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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:



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    • 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
    EMEA 2009
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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).
    EMEA 2009
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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
    EMEA 2009
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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
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    Source: European Medicines Agency


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