Community herbal monograph on
Arctostaphylos uva-ursi
(L.) Spreng., folium
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
Arctostaphylos uva-ursi
(L.) Spreng., folium
(bearberry leaf)
i) Herbal substance
Not applicable.
ii) Herbal preparations
a)
Comminuted herbal substance
b)
Powdered herbal substance
c)
Dry extract (DER 3.5-5.5:1), extraction
solvent ethanol 60% (V/V), containing 23.5-
29.3% of hydroquinone derivatives calculated
as anhydrous arbutin (spectrophotometry)
d)
Dry extract (DER 2.5-4.5:1), extraction
solvent water, containing 20-28% of
hydroquinone derivatives calculated as
anhydrous arbutin (spectrophotometry)
Well-established use
Traditional use
Herbal preparations in solid dosage forms or as
herbal tea for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1 The material complies with the Ph. Eur. monograph (ref.: 04/2008:1054).
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
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573460/2009
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4.1.
Therapeutic indications
Well-established use
Traditional use
Traditional herbal medicinal product used for
treatment of symptoms of mild recurrent lower
urinary tract infections such as burning sensation
during urination and/or frequent urination in
women, after serious conditions have been
excluded by a medical doctor.
The product is a traditional herbal medicinal
product for use in the specified indication
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Female adults and elderly
a) Herbal tea
1.5-4 g of the comminuted herbal substance in
150 ml of boiling water as an infusion,
2 to 4 times daily corresponding to the
maximum daily dose of 8 g.
1.5-4 g of the comminuted herbal substance in
150 ml of water as a macerate, 2 to 4 times
daily corresponding to the maximum daily dose
of 8 g.
The macerate should be used immediately after
preparation.
Herbal preparations b), c), d)
Single dose corresponding to 100-210 mg of
hydroquinone derivatives calculated as
anhydrous arbutin (spectrophotometry),
2 to 4 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’).
The use in men is not recommended (see section
4.4 ‘Special warnings and precautions for use’).
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Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573460/2009
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Duration of use
Not to be used for more than one week.
If the symptoms persist for more than 4 days or
worsen during the use of the medicinal product, a
doctor or a qualified health care practitioner
should be consulted.
Method of administration
Oral use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Kidney disorders.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under 18
years of age has not been established due to lack
of adequate data.
The use in men is not recommended because of
concerns requiring medical advice.
If complaints or symptoms such as fever, dysuria,
spasms, or blood in urine occur during the use of
the medicinal product, a doctor or a qualified
health care practitioner should be consulted.
Uvae ursi folium may cause a greenish-brown
coloration of the urine.
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
None reported.
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Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573460/2009
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4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
The use should be avoided during pregnancy (see
section 5.3 ‘Preclinical safety data’).
In absence of sufficient data, the use during
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.
4.8.
Undesirable effects
Well-established use
Traditional use
Nausea, vomiting, stomach-ache have been
reported.
The frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
Community herbal monograph on
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573460/2009
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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.
Available tests on genotoxicity of water and
ethanolic extracts of Uvae ursi folium are
inadequate. Reproductive toxicity has not been
studied. Available carcinogenicity studies have
been negative.
Arbutin, the principal component of Uvae ursi
folium, displayed some maternal and fetal toxicity
in rats after subcutaneous administration of 400
mg/kg/day. No effect on reproduction has been
observed at doses of 100 mg/kg/day.
Toxicity tests with hydroquinone, a hydrolysis
product of arbutin, have demonstrated some
evidence of genotoxicity and carcinogenicity. Risks
posed by the exposure of hydroquinone during the
short-term treatment with Uvae ursi folium
preparations are considered minimal.
Well-established use
Traditional use
Not applicable.
31 March 2011
Community herbal monograph on
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573460/2009
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Assessment Report
Table of contents
Assessment report on
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
Page 2/32
1. Introduction
1.1. Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Bearberry leaf (Uvae ursi folium) consists of whole or cut, dried leaf of
Arctostaphylos uva-ursi
(L.)
Spreng. It contains not less than 7.0% of anhydrous arbutin (C
12
H
16
O
7
;
M
r
272.3), calculated with
reference to anhydrous drug (European Pharmacopoeia)
Herbal preparation(s)
A) Comminuted herbal substance for herbal tea preparation
B) Powdered herbal substance
C) Dry extract (DER 3.5-5.5:1), extraction solvent ethanol 60% (V/V)
D) Dry extract (DER 2.5-4.5:1), extraction solvent water
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.
Herbal teas
Species anticystiticae: Betulae folium 20 parts, Uvae ursi folium 20 parts, Maydis stylus 20 parts,
Liquiritiae radix 20 parts, Graminis rhizoma 20 parts (Pharmacopoea Helvetica V, 1953)
Species anticystiticae: Betulae folium 25 g, Liquiritiae radix 30 g, Uvae ursi folium 45 g (Pharmacopoea
Helvetica VII (1993)
Species urologicae: Uvae ursi folium 35 parts, Herniariae herba 35 parts, Betulae folium 30 parts
(Österreichisches Arzneibuch 9, 1960)
Blasen- und Nierentee II: Uvae ursi folium 35 – 50%, Betulae folium 10 – 20%, Phaseoli fructus sine
semine 10 – 20%, Equiseti herba 10 – 30% (Standard Zulassungen, 1996)
Blasen- und Nierentee IV: Uvae ursi folium 35 – 50%, Ononidis radix 10 – 25%, Orthosiphonis folium
15 – 30%, Equiseti herba 10 – 30% (Standard Zulassungen, 1996)
Blasen- und Nierentee V: Uvae ursi folium 35 – 50%, Phaseoli fructus sie semine 10 – 20%,
Solidaginis or Solidaginis virgaureae herba 10 – 25%, Orthosiphonis folium 15 – 30% (Standard
Zulassungen, 1996)
Blasen- und Nierentee VII: Uvae ursi folium 35 – 50%, Betulae folium 15 – 25%, Graminis rhizoma 15
– 25% (Standard Zulassungen, 1996)
Urologicae species: Betulae folium 30 g, Uvae ursi folium 30 g, Herniariae herba 5 g, Menthae piperitae
herba 15 g, Ononidis radix 10 g, Petroselini radix 10 g (Slovenský farmaceutický kódex 1, 1997)
Combination teas reported by the Member States:
- Uvae ursi folium, Juniperi fructus, Betulae folium, Equiseti herba, Solidaginis herba, Orthosiphonis
folium (DK)
- Uvae ursi folium, Equiseti herba, Myrtilli herba, Chamomillae flos, Sambuci flos, Solidaginis herba,
Thymi herba (SK, CZ)
- Urticae folium, Uvae ursi folium, Betulae folium, Juniperi pseudo-fructus pulvis (HU)
- Betulae folium, Uvae ursi folium, Ononidis radix, Petroselini radix, Polygoni avicularis herba, Sambuci
nigrae flos, Urticae herba, Millefolii herba (CZ)
- Betulae folium, Uvae ursi folium, Herniariae herba, Menthae piperitae herba, Ononidis radix,
Petroselini radix (CZ)
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Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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Other combination products reported by the Member States
- Uvae ursi folii extractum 5:1, Taraxaci radicis cum herba extractum 5:1 - tablets (DK, NO)
- Uvae ursi extractum, Solidaginis giganteae herbae extractum, Orthosiphonis folii extractum -
tablets (DK)
- Extract of Solidaginis herba, Betulae folium, Cerasi stipites, Equiseti herba, Uvae ursi folium,
extraction solvent ethanol 45% V/V – oral liquid (HU)
- Extract of Uvae ursi folium, Urticae radix, Salviae officinalis folium, Betulae folium, Salicis cortex,
Millefolii herba, Urticae folium, extraction solvent ethanol 24% V/V – oral liquid (HU)
- Extract of Urticae radix, Salviae folium, Uvae ursi folium, Cucurbitae semen, Betulae folium, Salicis
cortex, Millefolii herba, Urticae folium, extraction solvent 20% ethanol (DER 1:4.2) – oral liquid (HU)
- Extract of Uvae ursi folium, Millefolii herba, Agrimoniae herba, Urticae folium, Equiseti herba, Betulae
folium, extraction solvent 20% ethanol (DER 1:4) - tincture (HU)
Vitamin(s)
1
Mineral(s)
Short overview on main active compounds
(Bradley 1992, ESCOP 2003, British Herbal
Pharmacopoeia 1996, Gruenwald et al. 2004, Barnes et al. 2002, Frohne 2004, Hänsel et al. 1993,
Britton et al. 1965, Frohne 1977, Jahodář et al. 1978)
Hydroquinone derivatives: arbutin (hydroquinone-
O-β
-D-glucoside) 5 - 16%; the arbutin content is
seasonally variable, leaf content over 17% has been reported; methyl arbutin (
O
-methyl
hydroquinone-
O-β
-D-glucoside) up to 4% according to origin of the drug; galloyl derivatives of arbutin
0.05% (
O
-galloyl hydroquinone-
O-β
-D-glucoside, 2´´
O
-galloyl arbutin, 6´´
O
-galloyl arbutin); free
hydroquinone usually less than 0.3% and methylhydroquinone
The amount of arbutin and methylarbutin is related to the photometric method with 4-aminoantipyrin-
Emerson reaction, while the currently used HPLC method can give different results.
Polyphenols (tannins): 10 – 20%, gallotannins including penta-
O
-galloyl-β-D-glucose and hexa-O-
galloyl-β-D-glucose, ellagictannine corilagin (1
-O
-galloyl-3.6-di-
O
-hexahydroxydiphenoyl
-B-
D-glucose),
catechin; anthocyanidin derivatives including cyanidin and delphinidin
Phenolic acids: approx. 0.25% in free form, mainly gallic, p-coumaric and syringic acids, but also
salicylic acid, p-hydroxybenzoic acid, ferrulic acid, caffeic acid and lithospermic acid (dimeric caffeic
acid) are mentioned in the literature
Piceoside: (4-hydroxyacetophenone-O-β-D-glucopyranoside)
Flavonoids: hyperoside (0.8 – 1.5%), quercitrin-3-β-D-O-6´´galloyl galactoside, quercitrin,
isoquercitrin, myricitrin, myricetin-3-O-βD-galactoside, 2 isomeric quercetin arabinosides, aglycones of
these compounds, kaempherol
Iridoid glucoside: monoterpein (0.025%)
Triterpenes: 0.4 – 0.8%, including ursolic acid, uvaol, α-amyrin, α-amyrin acetate, β-amyrin, lupeol,
mixture of mono- and di-ketonic α-amyrin derivatives
Enzymes: β-glucosidase (arbutase)
Other constituents: allantoin, resin (e.g. ursone), volatile oil (trace) and wax
1
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Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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Only applicable to traditional use
1.2. Information about products on the market in the Member States
Powdered herbal drug in solid dosage forms
Marketing authorisation of coated tablets containing 500 mg of powdered herbal substance in one
tablet is reported from
Germany
(authorised at least since 1976). The posology for adults and
adolescents over 12 years is 6 tablets (500 mg of powdered herbal substance/1 tbl) 4 times daily. The
product is used for treatment of inflammatory diseases of the urinary tract collection system. The
product should not be used longer than one week and not more than 5 times a year without medical
advice.
Powdered herbal substance in a form of capsules (1 capsule contains 270 mg of the powdered herbal
substance) is registered in
Spain
(since 1991). The dosage is 1 capsule 3 times daily. The product is
used as a diuretic. The use in children is not recommended.
There are hard capsules containing 350 mg of powdered herbal substance registered in
France
(since
1982). The posology is 2 capsules two times daily (up to 5 capsules per day). The product is
“traditionally used to promote the renal elimination of water and as an adjuvant to diuretic treatments
in benign urinary tract conditions”.
Comminuted herbal substance for tea preparation
Comminuted herbal substance in a form of herbal tea is registered/authorised in
Germany
,
Poland
,
Spain
and
Lithuania
for more than 30 years, in
Slovenia
since 1996 and in
Estonia
since 2005. The
tea prepared from 1.5 to 3 g of the comminuted herbal substance and 150 ml of boiling water should
be used 3 – 6 times daily. The teas are recommended for the treatment of uncomplicated, mild
infections of the lower urinary tract (Poland, Slovenia), for treatment of inflammatory diseases of the
urinary tract collection system (Germany, Lithuania) or as a diuretic and urinary tract disinfectant
(Spain, Estonia).
Dry extracts
Marketing authorisation for tablets containing 500 mg of dry extract (2.5:1), extraction solvent ethanol
50% (V/V) has been reported from
Belgium
(authorised since 2006). The dosage recommended for
adults and adolescents is 2 tablets 4 times daily. The duration of use is limited to 5 days. The product
is used as urinary antiseptic in cases of cystitis in adult women not having other health problems and
not pregnant.
In
Germany
, a marketing authorisation for coated tablets containing 238.7 – 297.5 mg of dry extract
(3.5-5.5:1) (since at least 1976), extraction solvent ethanol 60% (V/V), corresponding to 70 mg of
hydroquinone derivatives calculated as anhydrous hydroquinone has been granted. The posology is
2 tablets 3 times daily. Other marketing authorisations have been approved (since at least 1976) for
2 products – coated tablets - with a dry extract (3-4:1), extraction solvent water. One of them
contains 114 - 143 mg of the dry extract corresponding to 31.5 mg of hydroquinone derivatives
calculated as anhydrous arbutin and the other 228 – 315 mg of the dry extract corresponding to 63 mg
of hydroquinone derivatives. The dosage is 4 times 4 to 5 tablets respectively 4 times 2 – 3 tablets
daily. Additionally marketing authorisation for film coated tablets containing 425.25 – 519.75 mg of
dry extract (2.5-4.5:1), extraction solvent water corresponding to 105 mg of hydroquinone derivatives
has been reported (authorised since at least 1976). The dosage recommended is 2 tablets 2 to 4 times
daily.
All the above mentioned products are indicated for the treatment of inflammatory diseases of the
urinary tract collection system. All products are intended for adults and adolescents over 12 years and
should be used no longer than one week and not more than 5 times a year without medical advice.
In
Poland
, film coated tablets containing 215 mg of dry extract 2.5-4.5:1, extraction solvent water,
corresponding to 40 mg of arbutin are registered (since 2000). The dosage for adults and adolescents
Assessment report on
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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over 12 years is 4 tablets 3 times daily. The tablets are used in uncomplicated infections of the lower
urinary tract, when antibiotic treatment is not considered essential.
In
France
hard capsules containing 200 mg of dry extract 3.5–6.0:1, extraction solvent water is
registered (since 1992). The posology is 1 capsule twice daily. The product is “traditionally used to
promote the renal elimination of water and as an adjuvant to diuretic treatments in benign urinary
tract conditions”.
Liquid extract
In
Germany
, oral liquid containing an extract (1:0.54-0.99), extraction solvent water: calcium oxide
(44:1) is authorised (since 2006). The dosage is 1.8 – 3.6 ml of the product (corresponding to
101 – 207 mg of anhydrous arbutin) 4 times daily. The product is used for supportive treatment of
inflammatory diseases of the urinary tract in adults and adolescents over 12 years. The product should
be used no longer than one week and not more than 5 times a year without medical advice.
In
Iceland
, Uvae ursi folium would not be classified as food supplement.
For information on combination products marketed in the MS see section 1.1.
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA TRAD Other TRAD Other Specify: Combinations only
Belgium
MA TRAD Other TRAD Other Specify: + combinations
Bulgaria
MA
TRAD Other TRAD Other Specify: None
Cyprus MA TRAD Other TRAD Other Specify:
Czech Republic MA TRAD Other TRAD Other Specify: Combinations only
Denmark
MA TRAD Other TRAD Other Specify: Combinations only
Estonia
MA TRAD Other TRAD Other Specify: + combinations
Finland
MA
TRAD Other TRAD Other Specify: None
France
MA
TRAD Other TRAD Other Specify:
Germany
MA TRAD Other TRAD Other Specify: + combinations
Greece
MA
TRAD Other TRAD Other Specify: None
Hungary
MA TRAD Other TRAD Other Specify: Combinations only
Iceland
MA TRAD Other TRAD Other Specify: None – should not be
classified as food
supplement
Ireland
MA
TRAD Other TRAD Other Specify: None
Italy
MA
TRAD Other TRAD Other Specify: None
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: None
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(L.) Spreng, folium
EMA/HMPC/573462/2009
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Norway
MA TRAD Other TRAD Other Specify: Combinations only
Poland
MA
TRAD Other TRAD Other Specify:
Portugal MA TRAD Other TRAD Other Specify: None
Romania MA TRAD Other TRAD Other Specify:
Slovak Republic MA TRAD Other TRAD Other Specify: Combinations only
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 (date, search terms) and other sources used
Data bases PubMed (June 2009) and HSDB were searched using the terms “ uvae ursi”, “uva ursi”,
“bearberry leaf”, “arbutin” and “hydroquinone”. Handbooks and textbooks on the topic were also used.
Articles and data that were found to be relevant for assessment are included in the List of references.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Bearberry leaves use is for the first time literally documented in the Middle Ages in the Welsh
“Physicians of Nyddfai” from the 13
th
century. It seems that bearberry leaf was used in Northern areas
as a folk remedy long before it came to the Central Europe. In Renaissance herbaria bearberry was
only mentioned occasionally without any link to specified medicinal use. Bearberry is mentioned for
example in “Historia Rariorum Plantarum” by Carolus Clusius (Antwerp, 1601) and also by Linné in his
“Materia Medica” from 1749. In Germany, bearberry was used in larger scale since the middle of 18
th
century. From the beginning of 19
th
century bearberry is in official use. It was used for treatment of
different diseases such hydrops, lithiasis, in diabetes, for therapy of gonorrhoea, etc. Until now only
use as urinary tract disinfectant and diuretic remains. Bearberry leaf was used also in the “New World”
by the North American Indians for treatment of urinary tract diseases (Frohne, 1977).
The medicinal use has been documented continuously in many pharmacopoeias, pharmacognostical
texts and handbooks dating
e.g.
from 1926, 1938, 1947, 1953, 1960, 1977, 1986, 1998, 2002, 2003
and 2009 - Deutsches Arzneibuch 6. Ausgabe (1926), Československý lékopis 1. vydání (1947);
Hagers Handbuch der Pharmazeutischen Praxis (Frerichs et al. 1938), Pharmacopoea Helvetica V
(1953), Österreichisches Arzneibuch 9. Ausgabe (1960), Martindale, The Extra Pharmacopoeia (Wade
1977), Deutsches Arzneibuch 9. Ausgabe (1986), The Complete German Commission E Monographs
(Blumenthal et al. 1998), WHO monographs on selected medicinal plants 2002, ESCOP Monographs
2003 European Pharmacopoeia 6.5 (2009). Bearberry leaf is traditionally used for the treatment of
urinary tract disorders.
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(L.) Spreng, folium
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2.2. Information on traditional/current indications and specified
substances/preparations
The following traditional uses have been recorded for bearberry leaf:
The Complete German Commission E Monographs
(Blumenthal, 1998)
Uses: inflammatory disorders of the efferent urinary tract
WHO Monographs on Selected Medicinal Plants
(Volume 2, 2002)
Uses: described in pharmacopoeias and in traditional systems of medicine: as a mild urinary antiseptic
for moderate inflammatory conditions of the urinary tract and bladder, such as cystitis, urethritis and
dysuria
Uses: described in folk medicine: as a diuretic, to stimulate uterine contractions, and to treat diabetes,
poor eyesight, renal or urinary calculi, rheumatism and venereal disease, topically for skin
depigmentation
ESCOP Monographs
(2003)
Therapeutic indications: uncomplicated infections of the lower urinary tract such as cystitis, when
antibiotic treatment is not considered essential
British Herbal Compendium
(Bradley, 1992)
Bearberry leaf is used as a urinary antiseptic and astringent in mild infections of the urinary tract.
Herbal Medicines. A guide for healthcare professionals
(Barnes et al. 2002)
Martindale Extra Pharmacopoeia
(Wade, 1977)
Barberry is a diuretic and astringent and has been stated to exert an antiseptic effect on the urinary
tract. It has been employed in urethritis and cystitis.
British Herbal Pharmacopoeia
(1996)
Indications: mild infections of the urinary tract
PDR for Herbal Medicines
(Gruenwald et al. 2004)
Indications: infections of the urinary tract - for inflammatory disorders of the efferent urinary tract
Standard Zulassungen
(1996)
Used as an adjuvant in therapy of bladder and renal pelvis catarrhs
Martindale, The Extra Pharmacopoeia
(2004)
Bearberry has been reported to be a diuretic, bacteriostatic, and astringent and has been used in the
treatment of urinary-tract disorders.
(Bartleby, 2006)
Uva-ursi is used by both Native Americans and the Chinese for centuries for urinary tract infections
and sexually transmitted diseases that affect urination
Schindler
(2002)
Bearberry is traditionally used in the treatment of the urinary tract infections (i.e., acute cystitis) with
bacteriuria below 10
5
ml
-1
without risk factors and in symptomatic bacteriuria that does not necessarily
need treatment with antibiotics.
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Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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2.3. Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
The following posologies have been recorded for bearberry leaf:
The Complete German Commission E Monographs
(Blumenthal et al. 1998)
Dosage: 3 g drug to 150 ml water as an infusion or cold maceration or 100 – 210 mg hydroquinone
derivatives, calculated as water free arbutin up to 4 times daily
Route of administration: oral administration
Duration of use: not to be taken for longer than a week or more than five times a year without
consulting a physician
Interactions with other drugs: Preparations of bearberry leaf should not be taken together with drugs
that cause acidic urine since this reduces the antibacterial action
WHO Monographs on Selected Medicinal Plants
(Volume 2 2002)
Dosage: 3 g of the drug/150 ml as an infusion or cold macerate 3 to 4 times daily; 400 to 840 mg
hydroquinone derivatives; other preparations accordingly calculated as arbutin
Route of administration: oral administration, patients have been advised to avoid eating highly acidic
foods and to drink plenty of fluids
Duration of use: not to be used for prolonged period
ESCOP Monographs
(2003)
Dosage: adults – cold water infusions of the dried leaf corresponding to 400 – 800 mg of arbutin per
day, divided into 2 – 3 doses; equivalent preparations, not recommended for children
Route of administration: oral use. Patients should be advised to consume plenty of liquid during the
treatment. Alkalization of the urine may be beneficial
Duration of use: treatment could be continued until complete disappearance of symptoms (up to
maximum of 2 weeks), if symptoms worsen during the first week of treatment medical advice should
be sought
British Herbal Compendium
(Bradley 1992),
British Herbal Pharmacopoeia
(1996)
Dosage: three to four times daily: dried leaf – 1.5 – 2.5 g or in infusion or cold aqueous extract; liquid
extract (1:1), ethanol 25% 1.5 – 2.5 ml; tincture (1:5), ethanol 25% 2 – 4 ml
Route of administration: oral use
Duration of use: maximum 7 days
an “alkaline” diet should be taken during treatment
Herbal Medicines. A guide for healthcare professionals
(Barnes et al.
.
2002)
Dosage: dried leaves 1.5 – 4.0 g as an infusion three times daily, liquid extract (1:1), ethanol 25% 1.5
– 4.0 ml three times daily
Route of administration: oral administration, uva-ursi requires alkaline urine for it to be effective,
patients are advised to avoid eating highly acidic foods
Duration of use: prolonged use is not advisable; patients in whom symptoms persist for longer than 48
hours should consult a doctor
Martindale Extra Pharmacopoeia
(Wade 1977)
Dosage: fresh infusion 1:20 - 15 – 30 ml; concentrated infusion 1:2.5 - 2 – 4 ml; liquid extract 1:1 – 2
ml
PDR for Herbal Medicines
(Gruenwald et al. 2004)
Dosage: a daily dose of finely cut or powdered drug 10 g (corresponding to 400 – 840 mg of arbutin)
or 3 g of the drug/150 ml in a form of infusion or cold maceration up to 4 times a day or 400 to 840
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mg hydroquinone derivatives calculated as water-free arbutin; 0.4 g of dry extract in single dose;
liquid extract single dose 2 g; the urine should be alkaline
Standard Zulassungen
(1996)
Dosage: 1 cap of a decoct prepared from 1 teaspoon (approx. 2 g) of pulverised drug boiled with 150
ml of water for 15 minutes or a macerate prepared with cold water (after several hours maceration) 3
to 4 times daily
Route of administration: oral administration, vegetable diet is recommended to achieve alkaline urine;
additionally sodium hydrogen carbonate can be used
Duration of use: not to be used for long time without consultation with a doctor
Český lékopis
(2005)
Dosage: single dose 3.0 g, daily dose: 12.0 g
Duration of use: maximum 2 weeks
Proposed posology for the specified preparations based on the literature data and
information received from the Member States:
Specified preparation
Dosage
A) Comminuted herbal substance
for tea preparation
Single dose:
1.5 – 4.0 g for tea or macerate preparation up to
4 times daily
B) Powdered herbal substance
The amount corresponding to 100 – 210 mg of
hydroquinone derivatives calculated as anhydrous
arbutin (photometric) or corresponding amount of
arbutin (HPLC) 2 to 4 times daily
C) Dry extract (3.5-5.5:1), ethanol
6% (V/V)
The amount corresponding to 100 – 210 mg of
hydroquinone derivatives calculated as anhydrous
arbutin (photometric) or corresponding amount of
arbutin (HPLC) 2 to 4 times daily
D) Dry extract (2.5-4.5:1), water
The amount corresponding to 100 – 210 mg of
hydroquinone derivatives calculated as anhydrous
arbutin (photometric) or corresponding amount of
arbutin (HPLC) 2 to 4 times daily
There is different information on tea preparation in different literature sources. Herbal tea could be
prepared by decoction from the powdered herbal substance (DAB 9, Blumenthal et al. 1998; Standard
Zulassungen, 1996; Weiss, 1985) or as an infusion from cut or powdered herbal substance
(Blumenthal et al. 1998; Gruenwald et al. 2004) or by maceration for several hours (Standard
Zulassungen, 1996; Gruenwald et al. 2004). Results of the research done by Frohne (1970) are
summarised in the following table:
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No content of tannins had been taken into consideration by Frohne.
During decoction high amount of tannins is extracted while cold maceration prevents tannins elution.
Taking in consideration that in most literature sources there is a recommendation to use the
comminuted herbal substance in a form of cold macerate or infusion, the following instruction for use
should be included in the Community monograph:
To make a tea, pour 150 ml of boiling water over 1.5 to 4.0 g of comminuted herbal substance and
steep for 10 to 15 minutes. To make a macerate, pour 150 ml of cold water over 1.5 to 4 g of the
comminuted herbal substance and steep for minimum 30 minutes stirring frequently. The macerate
should be used immediately after preparation.
3. Non-Clinical Data
3.1. Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Arctostaphylos uva-ursi and its leaf preparations are generally considered to have antibacterial activity
and are traditionally used for treatment of the lower urinary tract infections. Published literature
provides information on antibacterial activity of bearberry leaf preparations together with several other
activities. Publicly available is also information on arbutin and hydroquinone which are the components
generally considered to be responsible for the antibacterial activity of the extract.
3.1.1. Primary pharmacodynamic
Bearberry leaf extract
Antimicrobial effect
Oral administration of 800 mg of arbutin or an infusion of the leaves containing an equivalent amount
of arbutin to healthy volunteers had strong antibacterial activity against
Staphylococcus aureus
SG 511
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and
Escherichia coli
, as measured in urine samples after adjustment of the urine pH to 8.0. Urine of pH
6 was ineffective (Frohne, 1970).
Bearberry leaf extract (fluid extract 1:5, extracted with ethanol 70%) has exhibited antimicrobial
activity towards a variety of organisms including
Staphylococcus aureus, Bacillus subtilis, Escherichia
coli, Mycobacterium smegmatis, Shigella sonnei
and
Shigella flexeneri
(Moskalenko, 1986).
The decoctions of bearberry (10 g/100 ml water) increased remarkably the hydrophobicity of both
E.
coli
and
Acinetobacter baumanii
strains
in vitro
. The leaves of bearberry possessed the antimicrobial
activity, there was no growth registered after the exposure of 20 different
E. coli
strains to the
undiluted decoction of bearberry and in case of two-fold dilution only one strain showed growth
afterwards in peptone broth. This antimicrobial activity could be connected to the ability of bearberry
leaf aqueous extract to increase aggregation of Gram-negative bacteria mainly caused by increased
hydrophobicity of their cell surface. (Türi et al. 1997). Similar effect possessed bearberry leaf aqueous
extract (decoction 1:10/30 min/100°C/pH 4.7) on
Helicobacter pylori
(Annuk et al. 1999).
Antimicrobial activity of the ethanolic extract (ethanol 80%) of the aerial parts of
Arctostaphylos uva
ursi
and its ethyl acetate fraction was tested
in vitro
against
Escherichia coli
,
Proteus vulgaris
,
Streptococcus faecalis
and
Enterobacter aerogenes
. Bearberry extract showed antimicrobial activity
against all the microorganisms tested. The inhibitory activity was compared to the antimicrobial
activity of streptomycin. The highest activity found in the experiment was approximately 1/100 of the
activity of streptomycin against
E. coli
and 1/300 against
P. vulgaris
. In case of
S. faecalis
the activity
corresponded to the activity of streptomycin; however, streptomycin is known to be less active against
these bacteria (Holopainen et al. 1988).
Antimicrobial activity of the extracts depends on the extraction solvent used. There is some evidence
that extracts prepared with ethanol of high concentration lose antibacterial activity. An aqueous extract
of the leaves inhibited the growth of
Streptococcus mutans
OMZ176
in vitro
(Namba et al.1981). A
30% ethanol extract of
Folium Uvae Ursi
inhibited the growth
in vitro
of
Bacillus subtilis
,
Escherichia
coli
,
Pseudomonas aeruginosa
,
Salmonella typhimurium
,
Serratia marcescens
and
Staphylococcus
aureus
(WHO, 2002). However, 95% ethanol or chloroform extracts had no antibacterial activity (Ríos
et al. 1987; Gottshall et al. 1949; WHO, 2002).
The bearberry leaf extract (95 % ethanolic extract – 15:100 material to solvent ratio) alone displayed
no antimicrobial activity against any of the 25 bacteria tested (Dykes, 2003).
Diuretic effect
An aqueous extract of bearberry leaves (no other information on the type of extract and DER) was
administered intraperitoneally to 10 male rats as a single dose of 50 mg/kg body weight; a control
group of 10 rats received hypotonic saline solution and another group of 10 rats received the diuretic
compound hydrochlorothiazide at 10 mg/kg bw. The urine volume from rats treated with the extract
was significantly higher (p<0.001 from the 4
th
to 8
th
hour after administration; p<0.05 over a 24-hours
period) that from the controls and was comparable to the volume after hydrochlorothiazide treatment.
No increase in sodium and potassium excretion was observed after administration of bearberry leaf
extract (Beaux et al. 1999).
In contrary to the above mentioned study there is another experimental study in which diuretic effect
of several flavonoid drugs including Uvae ursi folium was investigated. The following preparations were
administered to dogs: the flavonoid fraction isolated from the crude drug, a dry methanolic extract, a
dry aqueous extract, a decoction and an aqueous suspension of the pulverised drug. The starting
herbal drug contained 1.5% of total flavonoids. Preparations of uvae ursi folium inhibited diuresis
(Borkowski, 1960 – abstract).
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Additionally, no diuretic effect of uva-ursi tea is reported by Weiss, 1985. However, the author did not
provide any references supporting this statement.
Arbutin
Antimicrobial effect
In a study in humans, urine samples collected after administration of 0.1 or 1 g of arbutin with or
without additional use of 0.250 g of Diuramid (acetazolamide) to achieve alkaline urine have been
tested on antibacterial activity against 74 strains of bacteria including
Escherichia coli, Proteus
mirabilis, Proteus vulgaris, Proteus rettegeri Klebsiella, Enterobacter, Citrobacter freundii,
Pseudomonas aeruginosa, and Staphylococcus aureus.
The results were compared with results of other
20 antimicrobial compounds. Only arbutin (present in urine samples collected after administration of
1.0 g arbutin), gentamycin and nalidixic acid were active against all the strains tested. Antimicrobial
effect was apparent even after administration of 0.1 g of arbutin. The effect of arbutin was higher in
alkaline urine in comparison to urine with pH 6. In this study arbutin or free hydroquinone were not
detected in urine samples (Kedzia, 1975).
The antimicrobial activity of arbutin towards bacteria implicated in producing urinary tract infections
has been found to be directly dependent on the
-glucosidase activity of the infective organism. The
highest enzymatic activity was shown by
Streptococcus faecalis
,
Klebsiella
and
Enterobacter
genera
and by
Proteus vulgaris
and the lowest by
Escherichia coli
. The minimum inhibitory concentration of
arbutin is reported to be 0.4 – 0.8% depending on the microorganism (Jahodář et al. 1985). In
summary, it has been suggested that a direct relationship exists between the antibacterial action of
arbutin and the degree of enzymatic activity of the microorganism.
Arbutin and its metabolite hydroquinone showed inhibition of the growth of
Ureaplasma urealyticum
and
Mycoplasma hominis in vitro
(WHO, 2002; Robertson et al. 1987).
Hydroquinone
Other sources associate the antimicrobial effect of uva-ursi leaf extract with the aglycon hydroquinone
released from arbutin (transport form) or arbutin metabolites in the alkaline urine. The drug has urine-
sterilizing properties that are attributed to bacteriostatic hydroquinones, conjugates of glucuronic acid
and sulfuric acid (Gruenwald et al. 2004).
Despite various pharmacological investigations, it remains open to debate whether the antibacterial
effect in the urine is caused by hydroquinone esters, especially the sulphate ester, or by free
hydroquinone liberated from them in alkaline urine (Kedzia et al. 1975).
It has even been suggested that arbutin could be hydrolyzed directly to hydroquinone in the urinary
tract by
-glucosidase activity of pathogenic bacteria causing the infection (Jahodář et al. 1978).
Tannins
Tannic acid seems to be a component of bearberry aqueous extract with the highest activity to
decrease cell surface hydrophobicity as well as antibacterial activity against
H. pylori
(Annuk et al.
1999).
3.1.2. Secondary pharmacodynamic
Bearberry leaf extract
Anti-inflammatory activity
Anti-inflammatory activity (rat paw oedema tests) has been documented for
A. uva-ursi
against a
variety of chemical inducers such as carrageenan, histamine and prostaglandins (Herbal Medicines,
2008).
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The effect of 50% methanolic extract from bearberry leaf on immuno-inflammation was studied by
contact dermatitis caused by picryl chloride in mice. When given orally immediatelly before and 16
hours after the application of picryl chloride an inhibitory effect on the swelling was observed.
Significant therapeutic effect at a dose of 100 mg/kg or more has been demonstrated 24 hours after
application (Kubo et al. 1990 – abstract).
Other activities
An aqueous extract of the leaves (prepared from 1 part of the herbal substance and 10 parts of water)
had antiviral activity
in vitro
against
Herpes simplex
virus type 2, influenza virus A2 (Mannheim 57)
and vaccinia virus at a concentration of 10% (May et al. 1978; WHO, 2002).
Addition of an infusion of the leaves to the drinking-water (3 g/L) of rats fed a standard diet fortified
with calcium (8 g/kg body weight) had no effect on urinary calcium excretion and diuresis (Grases et
al. 1994; WHO, 2002).
The effect of 50% methanolic extract from bearberry leaf on melanin synthesis was investigated
in
vitro
. Bearberry leaf extract as well as arbutin isolated from bearberry leaves had an inhibitory effect
on tyrosinase activity. Furthemore bearberry leaf extract inhibited the production of melanin from dopa
by tyrosinase and from dopachrome by autoxidation (Matsuda et al. 1992a – abstract).
Water extracts (infusions) from a group of medicinal plants were studied in terms of their activity
enhancing the uterine tonus in a series of experiments with a preparation of an isolated rabbit and
guinea pig uterine horn. Infusion of bearberry leaves (
Arctostaphylos uva-ursi
L.) did not show any
uterotonic effect (Shipochliev, 1981).
Arbutin
In mice orally or intraperitoneally (i.p.) treated with arbutin (50-200 mg/kg [0.18-0.735 mmol/kg]), a
dose-dependent antitussive effect to ammonia-induced cough was observed. The antitussive effect of
arbutin (200 mg/kg [0.735 mmol/kg]) was as potent as that of codeine phosphate (30 mg/kg), but
arbutin had no analgesic or anesthetic effects. Additionally, arbutin had no effect on tracheal smooth
muscle contraction, respiratory activity, spontaneous behavior, blood pressure, heart rate or electrical
activity (Li et al. 1982 – Chin; NTP, 2006).
Unanaesthetized male and female cats were administered oral (p.o.) and intraperitoneal (i.p.) doses of
50 and 100 mg/kg [0.18 or 0.367 mmol/kg] of body weight arbutin in water and observed at 0.5-, 1-,
2-, and 5-hour intervals. Arbutin at 50 mg/kg bw (i.p. and p.o.) elicited a statistically significant
decrease in the number, intensity, and frequency of coughs. Similar results were recorded for the 100
mg/kg bw i.p. and p.o. doses; an increase in antitussive activity was not observed at this dose
(Strapkova et al. 1991).
Arbutin (in concentrations 90
g/ml and 40
g/ml) was not found to inhibit growth of the rat hepatoma
cells (Assaf et al. 1987; Barnes, 2002; Herbal Medicines, 2008).
3.1.3. Pharmacodynamic drug interactions
Bearberry leaf extract
In mice,
A. uva-ursi
extract or arbutin in combination with prednisolone or dexamethasone inhibited
swelling of contact dermatitis induced by picryl chloride (PC-CD) and sheep red blood cell delayed type
hypersensitivity (SRBC-DTH) response to a greater extent than either of the two chemicals alone
(Kubo et al. 1990 – abstract; Matsuda et al. 1990 – abstract; Matsuda et al. 1991 – abstract).
Water extracts from the leaf of
A. uva-ursi
increased the inhibitory effect of dexamethasone ointment
on PC-CD- and carrageenin-induced paw edema (Matsuda et al. 1992 b– abstract).
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An
A. uva-ursi
extract (95% ethanolic extract), enhanced the antimicrobial activity of nisin; bearberry
extract alone had no effect (Dykes et al. 2003).
Arbutin
Aloesin (an anti-inflammatory drug) and arbutin synergistically inhibit tyrosinase activity. In a study of
their effects on UV-induced pigmentation in human skin
in vivo
, co-treatment with both chemicals
(100 mg/g each) produced an additive effect; 63.3% suppression of pigmentation versus 34% with
aloesin and 43.5% with arbutin alone (Choi et al. 2002). Additionally, arbutin inhibited UV-induced
nuclear factor-kappaB activation in human keratinocytes (Ahn et al. 2003).
Arbutin plus indomethacin showed a stronger inhibitory effect than indomethacin alone in carrageenin-
induced edema and adjuvant-induced arthritis (Matsuda et al. 1991 – abstract).
Arbutin exhibited potent inhibitory effects on rat platelet aggregation induced by adenosine
diphosphate (ADP; IC50=0.12 mM) and collagen (IC50=0.039 mM) and displayed the same inhibitory
activities as the positive control, tetramethylene glutaric acid, on rat lens aldose reductase (Lim et al.
2003 [Korean with English summary]; NTP, 2006).
3.2. Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
In general, non-clinical pharmacokinetic information regarding crude extract or its components is very
poor and did not allow any relevant conclusion being made.
Arbutin, major constituent of Uvae ursi folium extracts, is a phenolic glycoside, which is broken down
to yield hydroquinone (HQ) and glucose (Jahodář et al. 1985). HQ is the recognised active substance
at the site of drug action, which is the lower urine tract. The total amount of HQ (free HQ and HQ-
conjugates) in urine is crucial for the therapeutic activity of the herbal preparation. Therefore, human
pharmacokinetic studies have been focused on the availability of total HQ in urine and the use of HQ
and arbutin as pharmacokinetic markers is plausible (Paper et al. 1993; Schindler et al. 2002; Quintus
et al. 2005).
Bearberry leaf extract
The ability of bearberry leaf to act against urinary infections is believed to be the result of action of
free hydroquinone cleaved from arbutin molecule in the urinary tract. It is not known in which tissue
this cleavage occurs
in vivo
and what amount of hydroquinone is present in the organisms after
treatment with arbutin. The cleavage is mediated via β-glycosidase, an enzyme which is usually not
present in mammalian cells but is present in microorganisms which occur in the gastrointestinal tract
or possibly in the urinary tract, when infected (Müller and Kasper, 1996 - abstract).
After ingestion of the leaves, arbutin is absorbed from the gastrointestinal tract, and is hydrolysed by
intestinal flora to form the aglycone, hydroquinone (Paper, 1993). Hydroquinone is metabolized to
glucuronide and sulfate esters that are excreted in the urine (Kedzia, 1975; Frohne, 1970). These
active hydroquinone derivatives exert an antiseptic and astringent effect on the urinary mucous
membranes when the urine is alkaline (pH 8.0). Their antibacterial action reaches a maximum
approximately 3-4 hours after ingestion (Blumenthal et al. 1998
;
Paper et al. 1993).
Bioavailability of gastro resistant coated tablets containing aqueous extract of Uvae ursi folium in
comparison to the genuine extract was studied in a crossover design with six healthy volunteers.
Arbutin equivalent has been determined in urine samples collected within 24 hours using the DAB 10
spectrophotometric method. Release of arbutin from the tablet compared to the extract was retarded
at least three hours. However, bioavailability showed comparable values. In the urine samples no free
hydroquinone was detected by HPLC method. In a pilot study the coated tablets and extract were
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administered together with 10 g sodium hydrogencarbonate. The pH of the urine changed from 6.5 to
7.4 and in one case to pH 8 for one hour. Free hydroquinone was found in therapeutic concentration in
urine only if the pH was alkaline (pH 8), in other urine samples hydroquinone concentrations was
bellow detection limit (1
g/ml – HPLC method). These findings are in agreement to Frohne, who
detected free hydroquinone only after adjusting samples to pH =8 (Frohne, 1970; Paper et al. 1993).
Arbutin
As arbutin is reported to hydrolyze easily in diluted acids to yield D-glucose and hydroquinone, it is
expected that ingested arbutin would be hydrolyzed to free hydroquinone by stomach acids. However,
a set of experiments suggested that absorbed hydroquinone is rapidly conjugated since it is not
detectable as free hydroquinone. Level of free hydroquinone in the body (urine and plasma samples) is
usually at or below total concentration of hydroquinone measured in the preexposure background
samples (Deisinger et al. 1996).
Female Wistar rats were given an aqueous solution of chromatographically pure arbutin, isolated from
Arctostaphylos uva-ursi
, and their excreted urine was evaluated by TLC, HPLC and spectral analysis.
Unchanged arbutin was excreted at 82% and 100% after 16 and 30 hours post-treatment,
respectively, corresponding to 90.7% of the total arbutin dose administered orally. Arbutin is not
changed in urine even in changed pH. As long as antimicrobial action of arbutin depends on the release
of hydroquinone, exoenzymatic
-
glucosidase activity of some microorganisms producing inflammatory
processes in the urinary tract must be taken into account (Jahodář et al. 1983).
The highest
glucosidase extracellular enzymatic activity was found in the genera
Streptococcus
faecalis
(100%),
Klebsiella
(95%), and
Enterobacter
(72%), the lowest in
Escherichia coli
(11.6%). A
direct dependence of the antimicrobial effect of arbutin on the level of the enzymatic activity of
microorganisms was found. The presumption of the autocidal action of some bacteria on arbutin was
confirmed. The minimal bactericidal concentration of arbutin ranges, in dependence on the species of
the microorganism, from 0.4 to 0.8% (Jahodář, 1985).
Oral administration of arbutin (500 mg/kg [1.84 mmol/kg]) to female rats which were overloaded with
fluid resulted in a four-fold excess of excreted urine during the second hour of dosing and a total
increase of 61% in the first day. No free hydroquinone was detected in the urine samples. Diuretic
activity from treatment with 200 mg/kg hydroquinone was greater than that observed in arbutin-
treated animals (NTP, 2006).
Investigations have been performed in animals to elucidate the absorption, metabolism and elimination
of arbutin. Isolated segments of intestine from the distal part of the duodenum and the caecum of
hamster and chicken were used in an
in vitro
model to study in detail the absorption process of
arbutin. Experimental data
in vitro
indicate that arbutin is absorbed via the Na+/glucose carrier in the
small intestine. The transport of arbutin in the small intestine was a freely reversible process, also
used by glucose and its analogues (Alvarado 1965, Alvarado and Monreal 1967).
Arbutin uptake (a model of an actively absorbed sugar) has been also investigated in human small
intestine obtained from biopsies of 18 patients with minor abdominal complaints without obvious
gastrointestinal disease. In three patients non-tropical sprue was diagnosed. The speciments were
differentiated in 4 morphological groups. A significant difference in arbutin uptake between the
morphological groups was found. Arbutin uptake was clearly reduced in the case with histological
evidence of jejunitis and in cases of non-tropical sprue (Semenza et al. 1969).
Hydroquinone
Oral administration of [
14
C]hydroquinone either in the diet or by gavage to Sprague-Dawley rats
results in almost complete absorption from the gastrointestinal tract, with only 4% being recovered
from feces. Of the absorbed material, about 99% of the radioactivity was recovered from urine. In a
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comparison of the kinetics of hydroquinone administered orally and dermally, it was reported that
dermal absorption was poor. However, pulmonary absorption, after intratracheal instillation, was very
rapid in male Sprague-Dawley rats, with [
14
C]hydroquinone being detectable in arterial blood within 5–
10 s. Later blood sampling (45–720 s) indicated rapid metabolism to glucuronides and elimination of
the parent compound.
Following oral administration to rats, by far the major proportions of metabolites are conjugates of
glucuronic (up to 67%) and sulfuric (up to 33%) acids. The remaining urinary metabolites consist of 0–
5 % mercapturates, 0–3% unconjugated hydroquinone, and
<
1% unconjugated 1.4-benzoquinone.
The oxidation of hydroquinone to the very reactive 1.4-benzoquinone, which can occur both
enzymatically and non-enzymatically could be of toxicological significance. Hydroquinone auto-oxidizes
at neutral pH to form 1.4-benzosemiquinone, which can undergo a disproportionation reaction to 1.4-
benzoquinone (McGregor, 2007).
3.3. Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Bearberry leaf extract
No data on single or repeated dose toxicity have been reported for bearberry leaf extract. There are no
data on reproduction toxicity or drug interaction available.
Genotoxicity
Uvae Ursi folium (dry water extract) has not been mutagenic in the
Salmonella
/microsome assay with
S. typhimurium
strains TA98 or TA100 as well as in the
Bacillus subtilis
rec-assay (Morimoto et al.
1982; WHO, 2002).
Cytogenetic effect of ethanolic extracts of Uvae ursi folium on irradiated human blood lymphocytes was
assessed. Micronucleus formation in unirradiated and irradiated samples of cultured blood lymphocytes
using the cytochalasin block micronucleus test was examinated. Treatment of cells with bearberry leaf
extract did not affect the level of micronuclei in any of the concentration studied (0.025, 0.05, 0.1, or
0.2 mg/ml) (Joksic et al. 2003; NTP, 2006).
Carcinogenicity
There was no evidence of carcinogenic activity of an aqueous extract of the uvae-ursi leaves in male
B6C3F1 mice (treated by gavage with 50-100 mg extract/kg body weight) (NTP, 1989, 2006; WHO,
2002).
Arbutin
Repeated dose toxicity of arbutin has been investigated in mice. At a dose of 8000 mg/kg
[29.38 mmol//kg] administered i.p. for two weeks, no toxic effects were observed (Li et al. 1982
[Chin.]; NTP, 2006).
Genotoxicity
Arbutin (up to 10
-2
M [2.73 mg/ml]) did not induce mutations in hamster V79 cells; however, after
preincubation of arbutin (≥1 mM [0.3 mg/ml]) with β-glycosidase, it did have a mutagenic effect. An
increase in mutation frequency was observed with concentrations of 10
-3
M arbutin and higher.
Hydroquinone which was used as positive control exhibited clear effects with a LOEC of about 10
-5
M.
In mice orally treated with arbutin (0.5-2 g/kg [2-7 mmol/kg] bw), there was no induction of bone
marrow micronuclei. Hydroquinone which was used as a positive control (50 and 100 mg/kg i.p.)
induced clearly elevated micronucleus incidence (Müller and Kasper, 1996 – abstract).
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Ames test and micronucleus test have been performed with urine containing arbutin. Results have
shown no indication of genotoxicity related to arbutin (Siegers et al. 1997).
Carcinogenicity
There are study results providing information that arbutin (2.5, 12.5, or 50 μg/ml [9.2, 45.9, 180 μM])
incubated for four days weakly inhibited the growth of human colon carcinoma HCT-15 cells (Kamei et
al. 1998; NTP, 2006).
Reproduction and developmental toxicity
Arbutin was administered subcutaneously at 25, 100 or 400 mg/kg of body weight daily to male
Sprague-Dawley rats 14 days before mating and to female rats for 20 days during pregnancy and
lactation. No effect on reproduction of male and female rats, or the development of the offspring was
observed at doses of up to 100 mg/kg body weight. Fetal toxicity (e.g. stunted fetus, reduced body
weight) but no deaths together with maternal effects (not specified) in the ovaries and fallopian tubes
were observed at doses of 400 mg/kg body weight. However, based on the fact that the dose is 33
times higher than the maximal dose recommended for oral use (840 mg/day, i.e 12 mg/kg/day) there
are no safety concerns in humans (WHO, 2002; Hänsel et al. 1993).
Immunotoxicity
Oral application of arbutin (10 or 50 mg/kg [0.037 or 0.18 mmol/kg]) quickly reduced the swelling of
PC-CD and SRBC-DTH within 24 hours (Matsuda et al. 1990, 1991 [Jpn.]). Arbutin (1 mg/ml [4 mM])
inhibited the binding of mouse monoclonal anti-dinitrophenyl immunoglobulin E (IgE[aDNP]) to DNP by
65% (Varga et al. 1991).
In macrophage cells from male Swiss mice, arbutin (2 mg/ml 7 mM]) failed to induce the release of
hydrogen peroxide (Moreira et al. 2001; NTP, 2006).
Cytotoxicity
Growth of human melanoma cells and normal human melanocytes was not inhibited by exposure to
100 μg/ml [0.367 mM] arbutin for five days. At 300 μg/ml [1.10 mM] arbutin treatment for five days,
cell toxicity and detachment of cells from the dishes were observed within 48 hours (NTP, 2006).
Arbutin (5-50 μM [1-14 μg/ml]) inhibited the growth of the roots of
Allium sativum
L. and produced
anti-mitotic effects. At 10 μM, the anti-mitotic effect was already visible within 24 hours and ended at
48 hours. At 20 μM [5.4 μg/ml], arbutin was very toxic, completely stopping root growth after day 1.
The effects were similar to those seen with hydroquinone at 5 μM (Deysson and Truhaut, 1957; NTP,
2006).
Hydroquinone
The toxicology of free hydroquinone (HQ) has been reconsidered on several published reviews and it
was concluded that there is no evidence to suggest that the toxicology of free HQ is of human
relevance (Deisinger et al. 1996; DeCaprio 1999; McGregor 2007).
In previous sections, it has been addressed that the active component of bearberry leaf extract,
arbutin is converted to free HQ to exert its antibacterial effect. Based on the pharmacokinetic profile of
arbutin, it has been shown that free HQ has an irrelevant accumulation risk since arbutin is very fast
conjugated and transformed in innocuous metabolites.
Only in a very low percentage (0.6% of the given dose) free HQ is eliminated in urine and (<1%) in
feces. Most of the arbutin is therefore transformed in HQ conjugated (70%) (Siegers et al. 1997;
2003). Free HQ is not accumulated in the animal or human organism and its potential accumulation is
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not justified by any pharmacodynamic/pharmacokinetic reason (English and Deisinger 2005; Siegers
1996).
Acute toxicity data on hydroquinone were published. The oral LD
50
of hydroquinone in 2% aqueous
solution has been determined as 320 mg/kg in rats, 400 mg/kg in mice 550 mg/kg in guinea pigs, 300
mg/kg in pigeons, 70 mg/kg in cats and 200 mg/kg in dogs (Woodard at al., 1949).
Acute exposure of rats to high doses of hydroquinone (over 1300 mg/kg body weight) caused severe
effects on the central nervous system, including hyperexcitability, tremor, convulsions, coma and
death (IPCS 1994).
The presence of food may increase oral LD50 values of 310 to 1050 mg/kg in rats. Thus, food showed
to decrease the rate and extent of free HQ absorption. LD50 values for free HQ by parenteral
administration have been reported as 115-160 mg/kg in the rat and 190 mg/kg in the mouse
(DeCaprio 1999-abstract). In the course of toxicological animal experiments, free HQ demonstrated a
very low toxicity since LD50 values were very high. In addition, the presence of food importantly
improves its safety.
Genotoxicity
Hydroquinone was negative for mutagenicity in
Salmonella typhimurium
strains TA98, TA100, TA1535,
and TA1537 in the presence and absence of metabolic activation (S9). In Chinese hamster ovary
(CHO) cells, it induced sister chromatid exchanges (with and without S9) and chromosomal aberrations
(with S9). Hydroquinone also induced trifluorothymidine resistance in mouse L5178Y/TK lymphoma
cells and was mutagenic in the micronucleus test. Inconclusive results, however, were obtained in
Drosophila
(NTP, 1989, NTP, 2006). However, hydroquinone was found to be mildly myeloclastogenic
in the micronucleus test in SPF mice after oral administration of a toxic dose (200 mg/kg) (Gad-El-
Karim et al. 1985).
The DNA reactivity of hydroquinone has been documented in animals and this enhanced activity is
presumably due to the oxidized forms of hydroquinone, 1.4-benzosemiquinone and/or 1.4-
benzoquinone, which can react with sulfhydryl groups and isolated calf thymus DNA and therefore have
the potential to contribute to the toxicity of hydroquinone (McGregor, 2007).
Hydroquinone is generally not active in bacterial tests for mutation, but it has been reported to cause
base-pair changes in the oxidant-sensitive strains
Salmonella typhimurium
TA 104 and TA 102, which
is consistent with the mutagenicity of 1.4-benzoquinone in several strains of
S. typhimurium
. This
result from a single study should not be overemphasized, since it has been suggested that there is
little difference in qualitative responses between these two strains and TA100, against which
hydroquinone has been tested to a 13-fold higher dose without any significant response. In other
submammalian genetic toxicity assays, hydroquinone induced forward mutations but not mitotic
recombination or gene conversion in
Saccharomyces cerevisiae
, and it did not induce sex-linked
recessive lethal mutations in
Drosophila melanogaster
when delivered either in the feed or by injection
– (McGregor, 2007).
Hydroquinone induced micronuclei and chromosomal aberrations in several studies in bone-marrow
cells of mice treated
in vivo
, but not sister chromatid exchanges in a single study. Hyperploidy and
chromosome loss (as demonstrated by centromere-positive micronuclei) but not polyploidy were also
found in mouse bone marrow. In mouse spermatocytes, chromosomal aberrations and hyperploidy
have been observed. In all of these studies
in vivo
dosing was by ip. injection; however, other dose
routes have been used in a small number of other studies. In the exceptions, subcutaneous injection
was used in one study finding a significant response and oral dosing was used in the other two, with a
significant but weak response being found in one gavage administration study and no effect resulting
from dietary administration for 6 days at the same dietary concentration (0.8% hydroquinone) as used
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by for the induction of renal tumors in F344 rats and, with less clarity, hepatocellular adenomas in
male B6C3F1 mice.
The administration route difference is probably significant and it is unfortunate that there has been
such a heavy emphasis on the ip. injection mode of administration. There are no germ cell studies of
hydroquinone mutagenicity in which routes other than ip. have been used. Unlike the adult human
anatomy, the testes of adult rats are likely to receive direct exposure to a chemical that is delivered by
the ip. route because the inguinal canal remains open. The ip. route would seem to largely destroy any
rationale for testing
in vivo
because exposure of many
in vivo
target cells in animals dosed by this
method differs little from that achieved
in vitro
. Although it is not clear that dominant lethal assays are
truly germ-cell mutation assays, they are usually assumed to be so. The only one conducted with
hydroquinone did not produce any significant response after dosing of male Sprague-Dawley rats with
up to 300 mg/kg body weight per day, 5 days per week, for 10 weeks – (McGregor, 2007).
Hydroquinone is mutagenic
in vitro
and
in vivo
, but the administration route used to demonstrate the
in vivo
activity is inappropriate and exposure by more appropriate routes, methods and doses allow
protective mechanisms to contain the potentially damaging effect of the oxidative properties of
hydroquinone (McGregor, 2007).
Carcinogenicity
Relatively more information on carcinogenicity is available for hydroquinone and its derivatives. The
health effects of hydroquinone have been extensively reviewed in IPCS Environmental Health Criteria
No. 157 and summarized in IPCS Health and Safety Guide No. 101 (IPCS, 1994, 1996; NTP, 2006).
Although extracts of the leaves do not appear to be carcinogenic, there is some evidence that
hydroquinone is carcinogenic. In a two-year carcinogenesis bioassay, hydroquinone (25 or 50, or 100
mg/kg) administered by gavage gave some evidence of carcinogenicity in male F344/N rats (kidney
tubular cell adenoma), female F344/N rats (mononuclear cell leukemia), and female B6C3F1 mice
(liver adenoma or carcinoma). Additionally, the incidence of thyroid follicular cell hyperplasia was
increased in female and male mice (WHO, 2002; NTP, 2006).
In a U.S. National Toxicology Program study, groups of 55 male and 55 female Fischer 344/N rats, 7 to
9 weeks of age, were administered 0, 25, or 50 mg/kg body weight hydroquinone (purity
>
99%) by
gavage on 5 days per week for 103 weeks. Survival was reduced in exposed rats. Also, the mean body
weight of exposed males was reduced and the relative kidney weights for high-dose males were
greater than those for vehicle controls (NTP, 1989).
Nephropathy was observed in nearly all male and most female rats of all dosed groups and vehicle
controls. The nephropathy was characterized by degeneration and regeneration of tubule epithelium,
atrophy and dilatation of some tubules, hyaline casts in the tubule lamina, glomerulosclerosis,
interstitial fibrosis, and chronic inflammation. In males, the nephropathy was more severe in the high-
dose (50 mg/kg bw per day) group, while in females no dose dependence was observed. Nephropathy
had also been observed in males in earlier 13-week studies. The presence of hyaline droplets was not
reported.
In exposed males, renal tubule-cell adenomas developed in 4/55 low-dose group rats (
p
= 0.069) and
8/55 high-dose group rats (
p
= 0.003), compared with 0/55 in control group rats. A low, non-
significant incidence of renal tubule hyperplasia also was reported in the high dose group of male rats
(2/55) compared with none in the other groups. There were no renal tumors found in female rats of
any group (NTP, 1989).
A reanalysis of the histology of the NTP study, in addition to demonstrating a low incidence of foci of
atypical tubule hyperplasia and small adenomas at both doses, also found substantial exacerbation of
chronic progressive nephropathy (CPN) to endstage grades of severity at the high dose (Hard et al.
1997).
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Briefly, CPN begins at about 2 months of age, when some rats develop basophilic renal tubules with a
thickened basement membrane. Progression involves an increase in number of tubules affected, tubule
degeneration and atrophy, and an ongoing tubule-cell proliferation in which mitotic figures may be
frequent (Hard and Seely, 2005). By the time that end stage (grade 8) is reached, there are virtually
no normal tubules remaining and death from renal failure is highly probable. It is important to
recognize that this degenerative and regenerative disease is not the result of any chemical treatment,
and it is necessary to distinguish its regenerative aspects from preneoplasia (atypical hyperplasia),
from which adenomas develop. These are usually small (≤0.5 mm). In general, the overall low
incidence of both atypical hyperplasia and tubule-cell adenomas may be increased by examining
additional step-sections of the kidney rather than relying exclusively on the more usual single, cross
and longitudinal section.
The histopathological reanalysis of the hydroquinone study (Hard et al. 1997) found that of the 8
tumors identified by NTP in the high dose, 4 were definite adenomas (one being a cystadenoma), 3
were very early adenomas (incipient adenomas), and 1 was a focus of atypical hyperplasia. In the low
dose, 3 of the 4 tumors diagnosed by NTP were similar to the high dose tumors diagnosed by Hard et
al. (1997), 2 being definite adenomas and 1 a very early adenoma; the fourth was considered to be a
metastasis from a mesothelioma that was present in the peritoneal cavity and certain lymph nodes in
this rat, which died at 56 weeks. Besides the 1 focus of atypical hyperplasia already mentioned, Hard
et al. (1997) found 13 other foci of atypical hyperplasia in 11 of the 51 rats examined, whereas only 2
were mentioned in the NTP report. Only one of these was confirmed in the reevaluation, with the other
probably representing an inflammatory lesion unrelated to neoplasia. In the high-dose group, 40% of
males showed exacerbation of CPN to end stage, compared with 5% in the control group males.
Cytotoxicity
Hydroquinone has been reported to show a concentration-dependent cytotoxic activity on cultured rat
hepatoma cells (HTC line). A dose 33
g/ml caused cellular mortality of 40% of cells after 24 h of
incubation and no cells remained viable after 72 h. A higher concentration of 66
g/ml killed all the
cells after a 24 h contact (Assaf et al. 1987; Barnes, 2002).
3.4. Overall conclusions on non-clinical data
Available pharmacodynamic data regarding antibacterial activity of bearberry leaf extract together with
experiments performed with arbutin or hydroquinone provide solid ground for bearberry leaf extract to
be assessed as useful antibacterial agent for treatment early symptoms of mild infections of the lower
urinary tract.
There are no data on safety pharmacology of bearberry leaf extract or its component arbutin and
metabolite hydroquinone available at present. It is not possible to conclude any information on drug
effect on central nervous system, cardiovascular system or respiratory system. Taking into account the
difference in metabolism of arbutin in human and animals, and metabolism ambiguity of arbutin to
hydroquinone together with the fact that bearberry extract seems to be more active in patients
compared to the healthy subjects further non-clinical evaluation is not considered necessary. Relevant
safety data can be obtained mainly from clinical trials.
Bearberry leaf extract
There is almost no information available on the toxicity of crude extract of bearberry leaves. Bearberry
crude extract was evaluated in Ames test using only two instead of five recommended strains. Results
of this study were negative; however, clear conclusion about genotoxicity of the extract could not be
made. Further bearberry leaf extract was negative in
in vitro
micronucleus test; however, this test was
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not performed according to ICH S2B. Studies in mice revealed there is no carcinogenic potential of
bearberry leaf extract.
Arbutin
Single dose toxicity study has not been performed with arbutin but repeat administration of doses
much higher compared to clinical practice revealed no toxic effects in mice.
Arbutin has been evaluated
in vitro
in Ames assay and micronucleus test showing no indication of
genotoxic potential. Chinese hamster V79 mutation test performed with arbutin gave negative results
but after preincubation of arbutin with
-glycosidase causing its cleavage to hydroquinone positive
results of the assay were found. Further
in vivo
mouse micronucleus test revealed no increase
incidence of micronuclei formation after treatment with arbutin compared to the hydroquinone, used as
positive control, providing clear positive results. Arbutin alone seems to be of no genotoxic concern in
animal studies, however, combination of arbutin with
-glycosidase together with the observed
difference between whole bearberry leaf extract and pure arbutin should be carefully considered. The
assessment of genotoxicity should be performed very carefully.
Carcinogenicity studies have not been performed with arbutin.
Reproduction and developmental studies performed in rats dosed with arbutin showed there is no risk
on male and female fertility and no deaths were observed in offsprings. The results of the study are
considered irrelevant to clinical practice since low doses of arbutin were used.
Hyroquinone
Acute toxicity of hydroquinone has been evaluated and lethal doses were established in several animal
species. High exposure of rats to hydroquinone led to severe toxic effect on the central nervous
system.
Genotoxicity and mutagenicity of hydroquinone has been extensively studied but clear conclusion could
not be made. While the standard Ames assay was negative, sister chromatide exchange, chromosomal
aberrations, mouse lymphoma assay and micronucleus test were positive after treatment with
hydroquinone. Unambiguous conclusion based on these results could not be made. Firstly, doses of the
hydroquinone used in the studies are much higher than is expected clinical dose after administration of
bearberry leaf extract. Secondly, in the
in vivo
studies hydroquinone was mainly administered
intraperitoneally. In case of oral administration results were often negative and toxic effects described
as mild. Further hydroquinone is naturally occurring substance and human body is commonly exposed
to this substance. Hydroquinone is present in coffee, tea or pears and low parts-per-million levels are
detectable in human body. Finally, after administration of bearberry leaf extract or arbutin
hydroquinone has been detected in human urine only in several studies and in very small amount.
After administration of bearberry leaf extract free hydroquinone in amount exceeding the detection
limit (1
g /ml – HPLC method) was found only at pH = 8. It should be also considered that
administration of bearberry leaf to humans is limited to very short period and the time of exposure of
human body to hydroquinone is also very short since it is rapidly transformed to its inactive and
nontoxic metabolites that are excreted via urine.
Free hydroquinone showed no mutagenetic risk in several
in vitro
and
in vivo
assays. The potential
mutagenicity of free hydroquinone occurred only at concentrations that excess more than 20 times the
maximal theoretical concentration reached in an animal or human organism (2.4 mg/kg; when all
arbutin was transformed in free hydroquinone). As a response to this possibility the organism has a
potent conjugation metabolism to neutralize the hydroquinone just after its formation.
Safety margin could be considered sufficient regarding toxicity and adverse effects.
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Further it should be considered that available data did not report any serious adverse and toxicity
effects in animals after administration of arbutin or hydroquinone doses relevant for human use and
assessment of human safety.
Provided that no adverse toxic reactions have been reported in scientific literature together with the
fact that several types of bearberry leaf extract are used for long period of time, non-clinical data on
bearberry leaf extract and its main components arbutin and hydroquinone can be considered sufficient
to support traditional use of herbal preparation bearberry leaf extract in the short term treatment of
mild lower urinary tract infections.
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
Bearberry leaf extract
The antiseptic and diuretic properties claimed for bearberry leaf extract can be attributed to the
hydroquinone derivatives, especially arbutin. Arbutin is absorbed from the GI tract virtually unchanged
and during renal excretion is hydrolysed to yield the active principle, hydroquinone, which exerts
antiseptic and astringent action on the urinary mucous membranes (Frohne, 1970).
The crude extract of bearberry leaf is reported to be more effective as an astringent and antiseptic
than isolated arbutin. This may be due to the other hydroquinone derivatives, in addition to arbutin,
that are present in the crude extract and which will also yield hydroquinone. It has been stated that
the presence of gallic acid in the crude extract may prevent
-glucosidase cleavage of arbutin in the GI
tract before absorption, thereby increasing the amount of hydroquinone released during renal
excretion (Herbal Medicines, 2008).
Pharmacodynamic drug interactions
Bearberry leaf extract
There were no drug interactions documented for bearberry leaf extract (Herbal Medicines, 2008).
However, it was observed that the sodium sparing effect of bearberry leaf extract may offset the
diuretic effect of thiazide and loop diuretics (Gruenwald et al. 2004).
Five bearberry leaf products were tested to determine their influence on CYP 3A4, 3A5, 3A7, 2C19 and
CYP19-mediated metabolism
in vitro,
as well as on p-glycoprotein efflux activity within human THP-1
and Caco-2 cells. There was difference in the range of inhibition of 3 isozymes of CYP3A family caused
by water extract of uvae-ursi. The degree of inhibition, from most to least, was in the order CYP3A5 >
CYP 3A7 > CYP3A4. Although CYP3A4 was inhibited to a lesser degree than CYP3A5 or CYP3A7, such
an inhibitory effect would likely have a greater influence on the elimination of xenobiotics as a result of
its biological importance. Methanolic extract inhibited P450 enzymes to lesser extent compared to the
water extract. From the pharmacology point of view the interaction of bearberry leaf extract with CYP
isozymes should be carefully considered (Chauhan et al. 2007).
Arbutin
In a study without controls, urine samples from healthy volunteers were collected 3 hours after oral
administration of 0.1 or 1.0 g arbutin. The urine samples (adjusted to pH 8.0) and 20 antibacterial
compounds (at their usual urine concentration) were tested
in vitro
using 74 strains of bacteria,
including
Escherichia coli
,
Proteus mirabilis
,
Pseudomonas aeruginosa
and
Staphylococcus aureus
. Only
arbutin (present in urine samples collected after administration of 1.0 g arbutin), gentamicin and
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nalidixic acid were active against all the strains tested. Antibacterial effect was observed also at 10-fold
lower doses of arbutin (0.1 g). Maximum effect was detected from 3 to 4 hours post-dose. Sample of
alkaline urine alone did not show any antibacterial effect. It could be concluded that metabolic products
of arbutin are responsible for antibacterial effect of uva-ursi leaves but these substances are active
only in alkaline urine (Kedzia, 1975; Frohne, 1977; WHO, 2002).
Oral administration of arbutin (800 mg) or an infusion of the leaves containing an equivalent amount of
arbutin to healthy volunteers had strong antibacterial activity, as measured in urine samples after
adjustment of the urine pH to 8.0 (Frohne, 1970). With respect to the slight toxicity of arbutin its
metabolic product could be used as an effective antibacterial substance in alkaline environment against
bacterial infection of urinary tract (Frohne, 1977).
The antibacterial effect of bearberry leaf extract according to the hypothesis formulated already in
1883 is ascribed to hydroquinone which is liberated from arbutin via glycoside cleavage. Therefore,
arbutin is the prodrug of the relatively toxic active principle hydroquinone. In the case of arbutin,
hydrolyzed by
-glucosidase, the formed aglycone hydroquinone may possibly be absorbed already in
the intestine or in the liver and detoxified through conjugation with glucuronic acid or sulfuric acid,
these conjugates do not have antibacterial activity, but they can be hydrolyzed by bacterial enzymes
(Frohne, 2004).
Hydroquinone
In urine hydroquinone exists in form of glucuronide and after alkalinization of the urine it splits to free
form having antibacterial activity (ESCOP, 2003).
It is still unknown which of the hydroquinone compound is responsible for the antibacterial effect.
Investigation data revealed that hydroquinone glucuronide could not be responsible for antibacterial
activity since its maximum in urine was detected 2 hours after administration of arbutin and maximum
antibacterial activity of urine was observed at 3-4 hours post-dose. This led to the conclusion that the
most probable compound responsible for the antimicrobial activity could be hydroquinone sulphate
instead of hydroquinone glucuronide (Kedzia, 1975).
Alkalization of urine
Urine samples from patients received arbutin-containing tea or pure arbutin showed after alkalinization
of the urine inhibition of growth of bacteria tested. Samples of normal urine and arbutin-containing
samples with or without alkalinization did not show any antibacterial activity (Frohne, 1970). It has
been experimentally proven that pH value of the urine sample is very important for its antibacterial
activity. Antibacterial effect of arbutin was increased and prolonged in alkaline urine pH 8.0 (when
compared to the urine sample at pH 6) (Kedzia, 1975).
Urine with high content of metabolic products of arbutin leaving on the air clearly showed low potency
for bacterial infections compared to the control urine sample. Bacterial culture incubation (
E. coli
and
Staphylococcus aureus
) showed clear inhibition effect of urine containing metabolic products of arbutin.
This urine sample has to be alkaline. Alkalization alone or addition of arbutin alone did not show any
bacteriostatic effect in the sample of urine (Frohne, 1977).
Whether the alkalizing of the urine – which, through the administration of sodium hydrogen carbonate,
can be attained only short-term – also has the same effect
in vivo
, is doubtful. In any case,
measurable levels of hydroquinone have not been detected in the urine (Paper et al. 1993; Frohne,
2004).
Concerning this the only problem is the way of making urine environment more alkaline. The common
daily dose of natrium hydrogencarbonate or dinatrium phosphate is able to alkalinize urine only for a
short period of time. Kedzia et al. (1975) suggested using of diuramid which is able to make urine
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alkaline for longer period; however, due to its toxicity it could be administered only for 3 or 4 days.
Further investigation of how to alkalinize urine in much more effective manner is necessary (Frohne,
1977).
Since concomitant acidification of the urine (by other remedies) may result in a reduction of its
antibacterial efficacy; patients have been advised to avoid eating highly acidic foods, such as acidic
fruits and their juices during treatment with Uvae Ursi folium (WHO, 2002; Barnes, 2002; ESCOP,
2003; Gruenwald et al. 2004).
However, a study from 2003 demonstrated that bacteria causing urinary tract infections participate in
the deconjugation of arbutin and liberate the toxic free hydroquinone. The free hydroquinone then can
damage the cell by destabilization of its membranes. Alkalization of the urine by intake of bicarbonate
is not necessary considering the effective bacterial deconjugation by
E. coli
, the principal agent in
urinary infections (Siegers, 2003).
4.1.2. Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
Major constituent of
Uvae ursi folium
extracts is arbutin, a phenolic glycoside which is broken down to
yield hydroquinone and glucose (Jahodář et al. 1985). Free hydroquinone is the recognized active
substance at the site of drug action that is the lower urine tract. The total amount of hydroquinone
(free hydroquinone and conjugated hydroquinone) in urine is considered crucial for the therapeutic
activity of the herbal extract. Therefore, pharmacokinetic studies have been mainly focused on the
availability of total hydroquinone in urine. The use of hydroquinone and arbutin as pharmacokinetic
markers is reasonable and justified (Paper et al. 1993; Schindler et al. 2002; Quintus et al. 2005).
Bearberry leaf extract
Four hours after ingestion of a single dose of a preparation containing bearberry leaf extract (945 mg
corresponding to 210 mg arbutin), 224.5 μmol/L hydroquinone glucuronide and 182 μmol/L
hydroquinone sulfate were recovered in the urine, which represented approximately half of the
administered arbutin dose (Glöckl et al. 2001).
In an open, randomized, two-way crossover study, 16 healthy volunteers (8 males, 8 females, mean
age of 25.4-years-old) received a single oral dose of bearberry leaf dry extract (BLDE) as film-coated
tablets (2 tablets containing 472.5 mg BLDE, corresponding to 105 mg arbutin) or as an aqueous
solution (945 mg BLDE, corresponding to 210 mg arbutin). Hydroquinone glucuronide and
hydroquinone sulfate were recovered in the urine during the first four hours but no metabolites were
detected after 24 hours. The rate of metabolism was faster in the group given BLDE in an aqueous
solution. The total metabolite concentration represented 66.7% of the administered dose in the tablets
and 64.8% in the solution. Hydroquinone glucuronide accounted for 67.3% and 70.3% of the total
arbutin metabolites recovered in each group, respectively (Schindler et al. 2002).
12 human volunteers (6 males and 6 females) received 3 x 2 dragees containing 238.7 – 297.5 mg of
bearberry leaf dry extract (DER 3.5 – 5.5:1, extraction solvent ethanol 60% V/V corresponding to
70 mg of arbutin) in one tablet. The urine was sampled for 36 hours and fractionated in periods of 6
hours. Free and conjugated hydroquinone was measured in the samples. Only 0.6% of the
administrated arbutin dose (420 mg) was excreted as free hydroquinone and in 6 out of 12 volunteers
no free hydroquinone was detected in urine (detection limit 0.3
g/ml), 70% of the arbutin dose was
found as hydroquinone conjugated to glucuronic and sulfuric acid.
Urine samples collected in this study were assayed with or without added glusulase (mixture of β-
glucuronidase, aryl-sulfatase and cellulase) or an
E. coli
suspension, and analyzed by HPLC for
hydroquinone content. Incubation of the urine with
E.coli
proved the ability of bacteria to deconjugate
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the hydroquinone glucuronide and sulphate to free hydroquinone. Deconjugation was 2.3-fold higher
than after incubation with glusulase (Seigers et al. 1997, 2003).
Arbutin
Arbutin was found to be extensively absorbed from the gastrointestinal (GI) tract and bioavailable as
hydroquinone. Volunteers (two males and two females, 36-45 years old) receiving a diet containing
high levels of arbutin and hydroquinone (coffee or tea, wheat cereal, whole wheat bread, wheat germ,
and Bosc pears) had significant increases in mean total hydroquinone (i.e., hydroquinone and its
conjugated metabolites) plasma levels. After 2 hours, it was 5-times the background concentration (at
0.15 μg/g [0.55 nmol/g]). Urinary total hydroquinone excretion rates were also significantly increased;
after two-three hours, levels were 12 times background levels. A low- hydroquinone diet (corn cereal,
2 % milk, cantaloupe, black cherry yogurt, and soft drink) resulted in a slight decrease in the mean
levels of hydroquinone in human plasma and urine (Deisinger et al. 1996).
Arbutin is a stable glucoside that is not hydrolyzed at pH 3.5 or 9.0. It has been investigated that
arbutin could be hydrolyzed enzymatically by virtue of
-D-glycosidase yielding to hydroquinone and
other phenol derivates (Kedzia, 1975).
Hydroquinone
Most studies of hydroquinone kinetics and metabolism following oral administration have used arbutin
or other form of bearberry leaf extract. For information on hydroquinone kinetics see sections above.
4.2. Clinical Efficacy
4.2.1. Dose response studies
Dose response has been investigated in healthy volunteers. Antibacterial effect has been observed
after administration of 0.1 or 1.0 g of arbutin. Lower dose provides lower antibacterial effect but
independently of the dose the pH value of urine was the most important factor determining the
antibacterial activity (Kedzia, 1975).
A study was performed of
-glucosidase extracellular activity of 225 strains of various species of
bacteria producing infections of the urinary tract as a condition of the antimicrobial action of arbutin.
The highest enzymatic activity was found in
Streptococcus, Klebsiella
and
Enterobacter
, and the lowest
activity in
Escherichia coli
. Direct dependence of the antimicrobial effect of arbutin on the level of the
enzymatic activity of microorganisms was found. The minimal bactericidal concentration of arbutin
ranges, in dependence of the microorganism species, form 0.4 to 0.8% (Jahodář et al. 1985).
According to Frohne (1970) effective concentration of arbutin should be higher than 0.3%.
Continuous long term use is not recommended in some sources (Blumenthal et al. 1998; Barnes et al.
2002; Bradley, 1992; ESCOP, 2003).
Recommended duration of use varies in the available literature sources from maximum 48 hours
(Barnes et al. 2002) to two weeks (ESCOP, 2003). It should not be used more than five times a year
without medical advice (Blumenthal et al. 1998).
4.2.2. Clinical studies (case studies and clinical trials)
Bearberry leaf extract
Clinical research assessing the effects of bearberry leaf extract as a single drug/preparation is not
available at this time.
Results of three controlled clinical trials with bearberry leaf extract in combination with other herbal
extracts are available.
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Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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In the first clinical trial effect of the combination product (combination of uvae-ursi folium, Betulae
folium, Equiseti herba, Virgauree herba, Juniperi fructus and Coccus cacti) in the treatment of urinary
tract infections and frequent /impared micturition was evaluated. Herbal preparation was compared to
the sulfonamide combination. Forty six patients suffering from acute urinary tract infection were
included in the trial. Both monitored symptoms were improved in the herbal treatment group. Authors
concluded that the treatment with the herbal combination demonstrated an improvement in micturition
and cured urinary tract infection in selected patients in a period of 3 weeks (Beeko et al. 1983). It
should be noted that the amount of bearberry leaf was relatively small in the tested preparation.
The effect on the treatment of urinary tract infection caused by a long term implantation of a urinary
catheter was evaluated in the open, controlled clinical study with 60 patients. Tested product -
combination of Uvae-ursi folium, Betulae folium, Equiseti herba and Solidaginis virgaureae herba- was
compared to trimethoprim-sulfamethoxazol. The effect of the product on the evaluated symptoms was
observed after 8 and 12 weeks of treatment compared to the antibiotic treatment with trimethoprim-
sulfamethoxazol (Albrecht J. and Kreyes G., 1988).
The third clinical study assessed prophylactic effect of another combination product (containing
hydroalcoholic extract of bearberry leaves with a standardized content of arbutin and methylarbutin,
and Dandelion root and leaves) on recurrent cystitis. The product had a prophylactic effect on
recurrent cystitis in a double-blind, prospective, randomized study of 57 women. The experiment led to
the conclusion that bearberry leaf extract is not the treatment of choice for acute cystitis but it could
have a possible prophylactic role in the treatment of recurrent urinary tract infections. However, this
conclusion cannot be made with certainty (Larsson et al. 1993).
Table 1 Overview of clinical studies with Uvae ursi folium preparations (combination products) in
urological indications:
Reference/Study
Number
Beeko et al.
1983
Albrecht and
Kreyes 1988
Albrecht and
Kreyes 1988
Study design
open,
controlled
compared to a
sulphonamide
combination
open, controlled
compared to
trimethroprim-
Sulfamethoxazol
controlled,
prospective,
randomised
double-blind
Number of
Patients
46
60
57
Specific
diagnosis
UTI
disorders of
micturition
UTI
>104 bacteria in
urine
symptoms: burning,
pain and pressure
feeling in the
bladder
cystitis
Preparation
used
Uvae ursi folium,
Betulae folium,
Equiseti herba,
Virgauree herba,
Juniperi fructus,
Coccus cacti
Betulae folium
,
Equiseti herba
,
Solidaginis
virgaureae herba,
Uvae ursi folium
Hydroalcoholic
extract of :
-
Uvae ursi
folium
-
Taraxacum officinalis, radix cum
herba
Dosage (daily)
3 teaspoons (15 ml) 3 x 5 ml
3 x 3 tablets
Duration of
administration
3 weeks
12 weeks
4 weeks
Criteria of
evaluation/
results
improved
micturate
disorders
UTI
improved
symptoms
(burning, pain and
pressure feeling in
the bladder) and
bacteriuria
prevent the
recurrence of
cystitis and
symptoms
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Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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Except for these controlled clinical trials there exist a final report summarizing clinical experience of 75
registered physicians in private practice with bearberry leaf extract preparations (both, mono and
combination products) in the treatment of urinary tract infections. The reported information was
obtained from a total of 186,122 patients during a period of 10 years (Schnitker, 1993). Treatment
effect of bearberry leaf medication on uncomplicated cystitis and urinary tract infections was evaluated
as very good or good by both patients and physicians. The mean time required to observe the efficacy
of the medication was 3 or 4 days for the group with uncomplicated cystitis or patients with urinary
tract infections, respectively. Mean treatment duration of 9 or 10 days for patients with uncomplicated
cystitis or urinary tract infections, respectively, complied with recommendation in existing
monographs.
4.2.3. Clinical studies in special populations (e.g. elderly and children)
There are no clinical studies in special population available for bearberry leaf extract or for arbutin.
4.3. Overall conclusions on clinical pharmacology and efficacy
Available controlled clinical trials evaluated the effect of bearberry leaf extract in combination with
other herbal substances. There are no clinical studies evaluating the efficacy of bearberry leaf extract
alone that would be suitable to support the well established use of this extract.
A report on the long-tem clinical experience with bearberry leaf extract in the treatment of
uncomplicated cystitis or urinary tract infections provide a compact data set supporting efficacy of the
bearberry leaf extract in the real clinical practise. However, although many patients were involved in
the report, the study is not acceptable to support WEU of bearberry leaf preparations as no real clinical
data (no results of laboratory findings, no description on inclusion criteria etc.) are included.
Based on results of
in vitro
tests on antimicrobial activity of bearberry leaf preparations containing
arbutin as a main active component and long standing use of bearberry leaf extract for treatment of
uncomplicated infections of the lower urinary tract, the traditional use of bearberry leaf extract in the
short-term treatment of uncomplicated lower urinary tract infections can be considered plausible.
Clinical significance of bearberry leaf extract administration with respect to the hydroquinone exposure
should be considered taking into account that even without administration of bearberry leaf extract
hydroquinone can be naturally found in the human body. Hydroquinone is naturally contained in coffee,
tea or wheat cereals.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
There is a lack of clinical safety and toxicity data for bearberry leaf extract and further investigation of
these aspects should be performed.
Bearberry leaf extract in combination with dandelion root and leaf extract, used in a treatment study of
57 women with recurrent cystitis, produced no side effects. At the end of one year of treatment, 5/27
women in the placebo group had a recurrence compared to 0/30 women in the treatment group.
Neither group reported side effects (Larsson et al. 1993).
5.2. Patient exposure
There are no special data on patient exposure to bearberry leaf extract or arbutin available.
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(L.) Spreng, folium
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Several cohort studies were performed with workers getting in daily contact with hydroquinone.
Workers were engaged in colour printing and processing, in a plant where hydroquinone was
manufactured, as litographers or in motion picture film processing.
Results of the study led to the conclusion that adverse effect could not be directly attributed to the
hydroquinone exposure the studies were mostly of poor quality. Some other substantial parameters
were not followed and evaluated such as cigarette smoking habits. Finally it should be considered that
many other chemicals are used in the examined working environment (McGregor, 2007).
5.3. Adverse events and serious adverse events and deaths
Internal use of Uvae ursi folium may cause nausea and vomiting due to stomach irritation from the
high tannin content (WHO monograph, 2002; Blumental et al. 1998; Gruenwald et al. 2004; British
Herbal Pharmacopoeia, 1996; ESCOP, 2003; Bradley, 1992). Stomachache has also been reported as
adverse effect (Gruenwald et al. 2004; Hänsel et al. 1993).
In a view of the high tannin content and toxicity of hydroquinone, prolonged use of bearberry leaf
extract may cause chronic liver impairment (Barnes et al. 2002; Herbal Medicines, 2008; Gruenwald et
al. 2004).
In persons with sensitive stomachs, nausea and vomiting are possible side effects after ingestion of
dried bearberry leaves (as low as 15 g). Other symptoms that have been reported in association with
bearberry leaf extract are irritability, insomnia, an increased heart rate (NTP, 2006).
Uvae ursi leaf extract use has also been linked to albuminuria, hematuria, and urine cast (Adesunloye,
2003; NTP, 2006).
In a 56-year-old female who drank tea containing bearberry leaf regularly for three years to prevent
recurrent urinary tract infection, bull´s eye maculopathy, paracentral scotomas, reduction in
electroretinography amplitude, and retinal thinning on optical coherence tomography were observed.
The maculopathy was suspected to result from bearberry leaf because of its ability to inhibit melanin
synthesis (NTP, 2006).
Due to the high tannin content of the leaves, the tea infusion tastes bitter and astringent which can
lead to nausea and vomiting in patients with sensitive stomachs. Hydroquinone appears to be non-
toxic with the administration of bearberry leaf tea; however, hydroquinone must remain in suspicion
with regard to having mutagenic and possibly carcinogenic effects (Frohne, 2004).
Uvae ursi folium should not be used for prolonged periods. Patients with persistent symptoms of a
urinary tract infection should consult a physician. Use of Uvae ursi folium may cause a greenish-brown
coloration of the urine that darkens on exposure to air due to the oxidation of hydroquinone (WHO,
2002).
5.4. Laboratory findings
Laboratory screening tests were performed before and after the treatment with bearberry leaf dry
extract as film-coated tablets (2 tablets containing 472.5 mg dry extract, corresponding to 105 mg
arbutin) or as an aqueous solution (945 mg dry extract, corresponding to 210 mg arbutin). These
included a differential blood count, prothrombin time (PT), partial thromboplastin time (PTT),
electrolytes (potassium, sodium, calcium, magnesium), blood glucose, urea, creatinine, bilirubin,
aspartate-amino-transferase, alanin-amino-transferase, gamma- glutamyl-transferase, alkaline
phosphatase, alpha-amylase, total protein, albumin, C reactive protein, triglycerides, cholesterol, and
semiquantitative urinalysis. After the treatment period, the laboratory parameters were screened again
except for PT, PTT, triglycerides, and cholesterol. There were no unexplained pathologic laboratory
Assessment report on
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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results that were suspected to be result of the treatment with bearberry leaf dry extract (Schindler,
2002).
5.5. Safety in special populations and situations
Safety of bearberry leaf extract in human is mainly based on the traditional use. There are only several
clinically reliable data regarding safety of the extract after administration in human.
Pediatric population
No data available. Use in children and adolescents is not recommended because data are not sufficient
and medical advice should be sought.
Overdose
An overdosing with bearberry leaf extract can lead to inflammatory irritation of bladder and urinary
tract mucosa accompanied with disuria and hematuria, or later with blood excreta. Finally overdosing
with the drug could lead to liver damage (hepatic impairment) (Gruenwald et al. 2004; Hänsel et al.
1993).
Extremely high doses of bearberry leaf extract (i.e., ten times the recommended amount) can cause
ringing in the ears, shortness of breath, convulsions, collapse, delirium, and vomiting. Liver damage is
a risk with long-term use (NTP, 2006).
Large doses of bearberry leaf extract are reported to be oxytocic, although
in vitro
studies have
reported a lack of utero-activity. In view of the potential toxicity of hydroquinone, the use of bearberry
leaf extract during pregnancy and lactation should be avoided (Herbal Medicines, 2008; Barnes, 2002).
Hydroquinone is reported to be toxic if ingested in large quantities: 1g (equivalent to 6-20 g of plant
material) has caused tinnitus, nausea and vomiting, sense of suffocation, shortness of breath,
cyanosis, convulsions, delirium and collapse. A dose of 5 g (equivalent to 30-100 g of plant material)
has been proved to be fatal (Herbal Medicines, 2008).
Long-term use
A. Uva-ursi
is not for unsupervised prolonged use (Gruenwald et al. 2004).
Long-term use of higher doses of bearberry leaf or its extracts could lead to the chronic poisoning with
following adverse effects: haemolytic anemia, emaciation, steatosis and depigmentation of hair (Hänsel
at al., 1993).
Prolonged use of Uvae ursi folium to treat urinary tract infection is not advisable since it may lead to
liver damage. Patients in whom symptoms persist for longer than 48 hours should consult their doctor
(Barnes, 2002).
Uvae ursi folium should not be used for prolonged periods. Patients with persistent symptoms of a
urinary tract infection should consult a physician (WHO, 2002).
Free hydroquinone could lead to the hepatic impairment especially in children after long-term use
(Hänsel et al. 1993).
Contraindications
Individuals with kidney disorders (WHO, 2002; British Herbal Pharmacopoeia, 1996; ESCOP, 2003),
with irritated digestive disorders and acidic urine should not take bearberry leaf extract (Gruenwald et
al. 2004).
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5.6. Overall conclusions on clinical safety
Available information leads to the conclusion that bearberry leaf extract corresponding to the 800 mg
of hydroquinone derivatives calculated as arbutin per day used for one week can be considered safe for
human use.
Patients using bearberry leaf extract should strictly follow recommendation on dose and length of use
since there is still the possibility of mutagenic effect of hydroquinone especially on the urinary tract.
6. Overall conclusions
Bearberry leaf extract has been documented to be used for a long period of time which supports the
traditional use of the herbal substance. Scientific evidence of its efficacy and safety in human is very
poor and considered insufficient to support well established use of the herbal substance extract.
Non-clinical data available from the published literature could be considered sufficient to support
traditional use for treatment of early sypmtoms of mild urinary tract infections such as burning
sensation during urination and/or frequent urination.
Clinical data describing pharmacology, efficacy and safety of any bearberry leaf extract or its main
component arbutin are very limited and provide only basic grounds for scientific evaluation of safety
and efficacy in humans.
The risk-benefit ratio can be considered positive. Long tradition of use of bearberry leaf extracts in the
treatment of uncomplicated bacterial infection of lower urinary tract, absence of serious adverse effects
directly attributable to bearberry leaf extracts and results of non-clinical
in vitro
and
in vivo
experiments proving antimicrobial activity are benefits supporting the use of bearberry leaf extracts as
traditional herbal preparation.
The only risk apparent from the available literature is the toxicity of hydroquinone. This substance
when used in large amount has been reported toxic to animals and also mutagenic in some
in vitro
and
in vivo
tests. However, the amount of hydroquinone corresponding to the recommended dose of
bearberry leaf extract is considered to be safe in short-term use.
In conclusion, the following points should not be omitted in the risk/benefit assessment.
Hydroquinone could be naturally present in the human body. It occurs in coffee, tea or wheat cereals.
In any of the presented studies hydroquinone above 1 mg/ml was not detected in the samples. This
amount is very close to the most conservative TTC value and together with limited period of
administration the risk benefit ratio can be considered positive.
Most of the animal experiments were performed in healthy animals. This is important because there is
no or a very low level of pathological bacteria in urinary tract of healthy animals resulting in very low
level of
-glycosidase in the organism.
-glycosidase is an enzyme causing decomposition of arbutin to
hydroquinone as was described in several
in vitro
studies.
Administration of bearberry leaf to humans is limited to very short period and the time of exposure of
human body to hydroquinone is also very limited since it is rapidly transformed to its nontoxic
metabolites that are excreted via the urine.
Nevertheless, as a precautionary measure, use in pregnancy and during lactation should be avoided.
Use in children and adolescents is not recommended as medical advice should be sought in this age
group.
Assessment report on
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
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Due to inadequate data on genotoxicity and unclear pharmacokinetic properties of arbutin an inclusion
in the Community list of herbal substances, preparations and combinations thereof for use in
traditional herbal medicinal products cannot be recommended.
Annex
List of references
Assessment report on
Arctostaphylos uva-ursi
(L.) Spreng, folium
EMA/HMPC/573462/2009
Page 32/32
Source: European Medicines Agency
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