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Orthosiphon (Orthosiphonis folium)

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Authorisation details
Latin name of the genus: Orthosiphon
Latin name of herbal substance: Orthosiphonis folium
Botanical name of plant: Orthosiphon stamineus Benth.
English common name of herbal substance: Java Tea
Status: F: Final positive opinion adopted
Date added to the inventory: 31/10/2007
Date added to priority list: 10/01/2008
Outcome of European Assessment: Community herbal monograph
Additional Information:





Product Characteristics
Community herbal monograph on Orthosiphon stamineus
Benth., folium
1. Name of the medicinal product
To be specified for the individual finished product.
2. Qualitative and quantitative composition 1 , 2
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Orthosiphon stamineus Benth., folium (Java tea)
i) Herbal substance
Dried, fragmented leaf
ii) Herbal preparations
a) Liquid extract (DER 1:1, ethanol 25% m/m)
b) Dry extract (DER 5-7:1, water)
c) Dry extract (DER 8-12:1 ethanol 60% V/V)
d) Dry extract (DER 7-8:1, ethanol 70% V/V)
3. Pharmaceutical form
Well-established use
Traditional use
Herbal substance or herbal preparation in solid or
liquid dosage forms or as herbal tea for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4. Clinical particulars
4.1. Therapeutic indications
Well-established use
Traditional use
Traditional herbal medicinal product used to
increase the amount of urine to achieve flushing
of the urinary tract as an adjuvant in minor
1 The material complies with the Ph. Eur. monograph (ref.: 01/2008 : 1229 corrected 6.0).
2 The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
Community herbal monograph on Orthosiphon stamineus Benth., folium
EMEA/HMPC/107436/2005
Page 2 / 5
Well-established use
Traditional use
urinary tract complaints.
The product is a traditional herbal medicinal
product for use in specified indication exclusively
based on long-standing use.
4.2. Posology and method of administration
Well-established use
Traditional use
Posology
Adults and Elderly
i) Herbal substance for tea preparation: 6 to 12 g
daily in divided doses.
ii) Herbal preparations:
a) Liquid extract: 2 g, 1 to 2 times daily.
b) Dry extract (5-7:1): 360 mg, 3 to 4 times
daily.
c) Dry extract (8-12:1): 200 to 400 mg, 3 times
daily.
d) Dry extract (7-8:1): 280 mg, 3 times daily.
The use is not recommended in children and
adolescents under 18 years of age (see section
4.4 Special warnings and precautions for use).
Duration of use
If the symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Method of administration
Oral use
To ensure an increase of the amount of urine,
adequate fluid intake is required during treatment.
4.3. Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
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4.4. Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under 18
years of age has not been established due to lack
of adequate data.
Appropriate fluid intake is recommended.
If complaints of symptoms such as fever, dysuria,
spasms or blood in the urine occur during the use
of the medicinal product, a doctor or a qualified
health care professional should be consulted.
The use of this product is not recommended in
case of oedema due to limited heart and kidney
function.
For liquid extracts containing ethanol, the
appropriate labelling for ethanol, taken from the
‘Guideline on excipients in the label and package
leaflet of medicinal products for human use”, must
be included.
4.5. Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
None reported.
4.6. Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established. In the absence of sufficient data
the use during pregnancy and lactation is not
recommended.
4.7. Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
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4.8. Undesirable effects
Well-established use
Traditional use
None known.
If adverse reactions occur, a doctor or a qualified
health practitioner should be consulted.
4.9. Overdose
Well-established use
Traditional use
No case of overdose has been reported.
5. Pharmacological properties
5.1. Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2. Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3. Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
6. Pharmaceutical particulars
Well-established use
Traditional use
Not applicable.
7. Date of compilation/last revision
11 March 2010
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Assessment Report
Table of contents
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Table of illustrations
Table 14: Baseline characteristics
Table 15: Diuresis (Week 4 and 12), Glomerular filtration rate, blood calcium content and urinary
calcium
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1. Introduction
The aim of this report is to assess the available preclinical and clinical data on Orthosiphonis folium
(Java tea) for preparing a community herbal monograph. This report is based on the documentation
provided by the European Medicines Agency (EMA) completed by additional researches and information
taken from monographs on Orthosiphonis folium (Commission E Monographs, 1998; ESCOP
monographs, 2003).
1.1. Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Java tea leaf and top of stems.
The composition of Java tea is very complex. The most characteristic compounds are minerals
(potassium 3%), diterpenes (orthosiphols A-E 0.2%), triterpenes, essential oil.(0.02 -0.06%)
(sesquiterpenes), lipophilic flavones like sinensetin (0.1 – 0.19%), isosinensetin and eupatorin flavonol
glycosides; rosmarinic acid (0.1 – 0.5%), and other caffeic acid depsides like mono and dicafeyl tartric
acid as well as lithospermic acid, pytosterols as b-sitosterol and up to 0.7% of essential oil, isositol,
pimarane, isopimarane and staminane diterepnes, triterpenes and chromenes (ESCOP 2003;
BRUNETON 1998, MATSUURA 1973;, BOMBARDELLI 1972;, PARIS and MOYSE 1971).
The European Pharmacopeia prescribes not less than 0.5% of sinensetin.
Herbal preparation(s)
Powder, dry extracts, liquid extract.
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
Not applicable.
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1.2. Information about products on the market in the Member States
Java tea, as single herbal substance, is authorized in Belgium, France, Germany, Poland and Spain.
The active substance is present on the market as:
Herbal substance
Dried leaves for herbal tea (Poland, 15 years; France, 1974).
Herbal preparation
Powder (Belgium, 1997; France, 1989; Spain, 1987, 1991).
Liquid extract (solvent ethanol 25% m/m, DER 1:1) (France, 1952, 2006).
Dry extract (solvent water, DER 5-7:1) (Germany, at least 1976, 1995).
Dry extract (solvent ethanol 25% m/m, DER 4-5:1) (France, 1991).
Dry extract (solvent ethanol 30% V/V, DER 4:1) (France, 1988).
Dry extract (solvent ethanol 60% V/V, DER 8-12:1) (Germany, at least 1976).
Dry extract (solvent ethanol 70% V/V, DER 7-8:1) (Germany, at least 1976).
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: Only in combinations
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Denmark
MA
TRAD
Other TRAD
Other Specify: Only in combination
Estonia
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products, may be as
food supplements
Finland
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Hungary
MA
TRAD
Other TRAD
Other Specify: Only as food or food
supplements
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
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Member State Regulatory Status
Comments (not
mandatory field)
products
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify:
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No herbal medicinal
products
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3. Search and assessment methodology
This report is based on the documentation provided by the European Medicines Agency (EMA) and
other national agencies completed by additional researches (Embase, Pubmed) and information taken
from monographs on Orthosiphonis folium (Commission E Monographs, 1998; ESCOP monographs,
2003).
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Orthosiphon stamineus Benth., syn. O. spicatus Bak., syn. O. aristatus Miq., belongs to the Lamiaceae
family. The plant is found in an area extending from tropical Asia to tropical Australia, and is a 40 to
80 cm high herb. The medicinal parts are the leaves and stem tips collected during the flowering
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season. Various herbal preparations (notably aqueous and ethanolic extracts) are used in traditional
medicines.
Orthosiphonis folium (Java tea) has traditionally been used in Java for the treatment of hypertension
and diabetes (Awale et al, 2003c)
It has also been used in folk medicine for bladder and kidney disorders, gout and rheumatism (Arafat
et al, 2008)
European countries became interested in Java tea with the scientific work made by the Dutchman Van
Itallie in 1886 (Paris and Moyse, 1971)
Java tea was mentioned in the Dutch Pharmacopoeia in 1926 and it was also listed in the French
Pharmacopoeia in 1974 as an herbal that has been present in the previous pharmacopoeias.
Early studies are published since the twenties and Java tea has been used as herbal substance or
herbal preparations since 1965 in France and 1976 in Germany.
2.2. Information on traditional/current indications and specified
substances/preparations
Four monographs are currently available. For each monograph, the indications, the Posology and the
method of administration are given:
1. The complete German Commission E Monographs (1998)
The monograph Java tea was published on March 13, 1986.
Therapeutic indication: “ Irrigation therapy for bacterial and inflammatory diseases of the lower urinary
tract and renal gravel”.
Dosage: Unless otherwise prescribed daily dosage: 6-12g herb; equivalent preparation.
Method of administration: Cut herb for infusions and other galenical preparations for oral use.
2. European Scientific Cooperative on Phytoterapy (ESCOP) 2003
The monograph Java tea was published on 1996.
Therapeutic indication: “ Irrigation of the urinary tract, especially in cases of inflammation and renal
gravel, and as an adjuvant in the treatment of bacterial infections of the urinary tract”.
Dosage:
Adults: An infusion of 2-3g of dried material in 150ml of water two to three times per day; equivalent
preparations.
Method of administration: For oral administration
Duration of administration: No restriction.
3. French Health Authority: Cahiers de l’Agence n°3 (AFSSAPS, 1998)
The first text on orthosiphon was published on 1986.
Therapeutic indication: “ Traditionally used to facilitate urinary and digestive elimination functions”.
“Traditionally used to promote the renal elimination of water”.
“Traditionally used as an adjuvant to slimming regimes”.
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4. British Herbal Medicine Association (BHMA) British Herbal Pharmacopoeia 1996
Therapeutic indication: “ Diuretic”.
In Belgium and Germany, Orthosiphonis folium is a well-established herbal medicinal product. The
current therapeutic indications in these European countries are:
In Belgium: to enhance the renal elimination of water, after all serious pathologies have been
excluded.
In Germany: as a purging in bacterial and inflammatory diseases of the urinary tract collection system
and in renal gravel.
In Spain, Poland and France, Orthosiphonis folium is a traditional herbal medicinal product. The current
therapeutic indications in these European countries are:
In Spain: traditionally used to increase the amount of urine.
In Poland: traditionally used as an adjuvant in the treatment of mild bacterial infections of the urinary
tract and as adjuvant in renal gravel.
In France: traditionally used to promote the renal elimination of water, or as an adjuvant to slimming
regimes.
2.3. Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Current posology for herbal medicines used as “well established use”:
Dry aqueous extract (DER 5-7:1): 360 mg 3 to 4 times daily or 500 mg 3 times daily.
Dry extract (solvent: ethanol 60% V/V, DER 8-12:1): 200 to 400 mg 3 times daily.
Dry extract (solvent: ethanol 70% V/V, DER 7-8:1): 277.5 mg 3 times daily.
Powder: 250 to 500 mg, 3 to 4 times daily.
Current posology for “traditional herbal medicines”:
Java tea for herbal tea: 6 to 12 g daily in divided doses.
Powder: 650 mg 2 times daily.
Liquid extract (solvent ethanol 25% m/m, DER 1:1): 2 g 2 times daily.
Dry extract (solvent ethanol 25% m/m, DER 4-5:1): 200 mg 2 times daily.
Dry extract (solvent ethanol 30% V/V, DER 4:1): 150 to 300 mg 3 times daily.
3. Non-Clinical Data
Overall strategy
This literature-based nonclinical assessment report provides a critical review of data related to the
experimental pharmacology, pharmacokinetics and toxicology studies performed with the herbal drug
or herbal preparations. When needed, data obtained with isolated substances were also taken into
consideration.
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3.1. Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Primary pharmacodynamics
Diuretic activity
To support the traditional use of herbal preparations obtained from Orthosiphon stamineus , the diuretic
activity of various extracts (aqueous or hydro-ethanolic) was evaluated in vivo in rats. The activity of a
few isolated compounds was also studied by some authors. Table 1 summarizes the overall study
results for extracts and Table 3 for isolated compounds. The corresponding studies are further detailed
in the paragraphs below.
Englert and Harnischfeger (1992) – see Table 1
To study the diuretic activity of an aqueous extract prepared from leaves of Orthosiphon stamineus ,
male rats were administered via oral gavage doses of 0 (water), 125, 750 and 1000 mg/kg. The loop
diuretic furosemide (100 mg/kg) was used as a reference compound.
Compared to controls, the urine volume measured in rats treated with either the extract or furosemide
was not increased. According to the authors, the extract enhanced ion excretion (Na + , K + , Cl ) to a
level comparable to that obtained with furosemide and optimum activity was reached at the dose of
750 mg/kg. In addition, the hypothesis that increased ion excretion is due to large amounts of
potassium (1-3%) in the extract was not confirmed based on results obtained in K + -aspartate fed rats.
The ratios of active doses in rats vs. therapeutic / traditionally used doses in humans amounted to 80-
180 for furosemide and 80 for Orthosiphonis folium. Therefore, it was suggested that rat is rather a
poor model for the known diuretic activity of furosemide in humans. Consequently, it was
recommended to further test the diuretic activity of Orthosiphon extract in a more appropriate model
such as the dog.
Assessor’s comment
In animals treated at 750 mg/kg, the urinary excretion of sodium and potassium ions was twice that
measured in controls and the urinary excretion of chloride ions increased almost 3-fold. This effect did
not further increase with dose for both potassium and chloride ions, whereas sodium ions excretion
further increased. The authors conclude that ion excretion obtained in animals treated with
Orthosiphon is comparable to that obtained with furosemide. This is not fully endorsed because the
effect of furosemide on sodium and chloride ions excretion appeared much more intense in
furosemide-treated rats than in the group treated with the extract at 750 mg/kg (please refer to Table
1 ).
The aqueous extract of Orthosiphon stamineus and furosemide did not induce an increase in urine
volume. This result is questionable at least for furosemide, which usually increases diuresis. The
authors indicate that rat is rather a poor model for furosemide, but it is also noted that furosemide (30
mg/kg) was shown to increase diuresis in rats in the study performed by Olah et al, 2003.
Overall, this study did not demonstrate that the extract tested has diuretic activity in male rats, but it
was shown to increase urinary excretion of sodium, chloride and potassium ions at doses of 750 mg/kg
and above, without a dose-effect relationship. The figures obtained were not tested for statistical
significance.
Kavimani et al (1997) – see Table 1
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The diuretic activity of an aqueous extract of Orthosiphon thymiflorus (whole plant) was evaluated in
male rats. The study design was comparable to that used by Englert and Harnischfeger (1992). In
particular, the route of administration, doses of extract and furosemide were the same.
According to the authors, optimum activity of the extract was noted at 750 mg/kg. No increase in urine
volume was observed. Sodium and chloride ions excretions increased 2.7-fold compared to controls. In
furosemide-treated rats, urinary excretion of sodium and chloride ions increased 6-fold and 4-fold,
respectively. It is concluded that the extract did not show any aquaretic activity but enhanced
considerably ion excretion almost to an extent similar to that produced by furosemide.
Assessor’s comment
The results obtained by Kavimani et al (1997) are comparable to those obtained by Englert and
Harnischfeger (1992). Again, the results obtained do not clearly allow to state that the effect of
O. thymiflorus extract on ion excretion is comparable to the effect obtained with furosemide, which is
more pronounced. Similarly to what was observed previously, the effect of the extract is not related to
the dose regarding potassium and chloride ions excretion.
An increase in urine volume was not reported, so that it cannot be concluded that the extract or the
positive control furosemide demonstrated diuretic activity in this study. No statistical test was
performed.
Olah et al (2003) – see Table 1
Extracts of Orthosiphon stamineus (leaves) were obtained either with ethanol 50% (v/v) or ethanol
70% (v/v). The diuretic activity was then tested in male rats after oral administration of water
(control), or 700 mg/kg of each extract. Furosemide (30 mg/kg, oral route) was used as a reference
compound.
Whereas urine volume was 2.5-fold higher in furosemide treated rats than in controls, it was only
slightly increased in rats treated with the 50% ethanolic extract (1.3-fold), and not increased in
animals receiving the 70% ethanolic extract. Sodium excretion was enhanced in all treated animals
compared to controls, and the natriuretic effect of the 50% ethanolic extract was above that of
furosemide. Potassium excretion was also increased, but remained below that obtained with
furosemide. Uric acid elimination was also improved.
Assessor’s comment
Compared to both studies presented before, furosemide administration induced a diuretic effect. This
seems surprising considering that the dose administered was 3-fold lower than that administered by
Englert and Harnischfeger (1992) and Kavimani et al (1997).
Otherwise, this study showed that the 50% ethanolic extract induced an increase in urine volume
compared to controls when administered orally at 700 mg/kg to rats. In terms of intensity, the effect
was half that observed in furosemide-treated animals. No effect on urine volume was reported in rats
treated with the 70% ethanolic extract, thus showing the importance of well-characterizing the mode
of preparation of herbal preparations. In addition to the effect on urine volume, the excretion of
sodium and potassium ions increased with both extracts. No statistical analysis was performed to test
the significance of the effects on urine volume or ion excretion.
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Table 1: studies performed to test the diuretic activity of Orthosiphon extracts upon acute administration
Reference
Extract / Substance
Species
Route Duration
of urine
collection
Doses (mg/kg)
Urinary parameters (compared to controls)
Plant
part
Urine
volume
Ion concentration in
urine
Ion quantity in urine
Plant
Type
[Na + ] u [K + ] u [Cl ] u Na + u
+ u Cl u
Adam et al,
2009
O.stam Leaves
Aq
Rat, males Oral
4 hours
5
10
Furosemide (10)
HCTZ (10)
x7.3
x15.5
x23.4
x21.6
x2.1
x1.8
x14.8
x19.6
x5.4
x10
x2
x2.6
x4
x3.3
x10.1
x11.9
O.stam Leaves MeOH
MeOH-
water
Rat, male Oral
24 hours
See text
8 hours
50
HCTZ (10)
O.stam ?
HA
Rat,males IP
50
24 hours
HCTZ (10)
Aq
Rat, males Oral
6 hours
18
x1.6
x2.4 x1.0 x1.4
180
x1.4
x2.2 x1.1 x1.6
O.stam Leaves
13.5
x1.6
x1.2
x0.7 x0.9
HA (70%) Rat, males Oral
6 hours
135
x1.4
x1.8
x0.9 x1.3
125
x1.1
x1.3
x1.1 x2.0
750
x1.2
x2.0
x2.0 x2.8
O.stam Leaves
Aq
Rat, males Oral
Not known
1000
x1.0
x5.9
x1.7 x1.7
Furosemide
(100)
x0.9
x5.8
x1.3 x4.2
125
x0.8
x1.3
x1.1 x2.2
Whole
plant
750
x0.9
x2.7
x1.3 x2.7
O.thym
Aq
Rat, males Oral
5 hours
1000
x0.9
x4.6
x1.3 x2.1
Furosemide
(100)
x1.3
x5.8
x1.3 x4.0
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Reference
Extract / Substance
Species
Route Duration
of urine
collection
Doses (mg/kg)
Urinary parameters (compared to controls)
Plant
part
Urine
volume
Ion concentration in
urine
Ion quantity in urine
Plant
Type
[Na + ] u [K + ] u [Cl ] u Na + u
+ u Cl u
Adam et al,
2009
O.stam Leaves
Aq
Rat, males Oral
4 hours
5
10
Furosemide (10)
HCTZ (10)
x7.3
x15.5
x23.4
x21.6
x2.1
x1.8
x14.8
x19.6
x5.4
x10
x2
x2.6
x4
x3.3
x10.1
x11.9
Arafat et al,
2008
O.stam Leaves MeOH
MeOH-
water
Rat, male Oral
24 hours
See text
HA (50%) Rat, males Oral
24 hours
700
x1.3
x1.6
x2.1
Furosemide (30) x2.5
x1.3
x4.6
O.stam Leaves
700
x0.9
x1.3
x1.5
HA (70%) Rat, males Oral
24 hours
Furosemide (30) x2.5
x1.3
x4.6
O.stam ? (herba) HA (50%) Dog
IV
?
18.8 mg/kg/min x1.3 a
x1.3 a x1.6 a x1.3 a
O.stam: Orthosiphon stamineus ; O.thym: Orthosiphon thymiflorus ; HA: hydro-alcoholic; Aq: aqueous; MeOH: methanol; HCTZ: hydrochlorothiazide
a no control group included, urinary parameters were compared to values obtained in the same animals before treatment
in bold: statistically significant
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Casadebaig-Lafon et al (1989) – see Table 1
Two types of extract produced from Orthosiphon stamineus (leaves) were tested for diuretic activity:
an aqueous extract, or a hydro-alcoholic (70%) extract. The oral doses administered to male rats
amounted to 18 and 180 mg/kg, or to 13.5 and 135 mg/kg, respectively. Urines were collected for 6
hours after administration of the test article. No positive control was used.
The increase in urine volume noted in all treated groups (compared to water-treated controls) was
statistically significant. The authors note that the aqueous extract is particularly interesting because
the increased diuresis occurred simultaneously with increased excretion of sodium at both dose levels.
At the highest dose level, the excretion of chloride ions was also significant. The same effect on
chloride ions excretion is observed in rats treated at the highest dose of alcoholic extract, without any
concomitant effect on sodium excretion. In all treated groups, the urinary excretion of potassium was
not enhanced.
Assessor’s comment
Casadebaig-Lafon et al reported in rats a diuretic effect for 2 extracts (aqueous and 70% ethanolic) of
Orthosiphon stamineus leaves, as shown by statistically increased urine volumes in treated animals vs.
controls. It can also be mentioned that this effect was not dose-dependent. Statistical increases in
sodium and/or chloride urinary excretion were also noted, notably in animals treated with the aqueous
extract.
The inclusion of a group treated with a reference compound would have allowed to better assess the
intensity of the effects observed.
Beaux et al, 1999 – see Table 1
The diuretic activity of a commercial hydro-alcoholic extract of Orthosiphon stamineus was tested by
intraperitoneal route in male rats. The dose administered to animals amounted to 50 mg/kg, and
hydrochlorothiazide (10 mg/kg) was used as positive control. Urines were collected for 8 and 24 hours
post-administration.
The urine volume collected was significantly increased (compared to controls) from 2 to 24 hours and
from 2 to 8 hours post-dose in animals treated with the extract and with hydrochlorothiazide,
respectively. In extract-treated animals, no effect was observed on sodium or chloride ion excretion,
while potassium excretion increased at 8 hours post-dose. In hydrochlorothiazide-treated animals,
sodium and potassium excretion were enhanced at 8 hours post-dose but not thereafter.
According to the authors, this experiment justifies the use of Orthosiphon stamineus (aerial parts) as a
diuretic agent in traditional medicine.
Assessor’s comment
A significant diuretic effect was obtained with the extract, but potassium excretion was enhanced in the
first 8 hours following extract administration. No effect on sodium or chloride ions excretion was
observed.
The therapeutic relevance of this experiment is questioned as the route of administration is not what is
used clinically. In addition, some elements are missing for the extrapolation of the results such as
proportion of ethanol in the extraction solvent and the part of the plant used.
Chow et al, 1979 – see Table 1
The pharmacological effect of a 50% hydro-ethanolic extract of Orthosiphonis herba was studied in
pentobarbital-anaesthetized dogs under saline diuresis. The urine volume, excretion of electrolytes
(Na + , K + , Cl - ) and fractional water excretion (V/GFR) were significantly increased by IV infusion of the
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drug (18.8 mg/kg/min) in dogs. A significant decrease in re-absorption of sodium and chloride ions
was also noted in renal tubules. A significant increase in the plasmatic concentration of potassium ions
was also observed, whereas those of sodium and chloride ions remained unaltered. The authors also
reported that the clearances of creatinine and para-aminohippuric acid (PAH), the urinary pH and blood
pH were not altered.
Assessor’s comment
This is the only study aiming at evaluating the diuretic activity of Orthosiphon stamineus in a non-
rodent species. It showed that an ethanolic (50% v/v) extract of Orthosiphon stamineus caused
significant increase of urine volume and electrolyte excretion (Na + , K + , Cl - ), and significant reduction of
reabsorption of Na + and Cl - ions in renal tubules. Plasmatic concentration of potassium increased.
It should be noted that the route of administration used is not therapeutically relevant, and that the
plant part used to prepare the extract is not known.
Arafat et al, 2008
The diuretic effect of different methanol extracts of Orthosiphon stamineus leaves was examined by
treating different groups of male Sprague–Dawley rats with either single (2000 mg/kg) or repeated
(500 g/kg/day for 7 days) oral doses of methanol and methanol-water (1:1) extracts.
Hydrochlorothiazide (10 mg/kg) was used as a positive control in the acute study only. Control animals
were administered tap water. Cumulative urine volume and electrolytes (Na + and K + ) concentrations at
different time intervals were measured.
In the acute study, it was shown that a single dose of methanol or methanol-water extract induced no
significant increase in urinary output, contrary to hydrochlorothiazide. Increases in urinary pH, and
sodium and potassium excretion were also noted with both extracts. Detailed results are reported in
Table 2 .
Table 2: effect of oral administration of HCTZ 10 mg/kg, MeOH and MeOH:water (1:1)
extracts 2g/kg on pH, cumulative urinary volume and cumulative urinary excretion of
sodium and potassium in rats (Arafat et al, 2008)
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Repeated administrations of methanol:water (1:1) extract at a dose of 500 mg/kg increased the
urinary output significantly from the 3 rd day compared to the negative control group. In the group
administrated the methanol extract, a significant increase in the cumulative urinary volume was noted
on day 7 only. Results are shown in Figure 1 . In addition, both extracts significantly increased urinary
sodium and potassium excretion from day 4 and 2, respectively.
Figure 1: effects of MeOH and MeOH:water extracts (500 mg/kg/day for 7 days) on
cumulative urine volume (mean SEM)
a: p< 0.05 – b: p<0.01
The authors conclude that the delayed diuretic effect of the methanol extract compared to that of
methanol:water extract can be explained by the presence of more polar components such as flavonoids
and rosmarinic acid which may act synergistically in the methanol:water extract.
Assessor’s comment
Methanol and methanol:water extracts are not reported to be used traditionally in humans, so that the
clinical relevance of this study can be discussed. However, it is interesting to note that while no
significant diuretic activity was reported after a single oral administration of each extract, repeated
administrations of the same extracts over 7 days induced an increased urinary volume. The effect was
observed earlier with the methanol:water extract, which contained more polar compounds (flavonoids,
rosmarinic acid).
This is the only study dealing with diuretic activity of Orthosiphon stamineus administered repeatedly.
Adam et al, 2009 – see Table 1
Water extracts were administered orally at doses of 0, 5 and 10 mg/kg to Sprague–Dawley rats.
Positive control groups were given either furosemide or hydrochlorthiazide at 10 mg/kg. Urine volume,
urine pH, urine density and urine electrolytes were determined every hour for 4 h. Blood was assayed
for glucose, albumin, blood urea nitrogen (BUN) and creatinine.
O. stamineus extract exhibited dose-dependent diuretic activity. However, excretion of Na+ and Cl−
was not markedly elevated, but urinary excretion of K+ was significantly increased. O. stamineus
extracts slightly increased the serum BUN, creatinine and blood glucose level. Although these levels
were statistically significant when compared to control, they were still within the normal range.
The authors conclude that O. stamineus exhibited diuretic activity, but was less potent than furosemide
and hydrochlorothiazide. Care should be taken when consuming this herb as a slight increase of kidney
function enzymes was recorded.
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Assessor’s comment
A diuretic effect is reported for this aqueous extract of O. stamineus administrered once, but it is less
potent than that of furosemide or hydrochlorothiazide administered at the same dose level. This
diuretic effect seems to be dose-related. Decreased kalemia is also noted.
Significant increases in renal function markers are reported (BUN, creatinine), but it is mentioned that
the values are within the normal range. The lack of an adequate repeat-dose toxicity study does not
allow putting this result in perspective, but current guidelines for traditional herbal medicinal products
indicate that the lack of repeat-dose toxicity is acceptable as it is covered by human experience.
Interestingly, an increased blood glucose level is noted; this result is in contradiction with that reported
by other authors ( Hypoglycaemic effects ).
Matsubara et al, 1999 – see Table 3
Methylripariochromene A (MRC) was isolated from the chloroform-soluble fraction of the water
decoction of Orthosiphon stamineus (leaves). According to Matsubara et al, MRC was a major
component of the aforementioned decoction (yield: 2.3%).
Rats were treated orally with MRC (25, 50 and 100 mg/kg); controls received vehicle (0.5% Tween 80
solution), and hydrochlorothiazide (25 mg/kg) was used as reference compound. Urines were collected
for 3 hours after administration of the test article.
No effect was noted up to 50 mg/kg MRC. The results obtained showed a significant 3-fold increase in
urine volume in the high dose group, and in hydrochlorothiazide-treated rats. The quantity of ions
(Na + , K + , Cl ) excreted in the urine was also significantly increased at 100 mg/kg MRC. The intensity of
the effect was half that reported for hydrochlorothiazide regarding the excretion of sodium and chloride
ions, while the quantity of potassium urinary excreted was twice that of controls for both high dosed
and hydrochlorothiazide-treated rats. The urinary concentration of each ion was not modified by MRC
treatment, whereas hydrochlorothiazide significantly increased the urinary concentration of sodium and
chloride ions. The authors conclude from the latter observation that the mechanism underlying the
diuretic activity of MRC may not be the same as that of hydrochlorothiazide.
Assessor’s comment
MRC was shown to possess diuretic activity in rats at the oral dose of 100 mg/kg. At this dose level,
urine volume increased 3-fold similarly to what is observed with the reference compound
hydrochlorothiazide. The quantity of sodium and chloride ions recovered in urine also increased but to
a lesser extent to what is observed in hydrochlorothiazide-treated rats. The quantity of potassium
excreted was similar in high-dosed rats and in rats treated with the reference compound. Contrary to
hydrochlorothiazide, the urinary concentration of each ion was not modified in animals undergoing MRC
treatment whatever the dose.
The diuretic activity of MRC was demonstrated at the oral dose of 100 mg/kg, but not at lower dose
levels (25 and 50 mg/kg). Therefore, it can be concluded that this compound may be part of the
diuretic effect of Orthosiphon stamineus, but that other compounds may also be involved.
Schut and Zwaving, 1993 – see Table 3
The flavonoids sinensetin and 3-hydroxy-5,6,7,4-tetramethoxyflavone were isolated from the leaves of
Orthosiphon stamineus . They were intravenously administered to anaesthetized male rats at 10
mg/kg. In a second experiment on the same experimental model, doses of 1 mg/kg of each compound
were compared to the reference compound hydrochlorothiazide (1 mg/kg).
For both compounds, the dose of 10 mg/kg induced a diuretic effect. The dose of 1 mg/kg also
produced a diuretic effect, but it was shown that hydrochlorothiazide acts faster and produces a larger
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quantity of urine in a shorter time (see Figure 2 ). The authors suggest that the longer lag time of the
flavones might be attributed to an action via metabolites, whereas hydrochlorothiazide is known to act
directly on the kidney which explains the shorter lag time.
The authors also state that the total diuretic activity of the leaves may not be attributed to these
compounds because only some tenths of milligrams are extracted by hot water from the leaves during
preparation of herbal tea. Therefore, they do not seem to be the main active constituents of
Orthosiphon stamineus .
Assessor’s comment
The relevance of this experiment to the use of herbal preparations in humans is questioned in view of
the route of administration used in rats. In addition, it seems that no negative control group was
included in the study so that any definitive conclusion cannot be drawn from the results obtained. No
statistical test was performed.
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Table 3: studies performed to test the diuretic activity of isolated compounds
Reference
Substance
Species
Route Duration of
urine
collection
Doses
(mg/kg)
Urinary parameters (compared to controls)
Urine volume
Ion concentration in
urine
Ion quantity in urine
[Na + ] u [K + ] u [Cl ] u Na + u + u Cl u
25
x0.9
x0.9
x0.9 x1.0 x0.8 x0.8 x0.9
MRC
Rat, sex
unknown
Oral
3 hours
50
x1.4
x0.8
x1.0 x0.9 x1.2 x1.5 x1.4
100
x3.0
x1.0
x0.8 x0.8 x2.9 x2.0 x2.4
HCTZ (25)
x2.9
x2.0
x0.7 x1.6 x5.8 x2.0 x4.7
1
Rat, males IV
4 hours
10
HCTZ (1)
3-hydroxy-5,6,7,4-
tetramethoxyflavone
1
Rat, males IV
4 hours
10
HCTZ (1)
HCTZ : hydrochlorothiazide; MRC: methylripariochromene A
in bold: statistically significant
Figure 2: production of urine of two flavones from Orthosiphon stamineus compared with hydrochlorothiazide (Schut and Zwaving, 1993)
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Hypouricemic activity and effect on calcium oxalate crystals
Orthosiphon stamineus being traditionally used for irrigation of the urinary tract in cases of renal
gravel, some authors investigated its hypouricemic activity in rats, and its effect on the growth of
oxalate crystals. It is also noted that diuretics have been used as prophylactic agents for urolithiasis
due to their key role in regulating kidney function and alleviating the urinary risk factors for stone
formation (Arafat et al, 2008).
Hypouricemic activity
Arafat et al (2008) investigated the effect of a methanol:water (1:1) extract of Orthosiphon stamineus
(leaves) on uric acid level in hyperuricemic rats. Experimentally, hyperuricemia was induced by
injecting potassium oxonate (uricase inhibitor) to groups of 6 male rats. The latter received the extract
orally one hour later, at either 250, 500, 1000 or 2000 mg/kg. Negative and positive controls received
saline and allopurinol (50 mg/kg), respectively. Uric acid concentration was then measured in samples
collected at 0, 2, 4, 6 and 8 hours post-injection.
Results reported in Table 4 below show that the uric acid concentration was statistically decreased in
rats treated with the extract at 500 mg/kg and above 6 hours after administration. The uric acid level
was statistically decreased at all time points. The authors conclude that the extract showed a marked
decrease in uric acid formation as late as 6 hours compared to the more effective allopurinol which
may indicate a level of similarity between Orthosiphon stamineus and the standard been used.
Table 4: effect of allopurinol and methanol:water (1:1) extract of Orthosiphon stamineus on
serum urate levels in hyperuricemic rats (Arafat et al, 2008)
Treatment
Time after administration (h)
0
2
4
6
8
KOn (250 mg/kg)
7.9 ± 1.2
16.6 ± 1.3 12.1 ± 1.3 13.6 ± 1.1 11.7 ± 2.2
KOn + allopurinol (50 mg/kg)
9.1 ± 1.0
9.9 ± 2.2* 3.2 ± 0.2* 2.9 ± 0.5* 4.2 ± 0.9*
KOn + MeOH:water 1:1 (2 g/kg) 9.5 ± 1.1
13.9 ± 1.6 9.2 ± 1.9
7.4 ± 0.7* 9.8 ± 1.4
KOn + MeOH:water 1:1 (1 g/kg) 9.4 ± 1.5
13.4 ± 0.9 11.4 ± 2.1 7.6 ± 1.1* 9.5 ± 2.1
KOn + MeOH:water 1:1 (0.5
g/kg)
9.9 ± 1.9
17.8 ± 1.9 11.5 ± 1.7 7.9 ± 0.8* 9.7 ± 1.8
KOn + MeOH:water 1:1 (0.25
g/kg)
8.3 ± 0.9
20.3 ± 2
14.6 ± 3.8 9.5 ± 1.9
10.8 ± 1.8
Mean SEM, n=6. KOn: potassium oxonate
*p<0.05 vs. KOn
Assessor’s comment
The effect on serum urate level obtained with the extract is slight compared to that obtained with a
much lower dose of allopurinol (50 mg/kg vs. 500 mg/kg) in terms of intensity and duration. This is
the only study found in the literature dealing with this issue which seems not sufficient to draw a firm
conclusion. In addition, it is noticed that the extract tested is not used traditionally making the
extrapolation to the clinical situation uncertain.
Effect on calcium oxalate crystals
Using a modified Schneider’s gel slide method, Dharmaraj et al (2006) studied the inhibition of calcium
oxalate crystal growth by a methanol (50%) extract of Orthosiphon stamineus (leaves) at the
concentration of 5000 ppm. Sodium citrate (10 ppm) was included as a positive control, and the
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experiment also included blank testing. It was concluded that both the extract and sodium citrate
inhibited the growth of calcium oxalate crystals at 24 hours (statistically significant effect).
Figure 3: the growth profile for blank, control and sample (adapted from Dharmaraj et al,
2006)
Assessor’s comment
This is the only study found in the literature dealing with this issue which seems not sufficient to draw
a firm conclusion. Similar effects were observed with sodium citrate and the extract, but the latter was
used at a considerably higher concentration (5000 ppm, vs. 10 ppm). It remains to know whether this
effect would be observed in vivo. In addition, it is noticed that the extract tested is not used
traditionally.
Anti-inflammatory activity
Effect on inflammation induced by TPA in mice
Masuda et al (1992) isolated orthosiphol A and B from a dichloromethane extract of Orthosiphon
stamineus (leaves) and studied the anti-inflammatory effect of each compound in mice using a tumour
promoter, TPA (12-O-tetradecanoylphorbol-13-acetate).
For each compound, a sample (200 µg) 1 and vehicle were applied to the inner part of the left and right
ear, respectively, of the same mouse. After 30 minutes, TPA (2 µg) 2 was applied to the same part of
both ears. After 6.5 hours, mice were killed, plugs of each ear obtained and weighed.
Each compound showed inhibitory activity, the ratio of which was 42% for orthosiphol A, and 50% for
orthosiphol B.
Assessor’s comment
Orthosiphol A and B were shown to decrease the inflammation induced by TPA applied on mouse ears.
However, similar data obtained with a therapeutically-relevant extract of Orthosiphon stamineus is not
available so that no conclusion can be drawn.
Inhibition of NO production
1 dissolved in 20 µg acetone
2 dissolved in 20 µg acetone
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A team of Toyama Medical and Pharmaceutical University (Toyama, Japan) conducted a series of
experiments to identify the biologically active components of Orthosiphon stamineus (Awale et al,
2003a, 2003b, 2003c, 2003d; Nguyen et al, 2004).
First, they found that a methanolic extract of aerial parts showed significant inhibition of NO production
in lipopolysaccharide (LPS)-activated macrophage-like J774.1 cells with an IC50 reaching 42 µg/mL.
Thereafter, they continued their efforts to characterize the NO production inhibitory activity of
diterpenes isolated from the methanolic extract, and to elucidate the chemical structure of these
compounds.
In these experiments, NO inhibitory assay was performed with cultures of J774.1 macrophage-like cells
incubated with LPS and test compound for 24 hours. Then, NO production was determined by
measuring the accumulation of nitrite in the culture supernatrant. For each compound, IC50 were
calculated. The results are shown in Table 5 and Figure 4 .
From the results obtained, it was concluded that 47 diterpenes isolated from Orthosiphon stamineus
significantly inhibited NO-production in the experimental model used, i.e. LPS-activated macrophage-
like J774.1 cells. The intensity of the effect depended notably on the chemical structure of each
compound.
Assessor’s comment
Forty seven diterpenes were isolated from methanolic extracts of Orthosiphon stamineus and all
inhibited NO-production by LPS-activated macrophage-like J774.1 cells with an IC50 lower than that
obtained with dexamethasone in the same experimental model. In addition, 15 were more potent than
the most potent positive control used (L-NMMA) based on IC50 values. The same effect was also
reported with a methanolic extract of Orthosiphon stamineus.
However, methanolic extracts are not reported to be used therapeutically. Therefore, it remains to be
determined whether such effect would occur with herbal preparations for human use (although it is
noted that diterpenes are involved in the NO production inhibitory effect). It would also have been
interesting to have results from another experimental model, but such data were not found in the
literature.
Table 5: inhibitory effects of constituents from Orthosiphon stamineus on NO production in
LPS-activated J774.1 cells
Compounds
Inhibition (%)
IC50
200 mM
100 mM
50 mM
20 mM
2 mM
1 Orthosiphol A
99.662.0*** 99.663.2***
91.763.7*** 61.661.1*** 13.568.2*
11.5
2 Orthosiphol B
98.662.7*** 99.662.0***
88.064.7*** 48.966.5*** 25.068.7
20.5
3 Orthosiphol C
75.863.0*** 97.563.2***
88.063.2*** 55.867.8*** 15.6610.0** 14.4
4
99.664.7*** 92.263.6***
65.867.6*** 26.767.0*
15.666.3** 34.5
5 Orthosiphol F
72.864.8*** 50.568.4**
47.867.2*** 41.367.6*** 30.4610.7** 87.9
6
67.161.5*** 30.063.6***
14.963.6** 9.664.8*
7.661.5**
145
7 Orthosiphol H
91.861.2*** 98.861.5***
89.560.7*** 39.964.9*** 12.562.0*** 24.1
8
88.363.1*** 48.764.3***
21.963.4*** 9.063.1**
5.064.9
102
9
97.163.5*** 65.261.3***
39.664.7*** 20.562.4*** 20.563.6** 66.3
10 Orthosiphol K
94.561.6*** 93.363.6***
86.161.2*** 31.566.1*** 1.560.6*
27.3
11 Orthosiphol L
94.561.6*** 73.0616.9*** 81.563.2*** 37.663.1*** 8.263.2**
25.1
12 Orthosiphol M
43.063.1*** 9.164.3**
8.863.6**
5.562.6*
5.561.4*** >200
13 Orthosiphol N
100.960.6*** 100.961.5*** 67.063.3*** 20.063.4** 6.762.6**
35.9
14
91.865.4*** 95.762.0***
85.361.7*** 30.468.3*
18.365.1*
27.7
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15 Orthosiphol P
98.664.2*** 99.162.0***
88.161.7*** 43.662.7*** 19.165.4*
22.8
16 Orthosiphol Q
101.662.3*** 76.664.4***
35.564.9*** 26.765.5** 23.164.7** 63.9
17 Orthosiphol R
101.666.0*** 93.863.0***
59.166.3*** 34.4610.0** 27.0610.3** 35.7
18
103.060.7*** 100.761.1*** 72.361.6*** 29.860.7*** 2.966.3
30.9
19
104.760.0*** 100.162.5*** 67.163.1*** 19.664.1*** 21.362.1
35.9
20 Orthosiphol U
85.761.1*** 61.463.9***
46.165.0*** 38.7618.5* 18.463.9*
59.7
21 Orthosiphol V
83.962.2*** 65.063.0***
47.964.1*** 29.466.5** 18.766.3*
54.5
22 Orthosiphol W
79.260.9*** 65.065.3***
46.269.5*** 22.564.3*** 4.966.9*
57.6
23 Orthosiphol X
97.761.0*** 101.560.9*** 98.561.4*** 77.966.4*** 21.7610.6** 6.4
24 Orthosiphol Y
89.564.5*** 82.268.5***
56.9618.0** 34.166.3** 21.764.9*
37.9
25 Siphonol A
10864.0***
98.361.6***
94.964.0*** 61.466.7*** 20.267.3** 10.8
26 Siphonol B
107.661.0*** 107.161.1*** 97.461.1*** 52.262.9*** 17.264.0*
17.3
27 Siphonol C
109.062.5*** 108.060.0*** 81.861.9*** 44.461.0*** 14.366.8*
22.9
28 Siphonol D
90.162.4*** 69.263.2***
51.765.7*** 29.966.0** 19.767.5** 46.5
29 Siphonol E
86.062.6*** 97.861.9***
81.861.5*** 44.262.4*** 3.764.9**
23.0
30
3-O-
deacetylorthosiphol
I
91.964.9*** 72.165.0***
48.963.2*** 28.067.7** 29.965.5
66.3
31
2-O-
deacetylorthosiphol
J
93.661.1*** 81.762.9***
69.3610.3*** 39.3614.9** 27.669.2
24.1
32
96.563.2*** 101.661.9*** 79.365.1*** 18.666.8*
4.4616.3*
32.1
33
7-O-
deacetylorthosiphol
B
102.161.3*** 97.062.8***
88.062.8*** 59.769.7*** 34.2614.6* 102
34
98.363.2*** 80.068.3***
32.2620.3** 22.666.2
29.169.5
64.7
35
101.860.0*** 93.160.0***
59.260.0*** 10.360.0*
27.260.0
42.1
36
78.160.0*** 35.560.0***
15.260.0** 13.560.0** 14.260.0** 127
37
86.264.6*** 55.967.0***
31.463.7** 9.569.9*
20.563.6*
84.6
38 Staminol A
79.769.5*** 96.660.0***
82.361.3*** 38.363.2*** 3.862.4
25.5
39 Staminol B
101.660.7*** 92.061.7***
16.762.3** 13.462.7** 24.862.3
67.9
40 Neoorthosiphol A
103.060.7*** 92.660.7***
59.265.5*** 18.064.2*** 2.664.4
40.7
41 Neoorthosiphol B
105.060.7*** 102.161.9*** 92.667.7*** 59.567.6*** 22.063.1
14.0
42 Norstaminol A
101.261.3*** 92.960.7***
55.862.9*** 11.162.3*
27.8619.4
44.4
43 Norstaminol B
92.962.5*** 88.061.3***
29.063.7** 13.462.0*** 21.265.1
64.0
44 Norstaminol C
105.361.3*** 106.061.8*** 103.965.0*** 84.767.8*** 27.168.0*
5.0
45
Norstaminolactone
A
97.562.2*** 74.266.8***
31.463.9** 21.264.5** 8.469.3*
67.6
46 Staminolactone A 101.961.9*** 90.062.5***
52.768.8*** 12.166.9*
3.9618.1
47.1
47 Staminolactone B 79.361.6*** 62.569.7***
53.563.1*** 16.2611.7* 28.0613.9
45.9
L-NMMA
101.663.1*** 86.462.5***
67.963.8*** 42.964.3*** 4.368.2
26.0
Polymixin B
(mg/ml)
94.4611.5*** 93.861.1***
73.966.3*** 36.7615.4** 19.464.4** 27.8
Dexamethasone
55.566.7*** 32.365.7***
17.362.1*** 2.763.5*
29.767.7
170
CAPE 122.864.4*** 119.867.7*** 116.265.1*** 116.261.9*** 34.467.1** 3.1
Each value represents the mean S.E.M. ( n= 4); significantly different from the control:  p , 0.001,
 p , 0.01,  p , 0.05.
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Figure 4: chemical structure of isopimarane- and staminane-type diterpenes isolated from
Orthosiphon stamineus methanolic extract and tested for NO-production inhibitory activity
(Awale et al, 2003a, 2003b, 2003c, 2003d; Nguyen et al (2004).
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Effect on arachidonic acid metabolism: inhibition of lipoxygenase
Lyckander and Malterud (1992) tested the effect of an ethyl acetate extract of Orthosiphon stamineus
(leaves) and 8 lipophilic flavonoids 3 isolated from this extract on the arachidonic acid oxidation
catalysed by 15-lipoxygenase. Arachidonic acid or linoleic acid (less expensive and more stable) was
used as enzyme substrate because results obtained with both compounds were comparable. Soybean
lipoxygenase was used. To justify the use of this experimental model, it is specified that soybean
lipoxygenase appears suitable for testing inhibitors of mammalian 15-lipoxygenase, but less so for 5-
and 12-lipoxygenase inhibitors. In addition, it is also mentioned that soybean lipoxygenase is easily
obtained, and in contrast to other lipoxygenases, inexpensive, fairly stable and easily assayed.
According to Russel et al (2008), comparison of 3-dimensional structures of soybean and mammalian
15-lipoxygenase demonstrated that these enzymes have similar topology and analogous active sites.
Results obtained show that the crude ethyl acetate extract inhibited 15-lipoxygenase with an IC50
value amounting to 0.018% (w/v). The two main flavonoids sinensetin and tetramethylscutellarein
showed dose-related inhibition with IC50 values of 114 µM and 110 µM. The IC50 of quercetin (positive
control) was 98 µM. The other flavonoids tested were less efficient. The total inhibitory activity of
flavonoids was found to be much lower than that of the crude extract so that it is hypothesized that
synergism occurred between components of the extract, or that it contains other lipoxygenase
inhibitors. Based on preliminary results of further work, the authors suggest that the second
hypothesis is favoured.
Assessor’s comment
Flavonoids isolated from an ethyl acetate extract of Orthosiphon stamineus (leaves) have been shown
to inhibit soybean lipoxygenase. The inhibitory activity of the extract was much higher in this
experimental model, but it is not used traditionally.
Antibacterial activity
The antibacterial activity of some isolated compounds or herbal preparations was tested by some
authors. These experiments are reported in the primary pharmacodynamics section because herbal
preparations of Orthosiphon stamineus are recommended by Commission E and ESCOP in case of
bacterial infections of the urinary tract. Available studies were summarized in Table 6 .
Assessor’s comment
Only one study was performed with a range of bacterial strains involved in the occurrence of urinary
tract infections. However none of the flavones tested showed an antibacterial activity in the
experimental conditions used.
Another study investigated more precisely the antibacterial effect of a chloroform extract of
Orthosiphon stamineus leaf against Staphylococcus aureus but the data available are scarce. For
example, the concentration tested is unknown and no MIC was determined. In addition, it should be
noted that the chloroform extract of Orthosiphon stamineus leaf is not used traditionally. Therefore, it
is considered reasonable not to take these results into consideration. It is also mentioned that
Staphylococcus aureus is not commonly isolated in patients suffering from lower urinary tract
infections; it is isolated in urinary tract infections secondary to hematogenous renal infection.
No therapeutically relevant extract was tested for antibacterial activity against bacteria
known to cause urinary tract infections.
3 Sinensetin, tetramethylscutellarein, eupatorin, 5-hydroxy-6,7,3’,4’-tetramethoxyflavone, 3’-hydroxy-5,6,7,4’-
tetramethoxyflavone, salvigenin, trimethylapigenin, tetramethylluteolin
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Other authors showed that an aqueous extract of Orthosiphon stamineus displayed an antibacterial
effect (intermediate to strong) towards Streptococcus mutans responsible for dental caries.
Figure 5 for detailed chemical structure). However, as mentioned by the authors, other Orthosiphon
species belonging to the flora of Southeast Asia (like Orthosiphon stamineus) possess staminane and
isopimarane derivatives.
Figure 5: structure of the labdane diterpenoids isolated from an ethanolic extract of
Orthosiphon labiatus by Hussein et al, 2007
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Table 6: antibacterial activity of herbal preparations or isolated compounds
Reference
Compound / herbal preparation
Bacterial strains tested
Results
Name
Concentration
Name
Pathogeny
Chen et al,
1989
Aqueous extract of
Orthosiphon stamineus
(whole plant)
0.5 to 250
mg/mL
Streptococcus mutans
serotype c (MT5091)
serotype d (OMS 176)
Dental caries
Due to the pathogeny of the bacterium in
humans, experiments were performed in
absence or presence of 5% sucrose in the
culture medium.
MIC (mg/mL) - 5%
sucrose
+ 5%
sucrose
Serotype c
7.8
7.8
Serotype d
23.4
46.9
It was concluded that the extract has strong
and intermediate antibacterial activity against
Streptococcus mutans serotypes c and d,
respectively.
Abdel
Sattar et al,
1995
Chloroform extract (leaf) ?
Staphylococcus aureus Superficial skin
lesions,
pneumonia, astitis,
phlebitis,
meningitis, urinary
tract infections,
osteomyelitis,
endocarditis…
Diameter of the inhibitory zone = 12 mm
Schut and
Zwaving,
1993
A – Sinensetin
B – 3-hydroxy-5,6,7,4-
tetramethoxyflavone
C –
Tetramethylscutellarein
10 and 100
µg/mL
Escherichia coli
Proteus mirabilis
Pseudomonas
aeruginosa
Staphylococcus aureus
Enterococcus
Urinary tract
infections
None of the compounds A, B or C showed any
antibacterial activity.
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Hussein et
al, 2007
Two labdane
diterpenoids a isolated
from an ethanolic extract
of Orthosiphon labiatus b
(fresh aerial parts)
Up to 650 µM Mycobacterium
tuberculosis (strain
H37RvATCC27294)
Tuberculosis
Compound 1: no activity up to the highest
concentration tested
Compound 2: inhibitory activity, MIC = 157
µM
MIC: minimal inhibitory concentration
a
see structure in Figure 5 ; b a species growing in South Africa
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Secondary pharmacodynamics
Antihypertensive effects
Methyl ripariochromene A (MRC) was administered subcutaneously at doses of 50 and 100 mg/kg to
conscious, stroke-prone, spontaneously hypertensive male rats (SHRSP). A decrease of 15-30 mmHg
in mean systolic blood pressure was observed from 3.5 to 24 hours with the higher dose whereas no
change was noted in control animals. The lower dose caused a significant decrease only at 8 hours. In
the same experiment, MRC caused significant decreases in heart rate in the high dosed group at 6 and
8.5 hours (-75 and -45 beats/min, respectively). The decrease noted in low dosed rats was slight but
significant, and noted at 6 hours only. Heart rate figures returned to baseline values after 24 hours.
Results are shown in Figure 6 (Matsubara et al, 1999; ESCOP, 2003).
MRC was also shown to suppress concentration-dependent contractions induced by high K+,
phenylephrine or prostaglandin F2 in endothelium-denuded rat thoracic aorta (Matsubara et al,
1999). In the same in vitro model, neoorthosiphols A and B, MRC, acetovanillochromene,
orthochromene A, sinensetin and tetramethylscutellarein were also shown to suppress concentration-
dependent contractions induced by K + .(Ohashi et al, 2000).
After cumulative applications at 3.8.10-5M and 1.2.10-4M to spontaneously beating isolated guinea pig
atria (ex vivo), MRC was also shown to significantly suppress the contractile force (-18.8% and -
54.7%, respectively) without significantly reducing the beating rate (Matsubara et al, 1999).
Figure 6: time courses of changes in systolic blood pressure (A) and heart rate (B) after
subcutaneous administration of MRC in conscious SHRSP (Matsubara et al, 1999)
MRC was administered at doses of 50 mg/kg ( ) and 100 mg/kg (●) (8 animals per group). The
vehicle was similarly given to 9 animals ( ). Each point is expressed as the mean±S.E. of changes
from the initial values. *p<0.05, **p<0.01, significantly different from the corresponding value in the
vehicle control group on the respective time (Dunnett’s multiple comparison).
Assessor’s comment
Results obtained in vivo in conscious stroke-prone spontaneously hypertensive male rats, in vitro and
ex vivo showed an antihypertensive effect for MRC, which is not completely unexpected in view of its
diuretic property reported previously (see Table 3 ). However, no data is available with a
therapeutically relevant extract so that the human relevance of these results remains unknown.
Hypoglycaemic effects
Mariam et al, 1996
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An aqueous extract of Orthosiphon stamineus (whole plant) was administered to either normal or
streptozotocin-induced diabetic rats by oral gavage at 0, 500 and 1000 mg/kg. Blood samples were
collected up to 7 hours post-treatment and blood glucose levels were measured.
In normal rats, no significant effect was observed over 7 hours at 500 mg/kg, but a significant
decrease was observed from 1 to 7 hours post-dose in animals treated with 1000 mg/kg compared to
controls. In diabetic rats, blood glucose levels were significantly lower in animal groups treated with
either orthosiphon extract (1000 mg/kg) or glibenclamide (10 mg/kg) than in controls. Effects of
extract and glibenclamide on blood glucose were reported to be similar (see Figure 7 ) .
Figure 7: Effect of the aqueous extract of Orthosiphon stamineus on blood glucose levels in
normal and diabetic rats (Mariam et al, 1996)
A- normal rats
B – diabetic rats
An oral glucose tolerance test was then performed by administering orally to normal rats either the
vehicle or extract (1000 mg/kg), followed after 15 minutes by an oral glucose load of 1500 mg/kg.
Blood samples were collected 30 minutes before the test and every 30 minutes thereafter for 4 hours.
Compared to controls, blood glucose levels measured in rats treated with the extract were lowered
over the whole observation period (see Figure 8 ).
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Figure 8: Effect of the aqueous extract of Orthosiphon stamineus on oral glucose tolerance
test in normal rats
According to Mariam et al (1996), these results suggest that the aqueous extract tested possessed
some hypoglycaemic activity in both normal and streptozotocin-induced diabetic rats. They indicate
that further research is needed to identify the substance(s) responsible for this activity and evaluate
the mechanism of action.
Sriplang et al, 2007
An oral glucose tolerance test was performed by administering orally to either normal or
streptozotocin-induced diabetic rats an aqueous extract of Orthosiphon stamineus (whole plant) at 0,
200, 500 and 1000 mg/kg. A group was also treated with 5 mg/kg glibenclamide as positive control.
After 30 minutes, an oral glucose load of 3000 mg/kg was given. Blood samples were collected 30
minutes before glucose loading and up to 210 minutes following glucose loading.
In normal rats, doses of 500 and 1000 mg/kg significantly reduced plasma glucose concentration by
18% and 25%, respectively, 30 min following glucose load. Those figures amounted to 15% and 34%,
respectively, after 90 minutes of glucose load. The reduction in plasma glucose concentration was
maintained up to the end of the experiment (210 minutes) in rats receiving 1000 mg/kg of extract (see
Table 7 ).
Assessor’s comment
The authors mention that glicenclamide reduced glucose levels in normal rats, but the figures reported
for glibenclamide (mean ± SEM, Table 7 ) are exactly the same as those reported for control animals.
This may be a typing error, but alters the conclusion that can be drawn from this experiment.
In diabetic rats, doses of 500 and 1000 mg/kg produced a significant reduction in plasma glucose
concentrations 90 min following glucose administration. Maximum reduction in plasma glucose
concentration amounted to 21% and 24% (210 min). As expected, glibenclamide also reduced glucose
levels (see
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Table 7: effect of Orthosiphon stamineus aqueous extract on plasma glucose concentration
in normal rats (Sriplang et al, 2007)
Table 8: effect of Orthosiphon stamineus aqueous extract on plasma glucose concentration
in diabetic rats (Sriplang et al, 2007)
In another experiment, diabetic rats were treated orally for 14 days with the extract (500 mg/kg/day),
distilled water (negative control), or glibenclamide (5 mg/kg/day, positive control). A group of normal
rats treated with distilled water was also included in the study. The last day, fasting plasma glucose
was measured, as well as total and HDL-cholesterol, and triglycerides. Histopathological examination of
pancreas, kidneys and liver was also conducted.
Results are presented in Table 9 . Significant reduction in plasma glucose levels were observed after 7
and 14 days of treatment with either the extract or glibenclamide, compared to diabetic controls. The
overall histopathological picture of pancreas, kidney and liver is not reported to be modified between
the groups.
Table 9: effect of oral administration of Orthosiphon stamineus aqueous extract on plasma
glucose concentration, cholesterol, triglyceride and HDL for 14 days (Sriplang et al, 2007)
Further experiments in perfused rat pancreas showed that the extract did not increase insulin secretion
in the presence of normal glucose concentration (5.5 mM). At a concentration of 100 µg/mL, the
extract potentiated glucose-induced insulin secretion. This effect was not observed at the other
concentration used (10 µg/mL).
Assessor’s comment
Two published articles dealing with the hypoglycaemic effect suggested for Orthosiphon stamineus
were found in the literature. They were performed with aqueous extracts of the whole plant, whereas
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the plant part traditionally is the leaf. Normal and diabetic (streptozotocin-induced) rats were used and
the route of administration was the same as that used in humans. It was shown in both normal and
diabetic rats that the extract (≥ 500 mg/kg) could decrease the plasma glucose concentration following
glucose load. In diabetic rats, repeated administrations of the extract at 500 mg/kg/day reduced
plasma glucose levels after 7 and 14 days. Results of experiments performed on perfused rat pancreas
suggest that the extract is able to potentiate glucose-induced insulin secretion when present at
sufficient concentration (100 µg/mL). However, an extrapolation of these results to humans is
uncertain in view of i) the limited number of articles dealing with this issue which were found in the
literature ii) the considerable gap shown in rats between effective doses of aqueous extract of
Orthosiphon stamineus (500 mg/kg/day) and positive control glibenclamide (5 mg/kg/day) iii) the lack
of any adverse effect reported in patients that may be related to such an activity in humans (see
monograph section 4.8). In addition, other authors reported increased blood glucose levels in rats
treated with an aqueous extract of Orthosiphon stamineus leaves (Adam et al, 2009, see Diuretic
Other effects
Antifungal activity:
Guérin and Réveillère (1985) tested a hydro-alcoholic extract of Orthosiphon stamineus (DER = 20%)
against 9 fungal species. They showed it inhibited the spore germination in 6 fungal species
( Saccharomyces pastorius, Candida albicans, Rhizopus nigricans, Penicillium digitatum, Fusarium
oxysporum, Trichophyton mentagrophytes ) and delayed the growth of remaining species ( Aspergillus
fumigatus, Aspergillus niger, Botrytis cinerea ). The authors mentioned that the antifungal activity of
Orthosiphon stamineus had not been established before. Consequently, further research on this plant
had to be performed.
Assessor’s comment
The antifungal activity of Orthosiphon stamineus was only reported in this article. We did not find any
other experimental study in the scientific literature to support these results.
Antitumour acitivty:
Malterud et al (1989) isolated sinensetin and tetramethylscutellarein (the 2 most abundant lipophilic
flavonoids found in the drug) from an ethyl acetate extract of Orthosiphon stamineus (leaves). They
tested the activity of these compounds towards Ehrlich ascites tumour cells in vitro in suspension
cultures. Both showed a concentration-dependent inhibitory effect with IC 50 reaching 30 µg/mL and 15
µg/mL, respectively. The authors further indicate that that no cytostatic activity had been reported
before for sinensetin. They also mention that tetramethylscutellarein had been previously tested on KB
cells (ED50 = 27 µg/mL) but was not reported to be effective on 3 tumours in vivo .
Estevez-Nieto (1980) tested the antitumoral activity of Orthosiphon stamineus (leaves) dry extracts
obtained with the following extraction solvents: ethanol (10%), ethanol (50%), ethanol (95%), water
HCl (10%), and methanol HCl (10%). The experimental tumours tested were hepatoma 22 of C3Ha
male mice (18-20 g), mammary adenocarcinoma 755 and Harding Pasey melanoma in C57BL male
mice (18 g), and leukaemia 1210 in DBA/2 male mice (18 g). Animals were treated by IP route.
No extract showed activity against hepatoma 22 tumours. High toxicity and some antitumoural activity
was reported for the ethanolic (50%) extract in animals bearing Harding Pasey melanoma. Some
antitumoural activity was also reported for some extracts against mammary adenocarcinoma 755. No
antitumoural activity against leukaemia was found for any extract.
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Assessor’s comment
Results obtained in vitro are not supported by in vivo studies for tetramethylscutellarein, and no in vivo
study is available with sinensetin. In our opinion, in vitro / in vivo discrepancies may be explained in
part by pharmacokinetic characteristics of each compound but data is lacking (see 3.2.). For example,
a first approach to evaluate the influence of metabolism on the activity of these compounds towards
Ehrlich ascites tumour cells could have consisted of adding a metabolic activation system in the culture
medium.
The results obtained by Estevez-Nieto (1980) are reported to be preliminary results, but we did not
find further articles dealing with this issue. The information provided is rather scarce, and there is little
information about the extracts used (DER, manufacturing process are not described). Most of them are
not used traditionally. In addition, the route of administration used is the IP route. Therefore, it seems
reasonable not to take these isolated results into account.
Choleretic activity:
While they were studying the diuretic activity of two flavones (sinensetin and 3-hydroxy-5,6,7,4-
tetramethoxyflavone) in rats, Schut and Zwaving (1993) also evaluated their choleretic activity by
measuring bile production every 15 minutes for a period of 4 hours (general study design detailed
previously). Doses of 10 mg/kg of these flavones did not increase the production of bile in the
experimental conditions used.
Assessor’s comment
Sinensetin and 3-hydroxy-5,6,7,4-tetramethoxyflavone (10 mg/kg, iv route) were not shown to
possess choleretic activity in male rats.
Anti-pyretic activity:
The anti-pyretic activity of a standardized methanol:water (50/50) extract of Orthosiphon stamineus
was investigated for its effect on normal body temperature and yeast-induced pyrexia in SD rats. The
extract showed no effect on normal body temperature. Doses of 500 and 1000 mg/kg bw significantly
reduced the yeast-induced elevation in body temperature. This effect persisted up to 4 h following the
administration of the extract, and was comparable to that of paracetamol 150 mg/kg (p.o.), a standard
anti-pyretic agent (Yam et al, 2009).
Assessor’s comment
An anti-pyretic effect was reported in one study for a standardized methanol:water extract of
Orthosiphon stamineus (not used traditionally).
Antioxidant activity
Water extracts of Orthosiphon stamineus (leaves) samples collected from different locations of
Malaysia showed antioxidant activity based on -carotene coupled with autoxidised linoleic acid
system. The results of this study indicated that all extracts showed antioxidant activity comparable to
that of quercetin and butylated hydroxylanisole (Akowuah, 2003).
Assessor’s comment
Antioxidant activity was reported in one study for water extracts of Orthosiphon stamineus leaves.
Safety pharmacology
No data found in literature.
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3.2. Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Overview of available data
No available data with an extract of Orthosiphon stamineus or isolated compounds were found.
Assessor’s comment
A comprehensive research in the scientific literature did not find any study designed to evaluate the
pharmacokinetics of neither any extract of Orthosiphon stamineus nor isolated compounds
(orthosiphols, staminols, etc.).
3.3. Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Single dose toxicity
The intraperitoneal LD50 of an ethanolic (50% v/v) extract of Orthosiphonis herba amounted to 19.6
g/kg in ICR mice (Chow et al, 1979).
Assessor’s comment
The acute toxicity of the extract tested by Chow et al (1979) is low. Unfortunately, the details of
symptoms observed in animals remain unknown (article in Chinese / abstract in English).
Repeat-dose toxicity
Chin et al (2008) recently conducted a 14-day toxicity study with a methanolic extract of Orthosiphon
stamineus (leaves). The study design and main results are presented in Table 10 .
According to the authors, this study was undertaken to examine the possible toxicity effect of oral
administration of methanol extract of O. stamineus in Sprague Dawley (SD) rats and hence to
determine the LD50, no-observable effect level (NOEL) and no-observable adverse effect level
(NOAEL). Fixed dose procedures (OECD guideline 420) were followed.
First, it is concluded that LD50 value could not be determined in this study as no mortality occurred at
doses up to 5 g/kg. A test compound that causes no adverse effect at a dose exceeding 5 g/kg will be
considered as ‘practically non-toxic’.
Second, the authors conclude that the extract displayed beneficial rather than adverse effects on the
liver, based on decreased serum AST and ALT levels observed at 1 and 3 g/kg/day, and 5 g/kg/day,
respectively. Increased relative liver weight was reported at the two highest dose levels, and is
suggested to be related to enhancement of activity of metabolizing enzymes. It is also mentioned that
this effect was reversible.
Third, according to the authors and based on the results obtained after analysing serum urea,
creatinine, total cholesterol and triacylglycerol, this study has demonstrated that repeated
administration of the extract had no direct adverse effect on kidney function and also lipid metabolism
in normal young female SD rats.
The NOAEL was determined at 5 g/kg/day, and the NOEL at 0.5 g/kg/day.
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Table 10: repeat-dose toxicity study conducted with a methanolic extract of Orthosiphon
stamineus (Chin et al, 2008)
Species Route,
duration, doses
Parameters monitored
Major findings
Rat (SD)
10F
/group
Oral route
14 days
0*, 0**, 0.5, 1,
3, 5 g/kg
Clinical symptoms, food and water
intake, body weight gain,
hematocrit and clinical
biochemistry at day 14 (AST, ALT,
ALP, urea, creatinine, total
cholesterol, triacylglycerol),
Clinical biochemistry
serum AST (1 and 3 g/kg)
serum ALT (5 g/kg)
Organ weights
relative liver weight (3 and
5 mg/kg) – not observed
after treatment-free period
5F/group sacrificed at the end of
administration period: macroscopic
examination and weight of some
organs (liver, kidneys, lungs,
spleen)
5F/group selected for a 14-day
recovery period: clinical
symptoms, food and water intake,
body weight gain, macroscopic
examination and weight of some
organs (liver, kidneys, lungs,
spleen)
* untreated animals; ** vehicle-treated animals
Assessor’s comment
The aim of the study is unclear, i.e. determination of endpoints related to both acute (LD50) and
subacute/chronic toxicity (NOAEL, NOEL). Groups of animals were treated for 14 days with the same
dose level, so that it seems to be rather a subacute toxicity study. In addition, it is pointed out that the
number of animals used is insufficient because only females were used.
Based on decreased ALT and/or AST levels, it is concluded that the extracts possess beneficial effects
on the liver. This statement cannot be supported, because the biological significance (e.g. dose-
relationship) and the cause of these effects were not investigated. For example, potential causes of
decreased serum activities of ALT and AST are reported to include: decreased hepatocellular
production or release of the enzymes, inhibition or reduction of the enzyme’s activity, interference with
the enzyme assay (PSD, 2007). In addition, increased liver weight is suggested to be related to
increased enzymatic activity. However, no definitive conclusion on liver effects can be drawn without
histopathological examination. This is also true for other organs. The authors underline the need of
histopathological examination.
Overall, it is considered that no definitive conclusion can be drawn from this study mainly due to the
lack of histopathological examination. It is also noted that the extract administered to the animals is
not used traditionally in humans so that the relevance of these data seems rather limited.
Genotoxic and carcinogenic potentials
No data available.
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Assessor’s comment
The monograph published by the ESCOP (2003) and the review made by Bradley (2006) present the
results of a somatic segregation assay on Aspergillus nidulans D-30 (Ramos Ruiz et al, 1996).
However, this test is not conventionally used for regulatory purposes in the evaluation of the genotoxic
potential of medicinal products (either chemical or herbal). Therefore, this study cannot be taken into
consideration.
According to nonclinical guidelines on herbal medicinal products (EMEA/HMPC/32116/05 and
EMEA/HMPC/107079/07), at least one Ames test should be performed for herbal substances /
preparations. As mentioned in the pharmacology part of this assessment report, some studies have
reported or suggested an antibacterial activity for Orthosiphon stamineus extracts (or isolated
compounds). When performing the Ames test with extracts for which registration will be
sought, attention will have to be paid to a potential bacteriostatic effect of tested
preparations in order to exclude any risk of false negative results .
Due to the lack of a carcinogenicity study, the duration of treatments with herbal medicinal products
prepared from Orthosiphon stamineus should not exceed 6 months.
The lack of genotoxicity and carcinogenicity studies will be reported in monograph section 5.3.
Reproduction toxicity
No data available.
Assessor’s comment
The lack of reproduction toxicity studies will be reported in section 5.3.
3.4. Overall conclusions on non-clinical data
Overall conclusions on non-clinical data
Pharmacology
Primary pharmacodynamics
In view of the traditional use claimed for the leaves of Orthosiphon stamineus , published data dealing
with diuretic, anti-inflammatory, antibacterial activities and effects on uric acid level and calcium
oxalate crystals were reviewed.
In rats, some authors reported a diuretic effect after oral administration of either aqueous or ethanolic
(50% and 70%) extracts, as shown by increased urinary volumes compared to controls. However, a
clear conclusion regarding the dose-effect relationship cannot be drawn. The oral effective doses are
approximately 10-18 mg/kg for the aqueous extract, and 13.5 mg/kg for the 70% ethanolic extract.
(Casadebeig-Lafon et al 1989, Adam et al 2009). However, the lack of effect of similar extracts
administered at doses up to 1000 mg/kg was also noted. This discrepancy may be related to
differences in the qualitative and quantitative composition of the extracts. In view of the results
obtained by Arafat et al (2008), it could also be hypothesized that the lack of diuretic activity observed
in some studies may be related to the fact that the extracts were administered only once and that a
diuretic effect may have been reported upon repeated administrations.
Other authors demonstrated a diuretic activity of an ethanolic extract of Orthosiphon stamineus in
male rats, but the clinical relevance of their results is questionable as the intraperitoneal route was
used. Similarly, Chow et al (1979) showed in dogs that the administration of a 50% ethanolic extract
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by the IV route induced an increase in urine volume. Although the route of administration is not that
used traditionally in humans, it is interesting that the tubular reabsorption of sodium and chloride ions
was reduced in treated animals.
According to the results published by Matsubara et al (1999), MRC is involved in the diuretic activity of
Orthosiphon stamineus preparations. However, as the effective oral dose amounted to 100 mg/kg, it is
concluded that other components may also be involved.
One study investigated the ability of a methanolic extract to decrease serum urate levels, and another
one that of a similar extract to inhibit the growth of calcium oxalate crystals. Firm conclusions cannot
be drawn, because the amount of data is not sufficient and the extracts used were not therapeutically
relevant regarding the traditional use. For instance, it may be considered that the traditional use of
Orthosiphon stamineus preparations in complaints of renal gravel is rather related to their diuretic
activity.
The anti-inflammatory activity of orthosiphon extracts not used traditionally or isolated compounds
was assessed. Their relevance to the administration to humans of extracts considered as traditionally
used is therefore uncertain. First, it was shown that orthosiphol A and B decreased the inflammation
induced by TPA applied on mouse ears. Second, it was also reported that a methanolic extract of
Orthosiphon stamineus , as well as 47 diterpenes isolated from this extract inhibited NO-production by
LPS-activated macrophage-like J774.1 cells. Third, flavonoids isolated from an ethyl acetate extract of
Orthosiphon stamineus (leaves) were shown to inhibit soybean lipoxygenase which appears suitable for
testing inhibitors of mammalian 15-lipoxygenase.
Antibacterial activity was not demonstrated against bacteria involved in urinary tract infections, for
either a therapeutically-relevant extract or isolated compounds. The traditional use of Orthosiphon
stamineus preparations in bacterial complaints of the lower urinary tract may therefore be related to
their diuretic activity.
Secondary pharmacodynamics
Results obtained in vivo in conscious stroke-prone spontaneously hypertensive male rats, in vitro and
ex vivo showed an antihypertensive effect for MRC, which is not completely unexpected in view of its
diuretic properties. However, no data is available with a therapeutically relevant extract so that the
relevance of these results to the clinical situation remains unknown.
Two publications dealing with the hypoglycaemic effect of oral aqueous extracts of Orthosiphon
stamineus (whole plant) in normal and diabetic rats were found in the literature. However, an
extrapolation of these results to humans is uncertain (see - Hypoglycaemic effects for more details).
Pharmacokinetics
A comprehensive research in the scientific literature did not allow finding any study designed to
evaluate the pharmacokinetics of neither any extract of Orthosiphon stamineus nor isolated
compounds (orthosiphols, staminols, etc.).
Toxicology
The available toxicological data is rather limited. The acute toxicity of an ethanolic extract of
Orthosiphonis herba is low by intraperitoneal route in mice, as shown by the LD50 which amounted to
19.6 g/kg.
A 14-day toxicity study was performed in rats by oral administration of a methanolic extract of
Orthosiphon stamineus leaves. However, this study is not considered relevant for risk assessment
notably in view of the insufficient number of animals used, the lack of histopathological examination,
and the lack of traditional use of the extract administered to animals.
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No conventional genotoxicity, carcinogenicity and reproduction toxicity studies are available.
Monograph section 5.3
Conventional genotoxicity, carcinogenicity and reproduction toxicity studies were not performed.
4. Clinical Data
Clinical data on efficacy and safety of Orthosiphonis folium are very limited in the different indications
as above listed.
4.1. Clinical Pharmacology
Clinical pharmacology on Orthosiphonis folium is not well documented.
4.1.1. Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
In the literature, only data about the diuretic and choleretic effects of Orthosiphonis folium and its
effect on urinary stone were found.
Diuretic effects and effects on urinary stone:
Early pharmacological studies (1927-1928) in three individuals, involving self-administration of
aqueous extracts of Java tea, demonstrated increases in urine volume (Bradley P.R. British Herbal
Compendium 2006). In these studies, increased diuresis was reported after oral administration of 400
ml/day of a 3.75% extract, 400 ml/day of a 15% extract and 500 ml/day of a 3.3% extract to healthy
volunteers (ESCOP Monographs).
Assessor’s comment:
These two publications Schumann R. 1927 and Westing J. 1928 which are the data source are not
available. Thus, we can not assess these data.
Only two publications are available. These studies are further detailed below.
Studies on the individual and combined diuretic effects of four Vietnamese traditional herbal
remedies ( Zea mays , Imperata cylindrica , Plantago major and Orthosiphon stamineus ) -
Doan Du Dat and al. 1992.
Orthosiphon stamineus was tested in a placebo, controlled, double-blind, and crossover study.
Methodology:
Forty healthy volunteers aged 18 to 27 years were recruited in a 4-day trial. Because of space
limitations, the subjects were divided up into two groups of 20, each of them subjected to a 4-day trial
within a period of two consecutive weeks.
On the first day, the volunteers were given full information about the study and they were examined
clinically. Blood samples were taken for measuring serum haemoglobin, creatinine, Na+ and K+.
On the second day, the volunteers received either the drug (decoction) or the placebo according to the
randomization.
On the third day, a ‘wash-out day’, the subjects were given only standardized food and fluid amounting
to the same quantity as during the treatment days.
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On the fourth day, they were given the alternative decoction, placebo or herbal drug. Three other
herbal remedies are also assessed on the same way ( Zea mays , Imperata cylindrica , Plantago major ).
The volunteers were not allowed to take any other medicines and smoking was forbidden.
A total volume of 1.2 L of fluids (water, soup, herbal drug or placebo) was consumed daily at fixed
regular intervals. All intakes of food and liquids was carefully supervised and recorded.
Urine was collected every day at 8h before the administration of the first dose of drug/placebo and at
10, 12, 14, 16, 18, 20 and 22h and the volume was measured. Urine was collected every 24h for
sodium and potassium determination.
Endpoints :
24 hours volume of urine output, 24h urine Na+ and 24h urine K+.
Extract :
For one daily dosage (600ml of water extract, 3 x 200 ml at 4 hour intervals), 10 g of the dried leaves
of Orthosiphon stamineus were used.
Results :
Tables 11 and 12 below summarise the main results of this study.
Table 11 : 24h volume of urine output in litres (+/- SD) during medication with orthosiphon
stamineus and the placebo respectively:
Orthosiphon
stamineus
Number
Remedy
Placebo
P value
Week 1 20 1.77 (0.48) 1.71 (0.32) NS
Week 2 20 1.79 (0.31) 1.82 (0.35) NS
Week 1 + 2 40 1.78 (0.40) 1.76 (0.34) NS
Table 12 : average 24h urine output of sodium and potassium before and after the herbal
drug and the placebo respectively. (mmol/l of urine, average +/- S.D.)
Orthosiphon
stamineus
Number
Intervention remedy
Placebo
Before After
Before After
24h urine Na+ 20 136 (28.0) 106 (19.0) 136 (22.0) 105 (15.2)
24h urine K+ 20 68.0 (2.7) 65.5 (1.3) 68.0 (3.6) 66.1 (1.3)
There was no statistically significant difference regarding the 24h urine output between Orthosiphon
stamineus and placebo.
Furthermore, no differences were recorded when totalling the urine output during the first 12h of the
day (1.16 (0.33) for Orthosiphon stamineus and 1.13 (0.24) for placebo - NS).
Comparing the output of urine sodium and potassium before and after the first day of treatment, there
was a non-significant reduction in the total amount of salt.
Assessor’s comment:
No influence was observed on 12- or 24-hour urine volume or excretion of sodium and potassium after
administration of 600 ml (3 x 200 ml at 4 hour intervals) of an aqueous decoction of java tea to 40
healthy young volunteers. The 24h sodium and potassium urine output remained unchanged before
and after the first treatment day.
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However, this trial has a very short duration (one day of treatment) and cannot measure any late
diuretic effect. The doses used might have been too low. Moreover, an impact of the environmental
temperature was logged during the trial. The average temperature in the ward during the 2 weeks of
trial was 2.1°C or more over that recorded during the other weeks of trial which might have influenced
the results.
Effects of folia orthosiphonis on urinary stone promoters and inhibitors - Nirdnoy and al.
1991.
Methodology:
This study was carried out upon 6 healthy male volunteers who had no history of renal stone, renal
bone and joint diseases.
On the control day, the volunteers drank 250 ml of water every 6 hours or 4 times per day. Urine
samples were collected into 3 aliguots between 8.00-14.00, 14.00-20.00 and 20.00-8.00 hours.
On the treatment day, the volunteers drank tea 250 ml four times in one day at 6 hour intervals and
the urine collection was done in the same moment as on the control day; at other times the volunteers
could drink water as usual.
Endpoints :
Urine pH, calcium, sodium, potassium, chloride, citrate, titratable acidity, ammonia, osmolarity,
magnesium, phosphorus, uric acid, oxalate, volume and creatinine were analysed.
Extract :
Decoction of Orthosiphonis folium ( Orthosiphon gradiflorus ) tea was prepared by boiling dry leaves and
flowers of the herb weighing about 5.3 g in one litre of water.
Laboratory analysis of the tea revealed pH 5.730, phosphorus 0.220 mg/100 ml, potassium 11.70
mg/100 ml, calcium 3.37 mg/100 ml and citrate 4.69 mg/100 ml.
Results:
Table 13 : urinary pH
Time
Control
Orthosiphon
08:00 – 14:00 6.088 +/- 0.266 6.477 +/- 0.185
14:00 – 20:00 6.138 +/- 0.250 6.202 +/- 0.266
20:00 – 08:00 5.868 +/- 0.102 5.844 +/- 0.126
An analysis of the urine showed an increase in the urinary pH of the first 6 hour period (8.00-14.00),
from 6.088 +/- 0.266 to 6.477 +/- 0.185 and the titratable acidity decreased significantly from 25.64
+/- 2.18 (control) to 22.94 +/- 2.15 mEq/day (p<0.05).
Java tea produced no significant changes in urine volume, or in excretion of sodium, potassium or
chloride compared to the control day. Osmolarity, creatinine, magnesium, phosphorus and ammonia
were not changed significantly.
Citrate, which is known to be a potent stone inhibitor, showed an increase in the value from 341.51
+/- 10.89 (control) to 430.76 +/- 13.80 mg/day (Orthosiphon) but it was not significant.
Uric acid also showed a non significant increase from 591.96 +/- 50.37 (control) to 699.85 +/- 76.36
(orthosiphon) mg/day.
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There was an increase of urinary calcium from 115.07 +/- 14.67 to 141.03 +/- 20.38 mg/day (p<0.1)
but it was not significant and the urinary calcium level was still within normal limits.
Oxalate showed a significant increase from 22.91 +/- 1.80 (control) to 30.10 +/- 2.20 mg/day
(Orthosiphon) (p< 0.05).
The increased level of uric acid may predispose to a higher risk of stone formation but the increased
alkalinity may prevent the uric acid precipitation. Citrate was increased, which is in favour of stone
prevention because citrate is a stone inhibitor. In the other hand, the increased excretion of oxalate in
the urine may result in higher risk of stone formation. Otherwise, the majority of results are not
statistically significant except for the titratable acidity and the urinary oxalate. In this study, which has
been done only on healthy volunteers, all parameters were within normal limits after treatment. Thus,
the authors concluded that Java tea may be beneficial in prevention of uric acid stone formation,
primarily due to decreased acidity of the urine.
Assessor’s comment:
The study of the effects of orthosiphon tea on healthy volunteers showed increased alkalinity of the
urine 6 hours after ingestion. The titratable acidity was significantly decreased but there were no
changes in the urine volume, creatinine and electrolytes. Only oxalate showed a statistically significant
increase in the orthosiphon group.
These results indicate that orthosiphon has no diuretic effect but could be helpful for the prevention of
recurrent uric acid stone due to its effect on the acidity.
However, due to the fact that this study has been carried out in a very limited sample size (6 healthy
volunteers) and results were assessed after only one day of treatment, the clinical relevance of such
results, whatever the parameters analysed, is limited and should be confirmed by additional clinical
data.
Choleretic effect:
In early experiments (1935) on healthy volunteers, it was shown by means of duodenal probes and X-
rays that intravenous administration of a Java tea preparation increased the production of bile and its
liberation from the gall bladder (Bradley P.R. British Herbal Compendium 2006 – Rutenbeck H. 1935).
Assessor’s comment:
The publication from Rutenbeck H. (1935) is a summary and experiments are not detailed.
Assessor’s overall conclusions on pharmacodynamics
Diuretic effects
Only two publications are available and can be assessed (Doan Du Dat and al. 1992 – and Nirdnoy and
al. 1991)
These two publications have methodological weaknesses although one has a double blind, placebo-
controlled, crossover design (Doan, 1992). The first study is a 4-day trial with 40 healthy volunteers
and the second study is a 1-day trial with only 6 volunteers.
In these two studies, Orthosiphonis folium produced no significant changes in urine volume or
excretion of electrolytes. Further clinical data are required to establish a real diuretic effect of
Orthosiphonis folium.
Effect on renal gravel
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In the study by Nirdnoy and al. 1991, there was a decrease in acidity and an increase in urinary pH
that was statistically significant. These results indicate that orthosiphon could be helpful for the
prevention of recurrent uric acid stone which depend on urinary pH. However, due to the fact that this
study has been carried out in a very limited sample size (6 healthy volunteers) and results were
assessed after only one day of treatment, the clinical relevance of such results are limited, whatever
the parameters analysed. The results should be confirmed by additional clinical data.
Choleretic effects
Only one publication is available (Rutenbeck, 1935). In healthy volunteers, Orthosiphonis folium
increased the production of bile and its liberation from the gall bladder but data are very scarce.
Other activities of Orthosiphonis folium have been raised in the different monographs and in the
literature. Moreover, Orthosiphonis folium has traditionally been used in Java for the treatment of
hypertension and diabetes . It has also been used in folk medicine for bladder and kidney disorders ,
gout and rheumatism . After review of the documentation, no pharmacodynamic study was found to
confirm the anti-inflammatory, antibacterial, antihypertensive, hypoglycaemic, and antifungal
activities/properties in line with this traditional use.
4.1.2. Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data are available. The pharmacokinetics of Orthosiphonis folium extract has not been studied.
4.2. Clinical Efficacy
4.2.1. Dose response studies
According to the provided literature, no dose-finding studies have been conducted with Orthosiphonis
folium.
Dosage recommendations found in available monographs are similar: 2-3 g of dried material in 150 ml
of water in the ESCOP Monograph to 6-12 g daily in the German Commission E Monograph.
In the clinical trials, the posology used is 10 g daily in the Doan study and 5.3 g/litre of water in the
Nirdnoy Study.
4.2.2. Clinical studies (case studies and clinical trials)
The information on the clinical efficacy of Orthosiphon stamineus Benth. is very limited. Only two
publications about the diuretic effect and the effect on renal gravel of Orthosiphonis folium were found.
These two studies are further detailed below.
Mercier F. and Mercier L.J. (L’Orthosiphon stamineus, médicament hépat-rénal. Stimulant de
la dépuration urinaire. Le bulletin médical, 1936).
This publication is related to the diuretic activity of Orthosiphonis folium but unfortunately, it is not
available. Only data were found from this article in two monographs (ESCOP Monograph and the British
Herbal Compendium).
Methodology
This was an open study involving 14 patients with azotaemic uraemia associated with various other
ailments. Patients were treated during 10 – 15 days with Java tea.
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Endpoints
Urine volume, elimination of urea and chloride
Extract
For one daily dosage, 500ml of a 12% infusion of Java tea were used (5x100 ml daily).
Results
Java tea increased urine volumes substantially, in some cases more than two-fold within 4-5 days,
together with increased elimination of urea and chloride.
Assessor’s comment:
The study from Mercier F and al. (1936) is not available. The data were found in two monographs only.
Thus, it is difficult to assess these data which are very scarce. However, even if not detailed
particularly in quantitative terms (statistical analysis, results), an increase in the urine volume was
observed in this study, which could partially sustain a diuretic activity of Orthosiphonis folium.
The therapeutic effect of Java tea and Equisetum arvense in patients with uratic diathesis,
Tiktinsky and al, 1983
This publication is related to the diuretic activity of Orthosiphonis folium and its effect on renal gravel.
Methodology:
The effect of orthosiphon (Java tea) and Equisetum arvense on the course of uratic nephrolithiasis was
studied in 67 patients with uratic diathesis throughout the three-month treatment course.
Patients were divided into two treatment groups. The first group (34 patients) was given Java tea and
the second group (33 patients) consumed Equisetum arvense tea.
Extract:
The composition of Java tea and Equisetum arvense tea was not known.
Endpoints:
Diuresis, urine pH, glomerular filtration rate (GFR), osmotic urine concentration, plasma content and
excretion of calcium, inorganic phosphorus and uric acid, renal clearance and daily urine volume.
Results:
The two groups were equivalent in terms of age (the majority of patients were between 41 and 60
years of age), length of time of disease, sex, metabolic disorders, urodynamic characteristics,
functional condition of the kidneys and other parameters.
Table 14 : baseline characteristics
Orthosiphonis folium
Equisetum arvense
Diuresis
1244 +/- 191.9 ml
1184 +/- 140.7 ml
Glomerular filtration rate 72.5 +/- 0.93 ml/min
74.5 +/- 0.97 ml/min
Blood calcium content
2.487 +/- 0.241 mmol/l
2.393 +/- 0.165 mmol/l
5.97 +/- 0.736
mmol/24h
45.4% of patients had a plasma level of uric acid between 0.357 mmol/l and 0.422 mmol/l and the
mean plasma level of uric acid was 0.27 mmol/l.
6.804 +/- 1.265
mmol/24h
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Urine calcium
Table 15 below summarises the main results of this study.
Table 15 : Diuresis at week 4 and 12, Glomerular filtration rate, blood calcium content and
urinary calcium
Endpoints
Orthosiphonis folium
Equisetum arvense
Diuresis (week 4) + 10% + 18%
Diuresis (week 12) + 15% + 24%
Glomerular filtration rate GFR 88.4 +/- 1.2 ml/min = + 18% 87.8 +/- 1.1 ml/min = + 22%
Blood calcium content
2.58 +/- 0.22 (p<0.1)
2.52 +/- 0.17 mmol/l (p<0.05)
Urine calcium
0.49 +/- 0.06 mmol/l
(p<0.01)
0.43 +/- 0.05 (p<0.001)
Blood phosphorus content
(week 4)
-
1.29 +/- 0.16 mmol/l (p<0.05)
Urine phosphorus (week 12) - 9.99 +/- 1.61 mmol/l (p<0.01)
Urine PH 7.69 +/- 0.228 (p<0.001) 5.35 +/- 0.241 (p<0.005)
Both agents increased diuresis and GFR. At week 12, Java tea increased diuresis by 15% and
Equisetum arvense by 24%. For GFR, Java tea increased GFR by 18%, while Equisetum arvense by
22%. Both agents had a diuretic effect, even if the diuretic effect of Orthosiphonis folium was smaller
than the diuretic effect of Equisetum arvense .
Long-term use of Java tea led to the alkalinization of the urine (up to pH 7.69 ± 0.228, p<0.001),
while Equisetum arvense, in the opposite, had acidifying effect (down to pH 5.35 ± 0.241, p<0.005).
This phenomenon was of paramount importance, since the low urinary pH during the long-term use of
Equisetum arvense explained the continued crystalluria of urates and the consequent development of
clinical symptoms.
There was a non-significant increase of the plasma level of calcium from 2.487 +/- 0.241 mmol/l to
2.58 +/- 0.22 (p<0.1) for Orthosiphonis folium. For Equisetum arvense , blood calcium content showed
a statistically significant increase from 2.393 +/- 0.165 mmol/l to 2.52 +/- 0.17 mmol/l (p<0.05).
Both agents improved the plasma content and the excretion of inorganic phosphorus. Both
preparations reduced osmotic urine concentration but had no effect on osmolarity of the blood.
Orthosiphon did not affect the plasma level and excretion of uric acid. Equisetum arvense reduced
uricemia, increasing uric acid clearance and excretion rates.
Assessor’s comment:
In the study from Tiktinsky OL and al. (1983), Java tea increased diuresis by 15% compared to 24%
with Equisetum arvense and increased GFR by 18% compared to 22% with Equisetum arvense. Thus,
we can conclude that Orthosiphonis folium has a low diuretic effect based on the increased diuresis and
glomerular filtration rate.
Otherwise, Java tea led to the alkalinisation of the urine and there was an increase in the urinary pH,
which was statistically significant. Thus, these findings indicate that Orthosiphonis folium could
eventually be helpful for the prevention of recurrent uric acid stone due to its effect on the urinary pH.
Finally, Java tea did not affect plasma levels or the excretion of uric acid. Thus, a hypouricemic activity
of Orthosiphonis folium is not demonstrated in this study.
Overall, the quality of this study cannot be evaluated. For example, the baseline characteristics of the
patients are incomplete as well as the design of the study. Moreover, the characteristics of the
Orthosiphonis folium extract are not specified. In addition, some parameters of interest have not been
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assessed in this study such as the plasma content and excretion of oxalate and citrate. Some results
are missing for Orthosiphonis folium such as blood phosphorus content at week 4 or urine phosphorus
at week 12. Thus, it is difficult to draw conclusions. These results should be confirmed by other clinical
studies.
4.2.3. Clinical studies in special populations (e.g. elderly and children)
After review of the provided literature, no clinical studies have been conducted with Orthosiphonis
folium in elderly, children and in pregnant women.
Therefore, no recommendation of the use of Orthosiphonis folium can be given in these target
populations.
4.3. Overall conclusions on clinical pharmacology and efficacy
The pharmacological and clinical documentation available for Orthosiphonis folium is very limited. Very
few data are available.
Diuretic effect:
Regarding the pharmacological effects of Orthosiphonis folium, only two publications are available
related to its diuretic effect . In these two studies, Orthosiphonis folium produced no significant changes
in urine volume or excretion of electrolytes.
Regarding the clinical effects of Orthosiphonis folium, only two publications are available related to the
diuretic effect of Orthosiphonis folium . In the study by Mercier F. and al (1936), an increase in the
urine volume (in some cases more than two-fold within 4-5 days) was observed. In the second study
by Tiktinsky Ol and al (1983), Java tea had a low diuretic effect based on the increased glomerular
filtration rate and diuresis. From these data, we can conclude that Orthosiphonis folium has a low
diuretic effect even if these results are not totally in line with results of the pharmacological studies.
Despite the methodological weaknesses of the studies and the limited results in terms of benefit, an
indication limited to the traditional use to increase the amount of urine to achieve flushing of the
urinary tract as an adjuvant in minor urinary tract complaints can be granted for Orthosiphonis folium.
This indication is acceptable as Orthosiphonis folium is safe for patients and can be used without any
supervision of a medical practitioner.
Choleretic effect:
Regarding the choleretic effect of Orthosiphonis folium, only one pharmacological publication is
available. In this pharmacological study performed in healthy volunteers, an increase in the production
of bile and its liberation from the gall bladder was observed; however, experiments are not detailed
and these data are very limited in terms of effect.
Effect on renal gravel:
In a pharmacological study, an effect on the acidity and on the urinary pH was also observed (from
Nirdnoy and al. 1991). In this study, there was a decrease in the acidity and an increase in the urinary
pH that was statistically significant. However, due to the fact that this study has been carried out in a
very limited sample size (6 healthy volunteers) and results were assessed after only one day of
treatment, the clinical relevance of such results is limited, whatever the parameters analysed. The
results should be confirmed by additional clinical data.
One clinical study was also found. In this clinical study performed by Tiktinsky Ol and al. (1983), Java
tea led to the alkalinisation of the urine and an increase in the urinary pH which was statistically
significant. These findings are in line with the results obtained in the pharmacological study performed
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by Nirdnoy and al. (1991). However, the effect on urinary pH is insufficient from a medical point of
view to recommend the use of this plant in this indication. Indeed, as the treatment of renal gravel
requires the supervision of a medical practitioner to confirm the diagnosis, prescribe and monitor
adequate treatments, such a traditional use indication without any supervision or medical examination
before treatment could lead to disadvantages for patients. For all these reasons, a traditional use
indication cannot be granted.
Hypouricemic activity:
Regarding its hypouricemic activity in the pharmacological study by Nirdnoy and al. (1991), uric acid
showed a non significant increase and in the clinical study performed by Tiktinsky Ol and al. (1983),
Java tea did not affect uric acid plasma levels, which limits the clinical relevance of such indication.
Other activities:
Other activities of Orthosiphonis folium have been observed in the different monographs and in the
literature. Moreover, Orthosiphonis folium has traditionally been used in Java tea for the treatment of
hypertension and diabetes . It has also been used in folk medicine for bladder and kidney disorders ,
gout and rheumatism . After review of the documentation, no pharmacodynamic study or clinical study
were found to confirm the anti-inflammatory, antibacterial, antihypertensive, hypoglycaemic, and
antifungal activities/properties in line with this traditional use.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
See sections 4.1, 4.2 and 4.3.
5.2. Patient exposure
See sections 4.1, 4.2 and 4.3.
5.3. Adverse events and serious adverse events and deaths
According to the provided literature, only one case report involving Orthosiphon stamineus has been
retrieved (Garcia-Moran S et al). This Spanish publication reports one case of hepatitis in a 25 year-old
female patient. She had taken two herbal products (capsules composed of powder of Green tea leaves
and capsules composed of Orthosiphon stamineus capsules) for two months before experiencing
asthenia, icterus and pruritus. Investigations showed abnormal transaminases values (AST 1943 UI/l
and ALA 2398 UI/l). Viral serologies were negative. The outcome was favourable after the
discontinuation of both products.
Assessor’s comments :
The authors specify that some Green tea containing products have been associated with liver
disorders. They remind that a product containing a hydroalcoholic extract of Green tea was withdrawn
in 2003 in France and Spain due to cases of hepatitis. Cases of liver disorders have been
spontaneously reported with products composed of powder of Green tea leaves . The responsibility or
contribution of Orthosiphon stamineus in this case is rather doubtful but cannot be excluded. It should
be noted that no other cases of hepatotoxicity involving this plant have been retrieved in the literature.
There is no justification to mention these data in the monograph.
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5.4. Laboratory findings
No relevant data available.
5.5. Safety in special populations and situations
Concerning section 4.4 “Special warnings and precautions for use”, information was found in some
monographs:
The Complete German Commission E Monographs (1998):
“Warning: No irrigation therapy in case of oedema due to limited heart and kidney function.”
The ESCOP monographs (2003):
“Special warnings and special precautions for use: Java tea should not be used in patients with oedema
due to impaired heart and kidney function.”
This warning is not supported by clinical data and no clinical studies have been conducted with
Orthosiphonis folium in patients with oedema due to impaired heart and kidney function. However, it is
a logical precautionary measure because fluid intake is not recommended in this case. Therefore, this
warning could be added in the monograph in section 4.4 “special warnings and precautions for use”.
No data on the safe use in children and adolescents are available. Thus, it should be added in section
4.4 “Special warnings and precautions for use” that Orthosiphonis folium should not be used in this
target population.
5.6. Overall conclusions on clinical safety
Clinical safety data are limited.
As there is no information on reproductive and developmental toxicity, the use during pregnancy and
lactation cannot be recommended
As no data on the use in children and adolescents are available, the use can only be limited to the
adults and elderly.
No safety problems concerning the traditional use of java tea or its preparations have been reported.
Java tea preparations are considered not harmful when used in the recommended dosages for specified
preparations
6. Overall conclusions
In conclusion, due to its long-standing use and based on the available documentation, we are of the
opinion that only a Traditional Use can be granted for Orthosiphonis folium. Only the preparations
which have been used for at least 30 years will be described in the monograph.
To be in compliance with the wording validated in the other monographs (e.g. monographs on
Equisetum arvense L., herba, Taraxacum officinale Weber ex Wigg., radix cum herba, Betula pendula
ROTH, folium), the monograph information should remain limited to the traditional use to increase the
amount of urine to achieve flushing of the urinary tract as an adjuvant in minor urinary complaints.
As there is no clinical studies conducted with Orthosiphonis folium in children under the age of 18
years, Orthosiphonis folium should not be used in this target population and should be limited to
adults.
Assessment report on Orthosiphon stamineus Benth., folium
EMA/HMPC/135701/2009
Page 48/49
 
 
 
 
Given that no reproductive toxicity studies have been conducted and there are no data from the use of
Orthosiphonis folium in pregnant woman, section 4.6 of the monograph is adapted accordingly and in
compliance with the wording validated in other monographs.
Annex
List of references
Assessment report on Orthosiphon stamineus Benth., folium
EMA/HMPC/135701/2009
Page 49/49
 
 


Source: European Medicines Agency



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