardizations, the results of the studies
performed on this PNE is specific only for this extract, and
therefore the results can not be extrapolated to other PNE
that have been processed differently than that described in
this publication.
Active biological secondary metabolites contained in the
specific PNE have been characterized as flavonoids, lignan,
isolignan, and alkaloids.1,6 In this regards, the PNE used in
these studies was made from standardized herbs extract to
ensure each pharmaceutical dosage contains only a certain
amounts of a specific flavonoid.
Studies Performed on the specific PNE
To ensure its safety, efficacy and quality standard, this
product has gone through serial tests and studies:
Pre-clinical study for safety and efficacy determination
Acute, sub-acute/sub-chronic toxicity tests have been
done on mice and rats and proved that this PNE was practically
non toxic6,9,10 The PNE also showed no harm effect, as proven
on liver biopsy and level of creatinin and BUN serum of rats.
Clinical Studies
Immunomodulator especially needed for condition where
immune system status will influence patient’s condition and
disease progressiveness, such as for adjuvant therapy in cases
involving bacterial, viral or fungal infections. In this regards,
we have previously performed various studies in patients with
pulmonary TB, Acute Respiratory Tract Infections (ARTI),
Hepatitis, Chronic Obstructive Pulmonary Diseases (COPD),
Varicella Zoster, as well as Candidiasis vulvovaginitis patients.
Results of each of these studies will be published separately
under different publications. On-going trials for Hepatitis
and HIV are still being perfomed as per the date of printing of
this publication. All of our clinical studies have been carried
in different teaching hospitals, collaborating with different
investigators strictly adhering to the Good Clinical Practice.
All protocols have examined and approved by The Ethics
Committee in respective hospitals.
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DEXA MEDIA No. 3, Vol. 18, Juli - September 2005
Immunomodulator testing on patients
Immunomodulator tests highly depend on the type of the
human disease infections. We performed tests for diseases
in which either extracellular or intracellular pathogens
as the culprits. In the case that the infections were caused
by extracellular bacteria, we tested for the immune system
response that played a role is humoral immune system,
including tests for antibody synthesis for IgG and IgM, or
IgA antibody if it is a mucosal immune response; and the
complement systems activity test. Specifically the following
tests were perfomed: B-Lymphocyte proliferation test and
cytokine secretion by Th2 subset (IL-4, IL-5 and IL-10) tests.
Additionally, for infectious diseases caused by intracellular
bacteria, such as tuberculosis, the following tests were
performed: proliferation test for T-Lymphocyte, followed by
cytokine secretion by Th1 subset quantification (IL-2, TNF-
α, IFN-γ and IL-12).
Results
Based on previously done pre-clinical studies by one of
us (Suprapto Ma’at), it was found out that the specific PNE
could enhance activities and function of immune system
component, both humoral and cellular immunities. A
series of clinical studies was then performed to validate the
correlation between the changes immunologic parameters
found in the pre-clinical and clinical phases. Comparison
between pre-clinical study results and clinical study results
were summarized in the table below.
ARTIKEL UTAMA
Test
Parameter
Pre-clinical study
(Mice)
Clinical Study
(Human) Research by: Case
Proliferation
of T-lympho-
cyte
- 1.24 x
(p<0.05) with
con-A Mitogen
agent- 1.66 x
(p<0.001) with
PHA mitogen
agent
1.52 x
(p<0.05) with
PHA mitogen
agent
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
Hepatitis
CD4 - 2.4 x
(p<0.001)
Univ. Anda-
las – Dr. M.
Djamil Hospi-
tal - Padang
TBC
Ratio
of
CD4/
CD8
- 6.4 x (p<0.01)
Univ. Anda-
las – Dr. M.
Djamil Hospi-
tal - Padang
TBC
CD8 -
(p=0.73)
Univ. Andalas
– Dr. M.
Djamil Hospi-
tal - Padang
TBC
Cytotoxicity
of CD8
(p= 0.788,
target cell
TGPEC ratio E:
T= 2.5:1)
(p= 0.786,
target cell
TGPEC ratio E:
T= 5:1)
Test Parameter Pre-clinical
study (Mice)
Clinical Study
(Human) Research by: Case
T helper 1
–Lympho
cyte (Th1)
IFN-
γ
(p=0.08) 2.1 x
(p<0.001)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
TBC
Trend
(p>0.05 NS)
Univ. Indone-
sia – Dr. Cipto
Mangunkusu-
mo Hospital
- Jakarta
TBC
35 x
(p<0.001)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
TBC
1.49 x
(p<0.001)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
ARTI
(p<0.05)Day-
7: 1.37
xMonth-1:
1.65 xMonth-
3: 1.41 x
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
Candi-
diasis
vagi-
nalis
TNF-
α
1.72 x
(p=0.016)
1.63 x
(p<0.001)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
Hepa-
titis
Trend
(p>0.05 NS)
Univ. Indone-
sia – Dr. Cipto
Mangunkusu-
mo Hospital
- Jakarta
TBC
IL-6 Trend
(p>0.05 NS)
Univ. Indone-
sia – Dr. Cipto
Mangunkusu-
mo Hospital
- Jakarta
TBC
Il-12
(p=0.961)
Trend
(p>0.05 NS)
Univ. Sri-
widjaja – Dr.
M. Hoesin
Hospital -
Palembang
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
TBC
Candi-
diasis
vagi-
nalis
IL-2 ¯ 0.7 x
(p<0.001) -
T-helper 2
Lympho-
cyte (Th2)
IL-4 2.85 x
(p<0.001) -
IL-10 ¯ 0.9 x
(p=0.033)
Trend ¯
(p=0.408 NS)
Univ. Sri-
widjaja – Dr.
M. Hoesin
Hospital -
Palembang
TBC
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DEXA MEDIA No. 3, Vol. 18, Juli - September 2005
It can be inferred from the table above that there is a strong
correlation between changes in immunological parameters
brought about by the specific PNE found in the animal studies
versus those found in the clinical studies done in patients,
with regards to expression of certain cytokines, proliferations
of T and B cells, production of specific antibodies, activation
of macrophages and the process of phagocytosis, activation
of the complement system, as well as activation of cytotoxic
Natural Killer cells. Although the scope of this publication
is limited to the discussion of changes in the immunological
parameters, however various investigators have found that
these changes are also correlated positively to the decrease of
disease progression studied in the different clinical conditions
and settings as well as the different patient types.
Discussion
Based on the table above, it can be inferred that the results
of majority of pre-clinical studies done on experimental
animals had a high degree of correlation to those done in
clinical studies in patients. Brief interpretation of tests and
results on immunologic parameter changes of PNE studies
suggest that the specific PNE acts by activating both humoral
and cellular immune system.11 - 14
On the the humoral immune system, PNE can be seen to
increase the antibody synthesis in both animal and human
studies, particularly the IgG and IgM, while the IgA increase
can be seen in one of the clinical studies. This suggests that
PNE fights on intracellular and extracellular pathogens by (a)
neutralization of toxin; (b) increasing the phagocytosis process
by phagocytes through opsonization; (c) increasing the activity
of the complement system due to antigen-antibody complex
(Ag-Ab complex) through the classical pathway, and finally,
(d) inhibiting proliferation of pathogens by forming Ag-Ab
complex. With regards to increased complement activation
through the classical pathway brought about by the PNE, it
can be inferred that PNE also help in the destruction (lysis)
of pathogens invaded by MAC (membrane attack complex)
formed by the various complement fragments, particularly
C5 to C9. Further, PNE also helps in the augmentation of
phagocytosis process by neutrophils, macrophages and other
immunocompetents cells, since C3b complement fragment
could act as antibody through the opsonization process, while
the C3a and C5a fragments could act as chemoattractants.11-14
Results of the studies shown above also explain that the
specific PNE acts as an immunomodulator via activation
of the cellular immune system. Specifically, PNE acts to
activate neutrophils, macrophages/monocytes, and T- and B-
lympocytes. The increase in the process of phagocytosis by
neutrophils suggest a speed up eradication process of invading
microbes, viruses or fungi, especially the extracellular foreign
pathogens and clean them from the body. On the other
hand, the increase of phagocytic profile of monocytes /
macrophages by PNE can be interpreted as that PNE speeds
up the lysis of cells infected by the intracellular microbes such
the Mycobacterium tuberculosis, and renders the microbes
exposed to other components of the immune systems in the
extracellular compartments. In relation to this aspect, it is
interesting that PNE can also expedite the lyses of cancer
cells or other mutated cells. While, the increase cytokine
expression and secretion, such as IFN-γ, TNF-α, IL-4, IL-6,
IL-12, and reduction of IL-10 can be interpreted that PNE
can also influence the reactions involving cellular immune
system.
The specific PNE can also affect proliferation of specific
T-lymphocytes. Increase in T-lymphocytes by PNE suggests
the involvement of T-helper cells or T-cytotoxic cells in the
neutralization of pathogens. Previous studies suggest that
cytokine secretion of T-helper lymphocytes (CD4) can be
ARTIKEL UTAMA
Test Parameter Pre-clinical
study (Mice)
Clinical Study
(Human) Research by: Case
Proliferation of B
lymphocyte
1.5 x
(p<0.07)
with LPS
mitogen
agent
1.67 x (p<
0.001) with
LPS mitogen
agent
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
Hepa-
titis
IgM 8.6 x
(p<0.001)
1.22 x
(p<0.05)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
ARTI
IgG 16,2 x
(p<0.001)
1.24 x
(p<0.001)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
ARTI
IgA 1.21 x
(p<0.05)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
ARTI
Phagocytosis
Macrophage/
monocyte
2.96 x
(p<0.01)
2.34 x
(p<0.01)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
Hepa-
titis
TNF-
α
Secretion
by monocyte
(p=0.363
NS) - -
Complement
1.38 x
(p<0.001)
Trend
(p>0.05 NS)
Persahabatan
Hospital
- Jakarta
COPD
Chemotaxis of
neutrophyl
2.37 x
(p<0.001) - -
Chemotaxis of
macrophage
1.56 x
(p<0.006)- - -
Cytotoxicity of
NK cell
1.41 x
(p<0.001)
(E:T = 12.5
: 1) 1.69 x
(p<0.001)
(E:T = 25
: 1)
1.56 x
(p<0.05)
Univ.
Airlangga
– Dr. Soetomo
Hospital
Surabaya
Hepa-
titis
Note: increase; decrease; no changes; NS= no statisti-
cally significance difference between treatment and control groups.
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DEXA MEDIA No. 3, Vol. 18, Juli - September 2005
differentiated by subpopulations of T-helper 1 and T-helper
2, which is summarized in the following table:11,14
In this case, interpreting T cells cytokine secretion should
be done carefully. Principally, if cytokine secretion is dominated
by Th1 cells, then the immune response is geared towards the
cellular immune system, on the other hand if it is dominated
by Th2 cells then the response is geared towards the humoral
immune system.11,13,14 As can be seen above, PNE affects the
two subpopulations of T-helper cells, because it expresses
the different cytokines associated with the different T-helper
cell subpopulation (Table). In this case, PNE can increase
the secretion of IL-4 in the animal study showing its role in
the increased proliferation of B-lymphocytes, regulation of
antibody secretion by the B-lymphocytes, as well as antibody
isotype switching. It is interesting to see that PNE decreases
the secretion of IL-10 by Th2 cells in both animal and human
studies. IL-10 has been previously implicated in the reduction
of activation of monocytes/macrophages, which in turn, can
also reduce the activation of Th1 cells.11,14 Our data suggest
that PNE is able to reverse the deactivation of macrophages/
monocytes, thereby increase the secretion of IL-1, IL-12,
chemokines and TNF-α. PNE also increases the expression
of the class II MHC, and the subsequent activation of T-
lymphocytes.
Specific PNE can also activate cytotoxicities brought about
by T-cytotoxic (CD8) Lymphocytes and those brought about
by the Natural Killer cells. With regards to the former, it has
been previously shown that action of T-cytotoxic lymphocytes
is MHC-1 restricted, meaning that it will only work if antigen
expressed with class-1 molecule.12,14 Cells that are infected
by fungi, intracellular bacteria, viruses or even cancer cells,
which express the class-1 MHC, will be bound and lysed,12,14
therefore the fact that the specific PNE can activate the T-
cytotoxic lymphocytes suggest that this extract participates in
the process of pathogen killing. Action of NK cells is similar
with T-cytotoxic (CD8), however they specifically do not
require the presence of class-1 MHC molecule.11,14 Rather,
they will directly stick to target cells and lyses them.11,14
On the other hand, the results reflecting on the increase of
chemotaxis reaction mediated by administration of specific
PNE (Table) suggest that the faster the inflammatory cells
(neutrophils, monocytes and lymphocytes) reach the injury
site; the faster the rest of immunology processes will occur.
We have shown in this publication evidence suggesting
that specific PNE acts on the body as an immunomodulator,
and that a positive correlation exists in the various
immunological parameters between the results of pre-clinical
and clinical studies. Because the development this specific
PNE have followed the prescribed guidance of the Indonesian
government,11,14 the Indonesian National Administration of
Drug and Food Control has granted the classification of the
specific PNE used in our studies as a phytopharmaca. By its
definition,11,14 this specific phytopharmaca extract can now
be used by physicians as an agent in the therapy or prevention
of infectious diseases. The use of this specific PNE by health
professionals in a naturalistic setting is yet another evidence
that herbal extracts which have undergone extensive scientific
studies can be complementing or substituting any chemically-
derived drug with the same indication in the formal medical
treatment.
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T-helper 1 (Th 1) T-helper 2 (Th 2)
IL-2 IL-4
TNF-
α
IL-5
IFN-
γ
IL-10
IL-12
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... Imunomodulator terutama dibutuhkan untuk kondisi dimana status sistem imun akan mempengaruhi kondisi pasien dan penyebaran penyakit, seperti pada kasus terapi ajuvan yang melibatkan infeksi bakteri, fungi atau virus (Tjandrawinata et al., 2005). Sel imun manusia terdiri atas sistem imun alami (innate immune system) dan sistem imun adaptif (adaptive immune system). ...
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Distinct cytokine profiles are clearly associated with and relate to the severity of several types of infections. Cytokine networks are apparent with selected human infectious diseases, such as mycobacterial infections (leprosy, tuberculosis), the parasitic infection leishmaniasis, human immunodeficiency virus (HIV) infection, and gram-negative sepsis. Cytokine profiles are determined to some extent by two functional subsets of T lymphocytes, Th1 and Th2. The Th1 cytokines (interferon gamma, interleukin-2 [IL-2], IL-12) enhance cell-mediated immunity, inhibit humoral immunity, and result in protective effect for pathogens that are removed primarily through cell-mediated immunity (Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania). The Th2 cytokines (IL-4, IL-5, IL-10, IL-13) enhance humoral immunity and inhibit cell-mediated immunity, and result in protective effect for pathogens removed primarily through humoral mechanisms. Progression of HIV infection is associated with a switch from a Th1 to a Th2 profile. For sepsis, uncontrolled activation of proinflammatory cytokines (IL-1, tumor necrosis factor-alpha, interferon-gamma) may be a fundamental defect that promotes the detrimental aspects of inflammation, whereas Th2 cytokines may be beneficial in controlling inflammation. Knowledge of basic cytokine immunopharmacology, networks, and relationships with infectious processes will aid clinicians in determining treatment approaches that are likely to be effective.
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Protein malnutrition leads to multiple detrimental alterations of host immune responses to mycobacterial infection. In this study, we demonstrated that splenocytes from low-protein (LP) guinea pigs vaccinated 6 weeks previously with attenuated Mycobacterium tuberculosis H37Ra failed to control the accumulation of virulent M. tuberculosis H37Rv in cocultured autologous peritoneal macrophages, despite the fact that they were able to control the accumulation of virulent tubercle bacilli in cocultured syngeneic peritoneal macrophages from normally nourished guinea pigs as successfully as did those from high-protein (HP) counterparts. Vaccine-induced growth control of virulent M. tuberculosis H37Rv in these cocultures appeared to be mediated by CD4 lymphocytes but not CD8 cells. Tuberculin (purified protein derivative [PPD])-induced lymphoproliferation was markedly impaired in vaccinated LP guinea pigs, and the depletion of CD4 lymphocytes significantly decreased lymphocyte proliferation whereas CD8 cell depletion did not. Protein malnutrition also impaired the abilities of cells from vaccinated LP guinea pigs to produce cytokines, including interferon, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta), in response to PPD, despite the demonstration of higher serum levels of TNF-alpha and TGF-beta after an intravenous injection of PPD into LP guinea pigs. In contrast, peritoneal macrophages from protein-malnourished guinea pigs produced a higher level of TGF-beta 4 days after infection in vitro with M. tuberculosis H37Rv than did those from protein adequate controls. These results suggest that dietary protein malnutrition impairs vaccine-induced resistance to M. tuberculosis, in part, by altering the cytokine profile to favor macrophage deactivation.
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