Definition

Folium Uvae Ursi consists of the dried leaves of Arctostaphylos uva-ursi (L.) Spreng. (Ericaceae) (1-3).

Synonyms

Arbutus uva-ursi L., Arctostaphylos media Greene, Arctostaphylos officinalis Wimm., Arctostaphylos procumbens Patzke, Mairania uva-ursi Desv., Uva-ursi buxifolia S.F. Gray, Uva-ursi procumbens Moench. (4).

Selected vernacular names

Achelblätter, Achelkraut, arberry, arctostaphylos, Bärenkraut, Bärentraube, Bärentraubenblätter, bearberry, bear’s grape, Beredruif, berry leaves, brockberry, busserole, coralillo, crowberry, dogberry, enab edhdhib, feuille de busserole, feuille de raisin d’ours, folia artostaphyli, folia garjubae, folia uvae-ursi, folia vaccinii ursi, foxberry, gayuba, herba garjubae, hog cranberry, hojas de gayuba, kinnikinnick, leesikas, lisc maçznicy, mealyberry, medveszölölevel, Moosbeerenblätter, mountain box, ptarmigan berry, raisin d’ours, red bearberry, sagochomi, Sandblätter, Steinbeerenblätter, upland cranberry, uva ursi, uvaursina, uwaurushi, Wolfsbeerenblätter (4-6).

Geographical distribution

Found in North America, Asia and northern Europe (6).

Description

Procumbent evergreen shrub with trailing stems bearing short ascending branches; branches bear leaves that are ovate, ovate-spatulate to spatulate. Flowers bell-shaped, pinkish-white, hypogynous and borne in small clusters at ends of branches; each flower consists of a calyx of 5 reddish sepals, a reddish-white urceolate corolla, gamopetalous but divided at the margin into 5 short reflexed segments, 10 short stamens with 2-lobed anthers, and syncarpous pistil of 5 carpels. Style portion of the pistil simple, longer than the stamens and ends in a knob-like stigma (6).

Plant material of interest: dried leaves

General appearance

Leaf entire or nearly entire; lamina obovate, oblong or spatulate, 7-30 mm long and 5-13 mm wide, apex obtuse or rounded, margin entire or slightly revolute, base cuneate, tapering to a short (about 5mm long), slightly pubescent petiole. Upper surface green to brownish-green, waxy, shiny and coriaceous, finely wrinkled due to depression of midrib and veins. Lower surface greyishgreen, reticulate. Young leaves ciliate on the margins, old leaves glabrous (1, 3, 6).

Organoleptic properties

Odour: slightly aromatic, tea-like; taste: astringent, bitter (1, 6).

Microscopic characteristics

Both epidermises covered with a thick cuticle; cells of the upper epidermis rectangular with straight, slightly thickened and distinctly pitted and beaded walls; cells of the lower epidermis similar but smaller; numerous large, anomocytic stomata in lower epidermis only. Occasional unicellular, thick-walled, conical trichomes on petiole and margin of young leaves; palisade usually of 3 layers, occasionally more; some spongy mesophyll cells filled with orange-brown pigment; prismatic crystals of calcium oxalate in parenchymatous cells surrounding the narrow, lignified sclerenchymatous fibres associated with the veins (1).

Powdered plant material

Greenish-grey or yellowish-green. Numerous cells of the mesophyll with chloroplasts and frequently irregular masses of carbohydrate; fragments of fibrovascular bundles showing spiral tracheae and narrow lignified sclerenchyma fibres associated with crystal fibres containing monoclinic prismatic crystals of calcium oxalate up to 30 µm in length; epidermis with polygonal cells and broadly elliptical anomocytic stomata up to 40 µm in length, surrounded by 5-11 subsidiary cells; pericyclic fibres lignified, of irregular shape with thick, porous, tuberculated walls and curved ends; trichomes unicellular, nonglandular, short, serpentine or straight; numerous fragments of cells containing yellowish-brown resin which turns blueish-black with iron (III) chloride test solution (3, 6).

General identity tests

Macroscopic and microscopic examinations, and thin-layer chromatography for the presence of arbutin, hydroquinone and gallic acid (2, 3).

Purity tests

Microbiological

Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for medicinal plants (7).

Foreign organic matter

Not more than 5% twigs and not more than 3% other foreign matter (2, 3).

Total ash

Not more than 5% (2, 3).

Acid-insoluble ash

Not more than 1.5% (2).

Water-soluble extractive

Not less than 25% (1).

Loss on drying

Not more than 10% (3).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (3). For other pesticides, see the European pharmacopoeia (3), and the WHO guidelines on quality control methods for medicinal plants (7) and pesticide residues (8).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (7).

Radioactive residues

Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (7) for the analysis of radioactive isotopes.

Other purity tests

Chemical, sulfated ash and alcohol-soluble extractive tests to be established in accordance with national requirements.

Chemical assays

Contains not less than 7% hydroquinone derivatives calculated as anhydrous arbutin, according to The Japanese pharmacopoeia (2). Contains not less than 8% hydroquinone derivatives calculated as anhydrous arbutin, according to the European pharmacopoeia (3). Quantitative analysis is performed by spectrophotometry at 455nm (3) or by high-performance liquid chromatography for the quantitative analysis of arbutin (2), hydroquinone and related derivatives (9).

Major chemical constituents

The major constituent is arbutin (5-15%). Related hydroquinone derivatives present include hydroquinone and methylarbutin (up to 4%). Gallic acid is the major phenolic carboxylic acid present, together with galloyl arbutin and up to 20% of gallotannins, flavonoids and triterpenes, mainly ursolic acid and uvaol (4, 10-12). The structures of the major constituents are presented below.

arbutin

hydroquinone

gallic acid

Medicinal uses

Uses supported by clinical data

None.

Uses described in pharmacopoeias and in traditional systems of medicine

Internally, as a mild urinary antiseptic for moderate inflammatory conditions of the urinary tract and bladder, such as cystitis, urethritis and dysuria (11, 13, 14).

Uses described in folk medicine, not supported by experimental or clinical data

As a diuretic, to stimulate uterine contractions, and to treat diabetes, poor eyesight, renal or urinary calculi, rheumatism and venereal disease (4, 5, 15). Topical applications have been used for skin depigmentation (15).

Pharmacology

Experimental pharmacology

Antimicrobial activity

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 (16). However, 95% ethanol or chloroform extracts had no antibacterial activity (17, 18). An aqueous extract of the leaves inhibited the growth of Streptococcus mutans OMZ176 in vitro (19). Ethanol and ethyl acetate extracts of the leaves were active in vitro against Escherichia coli, Proteus vulgaris, Streptococcus faecalis and Enterobacter aerogenes (20). Arbutin is responsible for most of the antibacterial activity (21). Arbutin and hydroquinone inhibited the growth in vitro of Ureaplasma urealyticum and Mycoplasma hominis (22). After ingestion of the leaves, arbutin is absorbed from the gastrointestinal tract, and is hydrolysed by intestinal flora to form the aglycone, hydroquinone (23). Hydroquinone is metabolized to glucuronate and sulfate esters that are excreted in the urine (24, 25). 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 (13).

An aqueous extract of the leaves had antiviral activity in vitro against herpes simplex virus type 2, influenza virus A2 (Mannheim 57) and vaccinia virus at a concentration of 10% (26).

Anti-inflammatory activity

Intragastric administration of a 50% methanol extract of the leaves (100mg/kg body weight) to mice inhibited picryl chloride-induced ear inflammation (27). The extract also potentiated the efficacy of prednisolone and dexamethasone in mice (27, 28). Arbutin, however, had no effect on the activity of the two steroids (28).

Effect on glucose levels

Administration of the leaves (6.35% of diet) to streptozocin-treated mice for 18 days did not reduce plasma glucose levels (29).

Effect on calcium excretion

Addition of an infusion of the leaves to the drinking-water (3g/l) of rats fed a standard diet fortified with calcium (8g/kg body weight) had no effect on urinary calcium excretion and diuresis (30).

Antitussive activity

Arbutin (50-100mg/kg body weight, administered intraperitoneally or intragastrically) was as active as codeine (10mg/kg body weight, administered intraperitoneally) as an antitussive in unanaesthetized cats with coughs induced by nylon fibres (31).

Effect on skin depigmentation

Extracts of the leaves have been widely used in cosmetic preparations to lighten the skin, with the active principles being hydroquinone and its derivatives (15).

Toxicity and overdose

The oral LD₅₀ of hydroquinone ranged from 300 to 1300 mg/kg body weight in rodents and dogs, but was only 42-86mg/kg body weight in cats. Acute exposure of rats to high doses of hydroquinone (over 1300mg/kg body weight) caused severe effects on the central nervous system, including hyperexcitability, tremor, convulsions, coma and death (32).

Clinical pharmacology

Antibacterial activity

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 nalidixic acid were active against all the strains tested (24). Oral administration of 800mg arbutin 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 (25).

Contraindications

During pregnancy (33) or lactation, or in children under the age of 12 years (13). Folium Uvae Ursi is also contraindicated in patients with kidney disorders (12).

Warnings

Folium Uvae Ursi should not be used for prolonged periods. Patients with persistent symptoms of a urinary tract infection should consult a physician. Use of Folium Uvae Ursi may cause a greenish-brown coloration of the urine that darkens on exposure to air due to the oxidation of hydroquinone.

Precautions

Drug interactions

Folium Uvae Ursi should not be administered with foods or medicines that acidify the urine.

Carcinogenesis, mutagenesis, impairment of fertility

Folium Uvae Ursi was not mutagenic in the Salmonella/microsome assay with S. typhimurium strains TA98 or TA100 (34, 35). Hydroquinone was also not mutagenic in the Salmonella/microsome assay with S. typhimurium strains TA98, TA100, TA1535 or TA1537, with or without metabolic activation (36).

Although extracts of the leaves do not appear to be carcinogenic, there is some evidence that hydroquinone is carcinogenic. Treatment of F344/N rats with hydroquinone resulted in a marked increase in tubular cell adenomas of the kidney in males, and an increase in mononuclear cell leukaemia in females. There was also some evidence of carcinogenic activity of hydroquinone in female B6C3F1 mice, as shown by an increase in hepatocellular neoplasms, mainly adenomas. There was no evidence, however, of carcinogenic activity of an aqueous extract of the leaves in male B6C3F1 mice (treated by gavage with 50-100mg extract/kg body weight) (36). The sources of human exposure to hydroquinone (including environmental sources) have been reviewed, as have data on its kinetics and metabolism, and its effects in animals and humans (32).

Arbutin was administered subcutaneously at 25, 100 or 400mg/kg body weight daily to male rats before mating, and to female rats 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 100mg/kg body weight. Fetal toxicity was observed at doses of 400mg/kg body weight (37).

Pregnancy: teratogenic effects

See Contraindications.

Pregnancy: non-teratogenic effects

See Contraindications.

Nursing mothers

See Contraindications.

Paediatric use

See Contraindications.

Other precautions

No information available on general precautions or precautions concerning drug interactions; or drug and laboratory test interactions.

Adverse reactions

Internal use of Folium Uvae Ursi may cause nausea and vomiting due to stomach irritation from the high tannin content (13, 38). The hydroquinone concentration in topical preparations is limited to 2% in Nigeria, the United Kingdom and the United States of America, following reports that preparations containing more than 2% hydroquinone caused exogenous ochronosis in black women in South Africa (39). Topical application of preparations containing less than 3% hydroquinone in different bases caused negligible effects in male volunteers from different racial groups. However, there are case reports suggesting that skin-lightening creams containing 2% hydroquinone have produced leukoderma as well as ochronosis. Hydroquinone (at a concentration of 1% in aqueous solution or 5% in a cream) has caused erythema and allergic contact dermatitis (32).

Dosage forms

Crude drug for infusions or cold macerates, extracts and solid forms for oral administration (13). Store in a well-closed container, protected from light (3).

Posology

(Unless otherwise indicated)
Daily dose: 3g crude drug in 150 ml water as an infusion or cold macerate, up to three or four times daily; 400-850mg hydroquinone derivatives. Other preparations accordingly calculated as arbutin (12, 13).

Patients should avoid highly acidic foods, such as acidic fruits or fruit juice, during treatment (25, 40), and be advised to drink plenty of fluids.

References

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2. The Japanese pharmacopoeia, 13th ed. (English ed.). Tokyo, Ministry of Health and Welfare, 1997.

3. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.

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16. Leslie GB. A pharmacometric evaluation of nine bio-strath herbal remedies. Medita, 1978, 8:3-19.

17. Rios JL et al. Antimicrobial activity of selected plants employed in the Spanish Mediterranean area. Journal of Ethnopharmacology, 1987, 21:139-152.

18. Gottshall RY et al. The occurrence of antibacterial substances active against Mycobacterium tuberculosis in seed plants. Journal of Clinical Investigation, 1949, 28:920-923.

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22. Robertson JA, Howard LA. Effect of carbohydrates on growth of Ureaplasma urealyticum and Mycoplasma hominis. Journal of Clinical Microbiology, 1987, 25:160-161.

23. Paper DH et al. Bioavailability of drug preparations containing a leaf extract of Arctostaphylos uva-ursi (L.) Sprengl. (Uvae ursi folium). Pharmacy and Pharmacology Letters, 1993, 3:66.

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25. Frohne D. Untersuchungen zur Frage der harndesinfizierenden Wirkungen von Bärentraubenblatt-Extrakten. Planta Medica, 1970, 18:23-25.

26. May G, Willuhn G. Antiviral activity of aqueous extracts from medicinal plants in tissue cultures. Arzneimittel-Forschung, 1978, 28:1-7.

27. Kubo M et al. Pharmacological studies on leaf of Arctostaphylos uva-ursi (L.) Spreng. I. Combined effect of 50% methanolic extract of Arctostaphylos uva-ursi (L.) Spreng (bearberry leaf) and prednisolone on immuno-inflammation. Yakugaku Zasshi, 1990, 110:59-67.

28. Matsuda H et al. Pharmacological study on Arctostaphylos uva-ursi (L.) Spreng. II. Combined effects of arbutin and prednisolone or dexamethasone on immunoinflammation. Yakugaku Zasshi, 1990, 110:68-76.

29. Swanson-Flatt SK et al. Evaluation of traditional plant treatments for diabetes: studies in streptozotocin-diabetic mice. Acta Diabetologia, 1989, 26:51-55.

30. Grases F et al. Urolithiasis and phytotherapy. International Urology and Nephrology, 1994, 26:507-511.

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34. Morimoto I et al. Mutagenicity screening of crude drugs with Bacillus subtilis rec-assay and Salmonella/microsome reversion assay. Mutation Research, 1982, 97:81-102.

35. Yamamoto H et al. Studies on the mutagenicity of crude drug extracts. I. Yakugaku Zasshi, 1982, 102:596-601.

36. Toxicology and carcinogenesis studies of hydroquinone (CAS No. 123-31-9) in F344/N rats and B6C3F1 mice (gavage studies). Washington, DC, Department of Health and Human Services, Public Health Service, National Institutes of Health, 1989 (National Toxicology Program Technical Report Series, No. 366).

37. Itabashi M et al. Reproduction study in rats by subcutaneous administration. Iyakuhin Kenkyu, 1988, 19:282-297.

38. Frohne D. Bärentraube. In Wichtl M, ed. Teedrogen, 2nd ed. Stuttgart, Wissenschaftliche Verlagsgesellschaft, 1989:72-74.

39. Williams H. Skin-lightening creams containing hydroquinone. The case for a temporary ban. British Medical Journal, 1992, 305:903-904.

40. Frohne D. Arctostaphylos uva-ursi: die Bärentraube. Zeitschrift der Phytotherapie, 1986, 7:45-47.