Community herbal monograph on
Leonurus cardiaca
L.,
herba
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Leonurus cardiaca
L., herba (motherwort)
i) Herbal substance
Not applicable.
ii) Herbal preparations
a) Comminuted herbal substance
b) Powdered herbal substance
c) Tincture (ratio of herbal substance to extraction
solvent 1:5), extraction solvent ethanol 70%
V/V
d) Tincture (ratio of herbal substance to extraction
solvent 1:5), extraction solvent ethanol 45%
V/V
e) Liquid extract (DER 1:1), extraction solvent
ethanol 25% V/V
Well-established use
Traditional use
Tinctures and liquid extract in liquid dosage forms
for oral use.
Powdered herbal substance for oral use.
Comminuted herbal substance as herbal tea for
oral use.
1 The material complies with the Ph. Eur. monograph (ref.: 01/2008:1833)
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 Leonurus cardiaca L., herba
EMA/HMPC/127428/2010
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Well-established use
Traditional use
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Indication 1)
Traditional herbal medicinal product used to
relieve symptoms of nervous tension.
Indication 2)
Traditional herbal medicinal product used to
relieve symptoms of nervous cardiac complaints
such as palpitations, after serious conditions have
been excluded by a medical doctor.
The product is a traditional herbal medicinal
product for use in the specified indication
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults and elderly
a) Comminuted herbal substance for tea
preparation:
single dose 1.5 to 4.5 g, daily dose 3 to 10 g.
b) Powdered herbal substance:
single dose 150 mg, 1-3 times per day.
c) Tincture 1:5, ethanol 70% V/V:
single dose 0.5- 1.0 g, 3-4 times per day.
d) Tincture 1:5, ethanol 45% V/V:
single dose 2-6 ml, 3 times per day.
e) Liquid extract:
single dose 2-4 ml, 3 times per day.
The use in children and adolescents under 18
years of age is not recommended (see section 4.4
‘Special warnings and precautions for use’).
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EMA/HMPC/127428/2010
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Well-established use
Traditional use
Duration of use
If the symptoms persist longer than 4 weeks during
the use of the medicinal product, a doctor or a
qualified health care practitioner should be
consulted.
Method of administration
Oral use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Not to be used in pregnancy.
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.
If the symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Tinctures, liquid extract: 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
Contraindicated during pregnancy.
The safety during lactation has not been
Community herbal monograph on Leonurus cardiaca L., herba
EMA/HMPC/127428/2010
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established.
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.
May impair ability to drive and use machines.
Affected patients should not drive or operate
machinery.
4.8.
Undesirable effects
Well-established use
Traditional use
None known.
If adverse reactions occur, a doctor or a qualified
health care practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
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.
Community herbal monograph on Leonurus cardiaca L., herba
EMA/HMPC/127428/2010
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Adequate tests on reproductive toxicity have not
been performed. Tests on genotoxicity and
carcinogenicity have not been performed.
Well-established use
Traditional use
Not applicable.
16 September 2010
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Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.1.1. Botanical and phytochemical characteristics ........................................................
4
1.2. Search and assessment methodology.................................................................. 1
3
2. Historical data on medicinal use ...................................................................................... 15
2.1. Information on period of medicinal use in the Community ...................................... 1
5
preparations and indications..................................................................................... 1
9
3. Non-Clinical Data ............................................................................................................. 20
preparation(s) and relevant constituents thereof ......................................................... 2
0
preparation(s) and relevant constituents thereof ......................................................... 2
8
preparation(s) and constituents thereof ..................................................................... 2
8
3.4. Overall conclusions on non-clinical data............................................................... 2
9
4. Clinical Data ..................................................................................................................... 30
4.1. Clinical Pharmacology ....................................................................................... 3
0
including data on relevant constituents ...................................................................... 3
0
including data on relevant constituents ...................................................................... 3
1
4.2. Clinical Efficacy ................................................................................................ 3
1
4.2.1. Dose response studies.................................................................................... 3
1
4.2.2. Clinical studies (case studies and clinical trials).................................................. 3
1
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 3
2
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 3
2
5. Clinical Safety/Pharmacovigilance................................................................................... 33
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 3
3
5.2. Patient exposure .............................................................................................. 3
3
5.3. Adverse events and serious adverse events and deaths ......................................... 3
3
5.4. Laboratory findings .......................................................................................... 3
3
5.5. Safety in special populations and situations ......................................................... 3
3
5.6. Overall conclusions on clinical safety ................................................................... 3
5
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
•
Herbal substance(s)
Leonuri cardiacae herba, Motherwort Ph. Eur. 6.0: Whole or cut, dried flowering parts of
Leonurus
cardiaca
L. Content: minimum 0.2% of flavonoids, expressed as hyperoside (Ph. Eur. 01/2008:1833
corrected 6.0).
Herba Leonuri cardiacae EB6: Dried above-earth parts of
Leonurus cardiaca
L.
var. villosus
(DESF.)
BENTHAM, collected during the flowering season (July – September) (EB6). This variety is covered by
the definition of the Ph. Eur.
Motherwort, Leonuri cardiacae herba (BHP 1974, 1990, 1994):
The dried aerial parts of
Leonurus cardiaca
L. collected when the plant is in flower. This definition is
covered by the Ph. Eur.
•
Herbal preparation(s)
powdered herbal substance (BHP 1994)
tincture 1 : 5, ethanol 70% V/V (Latvia, Mashkovskij 1972, Krylow 1993, Sokolov 1984)
tincture 1 : 5, ethanol 45% V/V (BHP 1974, Barnes 2007)
liquid extract 1 : 1, ethanol 25% V/V (Wichtl 2002, 2009, Bradley 1992, BHP 1974, Barnes 2007)
tincture 1 : 5, ethanol 34% V/V (Wichtl 2002, 2009)
tincture 1 : 5, ethanol 25% V/V (Bradley 1992)
dry extract 8-9 : 1, ethanol 40% m/m (Finzelberg 2000, Germany since 1993)
dry extract 7.5-8.8 :1, ethanol 40% m/m (Germany since 1994)
•
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.
Other related herbal substances used in traditional medicine:
Leonurus japonicus
HOUTT.:
Leonurus japonicus
HOUTT., herba
Dried above-earth parts of
Leonurus
japonicus HOUTT. (chin. Yi Mu Cao) (Körfers 2009)
Fresh or dried above earth parts of
Leonurus
heterophyllus SWEET (=
L. japonicus
HOUTT.) (chin.
yimucao) (Stöger 2009)
Dried above earth parts of
Leonurus
japonicus HOUTT., collected during flowering. (BfArM)
Leonurus japonicus
HOUTT., fructus
Dried fruits of
Leonurus
japonicus HOUTT. (chin.: Chong Wei Zi) (Körfers 2009)
Dried, ripe fruits of
Leonurus
heterophyllus SWEET (=
L. japonicus
HOUTT). (chin. chongweizi)
(Stöger 2009)
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Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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Leonurus
sibiricus L.
Leonus sibiricus L.,
semen( Korean:
충위자
,
익모초자
)
Leonuri Semen is the seed of
Leonurus sibiricus
L. (Korean FDA).
1.1.1.
Botanical and phytochemical characteristics
The genus
Leonurus
L. sensu stricto (
Lamiaceae
) comprises 24 species, divided in 3 sections and in 5
sub-sections. Section
Cardiochilium
(V.KRECZ. et KUPRIAN) KRESTOVSK, subsect.
heterophylli
(C.Y.
WU et H.W. LI) KRESTOVSK; ser.
heterophylli
C.Y. WU et H.W. LI comprises
Leonurus japonicus
HOUTT. Subsect.
sibirici
KRESTOVSK comprises
Leonurus sibiricus
L. and section
Leonurus
, subssect.
Leonurus
, ser.
Leonurus
comprises
Leonurus cardiaca
L. and
Leonurus quinquelobatus
GILIB. (Kartnig
2006).
The taxonomy of
Leonurus
is still controversial and any allocation of bibliographic information to a
defined species may be questioned under this aspect.
Although
L. sibiricus
is mentioned in the Korean Herbal Pharmacopoeia 2002 and some authors refer
expressly to
L. sibiricus
L., it cannot be excluded that
L. japonicus
HOUTT. (syn
L. sibiricus
auct. non
L.) has been used in the studies. Doubts may come from the fact that the authors usually refer to the
traditional use in TCM, without addressing the fact that
L. japonicus
HOUTT. is used in TCM and not
L.
sibiricus
L.
According to Bomme (2006) commercial seed material labelled as
L. sibiricus
represents in reality
L.
japonicus
HOUTT. Individual plants of
L. japonicus
with small flowers that were collected in Siberia
were falsely named
L. sibiricus
L.
Synonyms of
L. cardiaca
L:
Leonurus villosus
DESF. et SPRENG. (Wichtl 2002, 2009)
Leonurus campestris
ANDRZ. (Kartnig 2006)
Leonurus canescens
DUMORT (Kartnig 2006)
Leonurus trilobatus
(LAM.) DULAC (Kartnig 2006)
Cardiaca vulgaris
MOENCH (Penso 1983)
Cardiaca trilobata
LAM. (Kartnig 2006)
Cardiaca vulgaris
MOENCH (Kartnig 2006)
Synonyms of
Leonurus cardiaca
L. var. villosus DESF:
Leonurus quinquelobatus
GILIB. (Penso 1983)
Leonurus quinquelobatus
DESF. (Penso 1983)
Synonyms of Leonurus japonicus HOUTT.:
Leonurus artemisia
(LOUR.) S.Y. HU (Kartnig 2006)
Leonurus heterophyllus
SWEET (Kartnig 2006, Harley 2001)
Leonurus sibiricus auct
. non L. (Kartnig 2006, Harley 2001)
Leonurus sibiricus var. albiflora
MIQUEL (Lin 2007)
Phytochemical characteristics of
L. cardiaca
, herba:
•
Characteristic constituents are bitter tasting (Wichtl 2002, 2009) furanic diterpenens of the
labdane type such as leocardin (Kartnig 2006) or leosibiricin (Knoess 1996):
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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•
The main furanic labdane diterpen is leosibiricin that occurs mostly in flowers and young, fully
developed leaves (2.6 – 3.2 mg/g fresh weight) (Knöss 1996, Knöss 1998). The fresh herb may
contain up to 4 mg/g of furanic labdane diterpenes (Knöss 1998).
•
Diterpenes of the clerodane type that had been found in investigations conducted by Brieskorn
(1972, 1979) were neither found in the samples analysed by Knoess 1996 nor in other
investigations, e.g. Agnihotri (2008), Cai (2006), Malakov (1985), Papanov (1997a, 1997b). A
literature review covering investigations until 2006 stated that no other publications on the
clerodane-type substance exist. (Piozzi 2007)
•
0,35% stachydrine in the herb (Van Eijk 1952, Barnes 2007). Samples tested by HPTLC did contain
0.5 – 1.5 % of stachydrine (Kuchta 2009).
•
0.0068% of leonurin (4'-guanidino-n-butyl-syringate) (Barnes 2007). The structure of leonurin has
been confirmed by synthesis (Kishi 1968, Sugiura 1969).
Leonurin (Lin 2007)
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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•
Approximately 1% of lavandulifolioside was isolated from
L. cardiaca
herb collected in Poland
(Milkowska-Leyck 2002). Commercial samples did contain 0.2% (Ritter 2009).
Lavandulifolioside (Milkowska-Leyck 2002)
•
The herb is reported to contain "small amounts" of essential oil (Kartnig 2006); Iridoids: ajugosid (
= leonurid = 4-desoxyharpagid), ajugol, galiridosid, reptosid (no information on the concentration
available) (Kartnig 2006), 0.26% ursolic acid , 0.1% caffeic acid-4-O-rutinosid, flavonoids deriving
from quercetin, kaempferol, and apigenin, genkwanin and 5-9% of "tannins" of unknown structure.
(Kartnig 1985, 2006, Kozlowa 1964, Schultz 1973, Tschesche 1980). A sample tested by
Matkowski (2006) did contain 32.8 mg/g gallic acid equivalents (Folin Ciocalteu reagent).
Samples from Lithuania did contain 0.01-0.02% of essential oil with germacrene D (26-32%), ß-
caryophyllene (6-9%) and alpha-humulene (6-9%) as main constituents (Mockute 2006). Similar
results were found when samples from northern Iran were studied (Morteza-Semnani 2008).
During storage, ß-caryophyllene and alpha-humulene oxides are formed (Mockute 2005).
•
Ali et al. (2007) isolated 25 mg of ursolic acid from 2 kg of
L. cardiaca
herb. Interestingly, the
samples tested by Brieskorn (1952) did not contain any ursolic acid.
•
Herbal material cultivated in Italy and in Poland did contain 0.032 and 0.28% sterols, mainly ß-
sitosterol and stigmasterol (Senatore 1991).
•
The presence of cardiac glycosides is controversial. Old studies (Schultz 1961a, 1961b) were not
confirmed by other groups or more recent investigations. (Reuter 1970) No glucosides were found
(Romanowski 1960).
•
2.03 µg/g nickel and 0.6 µg/g chromium were found in the herb by atom absorption spectrometry.
65% of the Nickel and 51% of the chromium were extracted by tea infusion. (Bloniarz 2008) A
"high amount" of potassium nitrate was found (Kozlowa 1964). In herbal substance imported from
Poland, 27.5 +/- 11.4 mg/kg x 10-3 of lead and 0.32 +/- 0.12 mg/kg x 10-3 of cadmium were
found (Zitkevicius 2003). L. cardiaca, when grown on heavily polluted soil, did not accumulate
heavy metals in a specific way. However, the extraction of Cd from the herb by preparation of a
herbal tea was more efficient than for other herbs (Zheljazkov 2008).
•
Water soluble extractives (BHP 1990, 1994): not less than 15%
Tincture (1:5), ethanol 70% V/V
By a photometric method (Folin-Ciocalteu reagent) a total amount of 227 mg “gallic acid equivalents” /
mL were found. By HPLC analysis 46 µg/ml chlorogenic acid, 52 µg/ml rutosid, 17 µg/ml vitexin, 14
µg/ml isovitexin, 14 µg/ml hyperosid 8 µg/ml quercetin and 250 µg/ml ursolic acid were identified
(Bernatoniene 2009).
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L., herba
EMA/HMPC/127430/2010
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The optimum extraction parameters for a tincture were investigated by Bernatoniene (2003, 2004).
The yield of total flavonoids, calculated as quercetine was 0.0095%, 0.0193%, 0.0267%, 0.0269% and
0.0301% for ethanol 50, 60, 70, 80 and 90% V/V respectively. The dry residue increased from 2.4%
(ethanol 50%), to 2.99% (ethanol 60%) to 3.97 – 4.00% (ethanol 70-96% V/V). Production of the
tincture by maceration resulted in 2.56% dry residue and 0.0267% flavonoids, whereas percolation
resulted in 3.97 % dry residue and 0.0326% flavonoids.
About 14.5% of lead and cadmium that were present in the herbal substance were transferred into a
tincture prepared with ethanol 70% V/V (Zitkevicius 2003).
Other parts of
Leonurus cardiaca
L.
A lectin from
L. cardiaca
seeds agglutinates red blood cells with a CAD marker in a highly specific way.
The lectin is proposed as a specific reagent for the elucidation of red blood cell polyagglutinability (Bird
1979, Leger 1996).
The seeds contain 34.5% fat. 11.7% of the fatty acids are laballenic acid (18:2delta5,6 allene), 0.7%
20:1delta9c acid and 0.2% phlomic acid (Aizetmüller 1998).
Other related herbal substances used in traditional medicine:
1.
Leonurus japonicus
HOUTT.:
Leonurus japonicus
HOUTT., herba
Chinese Pharmacopoeoa:
•
water-extractable substances: > 15%
•
Stachydrine: > 0.50%, calculated as
•
Stachydrine hydrochloride (Stöger 2009)
The method of the Chinese Pharmacopoeia for determination of stachydrine was found “unreliable” by
Bomme (2006) 0.2-1.1% of stachydrine was found by HPTLC (Kuchta 2009) 0.1-0.2% stachydrine was
found in samples cultivated in China using ion-pair HPLC (Chao 2004).
L. japonicus
HOUTT, herba that had been cultivated in Germany (Bomme 2003), did contain 0.5 – 1.5
% (Bomme 2006), 0.5-1.0% (Heuberger 2008a) total Flavonoids. Commercial samples did contain
0.1-0.5% of total flavonoids (Heuberger 2008a).
Minimum of 0.3% of flavonoids, calculated as hyperosid (BfArM).
The above earth parts of
L. japonicus
are reported to contain 0.01-0.05% leonurin, syringic acid,
tiliroside, ajugoside and flavonoids. Blancafort 1977, Yeung 1977, Cong 2005, Qu 2006, Chao 2004)
Kong (1976) isolated 50 mg leonurin from 1 kg of herb.
Diterpenes of the labdane-type, ß-sitosterol, stigmasterol, flavones (genkwanin) (Giang 2005a, 2005b,
Hon 1991, Hon 1993, Widowitz 2009) ß-sitostenon (stigmast-4-en-3-one) (Horita 2002, Romero-
González 2006).
A linear furanocoumarine-glucoside (nodakenin) has been found in the herb. No information on the
quantity is available (Horstmann 1994).
Commercial samples of the herb originating from Asia complied with pharmacopoeial standards when
tested for lead, cadmium, mercury and pesticides (Heuberger 2008b).
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Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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Leonurus japonicus
HOUTT., fructus
The main Dragendorff-positive substance in the seeds is not leonurin or a similar alkaloid, but a cyclic
petide: cycloleonurinin. (Kinoshita 1991) A series of proline-rich cyclic nona-decapeptides
(cycloleonuripetides A, B, C, D, E, F) has been isolated from the fruits (Morita 1996, 1997 a-c, 2006).
Cycloleonurinin (Kinoshita 1991)
2.
Leonurus sibiricus
L.
The main components of the essential oil from the herb were identified by GC-MS as trans-
caryophyllene (33.43%), alpha-humulene (21.49%) and germacrene-D (24.95%) (Almeida 2005).
The herb contains furanic labdane diterpenes (Savona 1982, Satoh 2003).
The occurrence of leonurin, 4-guanidinobutanol-(1), arginin, and 4-guanidino-butyric-acid in the herb
have been reported (Blancafort 1977, Reuter 1971). 0.124± 0.065% leonurin were found by HPLC in
34 samples of the herb collected throughout the regions of Korea (Sung 2001).
The seeds contain 28.5% fat. 18.1% of the fatty acids are laballenic acid (18:2delta-5,6allene), 1.3%
20:1delta9c acid and 0.3% phlomic acid (Aizetmüller 1998).
It seems that the different
Leonurus
species, except
L. marrubiastrum
L., present a similar
phytochemical profile, especially when it comes to the presence of furanic diterpenes of the labdan-
type.
L.marrubiastrum
L. is the only species where non-labdane furano diterpenes of the abietan-type
were found. Genkwanin is proposed as a chemotaxonomic marker for the genus
Leonurus
(Malakov
1998, Piozzi 2007, Tasdemir 1998).
1.2. Information about products on the market in the Member States
France:
Combination products
Crataegi liquid extract 40 ml, Passiflorae tincture 10 ml, Valerianae tincture 15 ml, Avenae liquid
extract 10 ml, Melissae liquid extract 10 ml, Leonuri cardiacae tincture 15 ml; oral use; in cases of
palpitations: Adults 15 drops 3 times daily, in cases of sleep disorders: Adults 15 drops 2 times daily,
Children over 6 years : 6 drops 2 times daily; Traditionally used to reduce nervousness in adults,
particularly in the case of exaggerated awareness of heartbeat (palpitations) after any heart disease
has been shown to be absent; traditionally used to reduce nervousness in adults and children, notably
in cases of disorders of sleep.
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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Germany:
Single ingredient products
Dry extract 8 - 9:1, ethanol 40% m/m, 17 years of use, oral liquid, 80 mg, 3 times per day,
traditionally used to support the function of the cardiovascular system.
Dry extract 7.5 - 8.8:1, ethanol 40% m/m, 16 years of use, oral use, 200 mg, 3 times per day,
traditionally used to support the function of the cardiovascular system.
Combination products
150 mg Leonuri herba, powder, 160 mg dry extract from Equiseti herba 6 - 9 : 1, ethanol 30% V/V,
marketed for more than 34 years, oral use, 1 tablet 3 times per day, traditionally used to support the
function of the cardiovascular system.
Four combinations with 4-5 active substances and three with more than five active substances, among
them Crataegi fructus and Crataegi folium cum flore.
Hungary:
Combination products
1.
Tea-mixture against arteriosclerosis:
20 g Ribis nigri folium, 20 g Crataegi summitas, 20 g Leonuri
cardiacae herba, 20 g Plantaginis folium, 10 g Menthae piperitae folium, 10 g Visci albi stipes; 26
years of use, herbal tea, oral use,
3,5g, 1-2 times per day; Prevention of the development of
hypertension and arteriosclerosis, adjuvant therapy of mild cases of hypertension and
arteriosclerosis, adjuvant therapy of senile cardiovascular complaints. It improves the efficacy of
cardiac function, reduces the workload of the circulatory system by its mild diuretic effect.
2.
Tea-mixture against arteriosclerosis in filters: 0.24 g Ribis nigri folium, 0.24 g Crataegi summitas,
0.24 g Leonuri cardiacae herba, 0.24 g Plantaginis folium, 0.12 g Menthae piperitae folium, 0.12 g
Visci albi stipes) / 1 filter tasak (1,2 g teamixtures); 7 years of use; 2-3 filter sachet daily; 1-2
time per day; Prevention of the development of hypertension and arteriosclerosis, adjuvant
therapy of mild cases of hypertension and arteriosclerosis, adjuvant therapy of senile
cardiovascular complaints. It improves the efficacy of cardiac function, reduces the workload of the
circulatory system by its mild diuretic effect.
3.
Cardiac tranquillizer tea-mixture: 0.36 g Crataegi folium cum flore, 0.36 g Leonuri cardiacae herba,
0.36 g Melissae herba, 0.36 g Visci albi stipes, 0.06 g Valerianae radix / 1 filter; 9 years of use; 1
filter sachet 3 times per day; For relieve cardiac complaints due to overload, exhaustion,
nervousness and for relive of senile cardiovascular complaints. As adjuvant therapy of mild cases
of hypertension and angina pectoris.
Latvia:
Single ingredient products
Comminuted herbal substance, in use for 38 years, herbal tea, oral use, infusion of 2 teaspoons
comminuted herbal substance with 1 glass of boiling water, allow to infuse 20 minutes, 1/3 of glass 3
times per day, as a sedative in cases of hypersensitivity of central nervous system, treatment of heart
and blood system neurosis, early stages of hypertension.
Tincture 1:5, ethanol 70% V/V, in use for 40 years, oral use, adults and adolescents: 30-50 drops, up
to 4 times per day, for reduction of mild nervous tension, in cases of functional heart disorders; in
cases of pre-hypertension, isolated clinical hypertension, borderline hypertension; treatment of
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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functional heart disorders (heart neurosis, manifested as palpitations, intermission, short term stitchy
or long term pressure pain in heart) if there is no organic disease, but symptoms are caused by stress,
anxiety, hypersensitivity of nervous system. Also used to reduce heart symptoms (for example,
palpitations) caused by hyperthyreodism or hormonal changes during menopause.
Combination products
Eight combination products. Two contain vitamins and minerals; three combinations of Leonuri tinctura
with Valerianae tinctura, Crataegi tinctura or fluid extract and Menthae piperitae tincture as heart
function improving drops; two combinations of Leonuri herba with Valerianae radix, Lupuli flos, Mentha
piperitae folium, Melissae folium as sedative; one combination of Leonuri herba with Crataegi
inflorescentia, Crataegi fructus, Meliloti herba – as additional treatment of functional disorders of heart
function and blood system.
Other products
According to the database of Latvian Food Centre: three food supplements containing a single
ingredient; several combination products.
Lithuania:
Single ingredient products
Comminuted herbal substance, in use for 55 years, herbal tea, oral use, 4.5 g of herbal substance 1 -
3 times per day, to make an infusion, pour 150-200 ml of boiling water over 4.5 g of herbal substance.
Steep for 10 - 15 minutes, 1 - 3 times daily, neuroregulatory related disorder of heart function (e. g.
thyroid hyper function, climacteric period etc.), in absence of organic cardiovascular disease.
Tincture (1:5, extraction solvent ethanol 70 % V/V), in use for 55 years, oral liquid, 30-50 drops in a
half glass of water, 3-4 times per day, Stress-, anxiety-, nervousness, thyroid hyper function or
climacteric related heart dysfunction, in absence of organic cardiovascular disease.
heart complaints.
Combination products
Combination products contain 3-5 active substances, among them preparations from Valerianae radix
and Crataegi fructus.
Poland:
Single ingredient products
Leonuri herba, in use for 30 years, herbal tea, oral use, 1.5 – 2.5 g 2-3 times per day, sedative in
nervous heart complaints.
Combination products
1.
Leonuri herba + Melissae folium + Violae herba + Crataegi inflorescentia, 22 years of use, herbal
tea, oral use, 3.6 g 4 times per day, nervous heart complaints.
2.
Crataegi folium cum flore + Crataegi fructus + Leonuri cardiacae herba + Meliloti herba, 6 years of
use, herbal tea, oral use, 1 g 1-2 times per day, nervous heart complaints (palpitations).
3.
Lupuli strobulus + Melissae folium + Leonuri cardiacae herba + Lavandulae flos + Archangelicae
radix + Rosae fructus, 19 years of use, herbal tea, oral use, 2 g 4 times per day, excessive
nervous excitability.
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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4.
Chamomillae anthodium + Melissae folium + Valerianae radix + Leonuri cardiacae herba +
Crataegi inflorescentia + Lupuli strobuli, 15 years of use, herbal tea, oral use, 5 g 1-3 times per
day, adjuvant in nervous tension; difficulty in falling asleep.
5.
Solidaginis herba + Crataegi inflorescentia + Leonuri herba + Valerianae radix + Melissae folium +
Polygoni avicularis herba + Lupuli strobuli, 15 years of use, herbal tea, oral use, 5 g 1-3 times per
day, undue fatigue; supporting in initial phase of heart efficiency disorders
.
6.
Extractum compositum (1:3,5) ex: Leonuri herba, Lupuli strobilo, Melissae folio, Lavandulae flore;
extraction solvent – ethanol 70%(v/v), 7 years of use, oral liquid, 7.5 ml 3 times per day,
increased nervous tension; difficulty in falling asleep.
7.
Melissae herbae intractum + Lupuli strobuli tinctura + Chamomillae anthodii tinctura + Leonuri
herbae tinctura (extraction solvent – ethanol 70%(v/v)) + Crataegi inflorescentiae tinctura +
Valerianae radicis tinctura, 14 years of use, oral liquid, 2.5 mL 1-3 times per day, adjuvant in
nervous tension; difficulty in falling asleep.
8.
Crataegi folium cum flore + Crataegi fructus + Leonuri cardiacae herba + Meliloti herba, 16 years
of use, tablet, 2 tablets 2-3 times per day, adjuvant in initial phase of heart efficiency disorders
(when usage of other drugs is not necessary, without symptoms of circulatory stasis); heart
weakness in elder age.
9.
Valerianae radix + Lupuli strobilus + Melissae folium + Leonuri herba, 18 years of use, tablet, 2
tablets 3 times per day, temporary mild nervous tension; temporary difficulty in falling asleep.
United Kingdom:
Motherwort is included in the General sales List. Nine products that contain motherwort are reported
for the UK market (Barnes 2007). No further details on these products could be retrieved. None of
these is authorised or registered (see section I).
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: No medicinal products
authorised or registered
Belgium
MA
TRAD
Other TRAD
Other Specify: Two combinations with
9-10 ingredients
authorised in 1962; re-
evaluation ongoing. At
least one food
supplement
Bulgaria
MA
TRAD
Other TRAD
Other Specify: No products authorised
or registered. No
information on other
types of medicinal use.
Cyprus
MA
TRAD
Other TRAD
Other Specify: No traditional or other
products marketed
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered medicinal
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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Member State Regulatory Status
Comments (not
mandatory field)
products; one food
supplement (extract with
water from flowers)
Denmark
MA
TRAD
Other TRAD
Other Specify: No products on the
market
Estonia
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered medicinal
products; one food
supplement
Finland
MA
TRAD
Other TRAD
Other Specify: No products authorised
or registered
France
MA
TRAD
Other TRAD
Other Specify: One combination product
authorised in 1953
Germany
MA
TRAD
Other TRAD
Other Specify: Two single ingredient
products authorised in
1993 and 1994. Eight
fixed combinations
marketed since at least
1976
Greece
MA
TRAD
Other TRAD
Other Specify: No medicinal or other
product marketed
Hungary
MA
TRAD
Other TRAD
Other Specify: Three combination
products marketed since
1994
Iceland
MA
TRAD
Other TRAD
Other Specify: No information received
Ireland
MA
TRAD
Other TRAD
Other Specify: No information received
Italy
MA
TRAD
Other TRAD
Other Specify: No information received
Latvia
MA
TRAD
Other TRAD
Other Specify: Three single ingredient
and 8 combination
products marketed
(since 1970/1972).
Additional single
ingredient and
combination products
marketed as food
supplements
Liechtenstein
MA
TRAD
Other TRAD
Other Specify: No information received
Lithuania
MA
TRAD
Other TRAD
Other Specify: Single ingredient and
combination products
marketed since 1955
Luxemburg
MA
TRAD
Other TRAD
Other Specify: No information received
Malta
MA
TRAD
Other TRAD
Other Specify: No products marketed
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No information received
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
Page 12/35
Member State Regulatory Status
Comments (not
mandatory field)
Norway
MA
TRAD
Other TRAD
Other Specify: No medicinal or other
product marketed; L.
cardica is classified as
"medicinal herb" that
needs a marketing
authorisation /
registration
Poland
MA
TRAD
Other TRAD
Other Specify: Single ingredient
products marketed for
more than 30 years; 9
combination products
marketed for 6 to 22
years
Portugal
MA
TRAD
Other TRAD
Other Specify: No information received
Romania
MA
TRAD
Other TRAD
Other Specify: No information received
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No information received
Slovenia
MA
TRAD
Other TRAD
Other Specify: No data on marketed
finished products
available. Leonuri
cardiacae herba is
frequently mentioned in
the lay herbal
books/articles which
show the traditional use
of this herbal drug
Spain
MA
TRAD
Other TRAD
Other Specify: No products authorised
or registered
Sweden
MA
TRAD
Other TRAD
Other Specify: No products on the
market
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No products authorised
or registered; herbal
teas might be covered
by former "exemptions"
(no data available)
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.
1.2.
Search and assessment methodology
The term "
Leonurus
" has been searched on 28 December 2009 in following databases:
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
Page 13/35
CC00 - CCMED copyright ZBMED
CDSR93 - Cochrane Library - CDSR copyright Cochrane
DAHTA - DAHTA-Datenbank copyright Bundesministerium für Gesundheit
AR96 - Deutsches Ärzteblatt copyright DAEB
GA03 - gms copyright gms
GM03 - gms Meetings copyright gms
HG05 - Hogrefe-Verlagsdatenbank und Volltexte copyright Hogrefe-Verlagsgruppe
KR03 - Karger-Verlagsdatenbank copyright Karger-Verlag
KL97 - Kluwer-Verlagsdatenbank copyright Kluwer Academic Publishers
KP05 - Krause & Pachernegg Verlagsdatenbank copyright KuP
CDAR94 - NHS-CRD-DARE copyright Cochrane
INAHTA - NHS-CRD-HTA copyright NHS CRD 2009
SM78 - SOMED copyright LOEGD 2002
SPPP - Springer-Verlagsdatenbank PrePrint copyright Springer-Verlag
SP97 - Springer-Verlagsdatenbank copyright Springer-Verlag
TVPP - Thieme-Verlagsdatenbank PrePrint copyright Thieme-Verlag
TV01 - Thieme-Verlagsdatenbank copyright Thieme-Verlag
CCTR93 - Cochrane Library - Central copyright Cochrane
ME60 - MEDLINE copyright NLM
ZT00 - AnimAlt-ZEBET copyright BfR (ZEBET) 2009
MK77 - MEDIKAT copyright ZB MED
ED93 - ETHMED copyright IDEM 2009
HN69 - HECLINET copyright IFG 2002
CV72 - CAB Abstracts copyright CAB
CB85 - AMED copyright THE BRITISH LIBRARY 2009
NHSEED - NHS-EED copyright NHS EED 2009
AZ72 - GLOBAL Health copyright CAB
IA70 - IPA copyright Thomson Reuters
BA26 - BIOSIS Previews copyright Thomson Reuters
EM74 - EMBASE copyright 2009 Elsevier B.V.
DH64 - Derwent Drug Backfile copyright Thomson Reuters
EA08 - EMBASE Alert copyright 2009 Elsevier B.V.
DD83 - Derwent Drug File copyright Thomson Reuters
II78 - ISTPB + ISTP/ISSHP copyright Thomson Reuters
IS74 - SciSearch copyright Thomson Reuters
T165 - XTOXLINE copyright NLM 2006
TB69 - TOXBIO copyright Thomson Reuters
AN83 - Adis Newsletters copyright Wolters Kluwer Health - Adis International
748 documents have been retrieved from this search. No further restriction of search terms have been
used.
The RTECS database was consulted for toxicological facts. No additional information was found.
Literature and data submitted by the company Valentis, Vilnius, and by AESGP were consulted. Articles
and data that were found to be relevant for assessment are included in the list of references.
Assessment report on
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L., herba
EMA/HMPC/127430/2010
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2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
The continous medicinal use of Leonuri cardiaca herba in Europe is documented for several centuries:
Mattiolius (1626), Lonicerus (1679), Schröder (1685), (Benedum 2006), Wittstein (1882), Hoppe
(1949), Hoppe (1957), Hoppe (1975), Weiss (2009).
The
comminuted herbal substance
and the
powder
are describend in EB6 for more than 50 years
(EB6). The comminuted herbal substance, "Herba Leonuri cardiacae conc.", has been continuously sold
for more than 30 years in Germany as a herbal tea delivered to pharmacies and drug stores (Caelo
1979, Caelo 1994, Caelo 1997, Caelo 2003, Caelo 2009). The use of the herbal substance in tea
infusions in UK is documented by the BHP 1974, BHP 1990 and Bradley (1992). The comminuted
herbal substance has been used an herbal tea in Poland for more than 30 years (see above) and in
Lithuania for 55 years. A monograph from the Russian Pharmacopoeia 9
th
edition has been the basis
for marketing of the comminuted herbal substance in Lithuania; since 2000 in the Drug Register of
Latvia, however on the market since 1972 (Latvia).
A
tincture 1:5 with ethanol 70% V/V
has been on the market in Lithuania for 55 years and has
been registered in 1994 (registration certificate 94/843/9 issued by the Ministry of Health). Before
1994, the liquid extract was distributed to Lithuania from manufacturers originating from the former
UdSSR (Mashkovskij 1972, Krylow 1993, Sokolov 1984). According to a PSUR submitted by one
company, more than 380,000 packages (30 ml or 50 ml) of the liquid extract have been distributed in
both countries from 2003 to 2009.
Since 1993 in the Drug Register of Latvia, however on the market since 1970s when Motherwort
tincture was included in the register of the former USSR and therefore was on the market in Latvia as
its former part (Latvia).
A
liquid extract 1:1, ethanol 25% V/V
has been in continuous use for more than 30 years (Wichtl
2002, 2009, Bradley 1992, BHP 1974).
The limited information on a medicinal use of the
powdered herbal substance
makes it difficult to
establish a plausible traditional use. Although the powder is mentioned in EB6, limited evidence of
medicinal use as a single ingredient product could be found. The powdered herbal substance is
included in BHP 1994. However, a fixed combination with two ingredients has been marketed in
Germany for more than 34 years (see II.1.2.). As the combination of only two very distinct
ingredients, 150 mg Leonuri herba, powder, 160 mg dry extract from Equiseti herba 6 - 9:1, ethanol
30% V/V, could be considered as a "comparable product" and reference, the inclusion of the powder
into the monograph seems to be acceptable.
A
tincture 1:5, ethanol 45% V/V
has been mentioned in BHP (1974) and in Barnes (2007), but no
additional information of use could be retrieved.
No information on more than 30 years of traditional use has been found for the following preparations
that were found in literature and data submitted by AESGP:
•
Tincture 1:5, ethanol 34% V/V (Wichtl 2002, 2009)
•
Tincture 1:5, ethanol 25% V/V (Bradley 1992)
•
Dry extract 8-9:1, ethanol 40% m/m (Finzelberg 2000, Germany since 1993)
•
Dry extract 7.5-8.8:1, ethanol 40% m/m (Germany since 1994)
It might be questioned if the reported figures relating to the drug-extract-ratio of dry extracts
represent real differences.
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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2.2.
Information on traditional/current indications and specified
substances/preparations
Indications reported:
(comminuted) herbal substance:
•
reported to have cardiac activity, especially in neurosis (Hoppe 1957),
•
used as a sedative in neurogenic and functional heart complaints (Hoppe 1957),
•
nervous cardiac complaints, feeling of anxiety, cardiac palpitations, vegetative "heart neurosis"
(Schulze 1944),
•
trembling and palpitations of the heart (Mattiolius 1626),
•
relieves cardiac pain (Lonicerus 1679),
•
improves cardiac blood flow (Lonicerus 1679),
•
cardiac irregularities (Lonicerus 1679),
•
angina pectoris (Lonicerus 1679),
•
cardiac complaints, esp. in children (Schröder 1685),
•
nervous cardiac disorders (Wichtl 2002, 2009, Kommission E 1986, Thomson 1978),
•
traditionally used to support cardiovascular function (Kommission E from Wichtl 2002, 2009),
•
sedative in nervous heart complaints (Poland),
•
nervous cardiac disorders (Weiß 1938),
•
sedative, vegetative neurosis, vegetative-functional heart complaints, vegetative dystonia (Weiß
1944, Weiss 1974, Weiss 1980, Weiss 1997, Weiss 2009),
•
functional heart complaints (Kraft 2009),
•
heart disorders caused by anxiety and stress (no difference to
L. japonicus
HOUTT.) (Balch 2002),
•
sedative, cardiotonic, hypotensive (Bradley 1992),
•
neuropathic cardiac disorders, cardiac complaints of nervous origin (Bradley 1992),
•
palpitation of the heart arising from hysteric cause (Steinmetz 1954),
•
sedative, antispasmodic, cardiac debility, simple tachycardia, effort syndrome, amenorrhoea,
specifically for cardiac symptoms associated with neurosis. (Barnes 2007),
•
originally used in cardiovascular neurosis, angina pectoris, hypertonia, since the beginning of the
20
th
century as a sedative, e.g. in nervous conditions, psychasthenia, neurasthenia with insomnia,
stress, hyperreactivity, vegetative-vascular dystonia, nervous symptoms in the premenopausal
and postmenopausal period. Claimed to be 2-3 time more active than Valerian. (Sokolov 1984)
•
nervous symptoms, cardiovascular neurosis, early stages of hypertension (Mashkovskij 1972,
Krylow 1993),
•
neuroregulatory related disorder of heart function (e. g. thyroid hyperfunction, climacteric period
etc.), in absence of organic cardiovascular disease. (Lithuania),
•
treatment of heart and blood system neurosis, early stages of hypertension (Latvia).
•
as a sedative in cases of hypersensitivity of central nervous system (Latvia),
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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•
traditionally as a sedative (Wichtl 2002, 2009),
•
hysterical complaints (Steinmetz 1954),
•
relieves nervous irritability, calming action (Steinmetz 1954),
•
used in may traditions in trouble with concentrating, non-organic sleep problems, heart palpitations
(Abascal 2004).
•
Climacteric disorders, (Hoppe 1957),
•
traditionally in climacteric complaints, (Wichtl 2002, 2009),
•
to facilitate menstruation , "emenagogum", (Hoppe 1957),
•
traditionally in amenorrhoe (Wichtl 2002, 2009)
•
used in many traditions in "uterine weekness", (Abascal 2004),
•
premenstrual syndrome (no difference to
L. japonicus
HOUTT.). (Balch 2002)
•
India: in Unani medicine ("Baranjaasif", name also used for
Artemisia vulgaris
L. and
Achillea
millefolium
L.) in absent or painful menstruation, premenstrual tension, menopausal flushes (Khare
2007).
•
Spasms (Mattiolius 1626),
•
paralysis of the limbs (Mattiolius 1626),
•
historically (!) for the treatment of wounds, to expell phlegm from the lungs, to support gastric
function (Wittstein 1882),
•
pain of the stomach, pain caused by gall-stones (Steinmetz 1954).
•
Adjuvant in hyperactivity of the thyroid, (Wichtl 2002, 2009), (Kommission E 1986),
•
tachycardia associated with hyperthyreosis (Weiss 1974, Weiss 1980), but: "
L. cardiaca
has no
thyreostatic acitivity" (Weiss 1997).
Uses in US eclectic medicine:
Infusions in hysterical affections, sleeplessness, delirium, uterine pain and –disorders (Hatfield 1886).
Tincture (1:5), ethanol 70% V/V
•
Stress-, anxiety-, nervousness, thyroid hyperfunction or climacteric related heart dysfunction, in
absence of organic cardiovascular disease heart complaints (Lithuania).
•
Reduction of mild nervous tension, in cases of functional heart disorders; in cases of pre-
hypertension, isolated clinical hypertension, borderline hypertension; treatment of functional heart
disorders (heart neurosis, manifested as palpitations, intermission, short term stitchy or long term
pressure pain in heart) if there is no organic disease, but symptoms are caused by stress, anxiety,
hypersensitivity of nervous system. Also used to reduce heart symptoms (for example,
palpitations) caused by hyperthyreodism or hormonal changes during menopause (Latvia)
Liquid extract 1:1, ethanol 25% V/V
•
sedative, cardiotonic, hypotensive (Bradley 1992).
•
sedative, antispasmodic; cardiac symptoms associated with neurosis (BHP 1974).
•
neuropathic cardiac disorders, cardiac complaints of nervous origin (Bradley 1992).
•
sedative, antispasmodic,; cardiac debility, simple tachycardia, effort syndrome, amenorrhoea,
specifically for cardiac symptoms associated with neurosis (Barnes 2007).
Tincture 1:5, ethanol 45% V/V
•
sedative, antispasmodic; cardiac symptoms associated with neurosis (BHP 1974).
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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•
sedative, antispasmodic; cardiac debility, simple tachycardia, effort syndrome, amenorrhoea,
specifically for cardiac symptoms associated with neurosis (Barnes 2007).
Tincture 1:5, ethanol 25% V/V
•
sedative, cardiotonic, hypotensive (Bradley 1992).
•
neuropathic cardiac disorders, cardiac complaints of nervous origin (Bradley 1992).
Traditional uses of other
Leonurus
species:
Leonurus japonicus
HOUTT., herb:
•
The first reported use “to expel dead fetus and retained placenta” is described in the first official
Chines Pharmacopoeoa Tang Peng Ts’ao (659 A.D.) (Blancafort 1977).
•
Current TCM: Menstrual disorders, painful menstruation, amenorrhoea, prolonged menorrhoea,
edema with reduced elimination of urine, oedema in acute nephritis (Stöger 2009). Most frequently
used as an emenagogue in form of a decoction. In eastern parts of China to promote uterine
recovery after delivery (Kong 1976, Bensky 2004).
•
Premenstrual syndrome, heart disorders caused by anxiety and stress (no difference to
L. cardiaca
L.) (Balch 2002).
•
In a retrospective study in Taiwan,
L. japonicus
, herba was the most commonly prescribed herbal
substance for the treatment of symptoms related to menopause. The study investigated records of
3432 that were treated in the time period between January 2003 and December 2006 (Chen
2010).
•
Posology:
Single dose
9-30 g (Stöger 2009)
9-15 g (large doses up to 30 g) (Bensky 2004)
10-20 g as a decoction, 2-3 doses per day (Kong 1974)
Leonurus japonicus
HOUTT., fruit:
•
Current TCM: To activate blood circulation and regulate menstruation, to subdue hyperactivity of
the liver and to clear the eye from opacity. Used in menstrual disorders, amenorrhea,
hysmenorrhea, inflammation of the eye with formation of corneal opacity; dizziness and headache
(Pharm. Commission Chin. 1996).
•
Menstrual disorders, amenorrhoea, painful menstruation, inflammation of eye, corneal opacity,
dizziness, pain and sensation of tension (Stöger 2009, Jia 2006).
•
Posology:
Single dose
4.5-9 g (Pharm. Commission Chin. 1996, Stöger 2009)
3-9 g (Bensky 2004)
The daily dose should not exceed 15 g for because of possible toxicity (Bensky 2004).
Leonurus sibiricus
L., herb (see general comment in 1.1.1.)
Used in Korean traditional medicine for the treatment of uterine leiomyoma (Bajracharya 2009).
Assessment report on
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L., herba
EMA/HMPC/127430/2010
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2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Posology (oral use)
As a herbal tea:
•
single dose 1.5 g (EB6).
•
single dose 1.5 g, daily dose 4.5 g (Wichtl 2002, 2009; Kommission E 1986).
•
single dose 1.5 – 2.5 g, 2-3 times per day (Poland).
•
single dose 3 g, for a decoction, 2-3 times per day (Weiß 1938).
•
single dose 2 g, twice a day (Weiss 1944, Weiss 1974, Weiss 1980, Weiss 1997, Weiss 2009).
•
single dose 1 g, 2-3 times per day as an adjuvant in hyperthyreosis (Weiss 1997, Weiss 2009).
•
single dose 4.5 g, 1-3 times per day (Lithuania).
•
single dose 2-4 g, three times daily (Bradley 1992, Barnes 2007).
•
15 g/200 ml boiling water, take 1/3 of the tea preparation twice a day; if CNS suppression occurs,
doses are either reduced or treatment is interrupted for 5-7 days (Sokolov 1984). This
recommendation would correspond to: a single dose of 5 g, twice a day.
•
15 g/200 ml boiling water, 1 table-spoon 3-5 times per day (Mashkovskij 1972). Presuming that a
table spoon would correspond to 10–15 ml this would correspond to a single dose of 0.75–1.13 g,
3-5 time daily.
•
2 teaspoons comminuted herbal substance with 1 glass of boiling water, allow to infuse 20
minutes, 1/3 of glass 3 times per day (Latvia). Presuming that a teaspoon would correspond to 1 –
1.5 g a single dose would correspond to approx. 0.7–1 g, 3 times a day.
•
single dose 1 tea spoon (1-1.5 g) of comminuted herbal substance for tea infusions, twice a day
(Thomson 1978).
•
single dose: 2 teaspoons (2-3 g) comminuted herbal substance for tea infusions, twice a day (Kraft
2009).
•
single dose 2-4 g, three times per day (BHP 1974).
The majority of posologies proposed by authors would be covered by a single dose of 1.5 to 4.5 g, and
a daily dose of 3 to 10 g.
Powdered herbal substance:
The posology of the powder as part of the comparable fixed combination is 150 mg, 1-3 times per day.
No specific actions are expected from the Equisetum extract in the relevant indication. The posology is
plausible when compared with the posology of tinctures.
Tincture 1:5, ethanol 70% V/V:
•
single dose 30-50 drops, 3-4 times per day (Sokolov 1984, Mashkovskij 1972).
•
single dose 30-50 drops, up to 4 times per day (Latvia).
•
single dose 30-50 drops in a half glass of water, 3-4 times per day (Lithuania).
•
According to DAB 7, 1 drop of ethanol 70% corresponds to 18 mg, 55 drops = 1 g:
Assessment report on
Leonurus cardiaca
L., herba
EMA/HMPC/127430/2010
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•
single dose approx. 0.5 – 1.0 g, 3-4 times per day
Liquid extract 1:1, ethanol 25% V/V
single dose 2-4 ml, 3 times daily (BHP 1974, Bradley 1992, Barnes 2007, Wichtl 2002, 2009).
Tincture 1:5, ethanol 45% V/V:
single dose 2-6 ml, 3 times per day (BHP 1974, Barnes 2007).
Posologies of preparations without traditional use over at least 30 years:
•
tincture 1:5, ethanol 34% V/V single dose 2-6 ml, three times daily (Wichtl 2002, 2009)
•
tincture 1:5, ethanol 25% V/V single dose 4-10 ml three times daily (Bradley 1992)
Duration of use:
•
Long-term use (minimum 2 months) is required to obtain effects (Weiß 1938, Weiß 1944, Weiss
1974)
•
Long-term use is recommended (Kraft 2009)
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Action on free radicals / antioxidant action
A radical scavenging action in ABTS and DPPH radicals has been found with the tincture 1:5, ethanol
70% V/V. After 10 minutes 88% (ABTS) and 85% (DPPH) of the effect of the comparator Trolox was
found (Bernatoniene 2009).
According to Masteikova (2008) the antioxidant activity of
L. cardiaca
tincture, as compared to a
tincture from hawthorn fruits, does not correlate with the total phenol content and is mainly related to
the presence of rutoside (55 µg/ml). An antioxidant effect in vitro was found with an extract prepared
with methanol 60% from the herb, which was extracted first with chloroform (Matkowski 2006).
Antimicrobial activity
A dry extract of the herb with chloroform inhibited the growth of St. aureus in the agar diffusion test
and in the serial dilution test (MIC 500 µg/ml) (Sattar 1995).
The chloroform-soluble fraction of an extract prepared with methanol showed activity against a multi-
drug resistant strain of
P. falciparum
(IC
50
3.1 µg/ml; comparator artemisinin: IC
50
0.0027 µg/ml). No
relevant activity was found against Trypanosoma cruzi, T. brucei rhodesiense and L. donovani
(Tasdemir 2005).
Antiviral activity
Aqueous extracts from
L. cardiaca
herb inhibited almost completely tick-borne encaphalitis virus in
vitro in SPEV cell cultures. I.p. injection in infected (LD
50
dose of the virus) mice induced 34%
protection when given 7 days prior to infection (Fokina 1991).
Antiinflammatory action
Ali et al (2007) investigated a potential anti-inflammatory action of ursolic acid isolated from
L.
cardiaca
. In a "respiratory burst model" an inhibition of superoxide production by human neutrophils
was observed (IC
50
ursolic acid 140.76 µg/mL, comparing to Indomethacin 246.35 µg/ml and ASS
70.45 µg/mL).
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L., herba
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Analgesic action
10 mg/kg of non-specified furanic labdane diterpenes are reported to have reduced abdominal
contractions in mice that were induced by injection of acetic acid by 80-95%. The observed inhibition
by ASS or paracetamol was 35%. No further details are presented (Brand 1999).
An aqueous and an ethanolic extract are reported to have analgetic effects in the hot plate test in
mice. No further details are given (Szocs 1999).
Cardiovascular action
A purified extract with water from
L. cardiacae
herba was investigated in the isolated rabbit heart in
vitro. 0.1 to 3.0 mg/ml of the extract were applied intracoronarily. The extract reduced significantly
and in a dose-dependent way left ventricular pressure by 15 +/- 5mm Hg and heart rate by 14 +/- 1
bpm, enhanced relative coronary flow by 10 +/- 5% and atrioventricular conduction time by 5 +/- 1
ms. The ventricular propagation velocity was not affected. At 1 mg/ml, activation-recovery-intervals
and QTc were prolonged (QTc from 0.24 to 0.26) while dispersion was reduced by 23 +/- 18% .The
authors conclude that the extract exerts calciumantogonistic effects and class III like antiarrhytmic
effects. Other, non aquous extracts were not effective or toxic (Kuchta 2008, Dhein 2007).
The extract was subject of a patent application in 2005. According to the application, the extract is
prepared by purifying a lyophylized extract with water with lipophilic organic solvents, redissolving the
water soluble part in water, precipitating the solution with methanol and using the supernatant fluid.
This purified extract may be further purified by elimination of potassium (Dhein 2005, Ritter 2009).
The refined extract contained approximately 6% stachydrine, 0.1% rutosid, 0.2% verbascosid, 0.3%
lavandulifolioside (Kuchta 2009, Ritter 2009). Furanic diterpenes that were toxic to the isolated heart
preparation and resulted in cardiac arrest were eliminated by prior extraction with dichloromethane
(Ritter 2009). The refined extract was applied intracoronarily in isolated rabbit hearts perfused
according to the Langendorff technique. Mapping experiments with 256 electrodes on the heart surface
showed a reduction of left ventricular pressure and an increase of relative coronary flow at
concentrations of 1.0 and 2.0 mg/ml. Furthermore, the PQ-interval was prolonged and both the basic
cycle length and the activation recovery interval increased. In addition, voltage-clamp measurements
were performed on the following cell models in order to characterise the electrophysiological profile of
the extract: neonatal rat ventricular cardiomyocytes to investigate the effect on I (Na) and I (Ca.L),
sinoatrial node cells and ventricular myocytes isolated from adult guinea pigs to test effects on I (f)
and action potential (AP) duration, as well as HERG-transfected HEK 293 cells to analyse the influence
on the I (K.r). In these voltage clamp experiments the purified exerted a calcium-antagonistic activity
by I (Ca.L) blockade, reduced the repolarising current I (K.r), and prolonged the AP-duration, while I
(Na) was not affected. Although the extract displayed only weak effects on the I (f) amplitude and
voltage dependence, it significantly prolonged the activation time constant of I (f). Thus, the purified
extract acts on multiple electrophysiological targets, specifically I (Ca.L), I (K.r), and I (f), observed
both at whole organ and single cell level. The actions correspond to class III antiarrhytmic drugs,
however a proarrhytmogenic activity and a potential to induce torsade de points was not observed,
even at 2 mg/ml. In summary, a bradycardic action of "multi-ion channel blocker type" could be
confirmed (Ritter 2009).
The aerial parts of plant material collected in Poland were extracted first with chloroform and then with
methanol. The dry extract with methanol was further fractionated into ethyl ether, ethyl acetate and n-
butanol. From the n-butanol fraction lavandulifoliosid was isolated. In the Langendorff-heart from rats
the n-butanol fraction (50 – 2000 µg) significantly reduced the heart rate from 183 (control) to 94 min
-1
. 200 – 2000 µg Lavandulifoliosid reduced the heart rate from 231 to 164 min
-1
. The extract fraction
(50-2000 µg) and lavandulifoliosid (200-2000 µg) resulted in a significant reduction in the coronary
outflow. A significant prolongation of the P-Q, QRS and QT-intervals is reported with 100 – 2000 µg of
the extract fraction and 200 µg of the isolated substance. 50 mg/kg b.w. i.v. (1/20 LD
50
) of
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L., herba
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lavandulifolioside did not have any influence on the pulse rate or the blood pressure of normotensive
rats, whereas 77 mg/kg b.w. i.v. produced a significant decrease in systolic and diastolic blood
pressure (Milkowska-Leyck 2002).
Injection of 0.02 – 2.5 mg/ frog stachydrine isolated from
L. cardiaca
, is reported to reduce the systolic
heart rate. The effect is proposed for biological standardisation of
Leonurus cardiaca
– preparations
(Rodina 1968).
In a dog, i.v. injection of an ethanolic extract (corresponding to 0.5–8 g herb/animal), a decoction
(corresponding to 0.1-0.5 g of herb) or of minerals/ashes (corresponding to 2 g of herb) from
L.
cardiaca
(see sedative action) resulted in a small, short term reduction of blood pressure and in a
slight, short term increase of respiratory frequency. A week negative inotropic and negative
chronotropic action in the isolated frog heart is associated with the minerals present in water extracts
(Erspamer 1948).
Up to 10
-3
g/ml of dry extracts of the herb prepared with methanol 50% and chloroform did not have
any relaxant effect on KCl-induced contractions in rabbit aorta strips in vitro (Rauwald 1994). Lack of
Ca-antagonistic activity and even a slight increase in contraction is reported by Rauwald (1991).
Other actions on isolated organs
Isolated small intestine of guinea pigs: Ashes/minerals from
L. cardiaca
herb resulted in a strong
increase of the tonus, whereas a decoction or an ethanolic extract (see sedative action) resulted in a
week increase of tonus (Erspamer 1947).
Isolated small intestine of dogs: A decoction resulted in an increase of tonus that returned slowly back
to normal, an ethanolic extract resulted in an increase that was hardly reversible, whereas the ashes
induced an immediate increase in tonus easily reversible (Espamer 1947).
Isolated uterus of guinea pigs: 0.2 ml/8 ml of a 10% decoction; an ethanolic extract corresponding to
0.4 g herb/8ml and ashes corresponding to 0.4 g herb/8 ml resulted in a clear increase of the tonus
(Erspamer 1947).
Espamer (1947) concludes that
L. cardiaca
herb has a minor, mostly excitant action on the small
intestine and uterus that is, in part, associated with the minerals present in the herb.
Sedative action
Erspamer (1948) investigated potential sedative actions of
L. cardiacae
herba in frogs and mice. A
comparison between the effects of a 5% decoction (delivering 27-32% extractibles), an extract with
ethanol 95% (7.6-9.3% extractibles) and ashes prepared from the dry residue of the decoction (12.7-
13.2% of the herbal substance) were performed. The dry residue of extracts was used in experiments.
In frogs, a reduction or disappearance of the rightening reflex after injection in the dorsal lymph sack
was observed. With doses corresponding to 0.1 g herb (decoct), 0.25 g herb (extract with ethanol) and
0.2 g herb (ashes) a partial or complete paralysis was found. Comparing to infusions from Valeriana
officinalis root, the decoct from
L. cardiaca
was 2-3 times more effective. The author concludes that
the decoction is 2-3 times more active than the ethanolic extract and that the minerals contribute to
the effect of the decoction. In mice, the influence of the decoction or extract with ethanol on the
spontaneous motility was assessed. After injection of ethanolic extract corresponding to 1-2.5 g of
herb/mouse, a reduction in motility was observed. 5 g/mouse resulted in death of some animals after
3 or 9 h). The decoction given in doses corresponding to 0.2–0.6 g/mouse (injection) or 0.5 to 1.5
g/mouse (p.o.) resulted in a reduction of motility. The effect was dose dependent and lasted for 2 to
10 hours. After injection of a dose corresponding to 0.6 g/mouse 2/3 animals died after 30-55 min; a
dose of 1g/mouse killed all animals within 15 min. No lethal effects were seen after p.o. dosing. The
author concludes that the injection of the decoction is 3-4 times more efficient than the oral dose and
the relation between the minimal effective and minimal lethal dose after injection is 1:2. The injection
of the ethanolic extract is 6 times less effective than the decoction; the relation between the minimal
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L., herba
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effective dose and the minimal lethal dose is 1:5. Minerals/ashes are supposed to contribute to the
effect after injection, but they cannot explain the full effect of the decoction. Although the author
concludes that
L. cardiaca
has a weak sedative action, the models used and the limited number of test
animals without any statistical evaluation cannot confirm this type of action from a modern
perspective.
0.5-1.5 ml of the tincture were administered s.c. in rabbits with electrodes installed in their posterior
extremity. A "sedative action" was investigated by the d.c. amperage necessary to provoke a flexor
contraction of the muscle of the posterior extremity of the animals prior and after injection. 1 ml /
animal s.c. resulted in a higher amperage necessary to induce contraction (Polyakov 1962). No
conclusions on sedative actions can be drawn from this model.
800 and 1600 mg/kg b.w., intragastrically of lavandulifoliosid did not influence the locomotor activity
in mice. 800 mg/kg b.w. of a n-butanol fraction of an extract prepared with methanol (see
cardiovascular actions) reduced the locomotor activity significantly by 65% (Milkowska-Leyck 2002).
0.5 ml/mouse i.p. of an extract of the aerial parts of
Leonurus cardiaca
L. var. villosus DESF. with
water (10%) is reported to reduce the motor acitivity by 50% after 3h. The extract antagonized the
hypermotility induced by s.c. methyl phenidate (20 mg/kg b.w.), prolonged the ether-narcosis and
reduced the convulsant effect of pentetrazol. No details are given (Racz 1989).
3.5 ml/kg b.w., p.o. of an extract with ethanol (concentration not given) slightly prolonged the
hexobarbital sleeping time in female NMRI mice. 1.75 ml/kg b.w. had no significant effect (Weischer
1994).
Studies on related herbal substances/preparations
Leonurus japonicus
HOUTT, herba
Antioxidant action
An extract with acetone-water 7:3 V/V was active in the DDPH free radical scavenging assay (IC
50
76
µg/ml). The activity was mainly associated with gallic acid, kaempferol, quercetin, and myricetin that
were isolated from the extract (Qu 2006).
Antiinflammatory actions
The activity prostaglandin E 9-ketoreductase from swine kidney was increased in vitro by addition of an
aqueous extract from the herb. According to the authors, this may imply an increase in PGF 2 alpha
and, consequently, an inhibition of oxytocinase activity in human serum during pregnancy. The finding,
together with the induction of uterine contractions may explain the traditional use as abortive
medication (Hsieh 1985).
Haematological actions
2 mg/10 ml of a dry extract prepared with methanol inhibited the platelet-activating factor (PAF)
receptor binding in rabbit platelets by 51%. For an extract from Ginkgo leaves (positive control), a
80% inhibition was observed (Kang 2005).
Pre-incubation of human umbilical vein cells with 50 mg/ml of a lyophilised extract inhibited the tissue
factor expression induced by thrombin. The effect was time- and concentration-dependent (Yin 2008).
Leonurin isolated from the herb, inhibited rabbit platelet aggregation induced by thrombine (IC
50
97.22
µM), arachidonic acid (IC
50
31.03 µM) and collagen (IC50 44.48 µM) in vitro (Lin 2007).
A furanic diterpen, prehispanolone, isolated from the herb inhibited the binding of [3H]-PAF to rabbit
platelets (IC
50
= 14.1 +/- 7.9 µM It also inhibited platelet aggregation induced by 2 nM PAF in a
concentration-dependent manner, with an IC
50
of 28.4 +/- 7.3 µM. Positive controls, among them
ginkgolides (BN5221) showed IC
50
values of 4.8 resp. 3.3 µM. Aggregation induced by thrombin, ADP
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and collagen were not inhibited by 50µM Prehispanolone. The tetrahydrofuran ring is essential for
activity. In acidic conditions, prehispanolone is readily transformed into inactive hispanolone (Lee
1991).
Actions on the endocrine system
Prolonged administration of the herb in pigs and rats is reported to decrease the level of estrogene in
the urine and in the serum with no change in the menstrual cycle (Chen 1982).
No estrogenic or antiestrogenic activity was observed with a dry extract prepared from the herb with
ethanol 95% in a recombinant yeast system featuring both a human estrogene receptor expression
plasmid and a reporter plasmid (Kim 2008).
Cardiovascular actions
An extract of the herb with acetone 70% has shown anti-arrhythmic activity in vitro in digoxin-induced
arrhythmia using papillary muscle of guinea-pig. By activity guided fractionation, stigmast-4-en-3-one
(beta-sitostenone) was isolated as active constituent. The structure was confirmed by synthesis. The
ED
50
of anti-arrhythmic activity of beta-sitostenone was 35 µg/ml (Horita 2002).
Pretreatment with 400 mg/kg b.w./day with a dry extract prepared with water (approx. 5:1) that did
contain stachydrine, quercetin and kaempferol as main constituents did not influence the survival rate
of rats with a myocardial infarction caused by ligation of the coronary artery. An antioxidant effect is
attributed to the presence of flavonoids (Sun 2005).
Pretreatment over two weeks with 400 mg/kg b.w./day with a dry extract prepared with water
(approx. 5:1) that did contain stachydrine, quercetin and kaempferol as main constituents reduced
significantly the volume of cerebral infarction induced in rats by middle cerebral artery occlusion. A
neurological deficit score was reduced, although no significant effect is described. The pretreatment
antagonized significantly the drop in antioxidant capacity of the rat serum after induction of the
cerebral infarction. DNA oxidative damage was significantly reduced (Loh 2009).
In anesthetised rats with myocardial ischemia induced by ligature of the coronary artery, i.v. injection
of an extract (no details given) significantly reduced plasma fibrinogen, lowered platelet aggregation
rate induced by ADP and collagen (Yin 2003).
Actions on smooth muscle
Leonurin from
L. japonicus
stimulated in vitro the contraction of uterine smooth muscle from mice,
pretreated with oestrogen. Significant effects on frequency and amplitude are reported for 40 µg /ml
and 90 µg/ml. In smooth muscle from portal veins from rats, a dose dependent reduction of the
amplitude by 32 – 640 µM leonurin. The effect was comparable to 0.003–0.03 µM nifedipine. A
significant increase in frequency was only observed at the highest concentration of 640 µM leonurin,
whereas nifedipine produced significant effects over the total dose range (Chen 2000).
Leonurin (0.4 µg/ml) isolated from the herb, induced regular contractions of large amplitude in uterine
preparations from rats. Actively contracting uterine preparations from estrous rats responded by an
increased rate of contraction (Yeung 1977).
Leonurin induced concentration-dependent and endothelium-independent relaxation of phenylephrine
pretreated rat aorta rings (IC
50
86 µM). It caused a concentration dependent inhibition of vascular
contractile responses to KCl (IC
50
96 µM) and relaxed aortic contraction caused by prostaglandin F2-
alpha. All effects were reversible and did not affect the resting tension. Similar effects were observed
with 0.03 – 3.0 µM nifedipine (Chen 2001).
An extract prepared with water (0.3 mg/ml) stimulated slightly contractions of the the isolated rat
aorta with endothelium. Contractions induced by 3–10 µM phenylephrine were markedly enhanced by
the extract in a dose-depend, reversible way. A maximum effect was seen with 1-3 mg/ml. The effect
was not observed in rat aorta without endothelium. An extract with acetone 70% was active, whereas
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extracts with methanol 70% or ethanol 70% were not. By comparison to the effects of a NO synthase
inhibitor (L-NAME) the authors conclude that the extract may have a similar mode of action (Pang
2001).
Antiproliferative action
The effects of a freeze-dried extract with water of the dried, above earth parts of
L. japonicus
were
investigated. Results were expressed in equivalents of herbal starting material. An inhibition of
proliferation in vitro, after 48h hours incubation with the extract, is reported for the following tumor
cell lines (IC
50
expressed as raw herbal material): C-33A human cervix carcinoma (8 mg/ml), A-549
human lung carcinoma (20 mg/ml), MCF7 human breast adenocarcinoma (40 mg/ml), MDA-MB-453
human breast carcinoma (25 mg/ml), DU 145 human prostate carcinoma (20 mg/ml), LN CaP human
prostate carcinoma (20 mg/ml), TsuPr1 human prostate carcinoma (12.5 mg/ml). An apoptotic
mechanism involving mitochondrial depolarization, cytochrome-c release and caspase 3 activation is
proposed (Chinwala 2003).
Cytotoxicity of a dry extract from the aerial parts with 70% ethanol (approx. 28:1) was analyzed with
MTT assay on ER negative MDA-MB-231 and ER positive MCF-7 human breast cancer cell lines. The
extract caused cell death in a dose-dependent and time-dependent fashion in both ER positive (IC
50
96.2 µg/ml) and negative (IC
50
89.1 µg/ml) breast cancer cells. Morphology, Hoechst 33342 staining
and flow cytometry evidence all indicated the cell death is not in an apoptotic nature. Furthermore, low
concentrations of the extract caused cell cycle arrest at G2/M phase (Tao 2009).
Anticonvulsive action
The essential oil from
L. japonicus
from Brazil, up to 700 mg/kg b.w i.p., was not effective in
preventing pentylenetetrazol-induced convulsions in mice (Coelho de Souza 1998).
Actions on the uterus
Leonurin isolated from the herb increased the frequency and amplitude of contractions in uterine strips
from proestrous rats or ovarectomised rats pretreated with estradiol. In a concentration range of 0.2-
1.0 µg/ml a dose-dependent, reversible effect was found (Kong 1976).
In myometrium samples of patients undergoing total hysterectomy, an increase in frequency and
amplitude in uterine contractions was recorded in vitro after adding a dry extract prepared with
methanol from the herb to the organ bath. 4 samples from patients well beyond menopause did not
react (Kong 1974).
Other actions
Leonurin, isolated from the herb, inhibited in vitro rabbit muscle creatine kinase activity in
concentration- and time-dependent manners (at 0.75 and 1.51 mmol from 12 to 72 h). Similar effects
are described for guanidin-HCl. Leonurin first acts as a non-competitive inhibitor and then as an
irreversible inhibitor (Wang 2004).
Protective effects of synthetic leonurin against doxycycline (DOX)-induced cardiomyopathy in H9c2
cells were investigated. Pretreatment of isolated cells with 1-100 µM leonurin, 2 h before DOX
treatment could reduce DOX-induced (2 µM) apoptotic death of H9c2 cell, reduce MDA formation and
intracellular Ca2+ overload. The authors conclude that leonurin reduced DOX-induced apoptosis in
H9c2 cell by increasing anti-oxidant, anti-apoptotic ability and protecting mitochondrial function (Xin
2009).
Leonurus japonicus
HOUTT, fructus
Cycloleonurinin isolated from the fruits did not present any activity on the isolated guinea pig ileum,
the isolated rat aorta (up to 3 x 10
-5
M), or on the blood pressure in urethane anesthetized rats (5
mg/kg b.w. i.v.) (Kinoshita 1991).
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Cycloleonurinin inhibited the mitogen (concanavalin A) induced response of human peripheral-blood
lymphocytes (IC
50
28 ng/ml). The effect was comparable to cyclosporin A (IC
50
3 ng/ml) (Morita
1997a)
Cycloleonuripeptide B and C showed growth inhibition in p-388 lymphocytic leukemia cells (IC
50
6.0
µg/ml, 3.7 µg/ml) (Morita 1996).
A heat-stable antimicrobial protein, designated LJAMP2, was isolated. LJAMP2 exhibited a molecular
mass of 6.2 kDa. In vitro bioassays showed that LJAMP2 inhibits the growth of a variety of microbes,
including filamentous fungi, bacteria and yeast. The growth of three phytopathogenic fungi, Alternaria
brassicae, Botrytis maydis, and Rhizoctonia cerealis, were inhibited at 7.5 µM of LJAMP2, whereas
Bacillus subtilis was about 15 µM. The IC
50
of LJAMP2 for Aspergillus niger, B. maydis, Fusarium
oxysporum, Penicillium digitatum and Saccharomyces cerevisiae are 5.5, 6.1, 9.3, 40.0, and 76.0 µM,
respectively (Yang 2006).
Leonurus sibiricus
L. (see comment in 1.1.1.):
Antioxidant activity
The aqueous extract of
Leonurus sibiricus
L., herba was examined for its reducing power, scavenging
ability toward superoxide and hydroxyl radicals, and their inhibitory effect on lipid peroxidation. The
extract was found to be active on scavenging of superoxide radicals. The level of hydroxyl radical
scavenging activity tended to be lower than that for superoxide radicals. Inhibitory effects on lipid
peroxidation were examined using a rabbit erythrocyte-ghost system (Nam 2004).
Inhibition of the cytochromes
Lyophilised extracts with water from "Leonuri herba" commonly used in Korea (species not specified;
L.
sibiricus
L. or
L. japonicus
HOUTT.), were tested for inhibition of several cytochrome P450 (CYP)
isoforms and microsomal NADPH-CYP reductase. The abilities of 1-1000 µg/ml to inhibit phenacetin O-
deethylation (CYP1A2), tolbutamide 4-methylhydroxylation (CYP2C9), S-mephenytoin 4′-
hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), chlorzoxazone 6-
hydroxylation (CYP2E1), midazolam 1-hydroxylation (CYP3A4) and NADPH-CYP reductase were tested
using human liver microsomes. The following IC
50
(µg/ml) were found (comparator quercetin µM/ml):
CYP 1A2 830.9 (1.25), CYP 2C9 698.8 (19.2), CYP 2C19 342.1 (>30), CYP 2D6 >1000 (>30), CYP 2E1
>1000 (>30), CYP 3A4 712.9 (>30), NADH-CYP reductase >1000 (0.88) (Liu 2006).
The MeOH extract, CH
2
Cl
2
fraction, EtOAc fraction, n-BuOH fraction and H
2
O fraction of
Leonurus
sibiricus
herb showed significant inhibitory effects on Cyp 1A1/2, 2B1/2, 2E1. The IC
50
values of these
extracts were found to be below 50 µg/ml (Jeong 2002).
Antimicrobial action:
An in vitro antimicrobial action against St. aureus, S. epidermis, Strepotococcus pyogenes, E. coli,
Vibrio colerae, Shigella dysenteriae, and S. boydii has been found for CCl
4
and chloroform extracts of
the aerial parts. The zone of inhibition of 500 µg/disc of extract has been similar to 30 µg/disc of
kanamycin. No or a minor inhibition was observed with extracts prepared with methanol or acetone
(Ahmed 2006).
A methanolic extract from
L. sibiricus
herb from Brazil presented in vitro an inhibition of
B. subtilis
. No
inhibitory effect was observed in
St. aureus
,
St. epidermidis, E. coli, Micrococcus luteus, C. albicans, S.
cerevisiae
(Coelho de Souza 2004).
Dry extracts prepared by stepwise extraction with ethanol 96% and ethanol 70% were reported to
have a significant antifungal activity in vitro (< 2 µg/spot) Heinrich (1991).
An extract with ethanol 70% was reported to be active in vitro against
C. albicans, St aureus
and
Ps.
aeruginosa
(Wadt 1996).
Cytotoxic actions:
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A lyophilised water extract from
L. sibiricus
L, herba, (0.1 mg/mL) did not have any significant effect
on the growth of human myometrial or leiomyomal cells in vitro. The study could not confirm prior
results reported by Baek (2006) (Bajracharya 2009).
Furanic diterpenes, isolated from the herb, showed weak cytotoxic activity against L1210 leukaemia
cells in vitro (IC
50
50-60 µg/ml) (Satoh 2003).
Action on endogenous mediators (NO, TNF-alpha, Interleukines)
0.01 – 1 g/kg of a lyophilized extract with water (approx 10-20:1, contradictory information provided)
from the herb was investigated in mouse peritoneal macrophages in vitro. The concentration range was
chosen to reflect the traditional dose of
L. sibiricus
herb in man (0.1 g/kg). The test solution of extract
contained less then 10 pg/mL endotoxin, so that endotoxin related effects were excluded. Whereas the
extract had no direct effect on the NO production there was a marked increased action when combined
with recombinant interferon–gamma. The effect could be antagonized by pretreatment with pyrrolidine
dithiocarbamate (PDTC), an inhibitor of nuclear factor kappa-B. PDTC antagonized the increase of TNF-
alpha production in peritoneal macrophages stimulated with recombinant interferon-gamma (An 2008).
The anti-inflammatory effect of a lyophilised extract prepared with water on the secretion of tumor
necrosis factor (TNF)-alpha and interleukin (IL)-6 and IL-8 was investigated in a human mast cell line
(HMC-1). Incubation of HMC-1 cells with phorbol 12-myristate 13-acetate (PMA) plus calcium
ionophore A23187 and 0.1 and 1 mg/ml extract inhibited significantly the production of TNF-alpha, IL-
6, and IL-8 by 57%, 78.2% and 84.8% respectively (at 1 mg/ml). The extract had no cytotoxic effects
on HMC-1 cell viability. Stimulation with PMA plus A23187 induced NF-kappaB activation in HMC-1
cells, was inhibited by 1 mg/ml extract (Shin 2009).
Sedative action:
200 mg/kg and 400 mg/kg, i.p., of a dry extract (approx. 10:1) prepared with methanol 90% are
reported to reduce the onset of sleep and to prolong the sleeping ime in pentobarbital induced sleep in
mice. The same doses of the extract caused a significant decrease of scores in different exploratory
behaviour tests (open field test, hole cross test, hole board test) in mice (Ahmed 2005).
Antiinflammatory action
250 and 500 mg/kg i.p. of a dry extract from the herb prepared with methanol showed a significant
analgesic effect in acetic acid-induced writhing in mice. The writhing count was reduced by 44.15 rsp.
69.68%. 25 mg/kg b.w. i.p. of Diclofenac resulted in a 74.67% reduction. 200 and 400 mg/kg, p.o.
showed a significant anti-inflammatory activity against carrageenin induced paw oedema in rats. The
maximum inhibition after 3h was 27% resp. 40%, comparing to 42% inhibition by 100 mg/kg b.w. p.o.
phenylbutazone (Islam 2005).
Anticancer action
Feeding 5-7 month old and 8-12 months old C3H/He mice with 0.5% of a dry extract prepared with
methanol 60% in drinking water over 20 days significantly reduced the number and size of hyperplastic
alveolar nodules in the mammary glands in both age groups. No influence on estrous cycle, plasma
prolactin, anterior pituitary, adrenals or ovaries was found (Nagasawa 1990a).
Permanent feeding of multiparous GR/A mice with 0.5% of an dry extract prepared with methanol 60%
in drinking water over several litters enhanced the development of both pregnancy-dependent
mammary tumours (PDMT) and mammary cancers originated from PDMT: 1
st
litter 31.3% (extract) vs.
11.9% (water), 2
nd
litter 74.1% vs. 34.1%, 3
rd
litter 86.7% vs. 95.0%. By contrast, the treatment
markedly suppressed the development of mammary cancers that originated from hyperplastic alveolar
nodules (HAN) associated with the decreased formation of HAN. The incidence of uterine adenomyosis
was also inhibited in mice given motherwort (7.1% vs. 41.7%). The cause of discrepancy of the effects
of motherwort on mammary cancers due to their origins could not be explained (Nagasawa 1990b).
Administration of the extract could counteract the reduced lactation caused by PDMT (measured by the
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pub growth rate and weight) without any influence on the prolactin level. Mammary DNA and RNA
contents were increased in PDMT-positive mice. The authors conclude that the restoration of lactation
is principally attributed to its stimulation of mammary gland epithelial cell function and not by an
endocrine mechanism (Nagasawa 1991).
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No studies have been performed. In absence of constituents with known therapeutic activity, kinetic
studies are not required.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
L. cardiaca
L. var.
villosus
DESF., herba
Extract with water (1ml = 1 g dry material): LD
50
i.p., mouse, 10,800 mg/kg b.w. (Racz 1989).
L. cardiaca
, herba:
N-butanol fraction from an extract with methanol from L. cardiaca, herba (see cardiovascular effects):
LD50 i.v. 400 mg/kg b.w.; p.o. > 2,000 mg/kg bw (Milkowska-Leyck 2002).
Related herbal substances and isolated constituents
Acute / subchronic toxicity
The toxicity of the dried herb of
L. sibiricus L.
on Sprague Dawley male and female rats was evaluated
through 90-day sub-chronic studies. The rats were fed powdered herb at the rate of 0.5 (low dose), 5
(medium dose) and 25 (high dose) g/kg body weight. Minor treatment-related effects were observed
for body weights, organ weights and the lipid profile parameters and these did not appear to be of
toxicological significance. Signs of renal and liver toxicity were evident in the medium and high dose
groups when plasma creatinine and liver enzymes (ALT, AST) were found to be significantly higher
when compared with the control and the low dose groups. A decrease of alkaline phosphatase (ALP)
was observed in the medium and in the high dose groups. The haematology study revealed a
statistically significant mild anaemia in rats from the medium and high dose groups as indicated by
decreases in haemoglobin, red blood cell count and packed cell volume (haematocrit value).
Administration of the herb at medium and high dose was also found to cause adverse effects in
histopathological structure of the liver (mild-severe degeneration biliary hyperplasia, megalocytosis,
lymphocytic infiltration, degeneration of hepatocytes) and kidney (renal nephrosis) of both male and
female rats. The low dose group showed no significant differences compared to the control. According
to the authors, a dose of 0.5 g/kg bw is considered safe (Pin 2009).
Extract from
L. japonicus herb
(not specified), LD
50
, i.v., mice: 30-60 g/kg b.w. (Chinwala 2003).
Adult male rats fed on a diet with 50%
L. japonicus herb
for 80 days showed no toxic effects or change
in fertility (Kong 1976, Chinwala 2003).
Total alkaloids from
L. japonicus herb
(not specified), i.v., mice, 572 mg/kg b.w. (Chinwala 2003).
Lavandulifolioside isolated from
L. cardiaca
: LD50 i.v. approx. 1000 mg/kg b.w., p.o. > 2000 mg/kg
b.w. (Milkowska-Leyck 2002).
No adverse effects in rats after 2 mg/rat
leonurin
i.p. for 4 days (Kong 1976, Chinwala 2003).
30 mg/kg b.w. per day of
leonurin
, s.c., in rabbits over 2 weeks did not affect food intake, faecal and
urinary excretions and body weight (Chinwala 2003).
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L., herba
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Leonurin
of synthetic origin is reported to be non-toxic up to 4g/kg b.w. in rats. No details are given
(Chan 1983).
Toxicity on reproduction
A fed containing 50% of powdered
L. japonicus herb
did not affect fertility in male rats (Chinwala
2003).
The milk production in rats fed a diet with 1% of the herb, starting on day 18 of gestation, was
significantly increased on day 8, 13 and 18 of lactation by 15.22, 19.11 and 19.25% as compared to
non-supplemented controls. The pup weight on day 15 and 22 was increased by 9.99 and 9.01%
respectively. The daily weight gain on days 8-14, 15-21 and 1-21 was increased by 19.44%, 6.78%
and 11.11% (Shi 2007).
Rats given 0.5 mg/ml leonurin of synthetic origin as the only water source over 3 generations and
cross-bred with treated mates showed no sign of aberration in gross morphology, growth rate, sex
ratio, liter size and pup weight. No further details are given (Chan 1983).
3.4.
Overall conclusions on non-clinical data
Pharmacodynamic studies on Asian and European
Leonurus
species follow the different traditional
uses: sedative and cardiovascular effects for
L. cardiaca
were investigated in Europe whereas effects of
L. japonicus
on reproductive organs and haematological parameters were focused in Asia. There is
some overlap between the effects of both species, although it remains an open question if the different
studies reflect a different pharmacological profile or simply a different area of interest.
From a perspective of safety the bradycardic actions, renal and liver toxicity and the activity on the
uterus deserve attention. Water soluble components exert in vitro in relatively high doses of 1-2
mg/ml a negative inotropic and bradycardiac action. The relevance of these findings for the oral use of
the tincture or herbal tea is highly questionable. The finding that, even at that high concentrations, no
potential for induction of torsade-de-points is present, adds to the safety of traditional preparations.
The finding of renal and liver toxicity in animals after prolonged feeding of high doses of
L. sibiricus
powder is not considered relevant for the use of the herbal tea or the tincture under the conditions
proposed in the monograph. The maximum dose for preparation of an herbal tea is 10 g/day,
representing a safety margin of 2.5 (50 kg person) compared to the dose of powder that is considered
safe in the feeding experiment. The maximum daily doses of the liquid extract 1:1 (12 ml) would result
in a safety margin of 2 and of the powder (450 mg) in a safety factor of > 50. In addition to that, the
duration of use under OTC conditions is limited to 4 weeks vs. 90 days in the feeding study. As
clerodane-type furanic diterpenes that were found in Teucrium and that are known for hepatoxicity are
absent from
Leonurus
, the reason for the effects remain unknown. It may deserve additional studies
and calculations if the furanic part of the labdane-type diterpenes present in
Leonurus
represent some
structural alerts that need to be investigated further.
Although no studies have been performed with
L. cardiaca
on toxicity in reproduction, the data on
leonurin (present in
L. cardiaca
) and the studies in Asian
Leonurus
species point to a risk and confirm
the contraindication in pregnancy that is widely and consistently found in several handbooks.
No studies on genotoxicity and carcinogenicity have been found.
The data on sedative actions, although limited, contribute to the plausibility of the traditional use of
L.
cardiaca
in the indication covered by the monograph.
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4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
According to Ovanesov (2005) enhanced anxiety state is accompanied by a limitation of the color-
discrimination function of the retina in young humans. Chronic administration of tofisopam (grandaxin)
or tinctura leonuri is reported to have decreased anxiety and significantly improved the colour
discrimination function of retina with respect to all four colours studied. The author suggests that this
improvement may be related to an action upon the GABAergic processes both in the retina and in the
related cerebral structures. No details are presented.
After repeated administration of melatonin (0.75 mg at night, 10 days) a significant decrease in the
thresholds of retinal brightness sensitivity and an improved emotional state in anxious young subjects
have been observed. Similar, but less pronounced effects were observed after the treatment with
Leonurus cardiaca
tincture. The authors suggest that there might be a relation between the limitation
of anxiety and the improvement of visual function (sensitivity). No details are presented (Ovanesov
2006).
Other Leonurus species:
L. japonicus
HOUTT.:
Haematological parameters
The results of a clinical study, involving 105 men with "blood hyperviscosity" (hypertension 60,
atherothrombotic brain infarction 21, brain atherosclerosis 9, diabetes 3) are reported. The patients did
receive 10 ml of a preparation consisting of a decoction of the herb (5 g/ml) in 250 ml 5% glucose i.v.
per day for 15 days. No details on the preparation are available. Improvement of symptoms such as
vertigo, headache, insomnia, numbness in limbs, ability to stand on one leg with closing eyes, is
reported for the majority of patients. Platelet aggregation that was investigated in 65 patients was
significantly reduced (Zou 1989).
52 Patients with thrombocytopenic purpurea were treated by TCM "Huo Xue Hua Yu" medications, i.e.,
agents that are traditional associated with “activated blood flow and elimination of blood stasis”,
among them
Leonurus japonicus
. An overall response rate of 88%, with platelet and megakaryocyte
recovery is reported. The elevated PAIgG and the platelet count felt to normal levels in the majority of
cases. No detailed information could be found (Deng 1993).
Uterotonic activity
The effect of an infusion of the herb was investigated in 141 fertile women. A single dose of 150 ml of
a decoction prepared from 30 g of herb was administered orally. Intra-uterine pressure was measured
by a catheter filled with sterile saline-citrate solution. The base line was established through a
recording of 30-90 min before dosing. After dosing, pressure was monitored for another 1-2 hours. 121
cases were fit for evaluation. Of these, an effect was seen in 50 cases (success rate 41%). Two
additional cases presented an increase in contraction frequency without increased pressure. The
pressure increase corresponded to 150% to 300% of the base line pressure. Control with water
resulted in a 2.7% increase, control with 0.2 mg, i.m. Ergonovine resulted in a comparable increase of
intrauterine pressure. As the success rate of Ergonovive injection was 61%, p.o. application of the
decoction had a relative potency of 91%. Abdominal pain (4.1%) and increased diuresis (48%) were
observed. No influence on blood pressure or heart rate was seen. The uterotonic effect was
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independent from the stage of menstrual cycle, age, parity, uterine position in situ, blood pressure and
pulse rate. The authors associated the effect to leonurin (Chan 1983).
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No clinical studies have been performed. In absence of constituents with known therapeutic activity,
pharmakokinetic studies are not required.
4.2.
Clinical Efficacy
4.2.1.
Dose response studies
No information on dose-response studies was found.
4.2.2.
Clinical studies (case studies and clinical trials)
No clinical studies with single ingredient products containing
L. cardiaca
L. have been found.
Studies with combination products
Fifty male alcohol abusers (mean age 45.6 years) with sleep disturbances were enrolled in a cross-
over, placebo controlled study with a fixed combination product. On 2 consecutive nights, the
volunteers were given tablets containing 170 mg valerian (Valeriana officinalis) root, 50 mg hop cones,
50 mg balm (Melissa officinalis) leaves and 50 mg motherwort (
Leonurus
officinalis [sic]) herb, or the
placebo, which contained 5 mg valerian root. Treatments were taken orally 1 hour before bed. The
following morning a questionnaire was completed by the volunteers, concerning sleep quality, dream
recall, frequency of night awakenings, and fatigue and sleepiness in the morning. Statistical analysis
using the Wilcoxon matched-pairs signed-ranks test (using each subject as his own control) was
performed on the resulting data. The combination showed significant improvement in sleep quality, a
reduced feeling of sleepiness the next day, a decrease in the recall of bad dreams and a notable
decrease in night awakenings. No conclusion with respect to any contribution of
L. cardiaca
to this
effect can be drawn (Widy-Tyszkiewicz 1997).
Studies with preparations from
L. japonicus
, herba
85 patients with acute cerebral ischemic infarction were randomized to receive either 10 ml of a
"
Leonurus
injection" plus 500 ml 0.9% NaCl solution i.v. drip q.d. for 15 days or 20 ml of a "Salvia
miltiorrhiza injection" plus 500 ml 0.9% NaCl solution i.v. drip q.d. for 15 days. No details on the
extract are given. As compared to the start of the study, there was a significant difference favouring
the
Leonurus
preparation in the curative rate (neurological deficit status; 70% improvement vs. 31%).
The
Leonurus
preparation reduced serum lipids, fibrinogen and had an anticoagulant action (Xu 2002).
An injection prepared from
L. japonicus
herb (no details on the extract) was tested for preventing
postpartum haemorrhage after caesarean section in a prospective, randomized and single blinded
multi-centre study. 440 women underwent caesarean section (CS) indicated by obstetric factors were
enrolled from 15 teaching hospitals in China and assigned into three groups: group of motherwort: 147
cases were administered by motherwort 40 mg uterine injection during CS and 20 mg intramuscular
injection per 12 hours 3 times after CS; group of motherwort+oxytocin: 144 cases were administered
by motherwort 40 mg and oxytocin 10 U uterine injection during CS and motherwort 20 mg
intramuscular injection per 12 hours 3 times after CS and group of oxytocin: 149 cases were
administered by oxytocin 10 U uterine injection and oxytocin 10 U+5% glucose 500 ml intravenously
injection during operation and oxytocin 10 U intramuscular injection per 12 hours 3 times after CS. The
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following clinical parameter was collected and analyzed: (1) The amount of blood loss during operation,
at 2, 6, 12, 24, 48 hours after operation. (2) The total amount of blood loss in 24 hours after CS and
the incidence of postpartum haemorrhage. (3) The change of level of haemoglobin (Hb) and counting
of red blood cell (RBC) from prepartum to postpartum. (4) Adverse reaction. The mean amount of
blood loss during operation were (368+/-258) ml in group of motherwort, (255+/-114) ml in group of
motherwort+oxytocin and (269+/-141) ml in group of oxytocin, which exhibited significant difference
among three groups (P<0.01). No significant differences in the amount of blood loss among three
groups were observed at 2, 6, 12, 24, 48 hours after CS. The amount of blood loss of postpartum at 24
hours were (480+/-276) ml in group of motherwort, (361+/-179) ml in group of motherwort+oxytocin,
(381+/-179) ml in group of oxytocin, which showed significant difference among 3 groups (P<0.01).
The incidence of postpartum hemorrhage was 32.0% (47/147) in group of motherwort, 11.1%
(16/144) in group of motherwort+oxytocin, and 18.8% in (28/149) in group of oxytocin. The lowest
rate of postpartum blood loss in group of motherwort+oxytocin and the highest rate in group of
motherwort differed significantly (P<0.01). The decreased level of RBC and Hb were shown that RBC
(0.3+/-0.5)x10(12)/L and Hb (9+/-13) g/L in group of motherwort, RBC (0.2+/-0.4)x10(12)/L and Hb
(6+/-10) g/L in group of motherwort+oxytocin and RBC (0.2+/-0.4)x10(12)/L and Hb (7+/-30) g/L in
group of oxytocin respectively. The value of RBC and Hb in group of oxytocin and
motherwort+oxytocin showed significant difference (P<0.05). Two cases with allergic reactions were
observed. The authors conclude that combined use of motherwort injection and oxytocin to prevent
postpartum haemorrhagia during or after caesarean section is safe and effective (Lin 2009).
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No clinical studies of good quality have been found. The statement in a very old textbook (Schröder
1685) that preparations from
L. cardiaca
are "especially useful for the treatment of cardiac complaints
in children" is not substantiated by new studies, although the use of a combination product in France
that has been in use since 1953 points to the same direction.
A collection of case reports has been published by Orlandi (1950): 11 children were treated with a dry
extract prepared with water incorporated in granules. 6 g of granules per day, containing 0,03 g of dry
extract, were administered in three single doses. No further details on the extract are given. One infant
(15 months) presented complex symptoms associated with rachitis and central seizures among them
restlessness, irritability, and spasms. After treatment with
Leonurus
extract for one week, a general
improvement of the nervous symptoms is reported. Ten children (2.5 to 9 years) presenting
heterogeneous symptoms such as heart palpitations, extrasystolic tachycardia, vasomotoric
complaints, irritability, sleep disorders, nervousness, anxiety. Treatment for 5 days to 1 month
resulted in an improvement of nervous symptoms and heart palpitations. The author concludes that
the extract has a sedative action in children. In view of the small number of cases, the heterogeneity
of conditions and the limited availability of information on medication and other interventions applied
no conclusion on the safety and efficacy of
L. cardiaca
in the paediatric population can be drawn.
4.3.
Overall conclusions on clinical pharmacology and efficacy
The summary statement by Benedum (2006) that "traditionally the effects of the drug on palpitations,
anxiety attacks, cardiac asthenia, labile pulse, and altogether on nervous cardialgia are excellently
substantiated" cannot be fully endorsed. No studies on efficacy have been retrieved from literature
searches. The use as an adjuvant in hyperthyreosis (Kommission E 1986, Wichtl 2002, 2009) is not
supported by any clinical data. Initiation of treatment for any type of thyroid disorder should be
considered only under the supervision of an experienced medical doctor (American Botanical Council
2008). In absence of clinical studies, an indication in the area of well-established use is not possible.
Taking into account the continuous, long standing use of the comminuted herbal substance, the
Assessment report on
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EMA/HMPC/127430/2010
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powder, the tinctures and the liquid extract in symptoms of nervous tension the traditional use in this
indication is plausible. As specific expressions of symptoms of nervous tension such as cardiac
symptoms, climacteric symptoms, hyperthyreosis, or other indications such as anxiety require
intervention by a medical doctor for diagnosis, treatment and follow-up, such a differentiation is not
appropriate, although a traditional use could be easily extracted from literature.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
No clinical studies with single ingredient products were found.
5.2.
Patient exposure
The herbal substance has been continuously distributed in the EU for more than 30 years, it is present
in official pharmacopoeias for more than 50 years and the continuous use of the herbal tea is
documented for nearly 400 years (see above).
98,000 packages of 25 ml tincture have been sold in Lithuania in 2008. More than 350,000 packages
were distributed from 2003 until March 2009 (Valentis 2009).
5.3.
Adverse events and serious adverse events and deaths
Unknown (Krylow 1993).
A 94 year old woman was admitted at hospital for heart failure and bradyarrhytmia. She had been
treated before over three days with spironolactone and a combination product that contains
L. cardiaca
herb. ECG showed complete AV block, prolonged QTC, and late ventricular premature beats. As the
authors suspected a wrong OTC use of cardiac glycosides, digoxin plasma level was assessed (0.73
µg/l). The authors assume that glycosides present in
L. cardiaca
may have cross-reacted with the
assay. Electrophysiological tests showed nodal and intrahissian conduction disturbances that persisted
after the use of the combination was stopped. The authors conclude that the combination product may
have contributed to the cardiac disorders observed in the patient (Remblier 1999). No similar cases
have been reported to the French Agency; PSURS from 2002 and 2008 did not present any special side
effects.
The following information on adverse events is labelled for a tincture marketed in Lithuania and Latvia:
Very rarely hypersensitivity may occur; gastro-intestinal disorders (nausea, diarrhoea, stomach pain
may occur. No reports on AE were received in the period of PSUR (2003-2009) (Valentis 2009).
No case reports of allergic reactions, including contact allergy, were found in literature. The occurrence
of gastric complaints may be associated with the tannins or the bitter taste of the herbal preparations.
As such a "class labelling" is absent in monographs on Centaurii herba, or Hamamelidis cortex, the
inclusion of an ADR is in absence of any case reports not appropriate.
5.4.
Laboratory findings
None reported.
5.5.
Safety in special populations and situations
Potential for interactions:
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None documented (Barnes 2007).
Abebe (2002) has claimed that
Leonurus cardiaca
L would contain "coumarin" and might interfer with
NSAIDs with respect to decrease in blood coagulation / increased bleeding. Appropriate precautionary
mesures when taken with NSAIDs or in coagulation disorders are recommended. However, Coumarin
does not interfer directly with blood-coagulation and neither Coumarin nor Dicoumarole-like structures
have been reported as constituents of
L. cardiaca
herb. The article by Zou (1989) used for this claim
referred to a different species (
L. heterophyllus
=
L. japonicus
) and a different class of substances
(prehispanolone = labdane-diterpene). The statement from Yarnell (2009) "claiming that, because one
coumarin-derived family of molecules is anticoagulant, all coumaris are anticoagulant is bad science"
can be supported, although the authors classify prehispanolone as a "coumarin".
Miller (1998) and Harkness (2003) have reported that motherwort would contain cardiac glycosides
and significant interactions may occur. Although the presence of glycosides with "cardiac action" was
reported in old literature, no digitalis like cardiac glycosides has been found. The recommendation to
avoid taking motherwort for this reason has no scientific basis.
Potentiates the effects of hypnotics and analgetics (Krylow 1993).
Overdose:
A dose of 3,000 mg of solid extract per day, taken in capsule or tablet form, is likely to cause
diarrhoea, stomach irritation, or uterine bleeding (Balch 2002). This statement seems to refer to an
earlier statement from Van Hellemont (1986) that a dose in excess of 3.0 grams of a powdered extract
may cause diarrhoea, uterine bleeding, and stomach irritation. No details on the extract are recorded.
Pregnancy/Lactation:
Because of the traditional use for uterine stimulation, motherwort should not be used by pregnant
women (Balch 2002).
Contraindicated in pregnancy (Bradley 1992).
Not to be used during pregnancy; emenagogue / uterine stimulant (McGuffin 1997).
The use during pregnancy and lactation should be avoided (Barnes 2007).
Other Leonurus species:
Pregnancy/Lactation:
L. japonicus
Houtt., herba:
L. japonicus
Houtt., herba
is contraindicated during pregnancy (Stöger 2009) for uterotonic effect (see
4.1.1.)
Precautions for use:
L. japonicus
Houtt., fructus:
To be used with special care in patients with wide pupils (Stöger 2009).
Overdose:
L. japonicus
Houtt., fructus:
After ingestions of 20-30g toxic reactions may appear in 4-10 hours. Symptoms include generalised
weakness, paralysis of lower limbs, numb, painful sensation of the whole body, an oppressive
sensation in the chest and sweating (Bensky 2004).
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5.6.
Overall conclusions on clinical safety
Preparations of
L. cardiaca
are safe under the conditions of use included in the monograph. Preclinical
data, a clinical study with
L. sibiricus
and consistent information from handbooks are the basis for
establishing a contra-indication in pregnancy.
The adverse events mentioned for the tincture seem to be of a hypothetical nature. No case reports
have been found.
The duration of use should be limited to 4 weeks because of the clinical condition that would need a
medical diagnosis after that period of time and because of inconclusive signals for risks at higher doses
/ prolonged use from animal experiments. Information with respect to interaction with sedatives has
not been included, although it is reported in a general way without any case reports.
The potential for interaction with substances such as warfarin deserves careful consideration. Warnings
that can be found in handbooks are based on the wrong assumption that
L. cardiaca
may contain
relevant amounts of "coumarins" with an anti-coagulant effect. However, relatively high dosages of
preparations of Asian
L. japonicus
are reported to have influenced blood aggregation. As no case
reports were found for
L. cardiaca
preparations and the posologies included in the monograph, no
warning is included.
6.
Overall conclusions
In absence of clinical studies, an indication in the area of well-established use is not substantiated.
Taking into account the pharmacological data and the continous, long standing use of the herbal
substance and preparations thereof in symptoms of nervous tension the traditional use in this
indication is plausible. There is no need to consult a physician for diagnosis of this condition or for
follow up within the period of time forseen in the monograph. As specific expressions of symptoms of
nervous tension such as cardiac symptoms, climacteric symptoms, hyperthyreosis, or other indications
such as anxiety require intervention by a medical doctor for diagnosis, treatment and follow-up, such a
differentiation is not appropriate. However, the indication may cover gynaecological, cardiovascular or
gastro-intestinal symptoms of nervous tension. The indication "nervous tension" has been accepted for
Valerianae radix (WEU). The term, although used here in a traditional context, seems to be more
appropriate than the indication "symptoms of mental stress" that has been used e.g. for Passiflorae
herba, Melissae folium and others. It reflects better the endogenous causes traditionally attributed to
Leonuri cardiacae herba (vegetative dystonia, neurosis) rather than exogenous "stressors". Leonuri
cardiacae herba is often compared by authors with Valerianae radix and Melissae folium and
combinations often contain preparations of these substances.
Annex
List of references
Assessment report on
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EMA/HMPC/127430/2010
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