COMMUNITY HERBAL MONOGRAPH ON
GENTIANA LUTEA
L., RADIX
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
Gentiana lutea
L., radix (gentian root)
i)
Herbal substance
Notapplicable.
ii)
Herbal preparations
a)
Comminuted herbal substance
b)
Dry extract (DER 4.5-5.5:1), extraction
solvent ethanol 53% v/v
c)
Tincture (Ratio of herbal substance to
extraction solvent 1:5), extraction solvent
ethanol 70% v/v
d)
Liquid extract (DER 1:1), extraction
solvent ethanol 45% v/v
Well-established use
Traditional use
Comminuted herbal substance as herbal tea for
oral use.
Herbal preparation in solid or liquid dosage forms
for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Eur. Ph. monograph (ref.: 01/2008:0392).
2
The declaration of the active substance(s) for an individual finished product should be in accordance with
relevant herbal quality guidance.
EMEA 2010
2/6
4.1.
Therapeutic indications
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 specified indications
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults, elderly
Average daily dose
a)
Comminuted herbal substance for tea
preparation: 1-2 g, 3-4 times daily
b)
Dry extract: 2 capsules of 120 mg dry
extract each, 2-3 times daily
c)
Tincture: 1 ml, 1-3 times daily
d)
Liquid extract: 1 g, 2-4 times daily
For the indication “loss of appetite”, in the
literature, it is described that the liquid
preparations a), c) and d) are supposed to be taken
½ hour before meal.
Correspondingly, the solid dosage form b) is
supposed to be taken 1 hour before meal due to
the additional mechanism of disintegration of the
solid form.
The use in children and adolescents under
18 years of age is not recommended (see section
4.4 ‘Special warnings and precautions 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.
EMEA 2010
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Method of administration
Oral use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
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.
For tinctures and liquid extracts containing
ethanol, the appropriate labelling for ethanol,
taken from the ‘Guideline on excipients in the
label and package leaflet of medicinal products
for human use’, must be included.
4.5.
Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended (see
section 5.3 ‘Preclinical safety data’).
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.
EMEA 2010
4/6
4.8.
Undesirable effects
Well-established use
Traditional use
Gastrointestinal disorders have been observed.
The frequency was uncommon.
In rare cases, tachycardia and pruritus have been
reported.
Headache may occur. The frequency is not
known.
If other adverse reactions not mentioned above
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.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
For some xanthones which are among the
constituents of
Gentiana lutea
, positive results
EMEA 2010
5/6
were found in the AMES test (pre-incubation
method).
Assessment of preclinical safety requires further
studies towards these effects.
Well-established use
Traditional use
Not applicable.
12 November 2009
EMEA 2010
6/6
Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW
........................................................................................ 3
II.
ASSESSMENT REPORT
................................................................................................................. 5
GENTIANA LUTEA
L., RADIX ................................................................................................................ 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
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
Overall conclusions on pharmacology
........................................................................ 11
II.2.2
Pharmacokinetics
................................................................................................................ 11
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.2.2
..................................................................................................... 11
Overall conclusions on pharmacokinetics
................................................................... 12
II.2.3
Toxicology
........................................................................................................................... 12
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
II.2.3.2
.......................................................................................................................... 12
Overall conclusions on toxicology
.............................................................................. 13
II.3
........................................................................................................................... 13
Clinical Pharmacology
........................................................................................................ 13
II.3.1.1
Pharmacodynamics
...................................................................................................... 13
II.3.1.2
Pharmacokinetics
......................................................................................................... 14
II.3.2
Clinical Efficacy
.................................................................................................................. 14
II.3.2.1
Dose response studies
.................................................................................................. 15
II.3.2.2
Clinical studies (case studies and clinical trials)
......................................................... 15
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
.............................. 15
II.3.2.4
Longstanding use and experience
................................................................................ 15
II.3.3
Clinical Safety/Pharmacovigilance
..................................................................................... 17
II.3.3.1
Patient exposure
.......................................................................................................... 17
II.3.3.2
Adverse events
............................................................................................................ 17
II.3.3.3
Serious adverse events and deaths
............................................................................... 17
II.3.3.4
Laboratory findings
..................................................................................................... 17
II.3.3.5
Safety in special populations and situations
................................................................ 17
II.3.3.6
Overall conclusions on clinical safety
......................................................................... 18
II.4
.............................................................................................................. 18
III.
ANNEXES
III.1
....................................................................................................................................... 19
.......................................... 19
III.2
........................................................................................................... 19
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II.2.1.1
II.2.2.1
II.2.3.1
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
Austria
MA
TRAD
Other TRAD
Other Specify: Only combinations
Belgium
MA
TRAD
Other TRAD
Other Specify: Only combinations
Bulgaria
MA
TRAD
Other TRAD
Other Specify: Only combinations
Cyprus
MA
TRAD
Other TRAD
Other Specify: No response
Czech Republic
MA
TRAD
Other TRAD
Other Specify: Only combinations
Denmark
MA
TRAD
Other TRAD
Other Specify: 400mg G. Radix has been
assessed as safe in food
very old products
Estonia
MA
TRAD
Other TRAD
Other Specify: Only combinations
Finland
MA
TRAD
Other TRAD
Other Specify: No products
France
MA
TRAD
Other TRAD
Other Specify: No response
Germany
MA
TRAD
Other TRAD
Other Specify: Since 30 years on the
market
Greece
MA
TRAD
Other TRAD
Other Specify: No products
Hungary
MA
TRAD
Other TRAD
Other Specify: No response
Iceland
MA
TRAD
Other TRAD
Other Specify: No response
Ireland
MA
TRAD
Other TRAD
Other Specify: No products
Italy
MA
TRAD
Other TRAD
Other Specify: No licensed products
Latvia
MA
TRAD
Other TRAD
Other Specify: Only combinations
Liechtenstein
MA
TRAD
Other TRAD
Other Specify: No response
Lithuania
MA
TRAD
Other TRAD
Other Specify: No response
Luxemburg
MA
TRAD
Other TRAD
Other Specify: No response
Malta
MA
TRAD
Other TRAD
Other Specify: No response
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No products
Norway
MA
TRAD
Other TRAD
Other Specify: No response
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify: No response
Romania
MA
TRAD
Other TRAD
Other Specify: No response
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: Only combinations
Slovenia
MA
TRAD
Other TRAD
Other Specify: Only combinations
In 1999
there were two cases of
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
EMEA 2010
Page 3/19
Member State
Regulatory Status
Comments
2
acute poisoning with
Veratrum album
L. because
of adulteration of
Gentiana
pannonica
Scop. with
Veratrum album
L.
Spain
MA
TRAD
Other TRAD
Other Specify: No response
Sweden
MA
TRAD
Other TRAD
Other Specify: Only combinations as
natural remedies
United Kingdom
MA
TRAD
Other TRAD
Other Specify: And combinations
EMEA 2010
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II.
ASSESSMENT REPORT
GENTIANA LUTEA
L., RADIX
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
(WELL-ESTABLISHED USE)
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)
Gentiana lutea
L., radix (gentian root)
Herbal preparation(s)
a)
Comminuted herbal substance
b)
Dry extract (4.5-5.5:1) ethanol 53% v/v
c)
Tincture (1:5) ethanol 70% v/v
d)
Liquid extract (1:1) ethanol 45% v/v
Pharmaceutical forms
Comminuted herbal substance as herbal tea for
oral use.
Herbal preparation in solid or liquid dosage forms
for oral use
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term
Rapporteur
Dr. Werner Knöss
Assessor
Dr. Friederike Stolte
EMEA 2010
Page 5/19
II.1
I
NTRODUCTION
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Gentianae radix [European Pharmacopoeia]
Dried, fragmented underground organs of
Gentiana lut
ea L., with a characteristic odour and a strong and
persistent bitter taste. Gentian root occurs as single or branched subcylindrical pieces of various lengths
and usually 10-40 mm thick but occasionally up to 80 mm thick at the crown.
Gentianae radix is known under the synonyms: German: Großer Enzian, (Berg)-Fieberwurzel,
Hochwurzel; Engl.: Bitter wort, Common gentian, Great yellow gentian, Yellow gentian; French:
Gentiane jaune, Grande gentiane; Ital.: Genziana maggiore.
Gentiana lutea
is a species of the
Gentianaceae
family, growing to 1-2 m tall, with broad lanceolate to
elliptic
leaves
10-30 cm long and 4-12 cm broad. The
flowers
are yellow, with the
corolla
separated nearly
to the base into 5-7 narrow petals. The main root can be over 1 meter in length and can weigh up to 7 kg
(fresh). It grows in grassy alpine and sub-alpine pastures, usually on calcareous soils native to the
mountains of central and southern Europe. It grows naturally on uncultivated ground in France, Spain and
the Balkan mountains. The plant is under wildlife protection, therefore it will be cultivated for plant
production mostly in Germany and France [HagerROM 2006, Hänsel-Sticher 2007] .
The composition of the constituents (carbohydrates and essential bitters) is depending on the time of
harvesting. The content of sugars, decrease in spring and increase to their maximun content in July. In
contrast, the bitter substances reach their maximum content in spring and decrease according to the growth
of the sugar content [Franz 1985] .
It is important, that the plant is dried directly after the harvesting to avoid fermentative processes, which
reduce the extract content extremely and lead to changes in the colour [HagerROM 2006] .
Plants of the species Veratrum album
have often been taken by mistake for
Gentiana lutea
. The main
attribute to differentiate between these two genera, is that the leaves of
Veratrum
are alternate in contrast
to the opposite leaves of
Gentiana
. The medicinal use of Gentianae radix has a very long tradition.
However, Gentianae radix distillate is also used as an ingredient of a strong liqueur called “Enzian”.
Constituents: [H
AGER
ROM 2006, Wichtl 2002, Hänsel-Sticher 2007, Seitz 2005]
Bitter constituents
:
Bitter constituents (2-8%) are located mostly in the cortex of the root. The most bitter constituents belong
to the class of secoiridoid glycosides, with gentiopicroside (also known as gentiamarine and gentiopicrine)
as main component and a lower amount of amarogentine (0.025 – 0.4%). The occurrence of swertiamarine
and sweroside has been reported occasionally. The bitter value of gentiopicroside is 12000; that of
amarogentine is 58 mill., the most bitter substance known. The quantity of the bitter constituents depends
on the season as well as the age of the roots and the altitude. The total content increases with the altitude
and reaches its maximum in spring.
Xanthones
:
Up to 1% xanthones: gentisine, isogentisine, methylgentisine, gentiseine, 1-hydroxy-3,7-
dimethoxyxanthone, 1,3,7-trimethoxyxanthone, dihydroxy-1,3-dimethoxy-2,7-xanthone and gentisine-1-
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)
EMEA 2010
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O-primveroside and gentioside-7-O-primveroside. Xanthones are also responsible for the yellow colour of
the root.
Carbohydrates
:
30-55% carbohydrates in the dried root including monosaccharides (glucose and fructose), disaccharides
(saccharose and gentiobiose), trisaccharide (gentianose) and polysaccharides (e.g. pectins). During the
drying process, the bitter disaccharide gentiobiose or the sweeter disaccharide saccharose arise due to the
degradation of gentianose.
Volatile oil:
0.1 – 0.2% volatile oil; important mainly in the liqueur-production for giving its characteristic flavour.
Other constituents
:
phytosterols, triterpenes
Herbal preparation(s):
i)
Comminuted herbal substance
ii)
Dry extract (4.5-5.5:1) ethanol 53% v/v
iii)
Tincture (1:5) ethanol 70% v/v
iv)
Liquid extract (1:1) ethanol 45% v/v
Gentianae radix is used in combinations with many other bitter and/or aromatic herbal
substances / herbal preparations, usually for treatment of dyspeptic or choleretic complaints,
Typical examples of such combination partners are the following: Rumicis herba pulvis,
Sambuci flos pulvis, Primulae flos pulvis, Verbenae herba pulvis, Plantaginis folium,
Curcuma
zedoaria
Rosc. Angelicae radix,
Fraxinus ornus
L. (radix), Myrrha exudatum,
Carlina acaulis
L. (radix).
This monograph refers exclusively to Gentianae radix, although the use of such combinations
seems to be more traditional than the use of the mono-preparations.
Mineral(s) not applicable
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
The following herbal substances and herbal preparations have been on the European market for a period
of30 years and are proposed for the monograph on traditional use. The following data derive from the
overview of marketed products and from literature.
i) Comminuted herbal substance
ii) Dry extract (4.5-5.5:1) ethanol 53% v/v
iii) Tincture (1:5) 70% v/v
iv) Liquid extract (1:1) ethanol 45% v/v (Deutsches Arzneibuch – Ergänzungsband 6 - EB6)
Posology and indications of the traditional herbal substance and preparations of Gentianae radix:
4
According to the ‘Guideline on the clinical assessment of fixed combinations of herbal substances/herbal
preparations’ (EMEA/HMPC/166326/2005)
5
Only applicable to traditional use
EMEA 2010
Page 7/19
comminuted herbal substance as a herbal tea
Indication: digestive disorders such as loss of appetite, dyspepsia.
Posology: oral use 2-4 g comminuted herbal substance daily
dry extract from Gentianae radix (4.5-5.5:1) ethanol 53% v/v
Indication: digestive disorders (dyspeptic complaints) like loss of appetite, feeling of fullness
and bloating
Posology: 2 -3 times daily 2 capsules
Single dose: corresponding to approx. 1.2 g herbal substance
Daily dose: corresponding to approx. 2.4 -3.6 g herbal substance
tincture (1:5); extraction solvent: ethanol 70% v/v
Indication: digestive disorders (dyspeptic complaints) like loss of appetite, feeling of
fullness, bloating
Posology: 3 times daily 20 drops (= 1 ml)
Single dose: corresponding to approx. 1 ml (= 1 – 1.5 g) tincture (1:5)
Daily dose: corresponding to approx. 3 ml (= 3 – 4.5 g) tincture (1:5)
fluid extract (1:1); ethanol 45% v/v (EB6)
Indication:
Posology: 2-4 times daily 1g liquid extract
Single dose: corresponding to approx. 1 g fluid extract (1:1) [Haffner, Schulz]
Daily dose: corresponding to approx. 2-4 g fluid extract (1:1)
II.2
N
ON
-C
LINICAL
D
ATA
II.2.1
Pharmacology
There are some data which could support the hypothesis that the extract of Gentianae radix increases
gastric secretion due to effects in mouth and stomach [Leslie 1978, Borrissow 1903 and Moorhead 1915].
It is also supposed that that bitter substances may increase appetite independent of their effects in mouth
and stomach [Moorhead 1915, Gebhardt 1997, Wegner 1997].
[Borrissow 1903]
After direct application on the tongue, bitters increase the secretion of gastric fluid during
in vivo
experiments in dogs.
[Moorhead 1915]
The experiments should demonstrate whether the so-called stomachic or bitter tonics, acting in the
mouth or in stomach, could affect at first the appetite and than the quantity and quality of gastric
secretion and cachexia.
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II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
Note: There is no precise declaration of the Gentiana herbal preparations used in the different
experimental studies. There is no information about the use of fresh or dry herbal substance and about the
precise extraction solvent used or definition of the ratio of herbal substance to genuine herbal
preparation.
[Leslie 1978]
In rats, gentian extract increased gastric secretion in a dose-dependent way after direct ingestion in
the stomach. Only at the highest concentration of 4% the extract showed an influence on pH:
increasing it from 4.25 to 4.85.
More recent investigations are the following:
in vitro
:
[Gebhart 1997]
Isolated and enriched parietal cells from rat gastric mucosa were cultured in the presence of EGF
(epidermal growth factor) and insulin, expanding the cell population by 170% within 48 h.
Determination of the cellular accumulation of radiolabelled aminopyrine was used for indirectly
measuring acid production by parietal cells. Addition of 10
4
M histamine rose the aminopyrine ratio
more than 2-fold within 20 min. When an aqueous dry extract of
Gentiana lutea
L. root was added,
a concentration dependent rise of the aminopyrine ratio was observed leading to a 1.7-fold
stimulation at 100 μg/mL, while cytotoxic effects occurred above 5 mM only. No stimulatory effect
was exerted by an artichoke extract. The authors postulate that an aqueous dry
Gentiana
extract is
able to directly stimulate acid production by the gastric mucosa.
in vivo
:
[Öztürk,1998]
Effects of an ethanolic extract prepared from fermented
Gentiana lutea
roots (with ethanol, DER
2:1) on the bile production and liver in rats were investigated. The extract contained 21%
gentiopricroside, 5.2% swertiamarine and 2.55% sweroside. Bile flows of rats which were treated
by a single i.p. dose of CCI4, 24 h prior to experiments were measured after the cannulation of bile
duct under urethane anaesthesia. After an equilibration period of 1 h, the lyophilized extract were
administered intraduodenally (500 mg/kg i.p.), while control animals received physiological saline
only. To monitor the effect of multiple dose therapy, rats received the same dose of
G. lutea
extract
for 3 days (2 days prior to CC14 administration) and their bile flows were measured after the
cannulation. In all groups, bile samples were collected for 3 h with 15 min intervals. After the
completion of bile flow experiments, rat livers were removed and put in neutral formaldehyde
solution (10Y0) for the histological examination. According to the results obtained, multiple dose
treatment of rats with the plant extract normalized the decreased bile flow due to CCI4 whereas
single dose therapy was ineffective on the impaired bile flow. The authors declaimed, that these
data indicate that the studied extract has a potential hepatoprotective activity.
Secretolytic effect
[ESCOP, Kazakov 2003]
Gentian root infusion, administered orally to sheep at a daily dose of 5 g, before feeding, produced a
stimulant effect on secretion of enzymes in the small intestine.
[Chibanguza et al.1984]
During
in vivo
experiments in rabbits, bronchosecretion was elevated in comparison with control
animals after administration of gentian root extract (0.2 g Gentianae radix/ 100g ethanol 19% v/v)
directly in the stomach by gavage, for 3 days (the equivalent of 12.6 mg/kg/day of dried root).
Concerning secretolytic effects, a significantly increased activity was shown with production rate
levels of 37.7% and 104%, respectively, above the control group.
Other pharmacological activities
:
[Kusar 2006]
Free-radical scavenging activity of methanolic extracts of gentian leaves and roots (without further
particulars) were tested in two different systems using electron spin resonance (ESR) spectrometry.
Assays were based on the stable free radical 1.1-diphenyl-2-picrylhydrazyl (DPPH) and the
superoxide radicals (O2 +) generated by the xanthine/ xanthine oxidase (X/XO) system. The results
EMEA 2010
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of gentian methanolic extracts were compared with the antioxidant capacity of synthetic antioxidant
butylated hydroxyanisole (BHA). This study provides that gentian leaves and roots exhibit
considerable antioxidant properties, expressed either by their capability to scavenge DPPH or
superoxide radicals. Definite data are not given from these experiments. The authors postulate
further studies to prove the above mentioned thesis.
[Kumarasamy 2003]
Gentiopicroside (1), a secoiridoid glycoside isolated from the methanol extract of the aerial parts of
Centaurium erythraea, has been assessed for its antibacterial and free radical scavenging activities.
General toxicity of 1 has also been determined by brine shrimp lethality bioassay. Gentiopicroside
inhibited the growth of 12 of 17 pathogenic bacterial species tested. The minimum inhibitory
concentrations (MICs) were between 6.3 x10-3 and 1.0 x10-1 mg/ml.
[Kondo 1994]
The hepatoprotective activity of gentiopicroside was evaluated in the chemically and
immunologically induced acute liver injury rnodels in mice, after treatment with CCI4, and
LPS/BCG, respectively. When mice were given gentiopicroside for 5 days before treatment with
CCl4, or lipopolysaccharide (LPS)/Bacillus calmette-Guerin (BCC), liver injuries were significantly
suppressed at doses of 30- 60 mg/kg/day.
[Mahady 2005]
As part of an ongoing screening program, the study assessed the
in vitro
susceptibility of 15
Helicobacter pylori (HP) strains to botanical extracts, which historically are known for their
traditional use in the treatment of gastrointestinal disorders. Among the methanolic extracts
(without further particulars) with a minimum inhibitory concentration (MIC) of 100 μg/mL was that
of
Gentiana lutea
roots.
[Amin 2008]
Ketoconazole (KET) is an antifungal drug with a broad spectrum of activity that also induces
reproductive toxicity in humans and animals. The protective effect of
Gentiana
(GEN) extract
(
Gentiana lutea
) (without further particulars) against KET-induced testicular damage was evaluated
in male Wistar rats. GEN extract was administered orally (1g/kgbwt/day) for 26 days. Three weeks
after extract’s administration, KET was co-administered i.p. at a dose of 100 mg/kg once a day for 5
days. KET-induced reproductive toxicity was associated with clear reductions of the weights of
testes and epididymides, sperm indices and serum testosterone levels. KET also induced severe
testicular histopathological lesions such as degeneration of the seminiferous tubules and depletion
of germ cells. In addition, marked oxidative damage to testicular lipids and alterations of natural
antioxidants (catalase (CAT) and superoxide dismutase (SOD)) were reported in association with
KET toxicity. Most of the KET-induced effects were greatly decreased with the concomitant
application of GEN extract. The authors indicated a protective role of GEN extract that could be
attributed to its antioxidant properties.
[van der Sluis 1983; Guérin 1985]
Furthermore
Gentiana lutea
extracts (aqueous extract 1:4) and gentiopicroside showed
in vitro
fungitoxic effects.
[Zimmermann 1986]
It was shown that the concentration of the secretory immunoglobulin A (sIgA-level) in saliva,
which is increased by patients with inflammable gastro-intestinal diseases, was decreased with
Gentianae radix D1 (ethanolic tincture, 3 times daily 20 drops). For comparison healthy patients
were treated with the same dose of China D1 (Chinae cortex ethanolic tincture D1) as well as pure
ethanol as the control group. The sIgA-level of the patients treated with Gentianae radix were
decreased, while the treatment with Chinae cortex caused an increased sIgA-level in the saliva. The
author postulated a potential immunological influence of bitters.
EMEA 2010
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II.2.1.2
Overall conclusions on pharmacology
It is well-known that the bitter constituents stimulate the gustatory nerves in mouth and possibly increase
the secretion of gastric fluid and bile, thereby enhancing appetite and digestion, while the detailed
molecular mechanism of such activities is still to be investigated.
Bitter constituents are typical in many plant families, nevertheless, their chemical structures are very
heterogeneous. In many cases, bitter constituents have a lactone- or -CO-CH=CH- chemical structure,
which is also typical for bitters from gentian root.
The medicinal use of such bitter constituents, has also been documented in many well-known handbooks
dating since 1938 [Madaus 1938, Martindale 1977, Schulz et al. 1999, HagerRom 2006]
There are more recent publications that postulate an additional direct local effect in the gastrointestinal
tract.
Results from
in vitro
and
in vivo
studies on animals with Gentianae radix extracts support the traditional
use as appetite and digestion stimulant.
Other possible pharmacodynamic actions as antibacterial, antifungal, antioxidant, immunological and
hepatoprotective properties are also described. However, they do not seem to play a role for the known
traditional use.
The traditional use of Gentianae radix for the treatment of loss of appetite and for the symptomatic
treatment of dyspepsia and mild spasmodic disorders of the gastrointestinal tract is supported by the long
standing use and the above mentioned pharmacological data.
Note: There is no precise declaration of the Gentiana herbal preparations used in the different
experimental studies. There is no information about the use of fresh or dry herbal substance, the precise
extraction solvent used, nor the ratio of herbal substance to genuine herbal preparation
.
II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
[Wang 2007]
The pharmacokinetics and bioavailability of gentiopicroside (GPS), an active component of the
gentian plant species, from orally administered decoctions of
Gentiana
(DG), or in combination
with other plants in the prescription of Longdan Xiegan Tang (LXT) was compared in rats with oral
administration of GPS alone, using doses adjusted to deliver equivalent amounts of GPS
(150 mg/kg). Changes in plasma levels of GPS following oral administration of GPS could be fitted
to a one compartment open model with elimination half times of 3.35 +/- 0.76 h and 6.21 +/- 3.07 h,
respectively. Kinetics of plasma GPS following oral administration of LXT could be fitted to a two
compartments open model with an elimination half time f 3.83 & 1.54 h. The bioavailability of GPS
was markedly better, and that from LXT markedly worse, compared with GPS alone, as judged by
the area under concentration-time curve (AUC) values of 70.0 +/- 13.9 μg h/ml (DG), 32.7 +/-
12.9 μg h/ml (GPS) and 19.1 +/- 5.9 μg h/ml (LXT). The study demonstrated the marked variability
in pharmacokinetics and bioavailability of gentiopicroside (GPS) as the active component from
different herbal preparations.
[el-Sedawy 1989]
As a part of the studies on the metabolism of crude drug components by intestinal bacteria,
gentiopicroside (the secoiridoid glucoside isolated from
Gentiana lutea
), was anaerobically
incubated with various defined strains of human intestinal bacteria. Many species had ability to
transform it to a series of metabolites. Among them,
Veillonella parvula
subsp.
parvula
produced
five metabolites, which were identified as erythrocentaurine, gentiopicral, 5-
EMEA 2010
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hydroxymethylisochroman-1-one,5-hydroxymethylisochromen-1-one and trans-5,6-dihydro-5-
hydroxymethyl-6-methyl-1H,3H-pyrano[3,4-c]pyran-1-one.
II.2.2.2
Overall conclusions on pharmacokinetics
Limited data are available on pharmacokinetics. For the herbal substance or the herbal preparation no data
are available.
For gentiopicroside (the secoiridoid glucoside isolated from
Gentiana lutea
) some more data exist but they
are not relevant for the herbal substance or herbal preparations.
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
[Hager 2006]
For the herbal drug Gentianae radix the LD50 value is unknown.
[Chibanguza 1984]
Rabbits treated with 12.6 mg/day of gentian extract for 3 days did not exhibit symptoms of toxicity
nor abnormal clinical serum parameters, with the exception of slightly lower erythrocyte levels in
the treatment group, compared to a control group.
[Leslie 1979]
No treatment-related adverse effects were observed in rats treated orally for 13 weeks with
1.6 ml/kg of a combination product containing alcoholic extracts of gentian root, chamomile and
liquorice. No effects on reproduction, fertility or mating performance in female rats were observed,
and no teratogenic ones in rabbits. The acute oral LD50 in mice of 25 ml/kg of gentian extract (37%
ethanol and a bitterness value of 200 Ph.Helv. units/g) was the same of that of 30% ethanol.
[Morimoto 1983]
The mutagenic activities of 2 hydroxyxanthones, gentisine and isogentisine, obtained from the
methanol extract of Gentianae radix were investigated. The methanol extract of Gentianae radix,
which showed mutagenicity in the Ames test in Salmonella typhimurium strain TA100 with S9 mix,
was fractionated by column chromatography on Sephadex LH-20, and the fractions were purified
by preparative TLC and column chromatography on polyamide. Two mutagenic materials thus
obtained, S1 and S2, each gave a single band on TLC. Identification of S1 and S2 was
accomplished by comparing the analytical (mps, elementary analyses) and spectral (UV, IR, mass,
NMR) results for S1 and S2 with literature data for gentisine and isogentisine. At doses below
10 micrograms, S1 (gentisine) and S2 (isogentisine) had similar specific mutagenic activities. At
doses of over 10 to 50 micrograms, the mutagenic activities of S2 and S1 were 19.1 and 6.94
revertants per microgram, respectively. This much lower activity of S1 than S2 could be attributed
to its poor solubility possibly due to the presence of the OMe group at C-3. The combined yield of
S1 and S2 was about 76 mg (40 mg of S1 and 36 mg of S2), which accounted for 76% of the
content of mutagenic compounds (100 mg) estimated roughly from the total mutagenic activity in
the extract of the starting materials (100 g).
[Matsushima 1985]
The mutagenicity of naturally occurring xanthones were tested in Salmonella typhimurium TA100,
TA98, TA97, and TA2637 by the pre-incubation method. Xanthydrole, gentiseine, gentisine,
isogentisine, 1-hydroxy-3,7-dimethoxyxanthone, 1,3,7-trimethoxyxanthone, desmethylbellidifoline,
bellidifoline and dimethylbellidifoline were mutagenic, but unsubstituted xanthones were not
mutagenic to TA100, TA98, TA97 and TA2637. The β-O-glucosides, nor-swertianoline and
swertianoline, were only mutagenic when a metabolic activation system containing
EMEA 2010
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beta-glucosidase was used, while the C-glucoside mangiferine was not mutagenic even by using this
system.
II.2.3.2
Overall conclusions on toxicology
The above mentioned toxicological data are very limited referring to the studied extract and have not been
obtained according to current scientific guidance. There are some data for pure gentiopicroside, but they
cannot be transferred to the herbal preparation of gentian root, as it is a mixture of various different
chemical constituents.
There seems to be a potential mutagenicity (Ames-test in
Salmonella typhomorum
TA100, TA98, TA97,
and TA2637 tested with isolated xanthones) possibly caused by the content of gentiopicroside and other
xanthones. More data are required for the different herbal preparations of gentian root according to the
current guidelines. Because of the existing data from the above mentioned AMES test, it is to start with
in vitro
test on mammalian cells (e.g. mouse lymphoma assay), according to the “Guideline on the
assessment of genotoxicity of herbal medicinal substances/preparations” (EMEA/HMPC/107079/2007.
Additionally, the average amount of xanthone derivatives in the extracts in use or in herbal tea
preparations, shall be given (as range) and the test should be done (repeated) with extracts for which the
amount on xanthone derivatives content is at the upper end of the particular range.
The use in pregnancy and lactation should be excluded due to the insufficient data presented.
Due to the lack of preclinical safety (especially genotoxicity) a list entry for Gentianae luteae
radix cannot
be recommended.
II.3
C
LINICAL
D
ATA
II.3.1
Clinical Pharmacology
II.3.1.1
Pharmacodynamics
II.3.1.1.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Bitters stimulate the gustatory nerves in the mouth.
In two studies [Blumenberger 1966, Glatzel 1967] it could be shown that the secretion of saliva and
gastric fluid was stimulated after an oral dose of an ethanolic gentian root extract. In addition a
direct effect on the gastrointestinal tract could be demonstrated (cholagogic effect).
[Zimmermann 1986]
It was shown that the concentration of the sIgA-level in saliva, which is increased by patients with
inflammable gastro-intestinal diseases, was decreased with Gentianae radix D1 (ethanolic tincture,
3 times daily 20 drops). For comparison healthy patients were treated with the same dose of China
D1 (Chinae cortex ethanolic tincture D1) as well as pure ethanol as the control group. The sIgA-
level of the patients treated with Gentianae radix were decreased, while the treatment with Chinae
cortex caused an increased sIgA-level in the saliva. The author postulated a potential
immunological influence of bitters.
[Borgia 1981]
A controlled clinical study was performed to test the activity of an herbal preparation containing as
one component gentian tincture. Salivary secretion was measured in 24 healthy volunteers at 0-time
and during 120 minutes after six different treatments (complete herbal preparation, gentian tincture
2%, rhubarb fluid extract 2%, placebo, placebo with 7% ethanol, 4% citric acid as active control)
EMEA 2010
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administered according, to a 6 x 6 Latin square design replied 4 times. The complete preparation
and its components alone (including gentian tincture 2%) induced a significant increase of salivary
secretion over 30 minutes, similar to the active control, while placebo and placebo with ethanol had
no such effect. No differences were observed at later measurement times.
Bitters stimulate the gastrointestinal tract.
The postulated thesis of the direct effect of bitters on the gastrointestinal tract was confirmed in
previous studies, tested the influence of bitters on the secretion of the gastric fluid and of the gastric
mucosa [Ivancevic 1938, Amann 1988].
More recent studies show that bitter taste receptors can not only be found in the lingual epithelium but
also in the gastrointestinal tract of animals [Rozengurt
2006]. It is postulated that activation of bitter taste
receptors generate integrated responses as secretion, motility or absorption [Sternini
2006].
II.3.1.1.2
Overall conclusions on pharmacodynamics
Long standing use of preparations of Gentianae radix, pharmacological studies and current findings of
physiological properties establish the use of Gentianae radix for the treatment of loss of appetite and for
the symptomatic treatment of dyspepsia and mild spasmodic disorders of the gastrointestinal tract.
The plausibility of efficacy is based on the traditional use and experimental data mentioned above. Results
from these experimental data support the long known action of bitters, which increase the secretion of
gastric juice and bile due to the stimulation of gustatory nerves in the mouth and possibly direct
stimulation in the stomach.
Clinical pharmacological data of
Gentiana lutea
preparations according to the level of the current
scientific knowledge do not exist.
II.3.1.2
Pharmacokinetics
No data available.
II.3.1.2.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
II.3.1.2.2
Overall conclusions on pharmacokinetics
Due to lack of data no conclusions can be drawn.
II.3.2
[Wegner 1997]
In an open study, 205 patients (mean age 53.3 years, 65% female) with various dyspeptic symptoms
(heartburn, vomiting, stomach aches, nausea, loss of appetite, constipation, flatulence) were treated
with capsules containing 120 mg dry extract of gentian root (4.4-5.5:1) ethanol 53% v/v at a dosage
of 2-3 times daily. The average dosage was 4.8 capsules per day, which is equivalent to 2.9 g
Gentianae radix. The duration of the application was 15 days. Improvements in symptoms were
evident after 5 days in most cases and by the end of the study the average level of improvement was
68%. The efficacy of the preparation was assessed by the doctors as excellent (symptoms
eliminated) in 31% of patients, good in a further 55%, moderate in 9% and inadequate in 5% of
cases.
6
In case of traditional use the long-standing use and experience should be assessed.
EMEA 2010
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Note: The uncontrolled observational study supports the plausibility of the application of gentian root
dry extract in a solid dosage form and not only in a liquid form for the treatment of dyspeptic
symptoms.
[Borgia 1981]
A controlled clinical study was performed to test the activity of an herbal preparation containing as
one component gentian tincture. Salivary secretion was measured in 24 healthy volunteers at 0-time
and during 120 minutes after six different treatments (complete herbal preparation, gentian tincture
2%, rhubarb fluid extract 2%, placebo, placebo with 7% ethanol, 4% citric acid as active control)
administered according, to a 6 x 6 Latin square design replied 4 times. The complete preparation
and its components alone (including gentian tincture 2%) induced a significant increase of salivary
secretion over 30 minutes, similar to the active control, while placebo and placebo with ethanol had
no such effect. No differences were observed at later measurement times.
In a second approach, patients were subdivided into four groups of 20 patients each, which where
randomly allocated to receive one of the following treatments: (1) complete herbal preparation,
preparation, two pairs of its components: (2) a preparation with rhubarb (2% fluid extract) and
gentian (2% tincture) and (3) a preparation with boldo (1% tincture) and cascara (2% fluid extract)
(4) placebo. The therapeutic activity was evaluated in a double-blind, double controlled trial,
considering 30 different symptoms divided into four groups (loss of appetite, dyspepsia,
constipation and non-target symptoms). The results were significantly better with the complete test
preparation both when compared with placebo and with the two different pairs of its components.
II.3.2.1
Dose response studies
No data available.
II.3.2.2
Clinical studies (case studies and clinical trials)
No data available.
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
None reported.
II.3.2.4
Longstanding use and experience
Gentianae luteae radix has been used as a medicinal product in different preparations for a long time in
various indications. The medicinal use, primarily based on the content of bitters have been reported in
many European handbooks and Pharmacopoeia. The claimed indications are listed in the following table:
Bitter stomachic and stimulant; Intermittent fever attacks
Madaus (1938)
Strong bitter as an appetite stimulant, roburant and tonic;
gastrointestinal disorders and loss of appetite; aromatic bitters
and stomachic
Wichtl (2002): Herbal drugs and Phytopharmaceuticals.
Bitter
Martindale. 34
th
edition (2004)
Digestive disorders, such as loss of appetite, fullness,
flatulence
German Commission E (1985)
Bitter; Gastric stimulant; Sielagogue; Cholagogue
British herbal Pharmacopoeia (1983)
Loss of appetite; digestive disorders, such as fullness,
flatulence
Standardzulassung Nr.: 9199.99.99 (2004)
Stimulate appetite
Cahier de l’Agence n°3:Médicaments à base de plantes Ed.
Agence du Médicament, Paris, 1998.
EMEA 2010
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Loss of appetite, fullness and flatulence; tonic to stimulate bile
secretion
PDR for Herbal Medicines 3
rd
edition; Ed. Thomson PDR,
2004.
Anorexia e.g. after illness; dyspeptic complaints
ESCOP Monographs, 2
nd
ed. (2003)
Stomach trouble, e.g. due to a lack of gastric juice digestive
disorders, such as loss of appetite, fullness, flatulence
HagerRom (2006)
There are no dose response studies available. The following posology is described in literature.
Single dose
Daily dose
Madaus (1938)
10 drops (=1ml) tincture;
2.1 g comminuted drug as herbal tea (infusion)
1 tablet with 0.125 g comminuted drug
1 ml 2-3 times daily tincture;
2.1 g comminuted drug as herbal tea (infusion)
3 x 1 tablet with 0.125 g comminuted drug
Wichtl (2004)
1-2 g comminuted drug as herbal tea (infusion)
Haffner-Schulz 12.
Auflage (2008)
1 g as herbal tea (infusion)
0.2 g extractum siccum
1.0 g extractum fluidum
1.0 g tinctura
1 g 2-4 times daily as herbal tea (infusion)
1.0 g 2-4 times daily extractum fluidum
1.0 g 1-3 times daily tinctura
Com E (1990)
1 g – 3 g tincture (DAB6)
2 g – 4 g extractum fluidum (DAB6)
2 g – 4 g drug
BHP (1979)
0.6 g – 2 g drug, also as herbal tea (infusion or
decoction)
1 ml-4 ml tincture
0.6 g – 2 g 1-3 times daily drug, also as herbal tea
(infusion or decoction)
1-4 ml 1-3 times daily tincture
Standardzulassung
(2004)
1 g comminuted drug as herbal tea (infusion)
½ hour before meal for appetite and after meal
for digestive disorders
1 g 2-4 times daily comminuted drug as herbal tea
(infusion); ½ hour before meal for appetite and after
meal for digestive disorders
PDR for Herbal
Medicines (2004)
1 g – 2 g comminuted drug as herbal tea
(infusion)
1 ml – 4 ml tincture
2 g – 4 g comminuted drug as herbal tea (infusion)
several times a day including ½ hour before meal
1 ml – 4 ml 1-3 times daily tincture
2 g – 4 g liquid extract
ESCOP (2003)
0.1 g – 2 g comminuted drug as herbal tea
(infusion)
0.1 g – 2 g 1-3 times daily comminuted drug as
herbal tea (infusion)
1 ml 1-3 times daily tincture
1 ml tincture
hydroethanolic extract equivalent bitterness
value
HagerROM (2006)
1 g comminuted drug as herbal tea (infusion)
2 g-4 g comminuted drug as herbal tea (infusion)
several times a day including ½ hour before meal
2 g-4 g extractum fluidum
1 g-3 g tinctura
1 ml tincture
1.0 g extractum fluidum
Post-marketing-
authorithy study
[Wegner 1998]
2 capsule a 120 mg dry-extract (4.4-5.5:1)
extraction solvent ethanol 53% v/v
(corresponding to 1.1 g – 1.3 g = 1.2 g drug)
2 capsule a 120 mg extract 2-3 times daily
(corresponding to 2.2 g – 4.0 g = 3.0 g drug)
EMEA 2010
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The proposed posology for the specified preparation on the basis of the long-standing use and the data
given in the literature is summarized in the following table:
Specified preparation
Dosage
A) comminuted herbal substance
1 g - 2 g, several times daily
B)
dry extract (DER 4.5-5.5:1) extraction solvent ethanol 53% v/v
2-capsules of 120 mg dry-extract, 2-3 times daily
C) tincture (1:5); extraction solvent ethanol 70% v/v
1 ml 1-3 times daily
D) fluid extract (DER 1:1); EB6
1.0 g 2-4 times daily
For the indication “loss of appetite” it is described in the literature that the liquid preparations A), C) and
D) are supposed to be taken ½ hour before meal. Correspondingly, the solid dosage form B) is supposed to
be taken 1 hour before meal due to the additional mechanism of disintegration of the solid form.
Duration of use
No information could be found on the recommended duration of use.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
II.3.3.2
Adverse events
As a result of the observational study [Wegner 1998] the following adverse reactions have to be declared:
diarrhoea, spasmodic stomach-ache, tachycardia and pruritus.
The frequency of the adverse effects is based on this finished observational study. Therefore the reported
adverse reactions are ranked in the following frequency categories:
Diarrhoea uncommon (≥ 1/1.000 bis < 1/100)
spasmodic stomach-ache uncommon (≥ 1/1.000 bis < 1/100)
tachycardia rare (≥ 1/10.000 bis < 1/1.000)
pruritus rare (≥ 1/10.000 bis < 1/1.000)
Additionally, reactions like headaches in especially sensitive patients were classified as “uncommon”
[Wegner 1998, HagerROM 2006, ESCOP 2003].
II.3.3.3
Serious adverse events and deaths
[HagerRom,
Gentiana
]
Different cases of poisoning in humans are described. The most cases were due to an adulteration or
mistaken use of
Veratrum album
.
One case of hypertension after ingestion of ENZIAGIL (a solid
Gentiana
preparation) was reported
to the German agency. Hypertension was known in the medical history of the patient. Further
details are missing so that a definite assessment of a causal relationship is impossible.
II.3.3.4
Laboratory findings
No data available.
II.3.3.5
Safety in special populations and situations
No data available.
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II.3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors
No data available. Use in children and adolescents under 18 years of age is not recommended because data
are not sufficient and medical advice should be sought.
II.3.3.5.2
Drug interactions
No data available.
II.3.3.5.3
Use in pregnancy and lactation
No data available.
There are hints on mutagenicity in the literature probably based on the content of xanthones. Even if such
data were not obtained corresponding to the current scientific knowledge, they support the conclusion that
the use during pregnancy and lactation is not recommended.
No data available.
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 data available.
II.3.3.6
Overall conclusions on clinical safety
Clinical safety data are based on the long standing use and the observational study mentioned above.
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.
Because of the increase of the gastric fluid secretion after the administration of bitters, the use in patients
with gastric ulcer and duodenal ulcer is contraindicated.
II.4
O
VERALL
C
ONCLUSIONS
Gentianae luteae radix is a well known and traditional herbal medicinal product used for centuries in
European countries. The medicinal use has been documented continuously in a lot of well-known
textbooks.
For
Gentiana lutea
L., radix used in above mentioned herbal preparations, a period of at least 30 years in
medicinal use as requested by Directive 2004/24/EC for qualification as a traditional herbal medicinal
product is fulfilled.
All existing literature data support its traditional use for the following indications suitable for self-
medication:
Traditional herbal medicinal product used in mild dyspeptic/gastrointestinal disorders, and in temporary
loss of appetite.
The pharmacological studies
in vitro
and
in vivo
indicate the stimulation of the gustatory nerves in mouth
and stimulating effects on the gastric, intestinal and biliary secretion. The specific mechanism of the mode
of action of bitters is not finally known. It is fact that the bitter constituents stimulate the gustatory nerves
in the mouth and give rise to an increase in the secretion of gastric fluid and bile. In different experiments
it could be demonstrated that these effects enhance the appetite and digestion.
There are additional experimental data that support the use of Gentianae radix preparations in a solid
pharmaceutical dosage form. The data of an observational study [Wegner 1998] support the traditional use
of the encapsulated bitters and show that the reflex effect stimulating the gustatory nerves in the mouth is
EMEA 2010
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not the only mechanism of action for bitters. The data indicate a local gastric effect of the extract and
support the use of the solid pharmaceutical form.
Use of Gentianae radix is not recommended during pregnancy and lactation and Gentianae radix should
not be taken by children and adolescents under 18 years of age and patients with gastric and duodenal
ulcer.
As the minimum required data on mutagenicity (Ames’ test) are not available for herbal preparations of
Gentianae radix, an inclusion into the Community list of traditional herbal substances and preparations is
not recommended.
In ancient times, gentian root was used for other indications as an antipyretic and anthelminthic agent
[Madaus 1938, HagerRom 2006].
Gentianae radix is often used in combination with other bitters or other herbal substances preparations,
which are also used in dyspeptic/gastrointestinal disorders.
III.
ANNEXES
III.1
III.2
L
ITERATURE
R
EFERENCES
7
According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2)
8
According to 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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Source: European Medicines Agency
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