Community herbal monograph on
Quercus rob
petraea
.(Matt.) Liebl.,
Quer
ur
L.,
Quercus
cus pubescens
Willd., cortex
l product
To be specified for the individual finished product.
2.
Qualitative and quantitative compositi
on
1
,
2
Well-established use
Traditional use
With regard to the registration appli
Article 16d(1) of Directive 2001/
amen
cation of
83/EC as
ded
Quercus robu
and
Que
r
L.,
Quercus petraea
(Matt.) Liebl.
rcus pubescens
Willd., cortex (oak bark)
i) Herbal substance
Not applicable
ii) Herbal prepara
tions
a)
Comminuted herbal substance
b)
Powdered herbal substance
c)
Dry extract (DER 5.0-
solvent ethanol
6.5:1), extraction
50% m/m
Well-established use
Traditional use
Comminuted herbal substance as a herbal tea for
oral use or as a decoction preparation for
oromucosal or cutaneous use.
Herbal preparation in solid or liquid dosage forms
for oral use.
ld be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Ph. Eur. monograph (ref. no 01/2008:1887).
2
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
Community herbal monograph on Quercus robur L., Quercus petraea.(Matt.) Liebl.,
Quercus pubescens Willd., cortex
EMA/HMPC/3203/2009
Page 2/7
The pharmaceutical form shou
4.1.
Therapeu
tic indications
Well-established use
Traditional use
Indication 1)
Traditional herbal medicinal product for
nt of mild diarrhoea.
Indication 2)
raditional herbal medicinal product for
nt of minor inflammation of
.
Indication 3)
Traditional herbal medicinal product for
ng
haemorrhoids, after serious
conditions have been excluded by a medical
doctor.
product is a traditional herbal medicinal
product for use in specified indications exclusively
based upon long-standing use.
4.2.
Posology and method of a
dministr
ation
Well-established use
Traditional use
Posology
Adults, elderly
Indication 1)
a)
3 g comminuted he
rbal substance in 250
ml of water, three times daily.
b)
1 g powdered he
capsules/tablets for
daily.
rbal substance in
oral use, three times
c)
Dry extract: 140 mg, 4 times daily.
Indication 2)
a)
Decoction for oromucosal use: 20 g/L.
Indications 2) and 3)
b)
Decoction for bath preparation: 5 g
comminuted herbal substance/1L to be
added to the bath (bath duration 20
Community herbal monograph on Quercus robur L., Quercus petraea.(Matt.) Liebl.,
Quercus pubescens Willd., cortex
EMA/HMPC/3203/2009
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symptomatic treatme
T
symptomatic treatme
the oral mucosa or skin
symptomatic relief of itching and burni
associated with
The
Well-established use
Traditional use
minutes).
One full or partial bath da
ily.
Topical rinses or poultices seve
ral times daily.
years of age is not recommended (see section
4.4. ‘Special warnings and precautions for use’).
Duration of use
Indication 1)
Not to be used for more than 3 days.
If the symptoms persist during the use of the
r or a qualified health
consulted.
Indications 2) and 3)
Not to be us
ed for more than 1 week.
If the symptoms persist during the use of the
edicinal product, a doctor or a qualified health
e practitioner should be consulted.
Meth
od of administration
Oral use.
Cut
aneous use.
Oromucosal use.
Anorectal use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Use as bath additive:
Open wounds, large skin and mucosa injuries
and infection of the skin and mucosa.
Community herbal monograph on Quercus robur L., Quercus petraea.(Matt.) Liebl.,
Quercus pubescens Willd., cortex
EMA/HMPC/3203/2009
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The use in children and adolescents under
18
medicinal product, a docto
care practitioner should be
m
car
4.4. Special warnings and precautions for use
Well-established use
Traditional use
e use in children and adolescents under 18
years of age is not recommended due to lack of
adequate data.
Indication 1)
If recurrent diarrhoea or bloody stools occur, a
doctor or a qualified health care practitioner
should be consulted.
Indications 2) and 3)
Hot bathes should not be used in case of febrile or
nsufficiency and
hypertension.
Indication 3)
If rectal bleeding occurs during the treatment of
morrhoids a doctor should be consulted.
4.5.
Interactions with other m
edicinal products and other for
ms of
interaction
Well-established use
Traditional use
Indication 1)
Inte
medicine may be delayed. F
product should be taken 1
after intake of other medicina
rnal absorption of concomitantly administered
or this reason, the
hour or more before or
l products.
4.6.
Pregnancy and lactation
Well-established use
Tra
ditional use
ctation has not
cient
data, the use during pregnancy and lactation is
not recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
Community herbal monograph on Quercus robur L., Quercus petraea.(Matt.) Liebl.,
Quercus pubescens Willd., cortex
EMA/HMPC/3203/2009
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Th
infectious illnesses, in heart i
hae
Safety during pregnancy and la
been established. In the absence of suffi
4.8.
Undesirable effects
Well-established use
Traditional use
Allergic reactions have been reported. The
frequency is not known
.
ons 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
We
ll-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
amended.
5.2.
Pharmacokinetic properties
Well-established
use
Tra
ditional use
Not required as per Articl
Directive 2001/83/EC a
e 16c(1)(a)(iii) of
s amended.
5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
irective 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.
Well-established use
Traditional use
Not applicable.
Community herbal monograph on Quercus robur L., Quercus petraea.(Matt.) Liebl.,
Quercus pubescens Willd., cortex
EMA/HMPC/3203/2009
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If other adverse reacti
Directive 2001/83/EC as
D
25 November 2010
Community herbal monograph on Quercus robur L., Quercus petraea.(Matt.) Liebl.,
Quercus pubescens Willd., cortex
EMA/HMPC/3203/2009
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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..................................................................................... 1
0
3. Non-Clinical Data ............................................................................................................. 11
preparation(s) and relevant constituents thereof ......................................................... 1
1
preparation(s) and relevant constituents thereof ......................................................... 1
7
preparation(s) and constituents thereof ..................................................................... 1
8
3.4. Overall conclusions on non-clinical data............................................................... 2
0
4. Clinical Data ..................................................................................................................... 20
4.1. Clinical Pharmacology ....................................................................................... 2
0
including data on relevant constituents ...................................................................... 2
0
including data on relevant constituents ...................................................................... 2
0
4.2. Clinical Efficacy ................................................................................................ 2
1
4.2.1. Dose response studies.................................................................................... 2
1
4.2.2. Clinical studies (case studies and clinical trials).................................................. 2
1
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 2
1
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 2
1
5. Clinical Safety/Pharmacovigilance................................................................................... 21
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 2
1
5.2. Patient exposure .............................................................................................. 2
1
5.3. Adverse events and serious adverse events and deaths ......................................... 2
1
5.4. Laboratory findings .......................................................................................... 2
2
5.5. Safety in special populations and situations ......................................................... 2
2
5.6. Overall conclusions on clinical safety ................................................................... 2
3
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EMA/HMPC/3206/2009
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1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
The herbal substance is mentioned in several well known handbooks such as Madaus (1938),
Martindale (2007), Bisset and Wichtl (1994), PDR for Herbal Medicines (2000; 2004), German
Comission E Monograph and European Pharmacopoeia 6.0, Duke’s Handbook of Medicinal Herbs
(2002), Mills and Bone (2000), Schulz et al. 1998, Wagner and Wiesenauer 1995; Weiss and Fintelman
(1999).
In the European Pharmacopoeia, it is described as the cut and dried bark of young branches and the
lateral shoots of
Quercus robur,
Quercus petraea
and/or
Quercus pubescens.
It contains a minimal
amount of 3% of tannins, expressed as pyrogallol, calculated with reference to the dried herbal
substance.
The plant belongs to the family
Fagacae
, subfamily
Quercoideae
, genus
Quercus.
Oak bark is harvested in spring from March to April.
The oak bark contains highly variable amount of tannins (8-20%). The tannin content depends on the
time of the harvest, age of the branches and on the method of assay used. Tannins are polyphenolic
secondary metabolites of higher plants. They comprise either: galloyl esters and their derivatives
(gallotannins, ellagitannins and complex tannins) or they are oligomeric and polymeric
proanthocyanidins and can possess different interflavanyl coupling and substitution patterns
(condensed tannins) (Okuda et al. 1993; 2005). The oak bark contains both hydrolyzable and
condensed tannins (Ahn and Gstirner 1971; 1973; Bate-Smith 1972; Bruneton 1995; Chen 1970;
Evans 2009; Glasl 1983; Grundhöfer et al. 2001; Haddock et al. 1982; Haslam 2007; Haslam and Cai
1994; Herve du Penhoat et al. 1991a, 1991b; Ikram and Nowshad 1977; Ishimaru et al. 1987;
Khanbabaee and van Ree 2001; König et al. 1994; Mämmelä et al. 2000; Niemetz and Gross 2005;
Pallenbach et al. 1991, 1993; Roux and Evelyn 1958; Salminen et al. 2004; Scalbert et al. 1988;
1989, 1990; Schofield et al. 2001; Vivas et al. 1995; Vovk et al. 2003; Yoshida 1984).
Hydrolysable tannins
They are previously known as pyrogallol tannins. Principal types of hydrolysable tannins are
gallotannins and elagitannins. They are polyesters of glucose and can be hydrolysed by acids or
enzymes sych as tannase. They release sugar upon hydrolysis and either gallic acid or
hexahydroxydiphenic acid. Phenolic acids: gallic acid is present in gallotannins or hexahydroxydiphenic
acid in ellagitannins. The latter undergoes lactonization to produce ellagic acid (Okuda et al. 1989).
Gallotannins are the simplest hydrolysable tannins, containing a polyphenolic and a polyol residue
(mostly derived from D-glucose). Tannic acid is a polymer of about eight monomers of gallic acid and
glucose.
Ellagitannins (formed from the gallotannins by the oxidative coupling of at least two galloyl
units, yielding an axially chiral hexahydroxydiphenoyl (HHDP) unit) grandinin, castalagin,
pedmolagin, pedunculagin, roburin A-E, vescalin, vescalagin, 2,3-(S)-hexahydroxy diphenoyl
glucose (Bate-Smith 1972; Feldman 2005; Herve du Penhoat et al. 1991a; 1991b; Mämmelä
et al. 2000; Peng et al. 1991; Vivas et al. 1995).
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Flavano-ellagitannins: acutissimins A an B, eugenigrandin A, guajavin B, stenophyllanin C
(Khanbabaee and van Ree 2001).
Procyanidinoellagitannin: mongolicanin.
Ellagitannins are instable and hydrolysed over time with formation of free ellagic acid and decrease of
their solubility (Charrier et al. 1992; Klumpers et al. 1994; König and Scholz 1994; Mämmelä et al.
2000; Simon et al. 1999).
Present data suggest, that the pyrogallol phenols (+)-gallocatechin and leucodelphinidin, which are
formed in oak leves, are oxidated by polyphenoloxidases in the heartwood and leaves to phlobatannin
and are translocated to the bark. The increase in tannin concentration suggests a downward movement
of phenolic metabolites from the leaves to the phloem (Hathway 1958; 1959).
Condensed tannins (proanthocyanidins)
More than 20 compounds (catechins and low-molecular-mass, oligomeric, and polymeric
proanthocyanidins) have been isolated from the bark of
Quercus robur
.
Monomers: (
_
)-epicatechin, (
_
)-epicatechin gallate, (+)-catechin, (+)-catechin gallate, (+)-
gallocatechin, (
_
)-epigalloatechin, and (
_
)-epigallocatechin gallate; dimeric proanthocyanidins:
(+)-catechin-(4α-8)-(+)-catechin, 3-galloyl-(+)-catechin-(4α-8)-3-0-galloyl-(+)catechin, 3-)-
galloyl-(+)-gallocatechin-(4β-8)-(+)-gallocatechin, (
_
)-epicatechin-(4β-8)-3-0-galloyl-(
_
)-
epigallocatechin, 3-)-galloyl-(
_
)-epigallocatechin-(4β-8)-(+)-catechin.
Oligomeric proanthocyanidins: D14-D19 (Kuliev et al. 1997; Matthews et al. 1997; Thompson
et al. 1972).
Condensed tannins are not very stable; they can be oxidized into soluble phlobaphens, which have no
tanning properties anymore.
Triterpenes: friedelin, friedelinol, 3-friedelanol (Castola et al. 2002, Coquet et al. 2008;
Kohlmünzer 2000; Scalbert and Haslam 1987, Sousa et al. 2006)
Insoluble lipid polyesters: suberins (Graça and Santos 2007; Holloway 1983)
Volatile acids: acetic and formic acid (Balaban and Uçar 2003)
Herbal preparation(s)
(Hänsel et al. 1994, PDR for Herbal Medicines 2000, 2004, Matindale 2007)
Comminuted herbal substance (12 – 16% tannins)
Decoctions: 20 g/L of water
Infusions: 5 g/L of water
Extracts: dry extract (5.0-6.5:1), extraction solvent: ethanol 50% V/V
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
The herbal substance is also available in combination products. Main plants used in combination are:
Glycyrrhiza glabra, Triticum repens, Juglans regia, Potentilla erecta, Bistorta polygonum, Fucus
Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus
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vesiculosus, Althea officinalis, Foeniculum vulgare, Mentha piperita, Achillea millefolium, Salvia
officinalis
and
Thymus vulgaris
.
1.2.
Information about products on the market in the Member States
According to the information provided by the National Competent Authorities.
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify: The herbal substance is
present in combination
products and in food
supplements
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify: Not present
Estonia
MA
TRAD
Other TRAD
Other Specify:
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: Not present
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify:
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: The herbal substance is
present also in
combination products
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
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Member State Regulatory Status
Comments (not
mandatory field)
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
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
Databases assessed until July 2010:
Science Direct, PubMed, Embase, Medline, Proquest, Academic Search Complete, Agricola, Toxnet.
Search terms: Quercus, Oak, cortex, bark and robur, petraea, pubescens.
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
The
Quercus
genus comprises many species widespread in Europe, Asia and America. The genus
contains about 400 species. The most popular are, in central and northern Europe:
Quercus robur
,
Quercus pedunculata
and
Quercus petraea;
in southern Europe and in the Middle East:
Quercus
infectoria, Quercus ilex, Quercus pubescens
and
Quercus brantii;
in the Mediterranean region:
Quercus
cerris
and
Quercus coccifera;
in North America:
Quercus alba,
Quercus havardii
,
Quercus breviloba
,
Quercus gambelli
and
Quercus douglassi,
in the Far East (China, Japan and Korea):
Quercus acuta,
Quercus acutissima, Quercus aliena, Quercus ogilva, Quercus glauca, Quercus salicina,
Quercus serrata
and
Quercus dentate
. Several Quercus species were tested as described in non-clinical part. Further
data derive from accidental animal poisoning. Furthermore,
Quercus infectoria
and
Quercus ilex species
were examined due to their common therapeutical use in southern Europe.
Oak bark has been traditionally used as a tanning material in Europe since medieval times (Smout
2007). For commercial purposes, the timber and bark of
Quercus pedunculata
Ehrh. and
Quercus
sessiflora
Salisb. are not differentiated.
Quercus was mentioned in the writings of Dioskurides, Hieronimus Bock 1565, Matthiolus (1626),
Haller (1755), Hecker (1814), Clarus (1860), Rademacher (1851), Kissel (1863), (according to
Madaus“ Lehrbuch der Biologischen Heilmittel”, 1938), Spencer (1832) and Schimpfky (1900). Its
cultivation in Europe dates back to ancient and medieval times. The oak tree was held sacred by the
ancient Greeks and Romans and in the rest of Europe. The origin of its name is said to be derived from
the Celtic
quer
(fine) and
cuez
(tree).
The astringent effects of oak bark or nutgalls are known for centuries. Oak bark was applied topically
to burns and wounds, or applied orally in gastritis or diarrhoea. After precipitation of superficial
proteins, a protective coat is formed to protect healing of the damaged tissues.
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EMA/HMPC/3206/2009
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Especially valuable oak bark was used to tan leather. An infusion formed a dye, which was used in
rural regions to dye wool. Records of the bark use in folk medicine are found in many countries to
counter diarrhoea, infusions for gargle for sore throat and for adding to a hot bath for sore or
excessively perspiring feet or sprained ankle.
The infusions were also used for treatment of ulcers, toothache, neuralgia and rheumatism (Allen and
Hatfield, 2004). Oak bark powder of
Quercus robur
is used for prophylaxis of diarrhoea in cattle,
horses, pigs, sheep and chicken (EMEA Committee for Veterinary Medicinal Products 1997).
2.2.
Information on traditional/current indications and specified
substances/preparations
Belgium
Well-Established Use:
Is the Herbal Substance on the market?:
Yes
No
Status:
Authorised products Food supplements
Combination products: The herbal substance is only available in combination products. Herbal teas
(authorised since 1962).
Average number of combination substances: 2-3 3-5 >5.
What are the main combination substances?: Glycyrhizae radix, Triticum repens, Galium luteum,
Juglans regia, Potentilla erecta, Bistorta polygonum, Fucus vesiculosus, Althea officinalis.
Czech Republic
Traditional Use:
Preparations (kind of extract, extraction solvent, DER): comminuted herbal substance.
Since when are the preparations on the market?: 1998.
Pharmaceutical form (Standard Terms): comminuted herbal substance for infusion preparation or
decoction for bath preparation.
Posology (Route of administration in Standard Terms + daily dosage): for infusion - -100g/1.5 L of hot
water/25 minutes for bath - decoction from 1 spoon of herbal drug/1 L of water several times daily.
Indications: dermatitis, stomatitis, pharyngitis, inflammations of external genitals, haemorrhoids.
Risks (adverse drug effects, literature), contraindications: extensive necrosis of mucosa and skin,
third-degree burns, alkali burns, in case of bath weepy eczema.
Special warning: hot bath should not be used in case of febrile or infectious illnesses, in heart
insufficiency (III. and IV. stage NYHA) and hypertension (IV. stage WHO).
Undesirable effects: allergic reactions are reported. The frequency is not known.
Is the Herbal Substance on the market?: Yes
No
Were pharmacovigilance actions taken on medicinal products containing the herbal substance?:
Yes No
*
Registration was granted in the old legislative frame, not the 2004/24/EC Directive
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Additional comments:
Quercus cortex has been a subject of Czechoslovak/Czech Pharmacopoeia since 1947; recommended
dosage in the last version of the Czech Pharmacopoeia: single dose for oral use 1 – 1.5 g and for
topical use 5.0 g/L, daily dose for oral use 3.0 g and for topical use 20.0 g/L.
Czech name of the herbal substance: dubová kůra.
Denmark
Well-Established Use:
Preparations (kind of extract, extraction solvent, DER): Quercus cortex and calcium carbonate ana
partes.
Since when are the preparations on the market?: Old product. Withdrawn from the market in 1989.
Pharmaceutical form (Standard Terms): powder (pulvis).
Posology (Route of administration in Standard Terms + daily dosage): no information.
Indications: no information.
Is the Herbal Substance on the market?: Yes
No
Germany
Traditional Use:
Preparations (kind of extract, extraction solvent, DER): none.
Is the Herbal Substance on the market?: Yes
No
Well-Established Use
:
Dry extract (5.0-6.5:1), extraction solvent: ethanol 50% V/V.
German Standard Marketing Authorisation: see below under additional comments.
Since when are the preparations on the market?: At least since 1976.
Pharmaceutical form (Standard Terms): coated tablet.
Posology (Route of administration in Standard Terms + daily dosage): For oral use in adults and
adolescents over 12 years 4 x daily 1 coated tablet containing 140 mg dry extract.
Indications: Auxiliary treatment in unspecific acute diarrhoea.
Risks (adverse drug effects, literature): Interaction: enteral absorption of concomitantly administered
medicine may be delayed. For this reason the product should be taken 1 hour and more before or after
intake of other medicinal products.
Is the Herbal Substance on the market?: Yes
No
Status: Authorised products Registered products Food supplements
Were pharmacovigilance actions taken on medicinal products containing the herbal substance?: Yes
No
Combination products: In DE there are no authorized combination products.
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Additional comments:
German Standard Marketing Authorisations:
Single active ingredient: 1 (herbal tea).
Combinations products: 0.
*For completeness, all preparations for which marketing authorisations for traditional use have been
granted (with reference to former national regulations) are mentioned, regardless of the fact that some
of them are not in accordance with current community law (as defined in directive 2004/24/EC).
Traditional preparations were authorised in 10-50% of well-established use doses when in parallel the
same preparations were authorised under well-established use.
Greece
In Greece there no any product containing Quercus cortex as a single active ingredient primarily, as
well as in combination product.
Poland
Traditional Use:
Preparations (kind of extract, extraction solvent, DER): comminuted herbal substance.
Since when are the preparations on the market?: 1967.
Pharmaceutical form (Standard Terms):
1) powdered herbal substance, 350-375 mg in 1 tablet, standarized to 20 mg of tannins/1 tablet.
2) comminuted herbal substance for infusion preparation or decoction for bath preparation.
Posology (Route of administration in Standard Terms + daily dosage):
1) 1 g of comminuted herbal substance for oral use 3 times daily; 1 teaspoon (3g) of the comminuted
herbal substance in 1 cup (250 ml) of cold water and bring to a short boil, take 1 cup, 3 times daily.
2) for infusion - 20g/1 L of hot water/25 minutes; for bath - decoction from 5 g of herbal drug/1 L of
water several times daily.
Indications:
1) Diarrhoea
2) Stomatitis, pharyngitis, dermatitis, inflammations of skin.
Risks (adverse drug effects, literature), contraindications: extensive necrosis of mucosa and skin,
third-degree burns, alkali burns, in case of bath weeping eczema.
Special warning: hot bath should not be used in case of febrile or infectious illnesses, in heart
insufficiency and hypertension. Undesirable effects: allergic reactions are reported. The frequency is
not known.
Is the Herbal Substance on the market?: Yes
No
Status:
Authorised products Registered products* Food supplements
Combination products:
The herbal substance is also available in combination products.
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Average number of combination substances: 2-3 3-5 >5.
What are the main combination substances?: Foeniculum vulgare, Mentha piperita, Millefolii herba,
Salviae herba, Thymi herba, Potentilla erecta.
Registration was granted in the old legislative frame, not according to the 2004/24/EC Directive.
Were pharmacovigilance actions taken on medicinal products containing the herbal substance?: Yes
No
Additional comments:
Quercus cortex has been a subject of Polish Pharmacopoeia since 1947; recommended dosage in the
last version of the Polish Pharmacopoeia: single dose of comminuted herbal substance for oral use 1 –
1.5 g and for topical use 5.0 g/L, daily dose for oral use 3.0 g and for topical use 20.0 g/L.
Polish name of the herbal substance: kora dębu.
Additional comments:
Polish Standard Marketing Authorisations:
Single active ingredient: 3 (oak bark in tablets), 7 (herbal teas).
Combinations products: 2.
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
PDR for Herbal Medicines (2000, 2004)
Comminuted herbal substance: 3 g/day.
Tea: 1 g of comminuted oak bark is put to cold water, rapidly boiled and strained after some time (1
teaspoon corresponds to 3 g of drug).
Daily dosage: internally 3 g of oak bark, tea: 1 cup (250 ml) 3 times daily.
Externally: rinses/gargles: boil 2 dessert spoons finely cut drug with 3 cups water.
Bath additive: 5 g of oak bark is boiled with 1 L water and added to the full or hip bath.
Bath additive – duration: 20 minutes at 32 – 37
0
C.
Hänsel et al. (1994)
Internal use:
Comminuted oak bark:
Tea: 1 g comminuted oak bark is put to cold water, rapidly boiled and strained after some time. Daily
dose: 3 g of oak bark. Duration of use: 3 – 4 days.
External use:
For external use: 0.1 g of tannins/liter of water.
Rinses/gargles: boil 20 g of finely cut oak bark in 1 L of water.
Bath: 5g of oak bark is boiled with 1 L of water and added to the full or hip bath. Bath temperature: 32
– 37
0
C, duration: 20 minutes, 2 – 3 times per week, no longer than 2 – weeks.
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(Bundesanzeiger No 22a. 01.02.1990) Quercus cortex
Internal use: Comminuted oak bark, 3g daily. Preparations adequately.
External use: Rinses/gargles: 20 g of finely cut oak bark in 1 L of boiled water.
Baths: complete and partial: 5g of oak bark in 1 L of water.
Duration of use: If diarrhoea lasts longer than 3-4 days, qualified advice is required.
External use: no longer than 2 – 3 weeks.
Italian Monograph.Quercia (Quercus cortex)
Internal use: Comminuted oak bark, 3g daily. Preparations adequately.
External use: Rinses/gargles: 20 g of finely cut oak bark in 1 L of boiled water.
Baths: complete and partial: 5g of oak bark in 1 L of water.
Duration of use: If diarrhoea last longer than 3-4 days, qualified advice is required.
External use: No longer than 2 – 3 weeks.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Pharmacodynamics
Tannins are supposed to contribute to the therapeutic effect. Oak bark is used against chillblains,
mouth sores, haemorrhoids and indigestion.
Tannins occurring in oak bark are reported to have various activities: antisecretolytic, antiirritant,
antimicrobial and antiparasitic. Traditionally oak bark was used to treat nonspecific diarrhoea,
inflammation of mouth and throat and slightly injured skin (Madaus (1938), Martindale (2007), Bisset
and Wichtl (1994), Mills and Bone (2000) and Weiss and Fintelman (1999).
Astringent actions
The astringency of the extracts of Quercus bark is mainly due to its content of oligomeric
proanthocyanidins. By hydrogen binding the available polyhydroxyphenolic groups are crosslinking with
proteins. This effect is also involved in the process of leather tanning.
The phenolic groups of tannins may interact with proteins of saliva, mucus, gastric contents and
epithelial cells of the gastrointestinal tract.
The presence of tannins in food may limit digestion and is recognized as a feeling of dryness in the
palate, a feeling of roughness, dryness, constriction and loss of lubrication. Tannins are reported to
repel predators by their strongly astringent taste (Prinz and Lucas 2000).
Salivary proteins in saliva (proline-rich proteins and histatins) are precipitators of tannins (Bacon and
Rhodes 2000; Bennick 2002; Charlton et al. 1996; Fickel et al. 1999; Hu et al. 2007; Luck et al. 1994;
Murray et al. 1994; Schenkels et al. 1995).
The astringency – characteristics of wine, tea etc. is associated specifically with the interaction
polyphenols with proline rich proteins. They have high affinity for tannins and can act as postingestive
countermeasures against dietary tannins. Proteins secreted in saliva can bind to dietary tannins in oral
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cavity in the first stage of digestion. Proline rich proteins form approximately 70% of the protein
content of saliva (Helmerhorst and Oppenheim 2007; Henson et al. 2004; Lawless et al. 1994; Lu and
Bennick 1998; Luck et al. 1994). Polyphenols inhibit digestive enzymes, stabilize collagen, block
several receptors and channels and reduce bioavailability of iron as potential metal chelators (Baxter et
al. 1997; Kim and Miller 2005; Madhan et al. 2005; Zhu et al. 1997). Multivalent cross-linking leads to
astringency – reduction of the lubricating power of saliva by precipitating salivary proteins and
dewetting of the mucosal surface. Astringency increases with repeated use (Cai et al. 2006, Cai and
Bennick 2006; Charlton et al. 1996, 2002; He et al. 2006; Jöbstl et al. 2006; Shimada 2006; Skopec
et al. 2004).
It was shown, that the affinity for tannins is inversely related to the size of the polymer, and peptides
with less than six residues interact very weakly with tannin. The specificity of interaction depends on
size, conformation and charge of the protein molecules. Tightly coiled globular proteins like
ribonuclease A, cytochrome C, lysozyme and myoglobin have much lower affinities for tannin than
conformationally loose proteins like bovine serum albumine and histone F1. Proanthocyanidins may
precipitate one protein in the presence of a large excess of another protein. The high affinity
interactions between proanthocyanidins and some proteins may protect the plant from pathogens or
predators (Dawra et al. 1988; Hagerman and Butler 1981).
Kandra et al. (2004) have shown that tannin (gallotannin) inhibited human salivary α-amylase. For this
reason, tannin is suggested to be tested for the prevention of dental caries as some reports suggested
that tea consumption reduces dental caries in experimental animals and humans.
The antidiarrhoeal effect of tannins: tri-
0
-galloyl-β-D-glucopyranose and penta-
0
-galloyl βD-
glucopyranose was tested on isolated colon of guinea pigs in a model of experimental diarrhoea with
water secretion stimulated by rhein perfusion (Verhaeren and Lemli 1986). Both tested tannins in a
concentration of 0.1% completely inhibited the secretory effect of rhein. The antidiarrhoeal activity of
gallotannins is attributed to the astringent action on mucosal proteins resulting in the formation of a
protective layer (Verhaeren and Lemli 1986).
Comparison of astringency of ellegitannins and complex tannins from
Quercus petrea
bark has shown
that relative potency of the oak bark ellagitannins (pedunculagin, vescalagin, stenophyllanin C,
acutissimin A, eugenigrandin A, guajavin B) is rather low in the range of 0.45 % of the astringency of
the bark (König et al. 1994). This weak activity can be explained by their rigid and inflexible structures
and limited ability to complex with proteins. The astringency of the crude herbal substance is mainly
due to its content of oligomeric proanthocyanidins (Pallenbach et al. 1993).
Gastroprotective activity
The mucosal cells are able to resist damage against exogenous and endogenous factors and epithelium
acts as a barrier to the passive diffusion of harmful substances (Martin and Wallace 2006). Tannic and
phenolic acids are reported to protect the stomach mucosa against toxicants and can prevent
gastrointestinal inflammation.
Using an experimental model of ethanol induced gastric damage in rats Gharzouli et al. (1999) have
shown that an aqueous extract of
Quercus ilex
root bark or tannic acid may be gastroprotective. When
given orally to rats (3.62 mg/ml total polyphenols, n=9-10)
Quercus ilex
root bark extract induced a
reduction on lesion number compared to water (n=9-10) control (7.3
1.4 vs. 16.3
1.7, p<0.05) and
ulcer index (35.3
9.4 vs. 67.7
7.3, p<0.05). Plant extracts (5 ml/kg) were given orally 60 min
before administration of 50% ethanol and rats were killed 15 min after ethanol treatment. Lesions
were photographed at about 2.3 magnifications and the ulcer index was determined according to a 6
grade scoring scale.
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Khennouf et al. (2003) reported gastroprotective effects of 25, 50 and 100 mg/kg of 70% acetone
extracts of
Quercus suber
and
Quercus coccifera
leaves and of tannins (50 mg/kg of pedunculagin,
castalgin, phillyraeoidin A and acutissimin B) given orally in the mouse ethanol-induced gastric ulcer
model (n=8-10). Extracts and tannins were suspended in 5% carboxymethyl cellulose (CMC) and
administered by gavage 1 h before 40% of ethanol. The control group (n=8-10) received CMC only.
Lesions were delimited manually using an image tool program and the number and total area of the
lesions were determined. The average number of lesions in the control group was 45.0
13.9 on area
of 12.1
3.0 mm
2
of mucosa. Both extracts tested diminished the number of lesions (pooled mean:
11.7
3.6 and reduced area of lesions (pooled mean areas of the lesions were 3.1
1.5 mm
2
for the
Q. coccifera and
2.5
1.6 mm
2
for Q suber extract (p<0.05). The protection varied between 68 -91%
and neither extract produced dose-dependent protection. Purified tannins (50 mg/kg) were also
protective and the percent protection varied between 66 to 83%. Castalgin was most potent, but there
were no significant differences between tannins tested (p>0.05). Authors conclude, that the
gastroprotective properties of Quercus extracts and isolated tannins might be related to their strong
antiperoxidant activity. However, a dose-response relationship was not investigated.
Antiulcer activity of ethanolic extracts of several Jordanian plants was tested by Alkofahi and Atta
(1999) on a gastric ulcer ethanol model in rats. All extracts were given orally in a dose of 400 mg/kg,
twice in a day preceding the experiment and a third time 90 min before induction of gastric ulceration
with ethanol 50% (10 ml/kg). The control rats received distilled water. The strongest antiulcer activity
was found with use of
Quercus coccifera
L. (curative ratio 99.5%) and with
Quercus aegilops
L.
(curative ratio of 97.4%).
Antiviral activity
The antiviral effect of octyl gallate against influenza and other RNA viruses were studied
in vitro
by
Yamasaki et al. (2007). They tested three different types of viruses: vesicular stomatitis virus VSV
(
Rhabdoviridiae
family), influenza virus (
Orthomyxoviridiae
family) and poliovirus (
Picornoviridiae
family). The infected cells were incubated overnight in medium containing varying concentrations of
octyl gallate. At the end of infection, the amounts of infectious progeny viruses were counted and were
normalized to the virus yield in the absence of the octyl gallate. Octyl gallate inhibited multiplication of
all tested viruses and in addition exhibited virucidal activity against enveloped viruses. The VSV virus
yield was less than one hundredth of that in the absence of octyl gallate at concentration 4
g/ml, for
this effect 20
g/ml concentration was required for influenza virus and poliovirus. The addition of octyl
gallate at 2 h post infection almost completely abolished the formation. of the progeny viruses of
influenza.
Octyl gallate also suppressed the multiplication of HSV-1 at early stages within 6 h p.i. in the infected
Hep-2 or Vero cells. Moreover it induced inhibition of the multiplication of RNA viruses, such as VSV
and poliovirus (Uozaki et al. 2007).
Several tannins exhibit significant HIV-reversal transcriptase inhibition
in vitro
. It is suggested, that
their antiviral activity is rather due to interference with virus-cell adhesion. However comprehensive
study on HIV and reverse transcriptase inhibition showed that activity of tannins in cell cultures is due
to their toxic features. It was concluded, that relevance of tannins as anti HIV prospective treatment is
greatly limited by their toxicity (Matthée et al. 1999).
Plausibility of several plants,
Quercus infectoria
included, was tested
in vitro
against HCV protease and
significant inhibiting activity was reported (Jassim and Naji 2003).
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Antibacterial activity
Tannins have been traditionally used as antimicrobial agents and their antibacterial activity and
antiseptic treatment has long been recognized (Cowan 1999; Haslam 2007). Their mode of
antimicrobial action may depend on inactivation of microbial adhesins, enzymes and cell envelope
transport proteins. They may also form complexes with polysaccharide molecules. According to
comprehensive review (Scalbert 1991) tannins can be toxic also to fungi and yeasts.
Tannic acid was proposed as a protein precipitating agent in genomic and plasmid DNA bacterial
preparations. Tannic acid as the prototypical gallotannin was chosen as a model system. It is
environmentally friendly and biodegradable (Van Huynh 2008).
Antimicrobial and oxidative activity of a methanol extract of Quercus robur bark (80% (v/v) methanol
solution in water) were tested using agar diffusion method on
Staphylococcus aureus
,
Enterobacter
aerogenes
and
Candida albicans
(Andrenšek et al. 2004). Extracts were prepared using a stepwise-
gradient for preparative separation. Extracts of the oak bark were prepared by performing the
extraction three times with each extraction solvent successively before the extraction solvent of higher
polarity was applied. The total extractable dry matter from the bark was 8%. The substance related to
the activity of the fractions was screened simultaneously by thin layer chromatography (TLC) and
estimation of antioxidant activity. Extracts 10 and 12 [50% (v/v) MeOH in ethyl acetate] and extracts
16 and 18 [75% (v/v) MeOH in water] were bactericidal for
Staphylococcus aureus
. The less polar
extracts (75% ethyl acetate in
n
-hexane, 100% ethyl acetate and 5% MeOH in ethyl acetate; extracts
1-9) and 5% were bacteriostatic against Gram negative
Enterobacter aerogenes
and the yeast
Candida
albicans.
Extract 10 (95%MeOH in ethyl acetate) was bacteriostatic against
Enterobacter aerogenes.
The active substances against
Staphylococcus aureus
and against
Enterobacter aerogenes
and
Candida
albicans
were in lipophilic extracts.
Kolodziej et al. (1999) studied
in vitro
antimicrobial potency of 27 pure tannins and related
compounds. The chemotherapeutic activity was evaluated against
Bacillus subtilis
,
Staphylococcus
aureus
,
Escherichia coli
,
Klebsiella pneumoniae
,
Psedomonas aeruginosa
,
Proteus mirabilis
and yeasts:
Candida albicans
and
Cryptococcus neoformans
. Only weak to moderate antibacterial activity of tested
tannins was detected, but the activity against
Cryptococcus neoformans
was found quite potent for
gallic acid: MIC (minimal inhibitory concentration) = 250
g/ml) and hydrolyzable tannins: corilagin
(MIC = 250
g/ml) and phyllantusiin C (MIC = 125
g/ml).
The antimicrobial activities of
Quercus ilex
L. extracts were tested
in vitro
(Güllüce et al. 2004).
Quercus ilex
is an evergreen Mediterranean plant species used as a folk remedy to treat
haemorrhages, chronic diarhoea and dysentery. A total of 55 human and plant bacteria, one yeast and
four fungi were used in this study. The dried plant extracts were dissolved in methanol to a final
concentration of 30 μg/ml. The extracts of
Quercus ilex
showed antibacterial effects against 35
bacterial strains tested on disc diffusion method:
Brucella
,
Enterobacter
,
Escherichia
,
Neisseria
,
Pseudomonas
and
Bacillus
and
Candida albicans.
Quite potent antibacterial effects were shown against
Escherichia coli
(MIC – 16 μg/ml). Negative control with methanol did not show any influence on
diameter of inhibition zone.
Molochko et al. (1990) examined antistaphylococcal properties of plant extracts against several strains
of
Staphylococcus aureus
,
Staphylococcus epidermidis
and
Staphylococcus saprophyticus.
The most
active was a water/alcohol extract of oak bark.
Berahou et al. (2007) examined antibacterial activity of extracts of
Quercus ilex
L. bark. Plant material
was extracted with methanol (35.97%, w/w), dissolved in hot distilled water and successively
extracted with n-hexane, dichloromethane, ethyl acetate and n-butanol. Each extract was dried under
sodium sulphate and reduced to give: hexane extract (1.74%, w/w), ethyl acetate extract (1.5%,
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w/w), butanol extract (16.05%, w/w) and final aqueous layer (16.36%, w/w). Evident antibacterial
activity was reported against all tested strains for ethyl acetate,
n
-butanol, and final aqueous extracts
with MIC ranging from 128 to 512 μg/ml. The tested reference bacteria strains were:
Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Proteus mirabilis,
Klebsiella pneumoniae, Bacillus subtilis, Salmonella typhimurium, Vibrio cholerae, Streptococcus
pyogenes
and
Streptococcus agalactiae.
Akiyama et al. (2001) performed studies on the antibacterial action of several tannins against
Staphylococcus aureus
. They examined influence of tannins on plasma coagulation by
Staphylococcus
aureus
and the effect of conventional chemotherapy combined with tannic acid below the MIC. All
tannins inhibited coagulation below the MIC. Coagulation was significantly inhibited in plasma
containing tannic acid (100 mg/l, gallic acid (5000 mg/l), ellagic acid (5000 mg/l), (-)-epicatechin
(1500 mg/l), (-)-epicatechin gallate (500 mg/l) or (-)-epigallocatechin gallate (200 mg/l) after
incubation for 24 h. Also the MICs of oxacillin and cefdinir for
Staphylococcus aureus
were reduced to
0.06 mg/l with tannic acid (100 mg/l) at a concentration below MIC. These results indicate the
possibility of treatment of
Staphylococcus aureus
skin infections with tannic acid as adjuvant agent in
addition to beta-lactam antibiotics. Tannic acid at a sub-MIC concentration presents useful topical
application in
in vivo
conditions.
Voravuthikunchai and Kitpit (2005a; 2005b) investigated antibacterial effects of aqueous and ethanolic
extracts of several plants including
Quercus infectoria
against hospital isolates of methicillin-resistant
Staphylococcus aureus
(MRSA ATCC 25923). Aqueous and ethanolic extracts of
Quercus infectoria
showed activity against all MRSA isolates, with MICs of 0.2 – 0.4 mg/ml. It should be investigated if
Quercus infectoria
extracts might provide a new treatment effective against multiresistant
Staphylococcus aureus
infections.
Voravuthikunchai et al. (2006) tested the effects of ethanolic extracts of
Punica granatum
and
Quercus
infectoria
on 10 clinically isolated
Helicobacter pylori
strains. Both extracts were strongly effective
against
Helicobacter pylori
in the range of MIC from 0.78 to 6.25 and 3.12 to 6.25 mg/ml respectively.
There was no resistance to these extracts found in any isolates, irrespective of their antibiotic
resistance.
Aqueous and ethanolic extracts of 38 medicinal plants were used against enterohaemorrhagic
Escherichia coli
0157:H7 (Voravuthikunchai et al. 2004). The greatest inhibition zone was produced
from the ethanolic extract of
Quercus infectoria
with the MIC values of 0.09 mg/ml and MBC (minimal
bactericidal concentration) values of 0.78 mg/ml.
Limsuvan et al. (2005) tested an ethanolic extract of
Quercus infectoria
with E. coli 0157:H7 strain
with MIC values of 0.09 to 0.78 ng/ml. However no correlation was found between MIC and cell
aggregation.
Park et al. (2006) examined extracts from nine types of Korean oak trees (
Castanopsis cuspidata var.
sieboldii, Quercus acuta, Quercus acutissima, Quercus aliena, Quercus dentata,
Quercus ogilva,
Quercus glauca, Quercus salicina
and
Quercus serrata
) to determine their antibacterial activity against
Microcystis aeruginosa
. The most potent extracts of
Quercus
:
salicina, acuta, gilva
and
acutissima
,
inhibited the growth of M. aeruginosa by approximately 50% at 20 mg/l.
Antiprotozoan activity
Gallic acid was shown to have trypanocidal effects
in vitro
both against the bloodstream forms and
procyclic forms of
Trypanosoma brucei
(Koide et al. 1998). LD
50
values of gallic acid are 46.96
1.28
μM for bloodstream forms and 30.02
3.49 for procyclic forms. The authors suggest that the
pyrogallol moiety could be responsible for this activity.
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Antifungal activity
Hwang et al. (2001) reported the inhibitory activity for chitin synthase II from
Saccharomyces
cerevisiae
by tannins and related compounds. Seven tannins and related compounds identified as gallic
acid, methyl gallate and others inhibited chitin synthase II, with most potent activity of 3-
O
-galloyl-(-)-
shikimic acid (IC
50
value of 18 μM). Gallic acid, methyl gallate and ellagic acid have had IC
50
values
206, 87 and 149 μM, respectively.
Fungicidal activity of oils obtained by oak bark pyrolysis at temperature 400 – 450
o
C were tested
against brown rot fungus (
Gleophyllum trabeum
) and white-rot fungus (
Trametes
versicolor
) (Mohan et
al. 2008). The pyrolytic lignin-rich fractions consisted mainly of phenols and neutrals. The lignin-rich
fractions showed stronger fungal inhibition (45 – 58 kg/m
3
)
than whole bio-oils for an impregnation
solution of 10% concentration level.
Antiparasitic activity
Extracts of several plants including
Quercus robur
were tested
in vivo
by Paolini et al. (2004) against
nematodes living in small ruminants:
Teladorsagia circumcinta
,
Haemonchus contortu
s and
Trichostrongylus colubriformis
. Crushed oak bark (5 g) was extracted by 100 ml of water at 90
0
C for 2
h. The filtrate was concentrated to obtain dried powdered sample. Powders were dissolved in
phosphate-buffered saline and serially diluted immediately prior to incubation.
T. circumcinta
and
T.
colubriformis
extracts of oak bark significantly reduced migration of the larvae (1200
g/ml, p<0.01).
After incubation with oak bark extract (1200
g/ml) significant reduction of motility was only noted for
adult worms of
T. colubriformis
(p<0.01). Results confirmed that tannins were the source of inhibition
of motility of the 3
rd
-stage larvae and adult worms and could represent an alternative choice to
chemotherapy.
Antioxidant activity
Chen et al. (2007) showed protective activity of tannic acid, gallic acid, ellagic acid and propyl gallate
against reactive oxygen species (ROS) using human lung fibroblast IMR-90 cells model. All compounds
were incubated at concentration of 10
g/ml and alleviated H
2
O
2
-induced lipid peroxidation.
Compounds were also tested against the depletion of intracellular glutathione. When IMR-90 cells were
pretreated with 10
g/ml propyl gallate, it was demonstrated to be the only compound successfully
preventing depletion of GSH. Results of the study suggested, that tested compounds can protect cells
from oxidative stress.
Anticancer activity
Pan et al. (1999) showed induction of apoptosis by penta-
O
-galloyl-β-D-glucose through activation of
caspase-3 in human leukemia HL-60 cells. Penta-
O
-galloyl-β-D-glucose induced apoptosis in a
concentration and time dependent manner. HL-60 cells were incubated with different doses (5, 10, 20,
30, 40, 50 and 100
M) of penta-
O
-galloyl-β-D-glucose. The percentage of apoptotic HL-60 cells was
2.89%, 2.47%, 2.86%, 8.25%, 46.99% and 64.08% after 0, 3, 6, 12, 18 and 24 h of incubation with
penta-
O
-galloyl-β-D-glucose (50
M), respectively. The apoptosis potency of penta-
O
-galloyl-β-D-
glucose is correlated to its cancer chemopreventive efficacy in animal models.
Sehrawat et al. (2006) reported preventive effects of tannic acid on 2-acetylaminofluorene (2-AAF)
mediated hepatic oxidative stress and cell proliferation in rats. Treatment of rats with tannic acid (125
and 250 mg/kg bw) resulted in significant increase of glutathione hepatic levels, increase of
antioxidant activity and phase-II metabolizing enzymes as compared to saline treated control.
Inhibition of electrophilic species – significant decrease in lipid peroxidation, xanthine oxidase and
hydrogen peroxide generation was also reported. The tumor promotor markers parameters (ornithine
decarboxylase activity and DNA synthesis) were dose-dependently decreased.
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Influence on Angiotensin Converting Enzyme Activity (ACE)
Uchida et al. (1987) examined the effects of condensed tannins on angiotensin converting enzyme
activity. Procyanidin B-5 3.3’-di-
O
-gallate and procyanidin C-1 3.3’- di-
O
-gallate strongly inhibited
activity of the ACE enzyme. The IC
50
values for procyanidin B-5 3.3’-di-
O
-gallate and procyanidin C-1
3.3’- di-
O
-gallate were 1.3 and 1.7 x 10
-6
respectively. For inhibition of other proteases: trypsin,
chymotrypsin, leucine aminopeptidase, carboxypeptidase A and urinary kallikrein over one hundred
times the concentration was required.
Influence on the nervous system
The effects on central nervous activity of extracts of galls of
Quercus infectoria
were studied by Dar et
al. (1976) and Dar and Ikram (1979). The methanolic fraction of galls which has been identified as
syringic acid exhibited significant local anaesthetic (1 2% solution), analgesic and central depressive
activity in mice (doses of 250 and 500 mg/kg). Galls of
Quercus infectoria
are reported to contain also
ellagic acid and gallotannins.
The effects of tannic acid were shown by Takahashi et al. (1986). Tannic acid dose dependently (10 -
100 mg/kg) reduced abdominal constrictions in mice (writhing analgesic model induced by i.p. injection
of 0.6% acetic acid), increased nociceptive threshold measures by the hot-plate test and potentiated
pentobarbital sleeping time. Tannic acid (100 mg/kg) significantly inhibited locomotor activity in mice.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data are available concerning oak bark pharmacokinetics due to its complex phytochemical
composition.
The metabolism of polymeric proanthocyanidins by human colonic microflora has been investigated
in
vitro
in anoxic conditions
using
14
C-labelled purified proanthocyanidin (Déprez et al. 2000). Polymers
were degraded after 48 h of incubation. As metabolites, low-molecular-weight aromatic compounds:
phenylacetic, phenylpropionic and phenylvaleric acids were recognized by gas chromatography. The
results show, that proanthocyanidins can be metabolized by the colonic microflora into low-molecular-
weight aromatic acids.
Evaluation of polyphenol bioavailability was tested
in vitro
in isolated segments of the rat small
intestine (Carbonaro et al. 2001). As model compounds, tannic acid and catechin were used. The
results indicated a significant, concentration-dependent uptake of both compounds by the small
intestinal wall. Higher uptake (50%) was recorded for tannic acid compared with catechin (30%).
However, only catechin demonstrated a complete transfer through the gut wall, whereas tannic acid
remained in the gut wall via interaction with wall proteins. Both polyphenols were bound significantly
by proteins in the intestinal lumen.
Interactions
Incubation of isolated human serum proteoglycans, which play an important role in cell adhesion and
communication, with tannic acid and tannins, caused a dose dependent decrease in glycan content.
Tannic acid was more active than oak tannins (Savolainen 1997).
Oak bark (
Quercus petrea
) aqueous methanol extracts enhanced stability of casein micelles: increased
the heat stability of skim milk (at 140
0
C) and concentrated milk (at 120
0
C) and retarded rennet
coagulation
in vitro
(O’Connell and Fox 1999).
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Overview of pharmacokinetics
Due to lack of data on pharmacokinetics of oak bark no conclusions can be drawn. Tannic acid seems
to be retained in the gut lumen and wall after peroral administration, whereas for catechin a partial
absorption could be demonstrated.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Genotoxicity
No published data could be found on the genotoxicity of oak bark and on the oak bark preparations.
In the Ames test, Weissmann and al. (1989) did not observe any mutagenic activity of lipophilic
extracts of oak heartwood (
Quercus robur
) prepared step by step by petroleum/ether, aceton/water,
ethanol/water and water extraction. Extracts consisted of wax-like esters and free acids: gallic acid,
ellagic acid, ω-hydroxy fatty acids, cis- and trans-ferulic acid.
Oak tannins are genotoxic in cultured human embryonic MRC-5 lung cells (Zhou et al. 1995). Authors
evaluated the ability of solvent extracts of natural woods to induce chromosome aberrations. In
experiments three concentrations per extract with or without metabolic activation and 100 metaphase
cells were examined. No dose dependent activity was found with tested extracts in the presence of S9,
but dose-dependent chromosomal and chromatid breaks were caused by oak wood. No metabolic
activation was required for their effect.
Labieniec and Gabryelak (2003) showed that tannic, ellagic and gallic acids have genotoxic and
cytotoxic properties in Chinese hamster cell line B14 when using the Comet assay for detection of DNA
damage. Tannic, ellagic and gallic acids were exposed at concentration range of 15 – 240 μM. Tannins
decreased viability of the cells, with highest cytotoxicity at the concentration of 60 μM. The formation
of DNA single-strand breaks was observed.
Carcinogenicity
No published data could be found on the carcinogenicity of the oak bark and the oak bark preparations.
The International Agency for Research on Cancer (IARC) has evaluated the potential carcinogenicity
risk of wood dust exposures. It was observed, that wood dust exposure (mixture of oak, beech and
pine wood) significantly enhanced the incidence of neoplasia. Occupational sinonasal cancer risk is
associated with inhalation exposure to hardwood dust, although constituents responsible for
carcinogenicity are not known. Components of bark and sapwood in comparison with heartwood may
display both qualitative and quantitative differences. Moreover the studies of wood dust and cancer
lack quantitative exposure data. Due to the complex nature of the exposure it has not been possible to
prove the causal relationship.
Acute toxicity
No studies on acute toxicity have been performed with oak bark or oak bark preparations.
Acute toxicity (LD
50
) of tannic acid given intragastrically to rats was found to be 2.26
0.083 g/kg body
weight. Death was associated with hepatic necrosis and nephritis and acute gastroenteritis (Boyd et al.
1965).
In humans fatal liver damage after barium enemas containing 0.25% tannic acid were described in 5
adult patients. They died with symptoms of fulminating acute liver failure. Autopsy findings showed
hemorrhagic central necrosis of liver lobules (Anonymus 1964; Lucke et al. 1963).
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Oak leave toxicosis in ruminants
As hydrolysable tannins are considered to present greater risk to health, several cases of acute
poisonings of ruminants were noted due to ingestion of fresh leaves of several oak species.
Severe toxicosis in cattle was observed in Europe (
Quercus robur
), in China (6 different Quercus
species) and in USA (
Quercus havardii
,
Q. breviloba
,
Q. gambelli
). Oak poisoning occurred in cattle due
to consuming for 2 days immature oak leaves of
Quercus incana
in India (Garg et al. 1992; Reed
1995). Mortality was 70%. The cattle exhibited anorexia, constipation, depression and respiratory
distress. Significant decreases of blood hemoglobin and elevations in serum bilirubin were seen.
Symptoms of renal and hepatic damage were observed. There was bilirubinuria, proteinuria, and
increased activities of serum aspartate aminotransferase, lactate dehydrogenase and alkaline
phosphatase. The poisoning may be due to hydrolysable tannins and simple phenols. The levels of
tannins and condensed tannins were 97.7 mg tannic acid equivalent and 5.8 mg catechin equivalent/g
of dry leaves.
Toxicity of oak leaves (
Quercus robur
) was studied in 2 moose which were given oak leaves harvested
in June intraruminally by stomach tube for ten days. The daily dose was 58 g (30% dry matter) of oak
leaves per kg. This dose was above the maximum daily intake. There were no signs of disease in post-
dosing periods (Flaoyen et al. 1999).
Oak toxicosis cases in cattle were also registered in northern California. In April 1985 2700 cattle in
northern California died of oak toxicosis. After snow and freezing weather the cattle ingested toxic
amounts of oak buds (
Quercus douglassi
). Acute toxicosis was charcterized by diffuse renal damage,
gastrointestinal ulceration ascites, hydrothorax and hepatic necrosis. The toxicity was attributed to the
high concentration of gallotannins hydrolyzed in the rumen to gallic acid, pyrogallol, resorcinol and
several small phenolic molecules. Absorbed tannins bind to plasma proteins and to the endothelium of
blood vessels. This results in hemorrhages, edema and renal tubular necrosis (Spier et al. 1987).
Experimental toxicosis in two calves given immature blue oak (
Quercus douglassi
) leaves in spring
tested for gallic acid content (Plumlee et al. 1998). The oak leaves contained 1,542 ppm of gallic acid.
They consumed voluntarily oak leaves for 7 days (approximately 1.9, 2.7, 0.9, 1.4, 1.6, 0.7 and 0.2 kg
respectively). They refused to eat the oak leaves after day 7. Necropsy findings revealed perirenal
oedema, ascites and severe nephrosis with secondary nephritis. Commercial tannic acid (45% gallic
acid) was given orally for seven days (67, 94, 31, 49, 55, 24, and 7 mg/kg respectively on days 1 – 7).
Neither calf developed any abnormalities throughout the experiment.
Oak toxicosis in sheep was presented by Derakhshanfar et al. (2008) after experimental consumption
in sheep oak acorns of
Quercus brantii
(2.2 kg/day for 20 days). After the end of the experiment,
autopsy revealed mild hepatic fibrosis, lymphocytic hepatitis and interstitial nephritis as symptoms of
oak poisoning.
Repeated dose toxicity
No studies on repeated dose toxicity have been performed with oak bark or oak bark preparations.
To investigate the response of pancreas to tannins and changes in activities of enzymes in the lumen
of the small intestine, broiled cockerels were fed on increasing levels of tannin-containing diet (Ahmed
et al. 1991). The birds were fed with a diet consisted mainly of hydrolysable gallotannins for 4 weeks
at levels of 13.5, 25 and 50 g/kg. Weight of pancreas was significantly increased with increasing dose
of tannins. Activity of trypsin and α-amylase was also dose-dependently increased. Activities of
dipeptidase and sucrose α-glucosidase (disaccharidase) in the intestinal mucosa were inhibited. Growth
of the birds fed on tannins diet was adversely affected.
Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus
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EMA/HMPC/3206/2009
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Assessor’s overall conclusions on toxicology
Practically no toxicity studies on oak bark or oak bark preparations are available in the literature.
Tannins, which are considered as major therapeutically active compounds, are detectable in the bark of
oak species, in immature fruits and also in tea, coffee, cocoa and wine. The ability of tannins to form
strong complexes with proteins is considered as their most important activity for both therapeutic and
toxicological effects. Hydrolysable tannins are potentially toxic to ruminants. The acute cases of sheep
and cattle poisonings are associated with the consumption of oak leaves.
In Europe the toxicity occurs mainly due to
Quercus robur
, in America due to
Quercus havardii
,
Quercus breviloba
and
Quercus gambelli
ingestion. In China many lethal cases in animals are
registered due to ingestion of several different oak species.
Bacterial tannases hydrolyze galloyl esters to release gallic acid which is further metabolized by
bacteria to pyrogallol and other low-molecular-weight phenols.These substances are absorbed and
could cause necrosis of the liver and proximal tubular damage in the kidney. The toxic compound is
suggested to be tannic acid, pyrogallol or resorcinol.
Nasal cancer risk associated with occupational exposure to wood dusts via inhalation cannot be applied
to the oral use of oak bark preparations.
Due to the lack of data on acute and chronic toxicity, repeated dose toxicity, mutagenicity,
carcinogenicity, reproductive and developmental toxicity, a list entry for
Quercus cortex
cannot be
recommended.
3.4.
Overall conclusions on non-clinical data
Experimental preclinical data presenting astringent, gastroprotective, antibacterial and antiviral activity
of oak bark confirm long tradition and support plausibility of its therapeutic use.
Antifungal, antiprotozoan, antiparasitic, anticancer and other effects could be demonstrated when
single active constituents of oak bark were assayed. A general conclusion for oak bark cannot be
drawn.
The published data on pharmacological activities support the traditional use of preparations containing
oak bark in the proposed indications.
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
There are no data on human pharmacodynamics.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
There are no data on human pharmacokinetics.
Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus
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4.2.
Clinical Efficacy
4.2.1.
Dose response studies
There are no specific data available on dose-response studies.
4.2.2.
Clinical studies (case studies and clinical trials)
Observational studies.
In dermatological therapy oak bark is recommended for topical treatment of wounds as astringent,
helping to dry oozing and bleeding (Grimme and Augustin 1999). It is also used in treating dermatitis
by coagulating surface proteins of cells and reducing permeability and increased secretion in
inflammatory conditions. The precipitated proteins form a protective layer on the skin and have
antimicrobial properties (Bedi and Shenefelt 2002).
For the same purpose synthetic tannins are used in dermatology, frequently in neonates and children
(Fölster-Holst et al. 2007).
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No information available.
4.3.
Overall conclusions on clinical pharmacology and efficacy
There are no data available from controlled clinical studies; therefore the medicinal use of oak bark has
to be regarded as traditional.
Administration of preparations of oak bark can be regarded as safe and justified, especially at
therapeutic doses, concentrations and short time of use.
5.
Clinical Safety/Pharmacovigilance
There are no adverse effects reported from the Member States, however allergic reactions to
Fagaceae
family should be considered.
5.1.
Overview of toxicological/safety data from clinical trials in humans
There are no data from clinical trials available.
5.2.
Patient exposure
None reported.
5.3.
Adverse events and serious adverse events and deaths
Allergy
Sensitisation to pollen of
Quercus ilex
and
Quercus robur
was found in two patients suffering from
rhinoconiunctivitis and seasonal bronchial asthma between April and June. Specific IgE to
Quercus ilex
and
Quercus robur
and coniunctival challenge test to
Quercus robur
pollen was positive in two patients
(Bartra et al. 2004).
Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus
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Akhapkina and Zheltikova (2004) reported cross reactivity to pollen allergens from birch (
Betula
pendula
), hazel (
Corylus avelana
), alder (
Alnus glutinosa
), wormwood (
Arthemisia
absintium
), ash tree
(
Fraxinus excelsior
) and oak (
Quercus robur
).
Bronchial hyperresponsiveness and symptomps of asthma were associated with exposure of workers at
wooden furniture factories on beech (
Fagus
sp.) and oak (
Quercus
sp.) (Bohadana et al. 2000).
Cumulative exposure to dust was calculated for each worker by multiplying the duration of the work by
the intensity of exposure (years.mg/m
3
). The median cumulative exposure to dust was 110
years.mg/m
3
. Dose-response relationship was found between intensity of exposure, sore throat and
increased prevalence of positive metacholine bronchial challenge tests.
A single case of anaphylactic reaction to
Quercus ilex
acorn nut was investigated by Vega et al. (1998).
The acorn is edible, but is more used in animal feed than in human diet. The patient with previous
history of allergy (urticaria) to peanuts ingestion presented generalized urticaria, vomiting, diarrhoea,
angioedema, dizziness and hypotension. Skin-prick tests were positive for acorn and peanut, but also
for oaks (
Quercus robur
and
Quercus alba
).
Anaphylaxis by fruits of the
Fagaceae
family: acorn and chestnut were presented by Zapatero et al.
(2005). A 4 year old boy developed immediately after peeling and eating an acorn of
Quercus ilex
the
ocular itching, lip angioedema, unproductive cough, wheezing and dyspnea. Prick results were positive
for
Quercus ilex
and
Castanea sativa.
5.4.
Laboratory findings
No data available.
5.5.
Safety in special populations and situations
Intrinsic (including elderly and children)/extrinsic factors
There are no reports of use of oak bark in children. The use of oak bark is not recommended in
children younger than 12 years of age.
Use in pregnancy and lactation
The oak bark should not be used during pregnancy and lactation.
None reported.
Drug interactions
None reported for oak bark preparations. However, it is reported in literature that oak bark ingestion
causes reduction or inhibition of absorption of some alkaloids or alkaline drugs (Hänsel et al 1994;
(BAZ) No 22. 01.02.1990; Mills and Bone 2000; PDR for Herbal Medicines 2000, 2004; Poppenga
2002). Some authors mention that tannins may also interfere with iron absorption. Detailed studies are
necessary to clarify if this is a concern. For safety reasons it seems reasonable to avoid taking iron and
herbal preparations of oak bark together (Miller 1998, Mills and Bone 2000). However it is not clear,
whether these findings have definitely consequences on the medical use of oak bark.
Effect on ability to drive or operate machinery or impairment of mental ability
None reported.
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5.6.
Overall conclusions on clinical safety
There are no reports of adverse effects of oak bark from Member States.
The allergic reactions in patients allergic to Fagaceae should be considered.
6.
Overall conclusions
The available data are sufficient to include the traditional use of specified preparations of oak bark in a
Community herbal monograph. Oak bark fullfils the requirement of therapeutic use for at least 30
years (15 years within the European Union, Directive 2004/24/EC).
Indications for treatment: 1) Traditional herbal medicinal product for symptomatic treatment of mild
diarrhoea, 2) Traditional herbal medicinal product for symptomatic treatment of minor inflammation of
the oral mucosa or skin. 3) Traditional herbal medicinal product for symptomatic relief of itching and
burning associated with haemorrhoids after serious conditions have been excluded by a medical doctor.
The HMPC concluded that prior to using oak bark in symptomatic self-medication by haemorrhoid
patients, serious conditions should be excluded by a medical doctor.
Hemorrhoids are a common chronic condition with symptoms that include
rectal bleeding
, protrusion,
and itching. Because other conditions (
diverticulitis, vascular ectasias
,
colorectal cancer, colitis and
megacolon)
can lead to identical symptoms,
a
professional careful
rectal examination and
proctosigmoidoscopy
is justified for any patient who reports hemorrhoids.
Only medical doctors,
gastroenterologists and surgeons are qualified to accurately diagnose hemorrhoids and offer a
consequent, competent treatment plan.
Due to the lack of data on acute and chronic toxicity, repeated dose toxicity, mutagenicity,
carcinogenicity, reproductive and developmental toxicity, a list entry for
Quercus cortex
can not be
recommended.
Benefit/risk assessment
Oak bark is a subject of a European Pharmacopoeia monograph.
There are no concerns about serious side effects or interactions with oak bark preparations.
There are reported side effects concerning gastrointestinal reactions and allergic reactions due to the
oak bark preparations used. No serious adverse events with a therapeutic posology of the herbal
preparations are reported.
Despite limited toxicological data, levels of exposure associated with the use of oak bark, either by oral
or topical route of administration for limited times; most probably do not result in any significant risk
to human health.
It can be concluded that the benefit/risk assessment for oak bark preparations is positive for use in
therapeutical dosages in specific conditions of mild diarrhoea, in minor inflammatory conditions of the
oral mucosa or skin and in conditions of medically diagnosed haemorrhoids before anorectal use.
Annex
List of references
Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus
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EMA/HMPC/3206/2009
Page 23/23
Source: European Medicines Agency
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