Community herbal monograph on
Potentilla erecta
(L.)
Raeusch., rhizoma
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
Potentilla erecta
(L.) Raeusch., rhizoma
(tormentil)
i) Herbal substance
Not applicable.
ii) Herbal preparations
a) Comminuted herbal substance
b) Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction solvent
ethanol 70% (V/V)
3
c) Tincture (ratio of herbal substance to extraction
solvent 1:5), extraction solvent ethanol 45%
(V/V)
d) Liquid extract (DER 1:1), extraction solvent
ethanol 25% (V/V)
e) Dry extract (DER 3.5-4.5:1), extraction solvent
ethanol 60% (V/V)
Well-established use
Traditional use
Comminuted herbal substance as herbal tea for
oral use.
Comminuted herbal substance for infusion or
decoction preparation for oromucosal use.
Herbal preparations b), c), d) and e) in liquid
dosage forms for oral use.
1 The material complies with the Ph. Eur. monograph (ref.: 01/2008:1478).
2 The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
3 The tincture complies with the Ph. Eur. monograph (ref.: 01/2008:1895).
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(L.) Raeusch., rhizoma
EMA/HMPC/5513/2010
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Herbal preparation b) in liquid dosage forms for
oromucosal use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Indication 1)
Traditional herbal medicinal product for
symptomatic treatment of mild diarrhoea.
Indication 2)
Traditional herbal medicinal product for the
symptomatic treatment of minor inflammations of
the oral mucosa.
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
Indication 1)
(oral use)
a) Comminuted herbal substance:
As infusion: single dose 1.4-4 g, several times
daily up to a maximum daily dose of
12 g.
As decoction: single dose 1.4-3 g, several
times daily up to a maximum daily dose of
6 g.
b) Tincture (1:5, ethanol 70%):
Single dose: 1-2 ml in water, 3 times daily.
c) Tincture (1:5, ethanol 45%):
Single dose: 2-4 ml, 3 times daily.
d) Liquid extract:
Single dose: 2-4 ml, 3 times daily.
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(L.) Raeusch., rhizoma
EMA/HMPC/5513/2010
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e) Dry extract:
Single dose: 400 mg, 3 times daily.
The use in children and adolescents under
18 years of age is not recommended (see section
4.4 ‘Special warnings and precautions for use’).
Indication 2)
(oromucosal use)
a) Comminuted herbal substance:
As infusion: 1.3–2 g per 100 ml of water.
As decoction: 0.8–3 g per 100 ml of water.
Rinse the mouth several times daily.
b) Tincture (1:5, ethanol 70%):
Single dose: 1-5 ml per 150 ml of water.
Rinse the mouth several times daily.
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
Indication 1)
If the symptoms persist longer than 3 days during
the use of the medicinal product, a doctor or a
qualified health care practitioner should be
consulted.
Indication 2)
If the symptoms persist longer than 1 week
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Indication 1)
Oral use.
Indication 2)
Oromucosal use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
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(L.) Raeusch., rhizoma
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4.4.
Special warnings and precautions for use
Well-established use
Traditional use
Indication 1)
If recurrent diarrhoea or bloody stools occur, a
doctor or a qualified health care practitioner
should be consulted.
Indications 1) and 2)
The use in children and adolescents under
18 years of age has not been established due to
lack of adequate data.
If the symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
For tinctures 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
Indication 1)
Internal absorption of concomitantly administered
medicine may be delayed. For this reason the
product should be taken 1 hour or more before or
after intake of other medicinal products.
Indication 2)
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.
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(L.) Raeusch., rhizoma
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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.
4.8.
Undesirable effects
Well-established use
Traditional use
Indication 1)
Mild gastrointestinal complaints such as nausea
and vomiting 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.
Indication 2)
None known.
If adverse reactions occur, a doctor or a qualified
health care practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c (1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c (1)(a)(iii) of
Directive 2001/83/EC as amended.
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(L.) Raeusch., rhizoma
EMA/HMPC/5513/2010
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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.
Adequate tests on reproductive toxicity,
genotoxicity and carcinogenicity have not been
performed.
Well-established use
Traditional use
Not applicable.
25 November 2010
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(L.) Raeusch., rhizoma
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Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.3. Search and assessment methodology....................................................................
6
2. Historical data on medicinal use ........................................................................................ 6
2.1. Information on period of medicinal use in the Community ........................................
6
preparations and indications.......................................................................................
7
3. Non-Clinical Data ............................................................................................................... 9
preparation(s) and relevant constituents thereof ...........................................................
9
preparation(s) and relevant constituents thereof ......................................................... 1
1
preparation(s) and constituents thereof ..................................................................... 1
1
3.4. Overall conclusions on non-clinical data............................................................... 1
2
4. Clinical Data ..................................................................................................................... 12
4.1. Clinical Pharmacology ....................................................................................... 1
2
4.1.1. Overview of pharmacodynamic data regarding the herbal.................................... 1
2
including data on relevant constituents ...................................................................... 1
2
4.2. Clinical Efficacy ................................................................................................ 1
2
4.2.1. Dose response studies.................................................................................... 1
2
4.2.2. Clinical studies (case studies and clinical trials).................................................. 1
2
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 1
2
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 1
3
5. Clinical Safety/Pharmacovigilance................................................................................... 13
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 1
3
5.2. Patient exposure .............................................................................................. 1
3
5.3. Adverse events and serious adverse events and deaths ......................................... 1
3
5.4. Laboratory findings .......................................................................................... 1
3
5.5. Safety in special populations and situations ......................................................... 1
3
5.6. Overall conclusions on clinical safety ................................................................... 1
3
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1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Tormentillae rhizoma consists according to the European Pharmacopoeia of the dried rhizome, freed
from the roots of
Potentilla erecta
(L.) Raeusch. It contains not less than 7% of tannins, expressed as
pyrogallol (C
6
H
6
O
3
, Mr126.1) with reference to the dried herbal substance.
Tormentil (
Potentilla erecta
syn.
Tormentilla erecta
,
Potentilla tormentilla
) is an herbaceous perennial
belonging to the rose family (
Rosaceae
).
Constituents (according to Hänsel & Sticher 2007, Blaschek at al. 2008, Wichtl 2009):
1.
Tannins: 15-22% total tannins (15-20% condensed tannins, about 3.5% hydrolysable tannins)
- Condensed tannins: (–)- gallo- or (–)-epigallocatechingallat, the dimeric catechin derivatives [6,6′]-
all-trans-bi-(+)-catechin, [4,8]-all-trans-bi-(+)-catechin (= procyanidin B3), [4,6]-all-trans-bi-(+)-
catechin (= procyanidin B6) and [4,8]-2,3-trans-3,4-cis-bi-(+)-catechin
- Hydrolysable tannins: After hydrolysis gallic acid and ellagic acid were found. The main compound of
the hydrolysable tannins is agrimoniin, a dimeric ellagitannin, with a content of about 1% in the
herbal substance. Further hexahydroxy diphenic acid, pedunculagin, laevigatin B and laevigatin F
were isolated.
2.
Flavonoids: kaempferol, cyanidinglucoside and leucoanthocyanidin and the tannin monomers
catechin, epicatechin, gallocatechin and epigallocatechin
3.
Phenol carboxylic acids: p-coumaric acid, 3,4-dihydroxybenzoic acid, gallic acid, sinapic acid and
caffeic acid
4.
Triterpene saponins: quinovic acid, tormentillic acid and tormentosid (glycoside of tormentillic acid)
5.
Fatty acids: in extracts prepared with supercritical CO2 the following constituents are found: lauric
acid, linoleic acid, linolenic acid, palmitic acid, palmitoleic acid, pentadecanoic acid, stearic acid and
oleic acid.
Herbal preparation(s)
The following herbal preparations are in medicinal use in the community for more than 30 years:
Herbal preparation
References
a)
Comminuted herbal substance
for preparation of infusions
for preparation of decoctions (authorized products in
Poland, on the market for more than 30 years)
Madaus 1938
b)
Tincture (ratio of herbal substance to extraction solvent
1:5), extraction solvent ethanol 70% (V/V)
Monograph in the Czech
pharmacopoeia since 1970,
monograph in the Austrian
pharmacopoeia at least since
1960, replaced by the
monograph in Ph. Eur.
01/2008:1895
c)
Tincture (ratio of herbal substance to extraction solvent
British Herbal Pharmacopoeia
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(L.) Raeusch., rhizoma
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Herbal preparation
References
1:5), extraction solvent ethanol 45% (V/V)
1974
D
Liquid extract (DER 1:1), extraction solvent ethanol 25%
(V/V)
British Herbal Pharmacopoeia
1974
E
Dry extract (DER 3.5-4.5:1), extraction solvent ethanol
60% (V/V)
Authorised product in Germany,
on the market at least since
1976
Herbal preparations not considered in the monograph:
- Powdered herbal substance:
Traditionally suspended in red wine for the treatment of acute unspecific diarrhoea (Wichtl 2009).
Although the combination with tannins from red wine seems to be plausible this special
pharmaceutical form does not seem to be suitable for THMPs. Weiß (1985) proposes a pinch of the
powdered herbal substance several times daily. This posology seems to be too imprecise.
- Tincture (ratio of herbal substance to extraction solvent 1:10), extraction solvent ethanol 70% (V/V).
This herbal preparation is mentioned only in recent editions of handbooks on phytotherapy (e.g.,
Jänicke et al. 2003, Kraft 2000). It seems that the authors refer in the proposed posology to the
tincture (1:5).
For the tincture (1:10) mentioned in the market overview of Spain no further information on
extraction solvent and posology is available.
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
Tormentillae rhizoma and its preparations are used with many other herbal substances or herbal
preparations. This monograph refers only to Tormentillae rhizoma.
Vitamin(s)
Not applicable.
Mineral(s)
Not applicable.
1.2.
Information about products on the market in the Member States
The following information has been provided regarding monographs in national pharmacopoeias or
products on the market with relevance for this monograph:
CZ:
Tormentillae radix has been a subject of Czechoslovak/Czech Pharmacopoeia since 1970;
recommended dosage in the last version of the Czech Pharmacopoeia: single dose for oral use 1.5 g,
daily dose for oral use 4.0–6.0 g.
Tormentillae tinctura (ratio of herbal substance to extraction solvent 1:5), extraction solvent ethanol
70% (V/V), has been a subject of Czechoslovak/Czech Pharmacopoeia since 1970; recommended
dosage in the last version of the Czech Pharmacopoeia: single dose for local use 0.5-1.0 g.
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(L.) Raeusch., rhizoma
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DK:
The Danish Food Agency has accepted 200 mg
Potentilla erecta
, radix in a food supplement. This is not
an upper limit but a specific assessment in a specific case.
LI:
The comminuted herbal substance is on the market for more than 30 years. The products are for the
preparation of infusions for use in the proposed indications.
PL:
The comminuted herbal substance is on the market for more than 30 years. The products are for the
preparation of decoctions for use in the proposed indications.
Regulatory status overview
Member State Regulatory Status
Comments
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify: Food supplements
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: Combinations only
Denmark
MA
TRAD
Other TRAD
Other Specify: Food supplements
Estonia
MA
TRAD
Other TRAD
Other Specify: No product
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify: No product
Hungary
MA
TRAD
Other TRAD
Other Specify: Combination only
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: No product
Italy
MA
TRAD
Other TRAD
Other Specify: No product
Latvia
MA
TRAD
Other TRAD
Other Specify: Combination only
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify: No product
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No product
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify: Tincture (1:10)
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(L.) Raeusch., rhizoma
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Member State Regulatory Status
Comments
Sweden
MA
TRAD
Other TRAD
Other Specify: No product
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No product
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3.
Search and assessment methodology
Search terms:
Potentilla erecta
,
Potentilla tormentilla
, tormentil, Blutwurz
Databases: Pubmed, Medline and Toxnet
Libraries: University Vienna, center of pharmacy; Medical University Vienna, central library.
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
The medicinal use of Tormentillae rhizoma can be traced in literature back to the 15
th
century
(according to Madaus 1938), it is also mentioned by Lonicerus and Matthiolus in the 17
th
century (cited
in Benedum et al. 2006).
In fact, Tormentillae rhizoma has been in therapeutic use for many decades, a continuous use during
the last 30 years is documented in the literature.
Therefore for Tormentillae rhizoma 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 easily fulfilled.
Type of tradition: European.
2.2.
Information on traditional/current indications and specified
substances/preparations
Tormentillae rhizoma is traditionally used for acute, unspecified diarrhoea, externally for haemostasis,
mild inflammation of the oral and pharyngeal mucosa, prosthetic pressure points, frostbite, burns,
haemorrhoids and poorly healing wounds (Madaus 1938, List & Hörhammer 1977, British Herbal
Pharmacopoeia 1983, Weiß 1985, Blaschek et al. 2008, Fintelmann & Weiss 2002, Augustin & Hoch
2004).
Proposed indications for traditional use:
Indication 1)
Traditional herbal medicinal product for symptomatic treatment of mild diarrhoea.
Indication 2)
Traditional herbal medicinal product for the symptomatic treatment of minor inflammations of the oral
mucosa.
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(L.) Raeusch., rhizoma
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Tormentillae rhizoma is a traditional herbal medicinal product for use in specified indications
exclusively based upon long-standing use.
The high content of tannins makes the medicinal use in the proposed indication plausible.
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Posology
Indication 1): Diarrhoea
Herbal preparation
Posology
a)
Comminuted herbal substance for
preparation of infusions
Corresponding 4-6 g herbal substance daily
(authorised products in Lithuania for more than
30 years)
2-4 g 3 times daily (British Herbal
Pharmacopoeia 1974)
for preparation of decoctions
Corresponding 4-6 g herbal substance daily
(German Commission E cited in Blumenthal
1998, Wichtl 2009)
2-3 g in 150–200 ml of water: drink 2 times
daily (authorised products in Poland for more
than 30 years)
b)
Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction solvent
ethanol 70% (V/V)
30–50 drops in water, several times daily
(Weiß 1985)
c)
Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction solvent
ethanol 45% (V/V)
2-4 ml 3 times daily (British Herbal
Pharmacopoeia 1974)
d)
Liquid extract (DER 1:1), extraction solvent
ethanol 25% (V/V)
2-4 ml 3 times daily (British Herbal
Pharmacopoeia 1974)
E
Dry extract (DER 3.5-4.5:1), extraction
solvent ethanol 60% (V/V)
3 times daily 2 capsules, each containing 200
mg dry extract
Indication 1): inflammations in the mouth or the throat
Herbal preparation
Posology
a)
Comminuted herbal substance for
preparation of infusions
Corresponding 4-6 g herbal substance daily
(authorised products in Lithuania for more than
30 years)
for preparation of decoctions
2-3 spoons (= 8-12 g) of the rhizome per litre
of water. Rinse the mouth several times daily
(Fintelmann & Weiss 2002)
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Herbal preparation
Posology
Corresponding 4-6 g herbal substance daily
(German Commission E cited in Blumenthal
1998, Wichtl 2009)
6 g in 200 ml water: for washing oral cavity
(authorised products in Poland for more than
30 years)
b)
Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction solvent
ethanol 70% (V/V)
1 teaspoon per glass of water, rinse the mouth
(Fintelmann & Weiss 2002)
10-20 drops to one glass of water daily
(Blumenthal et al. 1998)
c)
Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction solvent
ethanol 45% (V/V)
No posology available, therefore not
considered in the monograph in this indication
d)
Liquid extract (DER 1:1), extraction solvent
ethanol 25% (V/V)
No posology available, therefore not
considered in the monograph in this indication
e)
Dry extract (DER 3.5-4.5:1), extraction
solvent ethanol 60% (V/V)
Not authorised for this indication
Use in children:
There are no data from clinical trials or observational trials for the above mentioned herbal
preparations available. Therefore the use should be restricted to adults.
The use of the dry extract was allowed in Germany for adolescents in case of unspecific acute
diarrhoea.
Duration of use
Indication 1)
If the symptoms persist longer than 3 days during the use of the medicinal product, a doctor or a
qualified health care practitioner should be consulted.
Indication 2)
If the symptoms persist longer than 1 week during the use of the medicinal product, a doctor or a
qualified health care practitioner should be consulted.
Method of administration
Indication 1)
Oral use.
Indication 2)
Oromucosal use.
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(L.) Raeusch., rhizoma
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3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Data obtained with traditional herbal preparations relevant for the proposed indications:
Antiviral effect
A decoction (DER 1:10) demonstrated antiviral activity in a plaque inhibition test against Herpes virus
HVP 75 (type 2) and vaccine virus (May & Willuhn 1978).
Further data:
Astringent effect
Tannins as polyphenols exhibit the potential for so called multidentate interactions with other
molecules, predominately with proteins. The binding on proteins may be irreversible (covalent binding)
or reversible (hydrogen bonds). The astringency results from this affinity for proteins. Externally, they
waterproof the external layers of the skin and mucosas, thus protecting the underlying layers; they
also have a vasoconstrictor effect on small superficial vessels (Hänsel & Sticher 2007). Thus, the
absorption of fluids from the intestinal lumen and the influx into this is reduced; the precipitate of the
protein-tannin complex serves as a protective layer. The absorption of toxins is impeded; the effects of
local irritants are reduced (Dingermann & Loew 2003). For most of these presumptions no
experimental data are available.
Antimicrobial effects
Tannins exhibit antimicrobial effects independent of their plant source (Hänsel & Sticher 2007). A
tannin complex isolated from Tormentillae rhizoma, which contained tannins, sugar and triterpenes,
prevented fully the growth of the following bacteria, in the following concentrations: 2.5 mg/ml:
Pasteurella pseudotuberculosis
,
Shigella boydii
,
Shigella flexneri
,
Shigella sonnei
; 5 mg/ml:
Proteus
vulgaris
,
Pseudomonas aeruginosa
,
Staphylococcus aureus
; 10 mg/ml:
Escherichia coli
055B5,
E. coli
0111B4,
Streptococcus faecalis
(Pourrat et al. 1963 cited in Blaschek et al. 2008). The mentioned
concentrations may be reached after consumption of a herbal tea of tormentil.
Antiinflammatory effect
Antiinflammatory properties are documented for a wide variety of tannins (Scholz 1994). Agrimoniin,
major tannin of tormentil, was identified as a potent direct inhibitor of human neutrophil elastase with
an IC
50
of 0.9 µM (Hrenn et al. 2006).
Immunostimulatory effect
A weak immunostimulating effect was detected with a crude extract of tormentil prepared with water
containing acetone (no details on the DER and the ratio water:acetone is provided). 25 mg crude drug
extract per kg bodyweight was given intraperitoneally to mice. After an hour oxazolon was applied to
the shaved belly of the animals for sensitization. After 7 days oxazolon was applied on one ear, which
led to an average increase of the ear thickness by 24%. Substances causing an increase by 50%, were
considered active by the authors. No further details are published regarding the number of mice or
statistical parameters (Lund & Rimpler 1985).
Drozd and Anuszewska (2005) demonstrated that the combination of decoctions from ellagitannin
containing pharmacopoeial raw materials (Cortex Quercus, Folium Uvae ursi and Rhizoma Tormentillae,
decoction in usual concentration = approximately 2 g tormentil per 150 ml water) and the antibiotics
cefuroxime, cefoperazone and doxycycline increases the survival of mouse thymocytes in cultures with
supplementation of hydrocortisone. A cytotoxic test was used for the evaluation. The results showed
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(L.) Raeusch., rhizoma
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that each of the applied aqueous extracts caused a better survival of mouse thymocytes when added
to the antibiotic in comparison to the antibiotic alone. The extract from Cortex Quercus showed the
highest activation when added to the culture with cefuroxime. The best stimulation with cefoperazone
was achieved when combined with the extract from Rhizoma Tormentillae. Doxycycline was most
effective when combined with the extract from Folium Uvae ursi. The authors conclude that the
combination of antibiotics and tannin raw materials could be advantageous for the immunological
system of patients.
Assessor’s comment:
The interpretation of the authors seems to be too optimistic. The conclusions made are far away from
practical consequences and cannot be taken into account for the monograph.
Interferon inducing effect
A weak effect was observed in a study on interferon induction. Mice received 100 mg crude drug
extract per kg bodyweight intraperitoneally. After 17 hours 0.05 ml of a dilution of Vaccinia-virus (IHD
strain) was applied intravenously. This concentration produced untreated 12 to 25 separate lesions on
the tail of each animal. Inhibition of these lesions on the eighth day by more than 50% is interpreted
as a possible interferon inducing effect. The observed inhibition was approximately 28%. No further
details are published regarding the number of mice or statistical parameters (Lund & Rimpler 1985).
Molluscicide effect
Aqueous and methanol extracts (5 g herbal substance in 100 ml) in concentrations of 400 ppm or 100
ppm are still active against the freshwater snail
Biomphalaria glabrata
, which is the intermediate host
of schistosomiasis. The tannins are considered to be the molluscicide principle of the drug
(Schaufelberger & Hostettmann 1983).
Hypoglycemic effect
Tormentic acid (isolated from the plant
Poterium ancistroides
, but also a constituent of tormentil)
lowered in a concentration of 30 mg/kg body weight the fasting plasma glucose level with a
corresponding increase in circulating insulin levels in rats. It also improved the glucose tolerance test
by increasing insulin secretory response to glucose. Tormentic acid did not alter the insulin and glucose
levels in streptozotocin-induced diabetic rats (Ivorra et al. 1988). Since no data on the concentration
of tormentic acid in tormentil are available, the relevance of this publication for the use of tormentil
cannot be assessed.
Antioxidant activity
Dimers and timers of procyanidins of tormentil displayed the highest anti-radical activity towards
lipoperoxidation compared to other fractions of a water soluble tormentil extract. The IC
50
of a total
extract was determined with 0.024 mg/ml. Pentamers and hexamers possessed the most marked anti-
elastase properties. The IC
50
of a total extract was determined with 0.044 mg/ml. These effects are
interpreted by the authors as a possible prevention of the aging effects of oxidative membrane
impairment. No standard antioxidants were included for comparison of the results (Vennat et al. 1994,
Bos et al. 1996).
Chandak et al. (2009) investigated pure gallotannin in rats with Streptozotocin (STZ)-induced diabetic
nephropathy. Poly (ADP-ribose) polymerase (PARP) is known to be activated under conditions of
oxidative stress and/or radiation exposure. Inhibition of PARP by specific inhibitors is known to prevent
the development of STZ induced diabetic nephropathy by reduction in oxidative stress induced
apoptosis. Gallotannin (20 mg/kg/day, i.p.) treatment for 4 weeks led to a significant reduction in the
levels of plasma creatinine which is a well known marker for diabetic nephropathy. Treatment with
gallotannin resulted in protection up to a certain level of glomerular damage, suggesting compensatory
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glomerular hypertrophy. As a PARG inhibitor gallotannin treatment also showed protection in PARP
cleavage which is a hallmark for apoptotic cell death signifying the protective role of gallotannin in cell
death signalling.
Tormentil (no details on the herbal preparation and concentration) showed antioxidant activity in a
cell-free oxidant-generating system as well as in sigmoid or rectal mucosal biopsies obtained from
patients with active ulcerative colitis (Langmead et al. 2002).
Effect on histamine release
The effects of tannins and related polyphenols on potassium superoxide- and compound 48/80-induced
histamine release from rat peritoneal mast cells were examined. Pre-treatment with hydrolysable
tannins (1-100 µM) significantly inhibited potassium superoxide-induced histamine release. For
example agrimoniin inhibited the potassium superoxide- induced histamine release wirh an IC
50
of 0.68
µM, the compound 48/80-induced histamine release with an IC
50
of 0.49 µM. The inhibitory effect on
histamine release caused by different stimulants suggested that ellagitannins act as cell membrane
stabilizers as well as radical scavengers (Kanoh et al. 2000).
Antitumor effects
Agrimoniin (concentration approximately 1% in the herbal substance) was identified as a potential
antitumor agent by Miyamoto et al. (1987). Agrimoniin inhibited almost completely the growth of
ascites type and solid type tumours in mice in a dose of 10 mg/kg when applied intra-peritoneally.
Murayama et al. (1992) found that agrimoniin induces the interleukin-1 secretion dose-dependently,
which was interpreted as possible mechanism for the antitumor activity.
Miyamoto et al. (1988) found that agrimoniin in a dose of 10 mg/kg enhanced
in vitro
the cytotoxic
potential of several effector peritoneal exudate cells with different induction kinetics. The earlier
response is an enhanced NK cell activity of non-adherent peritoneal exudate cells, later responses were
enhanced cytotoxic activity of adherent cells and an antibody-dependent macrophage-mediated
cytotoxic activity.
Assessor’s comment
:
Considering the low amount of agrimoniin in the herbal substance (about 1%) these findings seem to
be of minor relevance for the oral and oromucosal use of tormentil.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No specific data available.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Acute Toxicity:
Dry extract (extraction solvent acetone/water 75:25): in dosages of 300 mg/kg p.o. and 200 mg/kg
i.p. no signs of toxicity in mice (Lund & Rimpler 1985).
A dry extract prepared by maceration with water was applied to rats and mice by the intra-gastric
route in dosages of 2.5 g/kg and 6.8 g/kg respectively. Further, a single dose was applied
intraperitoneally in dosages of 3.8 g/kg in mice and 14.5 g/kg in rats. No signs of toxicity could be
observed, the macroscopical and microscopical investigation of the internal organs revealed no
pathological changes. The tested doses correspond to several hundreds of grams of extract for a
person with 75 kg (Shushunov et al. 2009).
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No tests on genotoxicity, carcinogenicity and reproductive toxicity have been performed.
Tannins may have carcinogenic potential; this is for example documented for oak (Labieniec &
Gabryelak 2003). It is not clear whether these findings are relevant for tormentil, too.
3.4.
Overall conclusions on non-clinical data
The astringent effect of the tannins makes the use of tormentil plausible in the proposed indications.
Although the data on toxicology are limited there are no safety concerns for the use as traditional
herbal medicinal product.
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data available.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
In the study of Huber et al. (2007, see 4.2.1) neither undegraded nor metabolized tannins could be
detected by LC-MS in 15 patient sera even after application of 3000 mg/d of an ethanolic dry extract.
No data available regarding other constituents of tormentil.
4.2.
Clinical Efficacy
4.2.1.
Dose response studies
In an open-label study Huber et al. (2007) investigated the safety, pharmacology and clinical effects of
different doses of a commercial ethanolic dry extract (tannin content 15-22%). No further data are
available with regard to the extract.
Fifteen patients with active ulcerous colitis finished the study. During treatment with Tormentil
extracts, the CAI (Colitis activity index) was reduced from a mean of 8.3 to 3.9 when participants took
2400 mg/d, which was statistically significant. In addition, stool frequency, bloody stool and C-reactive
protein decreased. Although the posology was very high, the reported adverse effects were mild
(heartburn, stomach discomfort, nausea).
4.2.2.
Clinical studies (case studies and clinical trials)
No data available.
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
Forty children in the age from 3 months to 7 years suffering from rotavirus diarrhoea were included in
a clinical trial by Subbotina et al. (2003). The children in the active group received 3 drops tormentil
extract per year of life three times daily until discontinuation of the diarrhoea or at maximum for 5
days. The study medication was a tincture (1:10, extraction solvent ethanol 40%). The placebo was an
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alcohol extract of Indian teas which were identical in appearance and taste with tormentil tincture.
The duration of the diarrhoea was in the treatment group 3 days, in the placebo group 5 days.
No side effects were reported.
Assessor’s comment:
There is no documented medicinal use of the study medication in the EU. The tincture used in this
study is less concentrated compared to the herbal preparations which comply with the requirements on
THMPs according to Dir. 2004/24 EC. Additionally, there is no posology for children and adolescents
published for any of the herbal preparations included in the monograph.
Therefore the use in children and adolescents cannot be recommended. However, the data support the
traditional use of tormentil for the treatment of diarrhoea in adults.
4.3.
Overall conclusions on clinical pharmacology and efficacy
The published clinical trials give only preliminary data. They support the traditional use of tormentil.
However, the level of evidence does not support well-established use.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
No data available.
5.2.
Patient exposure
None reported.
5.3.
Adverse events and serious adverse events and deaths
The only source of documented adverse effects is the study by Huber et al. (2007). All side effects
were mild, although 62% experienced mild gastrointestinal symptoms. One of the 15 patients
developed worsening of colitis and was hospitalized.
5.4.
Laboratory findings
No specific data available.
5.5.
Safety in special populations and situations
No specific data available.
5.6.
Overall conclusions on clinical safety
The medicinal use of Tormentillae rhizoma can be regarded as safe.
6.
Overall conclusions
Risk – benefit assessment
Since no specific risks are known regarding the oral and oromucosal use of herbal preparations of
tormentil, there are no limitations from the herbal preparation when used in adults.
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Persistent diarrhoea may cause dehydration and loss of electrolytes. Rehydration and substitution of
electrolytes are the primary therapeutic goals. Acute, unspecific diarrhoeas are in most cases self-
limiting diseases, a supportive treatment with astringents like tormentil may help to reduce the
duration and the severity of the complaints. However, if the symptoms persist for more than 3 days
the diarrhoea should be treated and monitored by a doctor.
Only limited data is available regarding the use of tormentil in children and adolescents in the case of
diarrhoea. Astringents like purified tannins are recommended in standard literature for children
because of their safety compared to therapeutic alternatives (Mutschler et al. 2008). However, acute
diarrhoea may be life-threatening especially for young children when not properly treated. Therefore
the use of tormentil in the case of diarrhoea in children and adolescents is not suitable for a traditional
herbal medicinal product. Moreover, no data on the safe use in children and adolescents are published
for the herbal preparations which are included in the monograph. Therefore the use should be
restricted to adults.
The use as a gargle in the case of inflammations in the mouth does not show any limitations. However,
there are no data regarding a posology in children and adolescents available. Therefore the use should
be limited to adults.
No data are available on the safe use during pregnancy and lactation. Therefore the use of tormentil is
not recommended during pregnancy and lactation.
Annex
List of references
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Source: European Medicines Agency
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