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Centaurium (Centaurii herba)

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Authorisation details
Latin name of the genus: Centaurium
Latin name of herbal substance: Centaurii herba
Botanical name of plant: Centaurium erythraea Rafn.
English common name of herbal substance: Centaury
Status: F: Final positive opinion adopted
Date added to the inventory: 23/11/2005
Date added to priority list: 23/11/2005
Outcome of European Assessment: Community herbal monograph
Additional Information:





Product Characteristics
COMMUNITY HERBAL MONOGRAPH ON CENTAURIUM ERYTHRAEA RAFN, HERBA
1. N AME OF THE MEDICINAL PRODUCT
To be specified for the individual finished product.
2. Q UALITATIVE AND QUANTITATIVE COMPOSITION 1, 2
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Centaurium erythraea Rafn s. l. including
C. majus (H. et L.) Zeltner and C. suffruticosum
(Griseb.) Ronn. (syn.: Erythraea centaurium
Persoon; C. umbellatum Gilibert; C. minus Gars.),
herba (centaury herb)
i) Herbal substance
Not applicable
ii) Herbal preparations
A) Comminuted herbal substance
B) Powdered herbal substance
C) Liquid extract (1:1; ethanol 25% v/v)
D) Tincture (1:5; ethanol 70% v/v)
E) Soft extract (1:10; water)
3. P HARMACEUTICAL F ORM
Well-established use
Traditional use
Comminuted herbal substance as herbal tea or
other herbal preparations in liquid or solid dosage
forms for oral use.
1 The material complies with the Ph. Eur. monograph (ref. 01/2005:0865).
2 The declaration of the active substance(s) for an individual finished product should be in accordance with
relevant herbal quality guidance
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4. C LINICAL P ARTICULARS
4.1. Therapeuticindications
Well-established use
Traditional use
Traditional herbal medicinal product used in mild
dyspeptic/gastrointestinal disorders, and/or in
temporary loss of appetite.
The product is a traditional herbal medicinal
product for use in the specified indications
exclusively based upon long-standing use and
experience.
4.2 Posology and method of administration
Well-established use
Traditional use
Posology
Adults and elderly
ii) Herbal preparations
A) Comminuted herbal substance for tea
preparation: single dose 1-4 g, up to
4 times daily
B) Powdered herbal substance: single dose
0.25-2 g, up to 3 times daily
C) Liquid extract: single dose 2-4 ml, up to
3 times daily
D) Tincture: single dose 1.5-5 g, up to
3 times daily
E) Soft extract: single dose 0.2 g; daily dose
1-2 g.
The use in children and adolescents under
18 years of age is not recommended (see section
4.4 ‘Special warnings and precaution for use’).
Duration of use
If the symptoms persist longer than 2 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Oral use.
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4.3. Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Active peptic ulcer.
4.4. Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under
18 years of age is not recommended 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.
For tinctures and extracts containing ethanol, the
appropriate labelling for ethanol, taken from the
‘Guideline on excipients in the label and package
leaflet of medicinal products for human use’, must
be included.
4.5. Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
4.6. Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
4.7. Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
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4.8. Undesirable effects
Well-established use
Traditional use
None known.
If adverse reactions occur, a doctor or a qualified
health care practitioner should be consulted.
4.9. Overdose
Well-established use
Traditional use
No case of overdose has been reported.
5.
P PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2 Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3 Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity with preparations of Centaurii
herba have not been performed.
6.
PHARMACEUTICAL PARTICULARS
Well-established use
Traditional use
Not applicable.
7.
DATE OF COMPILATION / LAST REVISION
12 March 2009
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Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW
............................................................................. 3
II.
ASSESSMENT REPORT
..................................................................................................... 5
II.1
I NTRODUCTION
II.1.1
.........................................................................................................................6
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
6
Information on period of medicinal use in the Community regarding the specified
indication
II.2
II.1.2
.........................................................................................................................................7
N ON -C LINICAL D ATA
II.2.1
..............................................................................................................8
Pharmacology
.................................................................................................................8
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.1.2
....................................................................................................8
Assessor’s overall conclusions on pharmacology
.........................................................10
II.2.2
Pharmacokinetics
..........................................................................................................10
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.2.2
..................................................................................................10
Assessor’s overall conclusions on pharmacokinetics
....................................................10
II.2.3
Toxicology
.....................................................................................................................10
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
and constituents thereof
II.2.3.2
.................................................................................................................10
Assessor’s overall conclusions on toxicology
...............................................................11
II.3
C L INICAL D ATA
II.3.1
.....................................................................................................................11
Clinical Pharmacology
..................................................................................................11
II.3.1.1
Pharmacodynamics
.......................................................................................................11
II.3.1.2
Pharmacokinetics
..........................................................................................................11
II.3.2
Clinical Efficacy / Longstanding use and experience
...................................................11
II.3.2.1
Posology
........................................................................................................................12
II.3.2.2
Clinical studies (case studies and clinical trials)
..........................................................14
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
...............................14
II.3.2.4
Assessor’s overall conclusions on (clinical) efficacy / the traditional medicinal use
...14
II.3.3
Clinical Safety/Pharmacovigilance
...............................................................................14
II.3.3.1
Patient exposure
............................................................................................................14
II.3.3.2
Adverse events
...............................................................................................................14
II.3.3.3
Serious adverse events and deaths
................................................................................14
II.3.3.4
Laboratory findings
.......................................................................................................14
II.3.3.5
Safety in special populations and situations
II.3.3.5.1
.................................................................14
Intrinsic (including elderly and children) /extrinsic factors
............................... 14
II.3.3.5.2
Drug interactions
................................................................................................ 14
II.3.3.5.3
Use in pregnancy and lactation
........................................................................... 15
II.3.3.5.4
Overdose
............................................................................................................. 15
II.3.3.5.5
Drug abuse
.......................................................................................................... 15
II.3.3.5.6
Withdrawal and rebound
.................................................................................... 15
II.3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
15
II.3.3.5.8
Contra-indications
.............................................................................................. 15
II.3.3.6
Assessor’s overall conclusions on clinical safety
...........................................................15
II.4
A SSESSOR S O VERALL C ONCLUSIONS
....................................................................................15
III.
ANNEXES
............................................................................................................................ 16
III.1
III.2
L ITERATURE R EFERENCES
..................................................................................................... 16
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II.2.1.1
II.2.2.1
II.2.3.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I. REGULATORY STATUS OVERVIEW 1
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’
Member
State
Regulatory Status
Comments 2
Austria
MA
TRAD
Other
TRAD
Other Specify:
as food supplement
C. herba in combination
products
Belgium
MA
TRAD
Other
TRAD
Other Specify:
as food supplement
C. herba in combination
products
Bulgaria
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Cyprus
MA
TRAD
Other
TRAD
Other Specify:
Czech
Republic
MA
TRAD
Other
TRAD
Other Specify:
Not Known
C. herba in combination
products
Denmark
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Estonia
MA
TRAD
Other
TRAD
Other Specify:
C. herba in combination
products
Finland
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
France
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Germany
MA
TRAD
Other
TRAD
Other Specify:
C. herba in combination
products
Greece
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Hungary
MA
TRAD
Other
TRAD
Other Specify:
Iceland
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Ireland
MA
TRAD
Other
TRAD
Other Specify:
Italy
MA
TRAD
Other
TRAD
Other Specify:
Latvia
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Liechtenstein
MA
TRAD
Other
TRAD
Other Specify:
Lithuania
MA
TRAD
Other
TRAD
Other Specify:
1 This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products
in the MSs concerned.
2 Not mandatory field
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Member
Regulatory Status
Comments 2
Luxemburg
MA
TRAD
Other
TRAD
Other Specify:
Malta
MA
TRAD
Other
TRAD
Other Specify:
The
Netherlands
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Norway
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Poland
MA
TRAD
Other
TRAD
Other Specify:
Portugal
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Romania
MA
TRAD
Other
TRAD
Other Specify:
Slovak
Republic
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
Slovenia
MA
TRAD
Other
TRAD
Other Specify:
C. herba in combination
products
Spain
MA
TRAD
Other
TRAD
Other Specify:
C. herba in combination
products
Sweden
MA
TRAD
Other
TRAD
Other Specify:
No C. herba on market
United
Kingdom
MA
TRAD
Other
TRAD
Other Specify:
C. herba in combination
products
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State
II.
ASSESSMENT REPORT
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC
AS AMENDED
(TRADITIONAL USE)
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Centaurium erythraea Rafn s. l. including
C. majus (H. et L.) Zeltner and C. suffruticosum
(Griseb.) Ronn. (syn.: Erythraea centaurium
Persoon; C. umbellatum Gilibert; C. minus Gars.),
herba (centaury herb)
The material complies with the Ph. Eur.
monograph (ref. 01/2005:0865).
Herbal preparation(s)
A) Comminuted herbal substance
B) Powdered herbal substance
C) Liquid extract (1:1; ethanol 25% v/v)
D) Tincture (1:5; ethanol 70% v/v)
E) Soft extract (1:10; water)
Pharmaceutical forms
Comminuted herbal substance as herbal tea or
other herbal preparations in liquid or solid dosage
forms for oral use.
Rapporteur(s)
Emiel van Galen/Burt Kroes
Assessor
Els Ensink
EMEA 2009
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II.1
I NTRODUCTION
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations
thereof
Herbal substanc e 3 :
Centaurii herba consists of the whole or fragmented dried flowering aerial parts of Centaurium
erythraea Rafn s. l. including C. majus (H. et L.) Zeltner and C. suffruticosum (Griseb.) Ronn.
(syn.: Erythraea centaurium Persoon; C. umbellatum Gilibert; C. minus Gars.) (Ph. Eur.).
Constituents : (Popov, 1969; BHP, 1979; Aquino et al. , 1985; van der Sluis, 1985 ;
Dombrowicz et al. , 1988; Hellemont, 1988; Hänsel et al. , 1992; Bisset, 1994; Schulz et al. ,
1998; Valentão et al. , 2002; Bellavita, 2003; ESCOP, 2003)
Secoiridoid glucosides are the characteristic bittertasting constituents, principally (75%)
swertiamarin and smaller amounts of gentiopicroside (gentiopicrin) and sweroside (bitterness
value ca. 12,000) and centapricin (bitterness value ca. 4,000.000). Other iridoids include bitter
m-hydroxybenzoyl esters of sweroside, and deacetylcentapicrin, centauroside (a dimeric
secoiridoid), secologanin, 6’-m-hydroxy-benzoyl-loganin, dihydrocornin (a cyclopentane
iridoid), gentioflavoside.
Analysis of different plant parts has shown a variety in the composition of the bitter ingredients.
Due to the occurrence of the very bitter secoiridoid esters centapicrin and desacetylcentapicrin,
fruits are more bitter than the flowers, leaves and stems. Swertiamarin is the major component
in all parts of C. erythraea .
Secoiridoid alkaloids: gentianine and gentianidin;
Xanthones : 6 methoxylated xanthones , including eustomin (1-hydroxy-3,5,6,7,8-penta-
methoxyxanthone) and 8-demethyl-eustomin and others;
Organic/Phenolic acids such as p-coumaric, o-hydroxyphenylacetic, ferulic, protocatechuic,
sinapic, vanillic, syringic, hydroxyterephthalic and 2,5-dihydroxy-terephthalic acids and
oleanolic acid (0.1%);
Phytosterols : β-sitosterol, stigmasterol, campesterol and others;
Coumarins: 5-formyl-2,3-dihydroisocoumarin;
Miscellaneous: flavone components and anthocyanes.
Herbal preparations specified for the individual final product
A) Comminuted herbal substance for tea preparation
B) Powdered herbal substance
C) Liquid extract (1:1; ethanol 25% v/v)
D) Tincture (1:5; ethanol 70% v/v)
E) Soft extract (1:10; water)
3 According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2) and the ‘Procedure for the preparation of Community
monographs for herbal medicinal products with well-established medicinal use’ ( EMEA/HMPC/182352/2005
Rev. 2).
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Combination preparations with Centaurii herba
Madaus (1938), Weiss (1974) and Hellemont (1988) mention formulas containing Centaurii
herba in combination with other herbal substances. At present authorised/registered combination
products containing Centaurii herba are on the market in several EU Member States, amongst
others: Czech Republic, Germany, United Kingdom, Austria, Poland, Spain and Estonia.
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
Centaurium erythraea Rafn is used for many decades in the European Union mainly for the
relief of digestive complaints (peptic discomfort) and lack of appetite. Centaurii herba was also
used for the treatment of diabetes, snakebites, malaria, wounds and as an antipyretic, tonic and
sedative. Preparations of this herb are described in different (old) Pharmacopoeias of European
Member States 4 :
Centaurii herba (based on Erythraea centaurium Persoon) has been documented in DAB 6
(1936) and Ned. Pharm. III (1889) (van der Sluis, 1985).
Centaurii minoris herba is described in Pharmacopoeias of following member states: Austria,
Czech Republic, Germany, Hungary, Poland, Romania and Spain (Martindale, 1977).
Erythraea centaurii herba florida is described: Ph. Ned. (1934), Belg. Pharm. IV (1940),
(Hellemont, 1988).
Erythraea centaurii extractum fluidum is described in: Belg. Pharm. IV (1940) (Hellemont,
1988).
Extractum centaur. minor is described in: Belg. Pharm. IV (1940) (Hellemont, 1988).
Extractum centaurii (a soft extract) is described in the ‘Ergänzungsband zum deutschen
Arzneibuch’ (EB 6, 1953) and (Hänsel et al. , 1992; HagerRom, 2006).
Centaury – Centaurii herba is described in Eur. Ph. (Eur. Ph., 2008).
The medicinal use has also been documented in well-known handbooks dating from 1938
(Madaus), 1954 (Steinmetz), 1977 (Martindale), 1988 (Hellemont) and 1992 (Hänsel et al. ) up
to 2003 (ESCOP).
In ancient times Centaurii herba was used as a febrifuge in intermittent fever attacks, at
dysmenorrhoea and as a sedative (Madaus, 1938; Hellemont, 1988).
According to Kneipp (1935) centaury has blood cleaning properties and is used for gastro-
intestinal complaints, Madaus (1938) claims it to be the best remedy against gastric juice
burning sensation.
Steinmetz (1954) describes Erythraea centaurium (common names: small centaury or small
knapweed) to be a bitter stomachic and febrifuge, to be used in chlorosis and jaundice; it also
‘purifies the blood, promotes the menses and improves the appetite’.
Bisset (1994) mentions its use as a bitter, for stimulating the appetite and increasing the
secretion of the gastric juice, especially in chronic dyspeptic states and achylia. In folk medicine
Centaurii herba was also employed as roborant and tonic.
4 The various pharmacopoeias are not in agreement regarding the species of Centaurium . These discrepancies
are due mainly to the confusion about the nomenclature and delimitation of C. erythraea s. l. and many
synonyms are used in literature for C. erythraea Rafn (van der Sluis, 1985). Hybridisation occurs frequently
causing morphological variability, resulting in taxonomic divergences. C. erythraea s. l. is an unresolved
assemblage comprising diploid to hexaploid species related to C. erythraea subsp. erythraea (Mansion,
2005), see also II.1.1.
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Centaury is used in dyspepsy and diarrhoea accompanied by liver and bile impairments or
caused by an unbalanced diet and can be effective in flatulence (Hellemont, 1988).
According to Hänsel et al. (1992) Centaurii herba can be applied in dyspeptic and stomach
disorders, and in lack of or for stimulation of appetite.
Newall (1994) mentions the traditional use of the infusion in anorexia.
In Germany extracts of Centaurii herba are components in registered gastrointestinal,
cholagogue and urological remedies (Bisset, 1994; Walther, 2004).
For an overview on the documented applications of Centaurii herba , see II.3.2.
II.2
N ON -C LINICAL D ATA
II.2.1
Pharmacology
II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
Documentation regarding the route of administration
Oral administration is the main route of administration for Centaurii herba preparations.
Centaurii herba has also been used topically in the treatment of inflammations, wounds (Hänsel
et al. , 1992), snakebites and eczema (Dweck, 1997).
Results from an animal study demonstrated a significant anti-inflammatory activity after
application of an aqueous extract of centaury in the air pouch granula test (Berkan et al ., 1991;
Hänsel et al. , 1992).
However, in the handbooks detailed information on composition of the preparation, posology,
duration of use and clinical data is lacking. Therefore, topical use as a traditional herbal
medicinal product does not fulfil the requirements of Directive 2004/24/EC.
Phytochemical research data on major components in Centaurium erythraea
- Xanthones and the secoiridoids sweroside, swertiamarin and gentiopicrin have been identified
in several Centaurium species. On the basis of chemical derivation, the authors concluded
sweroside to be probably identical with the compound known as ‘kantaurin’ (van der Sluis,
Labadie, 1981).
- An HPLC method was developed and used for the determination of gentiopicrin
(gentiopicroside) in Centaurium erythraea (Kaluzova et al ., 1995).
- Piatczak et al . (2006) demonstrated that the level of secoiridoids is modified by both
transformation by Agrobacterium rhizogenes and by the development stage of transformed
plants. The total content of the compounds (expressed as the sum of gentiopicroside, sweroside
and swertiamarin) in transformed plants was 280 mg/g dry weight and was 8 times the content
in the sample of commercially available C. erythraea herb.
- In the course of a phytochemical study of C. erythraea, six methoxylated xanthones
(1,5-hydroxy-3-methoxyxanthone, 1-hydroxy-3,5,6-trimethoxyxanthone, 1-hydroxy-3,5,6,7-
tetramethoxyxanthone, 1-hydroxy-3,5,6,7,8-pentamethoxyxanthone, 1-hydroxy-3,7,8-
trimethoxyxanthone and 1,8-dihydroxy-3,5,6,7-tetramethoxyxanthone) were isolated and
identified by spectroscopic means. Subsequently a detection method was developed for the
determination of these and other methoxylated xanthones occurring in the chloroform extract of
small centaury aerial parts. The methodology developed was applied to twelve samples, and in
all of them, nine xanthones were identified and quantified (Valentão et al ., 2002).
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- Kumarasamy et al . (2003) isolated the two secoiridoid glycosides, swertiamarin and sweroside
from the aerial parts of Centaurium erythraea .
Pharmacodynamics
Although the mechanism of action is still unclear, it is assumed that the bitter constituents
stimulate the gustatory nerves in the mouth and give rise to an increase in the secretion of
gastric juice and bile, thereby enhancing the appetite and digestion (Evans, 1996).
Pharmacological activities of whole extracts of centaury herb
- Increase in sputum (Hänsel et al. , 1992) and gastric juice secretion (Blumenthal et al. , 1998;
Hänsel et al. , 1992).
- Antipyretic activity of a dry aqueous extract of centaury was observed in rats after
administration of 50-100 mg/animal by gavage in a yeast-induced fever test (Berkan,1991;
Hänsel et al. , 1992; Newall, 1994). The antipyretic properties are assumed to be due to the
phenolic acid. No fever-lowering/antipyretic effects were observed after pretreatment with
centaury (Newall, 1994).
- Anti-inflammatory activity of a dry aqueous extract of centaury was observed in Freund's
adjuvant-induced polyarthritis in rats treated orally with 10-500 mg per day (Berkan, 1991).
Inhibition of carrageenan-induced paw oedema by 40% has been found after oral intake of 100
mg/kg body weight of a dry ethanolic extract of centaury (Capasso et al. , 1983; Hänsel et al. ,
1992; Newall, 1994).
- A diuretic effect was observed in rats after oral administration of 8% or 16% aqueous extract
of centaury at 10 ml/kg body weight daily for one week, with the most effective dose for water
and electrolyte excretion being 8%. From the fifth day of treatment urine volume increased
significantly with the lower dose and both doses led to a significant increase of sodium, chloride
and potassium excretion. At the end of the treatment a diminution in creatine clearance was
observed (Haloui, 2000).
- A hepato-protective activity of a methanol extract of the leaves of C. erythraea was evaluated
against acetaminophen-induced liver toxicity in rats. An oral dose of 300 mg/kg/day for 6 days
or a single dose of 900 mg/kg for 1 day exhibited a significant protective effect by lowering
serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT)
and lactate dehydrogenase (LDH). The hepato-protective activity was also observed by
histopathological examination of liver sections (Mroueh et al. , 2004).
- Antioxidant activity of small centaury infusion has been reported (Valentão, 2001; Valentão,
2003).
- An aqueous extract of C. erythraea did not show analgesic properties (Berkan, 1991).
Pharmacological activities of combination preparations
- A concentration-dependant relaxant effect was observed in rats fed on spontaneous ileum
contractions and on rat ileum pre-contracted with carbachol, after administration of an
hydroethanolic extract of four herbs, including Erythraea centaurium (L.) Borkh. (Botion et al. ,
2005).
Pharmacological activities of isolated compounds in centaury herb
- Antimalarial properties of gentiopicrin have been mentioned in handbooks (Newall, 1994).
- Antibacterial activity could be observed for swertiamarin and sweroside; both compounds
inhibited the growth of Bacillus cereus , Bacillus subtilis , Citrobacter freundii and Escherichia
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coli . While swertiamarin was also active against Proteus mirabilis and Serratia marcescens ,
sweroside inhibited the growth of Staphylococcus epidermidis (Kumarasamy et al ., 2002).
- Isolated swertiamarin showed anticholinergic activity , significantly inhibiting carbachol-
induced contractions of the proximal colon in rats in a dose-dependant manner after oral
administration at 150 mg/kg and 300 mg/kg body weight (Yamahara et al. , 1991).
- Isolated gentianine, administered to rats at 100 mg/kg body weight, showed besides anti-
ulcerogenic activity in the water immersion stress test an inhibitory action against gastric
secretion (Yamahara et al. , 1978).
- A depressive effect on the central nervous system is reported for mice treated orally with 30
mg/kg body weight gentianine. An inhibition of spontaneous movement activity and an increase
of hexo-barbital induced sleeping time were observed (Yamahara et al. , 1978).
- Two methoxylated xanthone derivatives, eustomin and demethyleustomin, isolated from the
aerial parts of Centaurium erythraea Rafn showed antimutagenic properties in Salmonella
typhimurium strains TA98, TA100, and TA102. The antimutagenic character of the compounds
was supported by the effects shown in post-treatment experiments as well as by results obtained
with recA mutants of E. coli and Bacillus subtilis . Isolated eustomin at 50 μg/plate showed
strong inhibition, 76% against 2-NF and 64% against 2-AA in strain TA-100;
8-demethyleustomin was also active, with results of 43% and 39% respectively, but no
inhibition was detected from secoiridoid or polar fractions of centaury (Schimmer, Mauthner,
1996).
II.2.1.2 Assessor’s overall conclusions on pharmacology
The traditional use of Centaurium erythraea Rafn, herba, as a (powdered) herbal drug, herbal
tea or hydroalcoholic extract, for the relief of mild dyspeptic/gastrointestinal
disorders/complaints and lack of appetite is well documented in a number of handbooks.
Results from in vitro and in vivo studies with extracts, and isolated constituents, support the
traditional use as appetite and digestion stimulant.
Experimental data to support the antipyretic activity are very limited. In addition, no specific
posology for this indication could be found. Therefore, the use as an antipyretic cannot be
recommended.
II.2.2
Pharmacokinetics
II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
No data available.
II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
No data available, no conclusion can be drawn.
II.2.3
Toxicology
II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s)
and constituents thereof
- No published data could be found on the toxicity of extracts of centaury. However one case
report has been found, reporting a possible relation between the acute and cytolytic hepatitis and
the intake of the herbal preparation Copaltra (containing Coutarea latiflora 50 mg and
Centaurium erythraea 50 mg). As it concerned a combination product, no conclusions on the
safety of Centaurium can be drawn (Wurtz et al ., 2002).
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- General toxicity of gentiopicroside, swertiamarin and sweroside was determined in the brine
shrimp lethality bioassay. LD 50 values measured for swertiamarin and sweroside were
8.0 microg/ml and 34 microg/ml, respectively. Podophyllotoxin, which was used as the positive
control showed an LD 50 of 2.8 microg/ml (Kumarasamy et al ., 2003a; Kumarasamy et al .,
2003b).
II.2.3.2 Assessor’s overall conclusions on toxicology
Toxicological data on centaury are very limited. Experimental data are only available for
isolated compounds. Nonetheless, neither the chemical composition nor the long-term
widespread use in the European Community suggest that there is a (potential) risk associated
with the use of centaury extract. Yet, due to the lack of data on acute and chronic toxicity,
repeated dose toxicity, genotoxicity, mutagenicity, carcinogenicity, reproductive and
developmental toxicity, a list entry for Centaurii herba cannot be recommended.
II.3
C LINICAL D ATA
Clinical studies could not been found. Therefore, only the use as a traditional herbal medicinal
product is recommended but a well-established use is not justified.
II.3.1 Clinical Pharmacology
No data available.
II.3.1.1 Pharmacodynamics
No data available.
II.3.1.2 Pharmacokinetics
No data available.
II.3.2 Clinical Efficacy / Longstanding use and experience
For centaury herb the following medicinal uses have been reported in European handbooks:
* (Chronic) digestive/dyspeptic/gastro-intestinal problems: achylia, gastric juice burning,
stomach, obstipation, anorexia, lack of appetite/appetite stimulation, chlorosis, jaundice,
functional disturbances in the bile system etc.
Gastric juice burning sensation
Madaus (1938)
Blood cleaning action, so used for all kinds of GI-
complaints
Kneipp (1935)
Bitter stomachic
Steinmetz (1954)
Increase in sputum and/or and gastric juice
secretion (esp. in chronic states and achylia)
Blumenthal et al. (1998),
Hänsel et al. (1992),
Bisset et al . (1994)
Enhancing of appetite
Steinmetz (1954),
Hellemont (1988),
Bisset (1994),
Newall (1994),
ESCOP (2003)
Bitter stomachic to be used in chlorosis and
Steinmetz (1954)
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jaundice
As a tonic
Newall (1994)
All kinds of dyspeptic complaints
Hellemont (1988),
ESCOP (2003)
* Fever/antipyretic
Febrifuge
Steinmetz (1954)
Intermittent fever attacks
Madaus (1938),
Hellemont (1988)
II.3.2.1 Posology
There are no dose response studies available. The following posology is described in the
literature:
A) Comminuted herbal substance for tea preparation (1:20)
Single dose, up to 4 times daily
Daily dose
Madaus (1938)
1.5 g
Hellemont
(1988)
1 g per cup infusion
Weiss (1974)
1-2 teaspoon 5 / cup before meals
Martindale
(1977)
30-60 ml infusion
BHP (1979)
2-4 g
Blumenthal et
al. (1998)
6 g
Bisset (1994)
2-3 g
Newall (1994)
2-4 g
ESCOP (2003)
1-4 g in 150 ml water
B) Powdered herbal substance
Single dose, up to 3 times daily Daily dose
Madaus (1938)
1-2 g
Hellemont (1988)
1-2 g
5 1 teaspoon = ca. 1.8 g (Bisset, 1994)
EMEA 2009
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Hänsel et al. (1992)
0.25-2 g
C) Liquid extract (1:1; alcohol 25% v/v)
Single dose, up to 3
times daily
Daily dose
ESCOP (2003)
2-4 ml
Hellemont (1988) 0.6-1 g (progressive)
Martindale
(1977)
2-4 ml
BHP (1979)
2-4 ml
Hänsel et al.
(1992)
2-4 ml
Newall (1994)
2-4 ml
D) Tincture (1:5; ethanol 70% v/v)
Single dose, 3 times
daily
Daily dose
Hellemont
(1988)
30 drops 6
Hänsel et al.
(1992)
2-5 g
E) Soft extract (1:10; water)
Single dose
Daily dose
Blumenthal et
al. (1998)
1-2 g
Hänsel et al.
(1992)
0.2 g
1-2 g
Proposed posology for the specified preparations
Specified preparation
Dosage
A) Cut herbal substance for tea
preparation
single dose: 1-4 g, up to 4 times daily
B) Powdered herbal substance
single dose: 0.25-2 g, up to 3 times daily
6 30 drops = ca. 1.5 g
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C) Liquid extract (1:1; ethanol 25%
v/v)
single dose: 2-4 ml, up to 3 times daily
D) Tincture (1:5; ethanol 70% v/v) single dose: 1.5-5 g, up to 3 times daily
E) Soft extract (1:10; water)
single dose: 0.2 g, daily dose: 1-2 g
Duration of use
No information could be found on the duration of use. As clinical safety studies are lacking, it is
recommended to limit the duration of use to 2 weeks.
II.3.2.2 Clinical studies (case studies and clinical trials)
No published data available 7 .
II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
No published data available.
II.3.2.4 Assessor’s overall conclusions on (clinical) efficacy / the traditional medicinal use
The available clinical data do not support well-established use.
The traditional use of Centaurium erythraea Rafn, herba, as a (powdered) herbal drug, herbal
tea or hydroalcoholic extract, for the relief of mild dyspeptic/gastrointestinal
disorders/complaints and lack of appetite is well documented in a number of handbooks. The
traditional use is supported by pharmacological data.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1 Patient exposure
No data available.
II.3.3.2 Adverse events
None known (Newall, 1994; Blumenthal et al. , 1998; Walther, 2004).
II.3.3.3 Serious adverse events and deaths
No data available.
II.3.3.4 Laboratory findings
No data available.
II.3.3.5
Safety in special populations and situations
II.3.3.5.1 Intrinsic (including elderly and children) /extrinsic factors
No data available.
II.3.3.5.2 Drug interactions
7 The electronic databases of PubMed, Embase and International Pharmaceutical Abstracts were searched with
the search terms ‘Centaurium erythraea’ combined with ‘human’, ‘clinical trial’ , ‘randomised controlled trial’
and ‘review’.
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None known (Blumenthal et al. , 1998).
II.3.3.5.3 Use in pregnancy and lactation
No data available. In accordance with general medical practice, the product should not be used
during pregnancy or lactation.
II.3.3.5.4 Overdose
No toxic effects have been documented. After intake of high dosages, stomach disturbances and
nausea have been reported (Hellemont, 1988).
This information has not been included into the monograph because the dosage is not given in
the reference.
II.3.3.5.5 Drug abuse
No data available.
II.3.3.5.6 Withdrawal and rebound
No data available.
II.3.3.5.7 Effects on ability to drive or operate machinery or impairment of mental ability
No studies on the effect on the ability to drive and use machines have been performed.
II.3.3.5.8 Contra-indications
Due to the reflexively stimulation of gastric juice secretion caused by bitter ingredients,
products containing Centaurii herba must not be used in case of active peptic ulcer disease
(Bisset 1994; Walther, 2004).
II.3.3.6 Assessor’s overall conclusions on clinical safety
Clinical safety data are lacking. However, up to now no (serious) side effects have been
reported. Furthermore, the chemical composition of centaury herb does not give reasons for
safety concerns.
As there is no information on reproductive and developmental toxicity, the use during
pregnancy and lactation cannot be recommended.
Data on use in children or adolescents are not available.
II.4
A SSESSOR S O VERALL C ONCLUSIONS
- The use of Centaurium erythraea Rafn has a long tradition in Europe, mainly in mild
dyspeptic/gastrointestinal disorders and in temporary loss of appetite. The medicinal use has
been documented continuously in well-known handbooks. Therefore, Centaurii herba fulfils the
requirements of Directive 2004/24 EC for classification as a traditional herbal medicinal
product. Its use in above-mentioned disorders is considered plausible on the basis of
bibliographic and pharmacological data.
- The pharmacological activity is attributed to the whole extract; however emphasis is put on the
group of secoiridoid glycosides (‘bitters’) with main components swertiamarin, gentiopicroside,
centapicrin and sweroside. Also xanthones, phenolic acids and other ingredients may contribute
to the pharmacological activity of Centaurii herba.
- Centaurii herba is used in the following pharmaceutical forms and posology:
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A) Comminuted herbal substance for tea preparation: single dose: 1-4 g, up to 4 times daily;
B) Powdered herbal substance: single dose 0.25-2 g, up to 3 times daily;
C) Liquid extract (1:1; ethanol 25% v/v): single dose: 2-4 ml, up to 3 times daily;
D) Tincture (1:5; ethanol 70% v/v): single dose: 1.5-5 g, up to 3 times daily;
E) Soft extract (1:10; water): single dose: 0.2 g; daily dose: 1-2 g.
- Toxicological data on centaury is very limited. Experimental data is only available for isolated
compounds. Nonetheless, neither the chemical composition nor the long-term widespread use in
the European Community suggests that there is a (potential) risk associated with the use of
centaury extract. Yet, due to the lack of data on acute and chronic toxicity, repeated dose
toxicity, genotoxicity, mutagenicity, carcinogenicity, reproductive and developmental toxicity, a
list entry for Centaurii herba cannot be recommended.
- There are no clinical safety data for extracts of Centaurii herba. In the documentation of the
traditional medicinal use within the Community, no serious adverse effects have been reported.
- Due to lack of data, Centaurii herba preparations cannot be recommended for children and
adolescents below the age of 18 years, in pregnancy and lactation and must not be used in case
of active peptic ulcer disease. During the public consultation, an interested party requested to
include a posology for adolescents. This was not endorsed because the claim was not supported
with experimental safety and/or exposure data.
III.
ANNEXES
III.1
C OMMUNITY H ERBAL M ONOGRAPH ON C ENTAURIUM ERYTHRAEA R AFN , HERBA
III.2
L ITERATURE R EFERENCES
EMEA 2009
16/16
 
 
 


Source: European Medicines Agency



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