Bearberry Leaf – Uvae ursi folium (Arctostaphylos uva-ursi (L.) Spreng.)
|Latin name of the genus:||Uvae ursi folium|
|Latin name of herbal substance:||Arctostaphylos uva-ursi (l.) spreng.|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Bearberry leaf|
Latin name of the genus: Uvae ursi folium
Botanical name of plant: Arctostaphylos uva-ursi (L.) Spreng.
English common name of herbal substance: Bearberry Leaf
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Bearberry leaf (Uvae ursi folium) consists of whole or cut, dried leaf of Arctostaphylos
The leaf, shiny and dark green on the adaxial surface, lighter on the abaxial surface, is generally 7- 30 mm long and
a)Comminuted herbal substance as herbal tea
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)
e)Liquid extract (DER 1:1), extraction solvent ethanol 25% V/V
Principal constituents of the herbal substance
(Bradley 1992; ESCOP 2003; British Herbal Pharmacopoeia 1996; Gruenwald et al., 2004; Barnes et al., 2002; Frohne 2004; Hänsel et al., 1993; Britton and Haslam, 1965; Frohne, 1977; Jahodář et al., 1978):
Hydroquinone derivatives: arbutin
The amount of arbutin and methyl arbutin is related to the photometric method with
Polyphenols (tannins): 10 – 20%, gallotannins including
Phenolic acids: approximately 0.25% in free form, mainly gallic,
Flavonoids: hyperoside (0.8 – 1.5%),
Iridoid glucoside: monoterpein (0.025%)
Triterpenes: 0.4 – 0.8%, including ursolic acid, uvaol,
Other constituents: allantoin, resin (e.g. ursone), volatile oil (trace) and wax
•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.
1.2. Search and assessment methodology
Databases and other sources used to research available pharmaceutical,
Relevant articles and references retrieved from databases: PubMed, MEDLINE, Embase, Biosis, SciSearch, TOXNET. Search term: Arctostaphylos, bearberry leaves, Uvae ursi folium.
Literature was provided by AESGP in response to the call for scientific data in January 2016.
Libraries: EMA library, library of the State Institute of Drug Control, Prague.
Textbooks, pharmacopoeias and monographs.
A literature search was performed in April 2016.
2. Data on medicinal use
2.1. Information about products on the market
2.1.1. Information about products on the market in the EU/EEA Member States
Information on medicinal products marketed in the EU/EEA
According to the information provided by the National Competent Authorities in the overview of the marketed products, the following herbal substances/preparations have been marketed in the EU/EEA.
Table 1: Overview of data obtained from marketed medicinal products
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
Information on relevant combination medicinal products marketed in the EU/EEA
Combination products which indications are the same or similar to the monocomponent products reported by the Member States:
−Extract of Uvae ursi folium, Millefolii herba, Agrimoniae herba, Urticae folium, Equiseti herba, Betulae folium, extraction solvent 20% ethanol (DER 1:4) – tincture; indication: mild urinary infections, cystitis or inflammations of the lower urinary tract due to sitting on a cold place; HU since 2001, reclassified to TU 2012.
−Sugar coated tablets containing 80 mg of extract (as dry extract) from bearberry leaf (Arctostaphylos
−Oral drops containing 715 mg of tincture from fresh bearberry herb (Arctostaphylos
−Oral liquid containing 0.875 ml of extract (as liquid extract) from couch grass herb (Agropyron repens (L) Beauv., herba) (1:1), extraction solvent: water; 0.5 ml of extract (as liquid extract) from Marshmallow root (Althaea officinalis L., radix) (1:1), extraction solvent: water; 1.125 ml of (as liquid extract) from Buchu leaf (Agathosma betulina (Berg) Pillans, folium) (1:2.5), extraction solvent: ethanol 25% V/V; 0.16 ml of extract (as liquid extract) from bearberry leaf (Arctostaphylos
Bearberry leaf is a component of many herbal teas marketed in the Member States with the same or similar indication as monocomponent products and the
−Uvae ursi folium, Equiseti herba, Myrtilli herba, Matricariae flos, Sambuci flos, Solidaginis herba, Thymi herba; indication: An adjuvant for treatment of symptoms of mild lower urinary
tract infections such as burning sensation during urination and frequent urination; Czech Republic, on the market since 1969, switched to TU in 2011, SK since 1969
−Urticae folium, Uvae ursi folium, Betulae folium, Juniperi
−Betulae folium, Uvae ursi folium, Ononidis radix, Petroselini radix, Polygoni avicularis herba, Sambuci nigrae flos, Urticae herba, Millefolii herba; indication: used as an adjuvant for treatment of symptoms of mild lower urinary tract infections such as burning sensation during urination and frequent urination; Czech Republic, on the market since 1969, switched to TU in 2011
−Betulae folium, Uvae ursi folium, Herniariae herba, Menthae piperitae herba, Ononidis radix, Petroselini radix; indication: used as an adjuvant for treatment of symptoms of mild lower urinary tract infections such as burning sensation during urination and frequent urination; Czech Republic, on the market since 1995, switched to TU in 2011
−Uvae ursi folium, Betulae folium, Orthosiphonis folium, Solidaginis virgaureae herba; indication: used for flushing of the urinary tract as supportive treatment of recurrent infections after serious conditions have been excluded; Austria – TU since 2012
−Uvae ursi folium, Betulae folium, Orthosiphonis folium, Solidaginis virgaureae herba; indication: used for flushing of the urinary tract as an adjuvant in minor urinary complaints and to decrease sedimentation of renal gravel; Germany, TU since 2013
−Betulae folium, Graminis rhizoma, Solidaginis gig. herba, Ononidis radix, Liquiritiae radix; indication: used for adjuvant treatment in mild inflammation (catarrh) of the bladder and the renal pelvis; DE – Standard Marketing Authorisation (Blasen- und Nierentee II), since 1987
−Uvae ursi folium, Ononidis radix, Orthosiphonis folium, Graminis rhizoma; indication: to increase the amount of urine in inflammation (catarrh) of the lower urinary tract, to prevent formation of renal gravel and uroliths; Germany – Standard Marketing Authorisation (Blasen- und Nierentee IV), since 1988
−Uvae ursi folium, Phaseoli fructus, Solidaginis gig. herba, Orthosiphonis folium; indication: used for adjuvant treatment in mild inflammation (catarrh) of the bladder and the renal pelvis; DE – Standard Marketing Authorisation (Blasen- und Nierentee V), since 1988
−Uvae ursi folium, Betulae folium, Graminis rhizoma; indication: used for adjuvant treatment in mild inflammation (catarrh) of the bladder and the renal pelvis; Germany – Standard Marketing Authorisation (Blasen- und Nierentee VII), since 1988
Information on other products marketed in the EU/EEA (where relevant)
2.1.2. Information on products on the market outside the EU/EEA
2.2. Information on documented medicinal use and historical data from literature
Bearberry leaves use is for the first time literally documented in the Middle Ages in the Welsh “Physicians of Nyddfai” from the 13th 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 a 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
18th century. From the beginning of 19th century, bearberry is in official use. It was used for treatment of various diseases such as hydrops, lithiasis, in diabetes, for the therapy of gonorrhoea, etc. Until now only the use as urinary tract antiseptic and diuretic remains. Bearberry leaf was used also in the “New World” by the North American Indians for the 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 DAB 6. Ausgabe (1926), Československý lékopis 1. vydání (1947), Hagers Handbuch der Pharmazeutischen Praxis (Frerichs et al., 1938), Pharmacopoea Helvetica V (1953), Österreichisches Arzneibuch ÖAB 9. Ausgabe (1960), Martindale- The Extra Pharmacopoeia (Wade 1977), Deutsches Arzneibuch DAB 9. Ausgabe (1986), the Complete German Commission E Monographs (Blumenthal et al., 1998), WHO monographs on selected medicinal plants 2002, ESCOP Monographs 2003 and European Pharmacopoeia 9.0 (2017). Bearberry leaf is traditionally used for the treatment of urinary tract disorders.
The following traditional uses and posologies have been recorded for bearberry leaf
The Complete German Commission E Monographs (Blumenthal et al., 1998)
Uses: inflammatory disorders of the efferent urinary tract. Posology: 3 g drug to 150 ml water as an infusion or cold macerate or
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. Posology: 3 g of the drug/150 ml in a form of infusion or cold macerate 3 to 4 times daily; 400 – 840 mg hydroquinone derivatives; other preparations accordingly calculated as arbutin. Duration of use: Not to be used for prolonged period. Patients have been advised to avoid eating highly acidic foods and to drink plenty of fluids.
ESCOP Monographs (2003)
Therapeutic indications: uncomplicated infections of the lower urinary tract such as cystitis, when antibiotic treatment is not considered essential. Posology: cold water infusions of the dried leaf corresponding to 400 – 800 mg of arbutin per day, divided into 2 to 3 doses; equivalent preparations; not recommended for children. 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. Patients should be advised to consume plenty of liquid during the treatment; alkalisation of the urine may be beneficial. Interactions with other drugs: concomitant acidification of the urine (by other remedies, for instance) may result in a reduction of efficacy
British Herbal Pharmacopoeia (1983)
Indications: acute catarrhal cystitis with dysuria and highly acid urine
Posology: dried leaves 1.5 – 4 g three times daily or by infusion; concentrated infusion (BPC 1934)
British Herbal Compendium (Bradley, 1992), British Herbal Pharmacopoeia (1996)
Indications: mild infections of the urinary tract. Posology: three to four times daily 1.5 – 2.5 g dried leaf, in infusion or cold aqueous extract; liquid extract (1:1) extraction solvent ethanol 25% V/V 1.5 – 2.5 ml; tincture (1:5), extraction solvent ethanol 25% V/V 2 – 4 ml. Duration of use: short treatment (maximum of 7 days). An “alkaline„ diet, high vegetables and fruit, should be taken during treatment.
Herbal Medicines. A guide for healthcare professionals (Barnes et al., 2002)
Barberry is a diuretic and astringent and has been stated to exert an antiseptic effect on the urinary tract. Traditionally, it has been for cystitis, urethritis, dysuria, pyelitis, lithuria, and specifically for acute catarrhal cystitis with dysuria and highly acidic urine. Posology: dried leaves 1.5 – 4.0 g as an infusion three times daily; liquid extract (1:1), extraction solvent ethanol 25% 1.5 – 4.0 ml three times daily.
Martindale Extra Pharmacopoeia (Wade, 1977)
Barberry is a diuretic and astringent and has been stated to exert an antiseptic effect on the urinary tract. Posology: fresh infusion (1 in 20)
PDR for Herbal Medicines (Gruenwald et al., 2004)
Indications: infections of the urinary tract – for inflammatory disorders of the efferent urinary tract Posology: 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 form of an infusion or cold macerate up to 4 times daily or 400 – 840 mg hydroquinone derivatives calculated as
Standard Zulassungen 1996 (Bärentraubenblätter monograph dated 1986), Hagers Handbuch der Pharmazeutischen Praxis (Hänsel et al., 1993)
Indications: used as an adjuvant in therapy of bladder and renal pelvis catarrhs. Posology: 1 cup of a decoct prepared from 1 teaspoon (approximately 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. 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. Interaction with other drugs: should not be taken together with drugs that cause acidic urine.
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.
Hagers Handbuch der Pharmazeutischen Praxis (Kern et al., 1972)
Indications: as a disinfectant in disorders of the urinary tract, particularly in chronic urethral and bladder catarrh. Posology: 1.3 – 4 g of the pulverised drug or as a decoction prepared from 1.5 g of the herbal substance per one cup, daily dose 10 to 15 g.
Český lékopis (2005)
Posology: single dose 3 g, daily dose 12 g. Duration of use: maximum 2 weeks.
Table 2: Overview of historical data
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 table 3:
The content of tannins has not been taken into consideration by Frohne (1970).
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, and the fact that the adverse reactions (gastrointestinal complaints) are in literature attributed to tannins content (Frohne, 2004; Hänsel et al., 1993; ESCOP, 2003), the following instruction is recommended:
To make an herbal infusion, pour 150 ml of boiling water over 1.5 – 4 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 – 4 g of the comminuted herbal substance and steep for minimum 30 minutes stirring frequently. The macerate should be used immediately after preparation.
2.3. Overall conclusions on medicinal use
Traditional medicinal use of Arctostaphylos
Table 4: Overview of evidence on period of medicinal use
The following indication is proposed for the European Union Monograph:
Traditional herbal medicinal product used for relief 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.
A daily dose 10 to 15 g of comminuted and powdered herbal substance is reported in several literature sources. The HMPC decided to keep for the comminuted herbal substance the daily dose of 8 g as approved in the previous version of the monograph and for powdered herbal substance to use the posology from the only marketed French product for which 30 years of medicinal use have been demonstrated. In addition, it is considered not advisable to increase the daily dose up to 15 g per day due to the fact that bearberry leaves contain relatively high amount of tannins, which are reported as responsible for gastrointestinal undesirable effects of bearberry leaf products (Frohne, 2004; Hänsel et al., 1993; ESCOP, 2003). The daily dose of liquid extract (DER 1:1), extraction solvent ethanol 25% (V/V) has been adapted to maximum 8 ml to be in line with the posology for comminuted herbal substance from the same reason as described above.
Two water extracts with DER
Based on the literature data and information received from the Member States and conclusions above, the following posologies are suggested:
Comminuted herbal substance
Female adults and elderly:
Powdered herbal substance
Female adults and elderly: 700 – 1050 mg twice daily, the maximum daily dose 1.75 g
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)
Dry extract (DER 2.5 – 4.5:1), extraction solvent water, containing 20 – 28% of hydroquinone derivatives calculated as anhydrous arbutin (spectrophotometry)
Female adults and elderly: Single dose corresponding to
Liquid extract (DER 1:1), extraction solvent ethanol 25% (V/V)
Female adults and elderly: 1.5 – 4 ml up to three times daily, the maximum daily dose 8 ml.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
3.1.1. Primary pharmacodynamics
Bearberry leaf extract
A bearberry leaf extract (liquid extract 1:5, extraction solvent ethanol 70%) exhibited antimicrobial activity towards a variety of organisms including Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Mycobacterium smegmatis, Shigella sonnei and Shigella flexneri (Moskalenko, 1986).
A decoction of bearberry leaf (10 g/100 ml water) increased remarkably the hydrophobicity of both E. coli and Acinetobacter baumannii strains. There was no growth registered after the exposure of 20
different E. coli strains to the undiluted decoction of bearberry and in case of
The antimicrobial activity of an ethanol extract of the aerial parts of Arctostaphylos
activity corresponded to the activity of streptomycin; however, streptomycin is known to be less active against these bacteria (Holopainen et al., 1988).
Aqueous and methanolic (extracts of bearberry leaves (5 g of the pulverised drug extracted with 100 ml of the solvent, at the end lyophilised; test solution 20 mg/ml) inhibited the growth of Streptococcus mutans OMZ176 in vitro (Namba et al., 1981).
A 30% ethanol extract of Uvae ursi folium inhibited the growth in vitro of Bacillus subtilis, E. coli,
Pseudomonas aeruginosa, Salmonella typhimurium, Serratia marcescens and Staphylococcus aureus
(Leslie GB, Medita 1978 in WHO 2002).
Ethanol extract (no details on ethanol concentration and DER) was demonstrated not active against
Mycobacterium tuberculosis, Staphylococcus aureus and E. coli (Gottshall et al., 1949).
A methanol extract (5 g of the drug macerated in 25 ml of methanol for 24 hours and subsequently dried) has been proved active against Klebsiella pneumoniae, Candida albicans and Mycobacterium phlei at MIC (minimal inhibitory concentration) 4 g/l and against Staphylococcus aureus at MIC 2 g/l related to the dried plant, while a chloroform extract prepared by the same way was demonstrated inactive (Ríos et al., 1987).
A bearberry leaf extract (95% ethanol extract – herbal substance to solvent ratio 15:100) alone displayed no antimicrobial activity against any of the 25 bacteria tested (Dykes et al., 2003).
A bearberry aqueous extract (decoction 1:10/30 minutes at 100 °C; tannins content 19.2 mg/ml) exhibited activity to decrease cell surface hydrophobicity (CSH) as well as antibacterial activity against Helicobacter pylori. As tannic acid tested in parallel to bearberry leaf water extract exhibited similar results it is suggested by the author that tannic acid may be the component of the extract with the strongest effect in relation the CSH of Helicobacter pylori (Annuk et al., 1999).
Different extracts of bearberry leave (aqueous, ethanol and ethyl acetate extracts prepared from 10 g of plant material and 600 ml of the solvent in three equal portions of 200 ml and subsequently evaporated to dryness) were tested for their antimicrobial activity against ten Enterococcus faecalis and E. coli strains. The aqueous extract showed stronger antibacterial effect on E. coli than the other tested extracts, while effect on Enterococcus faecalis were similar for all three extracts. Generally, extracts exhibited stronger antibacterial activity against
Aqueous and ethanol extracts from Arctostaphylos
An ethanol extract from Arctostaphylos
In an experimental study 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 methanol extract, a dry aqueous extract, a decoction and an aqueous suspension of the pulverised drug (no details on preparations are available). The starting herbal substance contained 1.5% of total flavonoids. Preparations of Uvae ursi folium inhibited diuresis (Borkowski, 1960 – abstract).
Additionally, no diuretic effect of Uvae ursi tea is reported by Weiss (1985). However, the author did not provide any references supporting this statement.
Contrary to the
Diuretic effect of crude aqueous extract of Arctostaphylos
Arbutin and hydroquinone
The antimicrobial activity of arbutin towards bacteria implicated in urinary tract infections was found to be directly dependent on the
Arbutin (at concentration 0,5% m/V) after its hydrolysis to hydroquinone showed inhibition of the growth of Ureaplasma urealyticum and Mycoplasma hominis in vitro (Robertson and Howard, 1987).
Table 5: Overview of the main
3.1.2. Secondary pharmacodynamics
Bearberry leaf extract
The effect of a 50% methanolic extract from bearberry leaf on the
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 and Willuhn, 1978; WHO, 2002).
The effect of a 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 the tyrosinase activity. Furthermore, 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 did not show any uterotonic effect (Shipochliev, 1981).
Addition of an infusion of the leaves to the
In mice orally or i.p. treated with arbutin
Male and female cats (none anaesthetised) were administered oral (p.o.) and intraperitoneal (i.p.) doses of 50 and 100 mg/kg [0.18 or 0.367 mmol/kg] body weight arbutin in water and observed at
Arbutin (in concentrations 90 g/ml and 40 g/ml) did not inhibit the growth of rat hepatoma cells (Assaf et al., 1987).
Potential of arbutin to protect
Effects of arbutin on TCCSUP human bladder carcinoma cell proliferation has been tested by Li et al.,
2011. Arbutin did not exhibit any cytotoxic effects in TCCSUP cells at concentrations < 500 μg/ml. To determine the effects of arbutin on cell proliferation, TCCSUP cells were treated with arbutin at various concentrations, and the cell proliferation was measured using the MTT assay. Arbutin significantly decreased TCCSUP cell proliferation in concentration- and
regulation. Results of the study suggest that arbutin inhibits TCCSUP cell proliferation via ERK inactivation and p21
There are study results providing information that arbutin (2.5, 12.5, or 50 μg/ml [9.2, 45.9, 180 μM]) incubated for 4 days weakly inhibited the growth of human colon carcinoma
3.1.3. Safety pharmacology
Bearberry leaf extract
Safety profile of crude extract of bearberry leaves in rabbits has been investigated. Dry ethanolic extract (DER 11:1; extraction solvent ethanol, concentration not specified) was administered orally for 90 days in male and female rabbits and haematology, biochemistry parameters and histopathology changes were analysed after 90 days. In results of it
Effect of hydroquinone on liver has been studied in a study with rats exposed to 25 and 100 mg/kg body weight of hydroquinone per day for 13 weeks. No hepatotoxicity was observed (Williams et al., 2007, Garcia de Arriba et al., 2013).
In experimental studies, CNS symptoms were observed at hydroquinone oral doses close to lethal dose of 50% (LD50). Repeat dosing in rat and mouse studies caused tremors and reduced activity at doses
≥ 64 mg/kg and convulsions at doses ≥400 mg/kg. These effects were reversible when exposure was discontinued (NTP 1989, 2006, 2009, IARC 1999). Topping et al., 2007 found that tremors occurred within 1 hour following dosing of 64 to 200 mg/kg bw per day to female and male rats for 13 weeks without neuropathological changes.
An NOEL for all CNS effects was experimentally estimated at 20 mg/kg bw per day (IPCS1994, 1996, OECD/SIDS 2002, Garcia de Arriba et al., 2013).
Hydroquinone nephrotoxicity has been linked to the presence of
Hydroquinone administered via gavage for 6 weeks at 50 mg/kg bw to male F344 rats caused proximal tubular damage, as supported by increases in the rate of excretion of renal
There are no data on safety pharmacology of arbutin available at present.
3.1.4. Pharmacodynamic interactions
Bearberry leaf extract
In mice, Arctostaphylos
Water extracts from the leaf of Arctostaphylos
Arbutin plus indomethacin showed a stronger inhibitory effect than indomethacin alone in carrageenan- induced oedema and
Arbutin exhibited potent inhibitory effects on rat platelet aggregation induced by adenosine diphosphate (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).
Bearberry leaf extracts and arbutin were tested against several bacterial species, among them bacteria that are representative for uncomplicated urinary tract infections (e.g. E. coli, Shigella spp,
Streptococcus faecalis, Klebsiella spp, Enterobacter spp). It is not clear whether the inhibitory concentrations tested can be reached in human therapeutic conditions.
However, difference in metabolism of arbutin in humans and animals, and metabolism ambiguity of arbutin to hydroquinone should be taken into consideration.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Arbutin, the major constituent of Uvae ursi folium extracts, is a phenolic glycoside, which splits into hydroquinone and glucose (Jahodář et al., 1985). Hydroquinone is the recognised active substance at the site of drug action, which is the lower urine tract. The total amount of hydroquinone (free hydroquinone and hydroquinone conjugates) in urine is crucial for the antimicrobial activity of the herbal preparation. Therefore, human pharmacokinetic studies have been focused on the availability of
total hydroquinone in urine and the use of hydroquinone 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 the 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
Five bearberry leaf products (powdered leaves, powdered leaves in capsules, aqueous and methanol extracts; no additional information the extracts) were tested to determine their influence on CYP 3A4, 3A5, 3A7, 2C19 and
Female Wistar rats were given an aqueous solution of chromatographically pure arbutin, isolated from Arctostaphylos
The highest β−glucosidase extracellular enzymatic activity was found in the genera Streptococcus faecalis (100%), Klebsiella (95%), and Enterobacter (72%), the lowest in E. 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 from 0.4 to 0.8%, in dependence on the species of the microorganism (Jahodář et al., 1985).
Oral administration of arbutin (500 mg/kg [1.84 mmol/kg]) to female rats which were overloaded with fluid resulted in a
Investigations were performed in animals to elucidate the absorption, metabolism and elimination of arbutin. Isolated segments of the 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 has been also investigated in human small intestine obtained from biopsies of
18 patients with minor abdominal complaints without obvious gastrointestinal disease. In 3 patients,
Studies to determine the absorption, tissue distribution, excretion, and metabolism of [14C]- hydroquinone in male and female rats following single oral, repeated oral, or
Oral administration of [14C]hydroquinone either in the diet or by gavage to
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 (DiVincenzo et al., 1984, English et al., 1988 in McGregor 2007).
The oxidation of hydroquinone to the very reactive
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
In previous sections, it has been addressed that arbutin, a component of bearberry leaf extract is converted to free hydroquinone to exert its antibacterial effect. Based on the pharmacokinetic profile of arbutin, it has been shown that free hydroquinone 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 hydroquinone is eliminated via the urine and (<1%) in faeces. Most of the arbutin is therefore transformed in to hydroquinone conjugates (70%) (Siegers et al., 1997; 2003). Free hydroquinone is not accumulated in the animal or human
organism and its potential accumulation is not justified by any pharmacodynamic/pharmacokinetic reason (English and Deisinger, 2005).
The toxicology of free hydroquinone has been reconsidered in several published reviews and it was concluded that there is no evidence to suggest that the toxicity of free hydroquinone is of human relevance (Deisinger et al., 1996; DeCaprio, 1999; McGregor, 2007).
3.3.1. Single dose toxicity
Bearberry leaf extract
No data on single dose toxicity have been reported for bearberry leaf extract.
No data available.
The oral LD50 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 et 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 hydroquinone absorption. LD50 values for free hydroquinone by parenteral administration have been reported as 115 – 160 mg/kg in the rat and 190 mg/kg in the mouse (DeCaprio, 1999). In the course of toxicological animal experiments, free hydroquinone demonstrated a very low toxicity since LD50 values were very high. In addition, the presence of food importantly improves its safety.
3.3.2. Repeat dose toxicity
Bearberry leaf extract
No data on repeated dose toxicity have been reported for bearberry leaf extract.
Repeated dose toxicity of arbutin has been investigated in mice. At a dose of 8 g/kg [29.38 mmol/kg] administered i.p. for 2 weeks, no toxic effects were observed (Li et al., 1982 [Chinese]; NTP 2006).
Bearberry leaf extract
Uvae ursi folium (dry aqueous extract prepared by extraction of 50 g of powdered drug with 300 ml of solvent (40 °C/5 hours) and subsequently dried) has not been mutagenic in the Salmonella/microsome assay with S. typhimurium strains TA98 or TA100 as well as in the Bacillus subtilis
The cytogenetic effect of ethanolic (70%, DER not specified) 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 examined. The 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).
Arbutin (up to
The Ames test and the micronucleus test have been performed with urine containing arbutin. Results have shown no indication of genotoxicity related to arbutin (Siegers et al., 1997).
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 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)
The DNA reactivity of hydroquinone has been documented in animals and this enhanced activity is presumably due to the oxidised forms of hydroquinone,
Hydroquinone is generally not active in bacterial tests for mutation, but it has been reported to cause
Hydroquinone induced micronuclei and chromosomal aberrations in several studies in
as that used for the induction of renal tumours in F344 rats and, with less clarity, hepatocellular adenomas in male B6C3F1 mice (McGregor, 2007).
There are no germ cell studies of hydroquinone mutagenicity in which routes other than i.p. 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 i.p. administration because the inguinal canal remains open. The i.p. 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
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).
Bearberry leaf extract
No data available.
No data available.
The health effects of hydroquinone have been extensively reviewed in IPCS Environmental Health Criteria No. 157 and summarised in IPCS Health and Safety Guide No. 101 (IPCS, 1994; IPCS, 1996; NTP, 2006).
McGregor (2007) refers in his review to U.S. National Toxicological Program Study. In the 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. Nephropathy was observed in nearly all male and most female rats of all dosed groups and vehicle controls. The nephropathy was characterised 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 body weight per day) group, while in females no dose dependence was observed. Nephropathy had also been observed in males in earlier
group rats (p=0.069) and 8/55
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 end stage grades of severity at the high dose (Hard et al., 1997). 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
The histopathological reanalysis of the hydroquinone study (Hard et al., 1997, McGregor 2007) found that of the 8 tumours 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 tumours diagnosed by NTP were similar to the high dose tumours 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
3.3.5. Reproductive and developmental toxicity
Bearberry leaf extract
No data on reproductive and developmental toxicity is available.
Arbutin was administered subcutaneously at 25, 100 or 400 mg/kg of body weight daily to male and female
In the study, the maximum
The overall in vitro and animal toxicity database indicates that hydroquinone may cause maternal toxicity, which is essentially the same as that seen in
3.3.6. Local tolerance
No data available.
3.3.7. Other special studies
Oral application of arbutin (10 or 50 mg/kg [0.037 or 0.18 mmol/kg]) quickly reduced the swelling caused by picryl chloride and sheep red cell delayed type hypersensitivity in mice within 24 hours (Matsuda et al., 1990, 1991 [Japanese, abstract]). Arbutin (1 mg/ml [4 mM]) inhibited the binding of mouse monoclonal
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).
Growth of human melanoma cells and normal human melanocytes was not inhibited by exposure to
100 μg/ml [0.367 mM] arbutin for 5 days. At 300 μg/ml [1.10 mM] arbutin treatment for 5 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
The effects were similar to those seen with hydroquinone at 5 μM (Deysson & Truhaut, 1957; NTP, 2006).
Hydroquinone has been reported to show a
Bearberry leaf extract
There is almost no information available on the toxicity of crude extract of bearberry leaves. Bearberry water extract was evaluated in Ames test using only 2 instead of 5 recommended strains. Results of this study were negative; however, clear conclusion about mutagenicity of the extract could not be made.
Bearberry leaf ethanolic extract (extraction solvent ethanol 70%, DER not specified) was also negative in the in vitro micronucleus test; however, this test was not performed according to ICH S2B standard. Tests on reproductive toxicity and carcinogenicity have not been performed with bearberry leaves and/or preparation thereof.
Single dose toxicity study has not been performed with arbutin but repeat administration of doses much higher compared to that in 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. The Chinese hamster V79 mutation test performed with arbutin gave negative results. Whilst after preincubation of arbutin with
Carcinogenicity studies have not been performed with arbutin.
Reproduction and developmental studies performed in rats dosed with arbutin administered subcutaneously showed that 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 and a different route of administration was applied.
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 as 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. Furthermore, hydroquinone is a naturally occurring substance and the human body is commonly exposed to this substance. Hydroquinone is present in coffee, tea or pears and low parts-
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 neutralise the hydroquinone just after its formation.
The safety margin could be considered sufficient regarding toxicity and adverse effects.
Furthermore, 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.
No adverse toxic reactions at the doses comparable with the recommended dose of bearberry leaves have been reported in scientific literature and several types of bearberry leaf extract have been in medicinal use for many years. Therefore,
3.4. Overall conclusions on
The ability of bearberry leaf to act against urinary infections is probably the result of action of free hydroquinone cleaved from the arbutin molecule in the urinary tract. The cleavage is mediated via β- glycosidase as described in several in vitro tests.
Adequate tests on genotoxicity are not available
Carcinogenicity studies performed with extract of the Uvae ursi leaves and/or arbutin are not available. Toxicity tests with hydroquinone, a hydrolysis product of arbutin, have demonstrated some evidence of genotoxicity and carcinogenicity. However, risks posed by the exposure of hydroquinone during the
Reproductive toxicity with bearberry leaf or preparations thereof has not been studied. Nevertheless, arbutin, the principal component of Uvae ursi folium, displayed changes in body weight of female foetuses and in ovary weight in females at age 7 and 10 weeks after subcutaneous administration of the dose 400 mg/kg per day to rats before mating and during pregnancy and lactation. No effect on reproduction has been observed at doses of 100 mg/kg per day. No risk on male and female fertility and no deaths were observed in offsprings. However, the results of the study are considered irrelevant to clinical practice since low doses of arbutin were used and different route of administration was applied.
Oral administration of bearberry leaves can be regarded as safe at the recommeded doses.
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
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).
In a study without controls, urine samples from healthy volunteers were collected 3 hours after oral administration of 0.1 or 1 g arbutin. The urine samples (adjusted to pH 8) and 20 antibacterial compounds (at their usual urine concentration) were tested in vitro using 74 strains of bacteria, including E. coli, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus. Only arbutin (present in urine samples collected after administration of 1 g arbutin), gentamicin and nalidixic acid were active against all the strains tested. An antibacterial effect was observed also at
Oral administration of arbutin (800 mg) or an infusion of the leaves containing equivalent amount of arbutin to healthy volunteers had strong antibacterial activity against Staphylococcus aureus SG 511 and E. coli, as measured in urine samples after adjustment of the urine pH to 8.0. Urine of pH 6 was ineffective (Frohne, 1970). With respect to the slight toxicity of arbutin, its metabolic product could be used as an effective antibacterial substance in the alkaline environment against bacterial infection of the 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, hydrolysed by
In urine hydroquinone exists in a form of glucuronide and after alkalinisation of the urine, it splits to the free form having antibacterial activity (ESCOP, 2003).
It is still unknown which of the hydroquinone compounds are 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 to 4 hours
Pharmacodynamic drug interactions
Bearberry leaf extract
There were no drug interactions documented for bearberry leaf extract. 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). As information on sodium sparing effect is not supported by any published case report, this interaction is not included in the European Union herbal monograph.
Alkalisation of urine
Urine samples from healthy volunteers received
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 (when compared to the urine sample at pH 6) (Kedzia et al., 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 a clear inhibitory effect of urine containing metabolic products of arbutin. This urine sample has to be alkaline. Alkalisation alone or addition of arbutin alone did not show any bacteriostatic effect in the sample of urine (Frohne, 1977).
Whether the alkalising of the urine – which, through the administration of sodium hydrogen carbonate, can be attained only
A problem is the way of making the urine environment more alkaline. The common daily dose of natrium hydrogencarbonate or dinatrium phosphate is able to alkalinise urine only for a short period of time. Kedzia et al., 1975 suggested using acetazolamide which is able to make urine alkaline for longer period; however, due to its toxicity, it could be administered only for 3 or 4 days. Frohne stated that further investigation of how to alkalinise urine in a 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, several references included statements on patients being advised to avoid eating highly acidic foods, such as acidic fruits and their juices during treatment with Uvae ursi folium (WHO, 2002; Barnes et al., 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 destabilisation of its membranes. Alkalisation of the urine by intake of sodium bicarbonate is not necessary considering the effective bacterial deconjugation by E. coli, the principal agent in urinary infections (Siegers et al., 2003).
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
The main constituent of Uvae ursi folium extracts is arbutin, a phenolic glycoside, splits in hydroquinone and glucose (Jahodář et al., 1985). Pharmacokinetic studies have been mainly focused on the availability of total hydroquinone in the 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
After ingestion of the leaves, arbutin is absorbed from the GI tract, and is hydrolysed by intestinal flora to form the aglycone, hydroquinone (Paper et al., 1993). Hydroquinone is metabolised to glucuronide and sulphate esters that are excreted in the urine (Kedzia et al., 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). Their antibacterial action reaches a maximum approximately 3 – 4 hours after ingestion (Blumenthal et al., 1998; Paper et al., 1993).
In a study with one healthy volunteer, 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 sulphate were recovered in the urine, which represented approximately half of the administered arbutin dose (Glöckl et al., 2001).
The bioavailability of
In an open, randomised,
Twelve human volunteers (6 males and 6 females) received 3 x 2 coated tablets 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
As arbutin is reported to hydrolyse easily in diluted acids to yield
Arbutin was found to be extensively absorbed from the GI (gastrointestinal) tract and bioavailable as hydroquinone. Volunteers (2 males and 2 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, hydroquinone 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 2 to 3 hours, levels were 12 times background levels. A
Most studies of hydroquinone kinetics and metabolism following oral administration have used arbutin or another form of bearberry leaf extract. For information on hydroquinone kinetics, see sections above.
4.2. Clinical efficacy
4.2.1. Dose response studies
Bearberry leaf extract
No data available
Dose response has been investigated in healthy volunteers. Antibacterial effect has been observed after administration of 0.1 or 1 g of arbutin. Lower dose provided lower antibacterial effect but, independently of the dose, the pH value of urine was the most important factor determining the antibacterial activity (Kedzia et al., 1975).
According to Frohne (1970), the effective concentration of arbutin should be higher than 0.3%.
4.2.2. Clinical studies (case studies and clinical trials)
Clinical research assessing the effects of bearberry leaf extract as a single substance/preparation is not available at the time of the preparation of this report.
4.3. 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.
4.4. Overall conclusions on clinical pharmacology and efficacy
There are no clinical studies evaluating the efficacy of bearberry leaf extract that would be suitable to support the
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.
5.2. Patient exposure
Aside from market presence and data from studies there is no special data on patient exposure to bearberry leaf extract available.
No special data is available on patient exposure to arbutin.
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 lithographers or in motion picture film processing. The most serious human health effect related to hydroquinone is pigmentation of the eye and, in a small number of cases, permanent corneal damage. This effect has been observed in HQ (hydroquinone) production workers, but the relative contributions of HQ and BQ
Dietary sources of hydroquinone/arbutin as well as other products such as cigarettes consumed daily by many humans have shown to generate comparable or even higher exposure levels to free hydroquinone than to the recommended dosage of Uvae ursi folium and preparations thereof. It should be noted that these products are consumed many times a day over the course of a lifetime, by all segments of the overall population. The level of free hydroquinone produced by the administration of the recommended dose of Uvae ursi folium or preparations thereof was estimated to be in the order of 11 mg/kg bw/d. This exposure level represents 11% of the permitted daily exposure (PDE) below which there is a negligible risk to human health (Garcia de Arriba et al., 2013).
5.3. Adverse events, serious adverse events and deaths
The oral administration of preparations of Uvae ursi folium may cause nausea and vomiting due to stomach irritation from the high tannin content (WHO, 2002; Blumenthal et al., 1998; Gruenwald et al., 2004; British Herbal Pharmacopoeia 1996; ESCOP 2003; Bradley 1992). Stomach ache has also been reported as adverse effect (Gruenwald et al., 2004; Hänsel et al., 1993).
In 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; Gruenwald et al., 2004).
Due to the high tannin content of the leaves, in persons with sensitive stomach, nausea and vomiting are possible side effects after ingestion of dried bearberry leaves (as low as 15 g) or tea infusion (Frohne, 2004). Other symptoms that have been reported in association with bearberry leaf extract are irritability, insomnia and increased heart rate (NTP, 2006).
Bearberry leaf extract use has also been linked to albuminuria, haematuria and urinary cast (Adesunloye, 2003; NTP, 2006).
The maculopathy was suspected to result from bearberry leaf because of its ability to inhibit melanin synthesis (NTP 2006).
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
5.4. Laboratory findings
Laboratory screening tests were performed within an open, randomised,
5.5. Safety in special populations and situations
The 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.
Incidence of urinary tract infections (UTIs) in men
UTIs are the second most common form of infection, accounting for nearly 25% of all infections. Incidence of UTIs is significantly higher in women than in men. Incidence of UTIs in men is increasing with age. Asymptomatic bacteriuria is believed to affect up to 50% of geriatric women and 30% of geriatric men. Asymptomatic bacteriuria is prevalent in elderly population but it frequently resolved without treatment and has no
For males aged 17 – 79 years, the mean annual UTIs incidence is 2.2%, for males aged ≥ 80 years, the mean annual UTIs incidence rises to 5.3% and risk factors in this age include presence of an indwelling urinary catheter, hospitalization and anatomical abnormalities associated with aging or disease (e.g. benign or malignant prostatic hyperplasia). In women aged 15 – 39 years, the mean annual UTI incidence is 15.2% and with age falls to 11.4% for women aged 40 – 59 years and to 9.7% for women aged 60 – 79 years (Guay, 2008). Guay (2008) also conducted epidemiological study of UTIs in a non- selected
Much higher incidence of UTIs in females during adolescence and childbearing years (adult women are 30 times more likely than men to develop a UTI) is reported also by Brusch (2011). The frequency of UTI in men approaches that of women only in men older than 60 years; in men aged 65 years or older, 10% have been found to have bacteriuria, as compared with 20% of women in this age group. In the normal host, UTI in men may occur due to infection of other parts of the genitourinary tract, typically the prostate. Older males with prostatic hypertrophy have incomplete bladder emptying, predisposing them to UTI on the basis of urinary stasis. However, in males aged 3 months to 50 years, the incidence of UTI is low; therefore, the possibility of anatomic abnormality must be considered. In males older than 50 years, prostatic hypertrophy with partial obstruction is the main contributor to the increase UTI (Brusch, 2011).
Among complications of benign prostatic hyperplasia (BPH) resulting from persistent failure of the bladder to empty or store urine recurrent urinary tract infections are mentioned (Lee, 2000). In patients with mild symptoms of BPH, whose symptoms do not cause unacceptable distress, no drug therapy with
Neisseria gonorrhoeae and Chlamydia trachomatis are clinically important infectious causes of urethritis (Workowski and Berman, 2006).
According to reports on the traditional use no differentiation between the genders was done. Recurrent mild infections of the lower urinary tract are usually uncomplicated in women. In men, due to the anatomical disposition of the lower urinary tract, a risk of severe inflammations of lower urinary tract of various origin exists and therefore urinary tract infection always requires medical examination.
A delayed consultation of a medical doctor may imply serious risks for men. In men over 50 years, incidence of UTIs is increasing due to prostatic hyperplasia (benign or malignant) and presence of an indwelling catheter. Both, prostatic hyperplasia and indwelling catheter require medical supervision.
The criterion of the Article 16 a) of Directive 2001/83/EC for traditional herbal medicinal products “they have indications exclusively appropriate to traditional herbal medicinal products which, by virtue of their composition and purpose, are intended and designed for use without the supervision of a medical practitioner for diagnostic purposes or for prescription or monitoring of treatment” is not fulfilled for use in men. Therefore, the use in men is excluded from the traditional use and traditional use can be recommended for females only.
Although men are excluded from the traditional use, Uvae ursi folium or preparations thereof can be used when advised by a medical doctor.
5.5.1. Use in children and adolescents
A posology for children and adolescents was published in “Kinderdosierungen von Phytopharmaka” (Dorsch et al., 1998) for bearberry leaf:
Dosage in children:
However, posology data for children is not supported by any clinical data (clinical studies, post marketing reports). The data published by Dorsch et al., 1998 are derived from calculations only.
Furthermore, the use in children and adolescents cannot be recommended for traditional use because infections of the urinary tract, even in their early stage, in children and adolescents should be treated under medical supervision.
Bearberry leaf and the preparations thereof should not be used by patients with known hypersensitivity to the herbal substance.
Following phytotherapeutic monographs such as ESCOP (2003) and WHO monograph (2002), monograph Arctostaphylos
Bearberry is listed among the supplements and herbal remedies which should not be used in chronic kidney disease (Management of Chronic Kidney Disease, 2015).
5.5.3. Special warnings and precautions for use
The use in children and adolescents under 18 years of age is not recommended because of concerns requiring medical advice.
The use in men is not recommended because of concerns requiring medical supervision.
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
5.5.4. Drug interactions and other forms of interaction
There are no drug interactions documented for bearberry leaf or preparations thereof.
Inhibitory effect of aqueous and methanolic extracts on CYPA3 isoenzymes was proved by Chauhan et al., 2007 in an in vitro test (for details see section 3.2). Nevertheless, as information on effect on CYPA3 isoenzymes is not supported by any published case report, this interaction is not included in the European Union monograph.
5.5.5. Fertility, pregnancy and lactation
No fertility data is available.
Safety during pregnancy and lactation has not been established. In absence of sufficient data, the use during pregnancy and lactation is not recommended.
An overdosing with bearberry leaf extract can lead to inflammatory irritation of the bladder and urinary tract mucosa accompanied with dysuria and haematuria, or later with blood excreta. Finally,
overdosing 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 tinnitus, shortness of breath, convulsions, collapse, delirium, and vomiting. Liver damage is a risk with
Large doses of bearberry leaf extract are reported to be oxytocic, although in vitro studies have reported a lack of
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
No studies on the effect on the ability to drive and use machines have been performed.
5.5.8. Safety in other special situations
For use in men see section 5.5.
5.6. Overall conclusions on clinical safety
There are no clinical safety data available for bearberry leaf and preparations thereof. Nevertheless, in some of literature sources the adverse reactions (gastrointestinal complaints) are attributed to tannins which are presented in bearberry leaves in relatively high amount (10 to 20 %). To reduce elution of tannins as much as possible it is recommended to prepare herbal tea from bearberry leaves by maceration or infusion and not by decoction. The macerate should be used immediately after preparation.
Based on long experience with herbal medicinal product used with the daily dose of the extract corresponding to 840 mg of hydroquinone derivatives, use bearberry leaf and preparations thereof in the doses corresponding to 840 mg of hydroquinone derivatives calculated as arbutin per day for one week can be considered as safe for human use.
6. Overall conclusions
Based on the data documented in the assessment report, a European Union herbal monograph is established on the traditional uses of several preparations of Arctostaphylos
The efficacy is plausible on the basis of
Traditional herbal medicinal product used for relief 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.
Clinical data describing efficacy and safety of bearberry leaf and any preparations thereof or its main component arbutin are not available.
The benefit/risk ratio can be considered positive. The
The only risk apparent from the available literature is the toxicity of hydroquinone. This substance when used in large amount has been reported to be toxic to animals and also mutagenic in some in vitro and in vivo tests. In any of the studies performed with arbutin and/or bearberry leaf and preparations thereof, hydroquinone was not detected in the samples in the level above 1 mg/ml. This amount is very close to the most conservative Threshold of toxicological concern (TTC) value. Moreover, 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. Therefore, the recommended dose of bearberry leaf or preparations thereof is considered safe in
No data on fertility are available. Safety during pregnancy and lactation has not been established. In absence of sufficient data, the use during pregnancy and lactation is not recommended.
The use in children and adolescents is not recommended as medical advice should be sought in this age group.
The therapeutic areas for browse search on the EMA website are “Urinary tract and gynaecology disorders”.
Based on the available information arbutin is considered an analytical marker by the HMPC.
A European Union list entry is not supported due to lack of adequate data on genotoxicity.