Definition

Radix Urticae consists of the dried roots and rhizomes of Urtica dioica L., U. urens L. (Urticaceae), their hybrids or mixtures thereof (1, 2).

Synonyms

Urtica dioica L.

Urtica gracilis Ait., U. major Kanitz., U. urens maxima Blackw. (3, 4).

Urtica urens L.

Urtica minor Fuchs, U. minor Moench., U. urens minima Dod. (3, 4).

Selected vernacular names

Urtica dioica L.

Brennesselwurzel, common nettle, csalángyökér, gazaneh, grande ortie, greater nettle, grosse Brennessel, Haarnesselwurzel, Hanfnesselwurzel, hhurrayq, Nesselwurzel, nettle root, ortica, ortie, ortiga, pokrzywa, qurrays, racine d’ortie, raiz de ortiga, stinging nettle, tsuknida, zwyczajna (4-6).

Urtica urens L.

Dwarf nettle, Eiternessel, kleine Brennessel, lesser nettle, ortica minore, ortica piccola, ortie brulante, petite ortie, sha’reláguz, small nettle (4, 6-9).

Geographical distribution

Urtica dioica is indigenous to Africa and western Asia, but is now found in all temperate regions of the world in Africa, North and South America, Asia, Australia and Europe (3, 4, 6, 7, 10).

Owing to the difficulty in botanical differentiation between Urtica dioica and U. urens in the wild, they are often harvested together. Although both species have a similar distribution, U. urens has become less widely distributed due to the reduction of its habitat (3).

Description

Urtica dioica L.

A herbaceous perennial with erect, green to purplish square stems, 30-150 cm high, with creeping roots; whole plant covered with stinging hairs. Leaves opposite, cordate at the base, oblong or ovate, finely toothed; upper surface dark green and underside paler. Flowers incomplete, small, green, dioecious (plant has either male or female flowers in separate inflorescences) and occur as racemes in axils of upper leaves; male or barren flowers have a perianth of 4 segments and 4 stamens, which are bent inwards at bud stage; female or fertile flowers have similar perianth surrounding a single 1-seeded carpel, bearing 1 style with a brush-like stigma. Fruit an achene (3, 8).

Urtica urens L.

A herbaceous annual resembling Urtica dioica, but is smaller (usually up to 30 cm high), has smaller leaves and flowers are in short, mostly unbranched clusters; male and female flowers appear together in the same raceme. Glabrous except for the stinging hairs (8, 11).

Plant material of interest: dried roots and rhizomes

General appearance

Rhizome cylindrical and tapering, occasionally branched, up to about 6mm thick at upper end; outer surface yellowish-brown; internodes with deep longitudinal furrows, numerous smooth, very thin and wiry roots arising from the nodes; in the outer part, inner surface creamy-white with a central hollow; fracture fibrous and tough.

Root greyish-brown, irregularly twisted, about 5mm thick, distinct longitudinal furrows; hollow in cross-section, cut surface white; fracture fibrous and tough (1, 7).

Organoleptic properties

Odourless; taste: faintly aromatic, characteristically bitter (1).

Microscopic characteristics

Rhizome: thin cork composed of brown, thin-walled cells, a few rows of tangentially elongated cortical parenchyma and a pericyclic region with fairly numerous fibres; fibres usually in small groups, sometimes single; individual fibres greatly elongated with very thick, lignified walls; some cells of pericycle and outer part of the secondary phloem contain fairly large cluster crystals of calcium oxalate. Cambial region distinct and continuous, with narrow radial groups of vascular tissues separated by wide medullary rays; secondary phloem mainly parenchymatous, whereas secondary xylem dense and completely lignified; medullary rays in secondary xylem show alternating areas of lignified and unlignified cells; lignified cells have moderately thickened walls and numerous simple pits. Pith composed of rounded, unlignified parenchyma.

Root: very thin cork, narrow phelloderm and secondary phloem and xylem with alternating areas of lignified and unlignified parenchyma in the wide medullary rays, as in the rhizome; a strand of primary xylem in the centre with a few small vessels (1).

Powdered plant material

Fibrous and pale beige. Fragments of greatly elongated pericyclic fibres, occurring singly or in groups, with thick and lignified walls, xylem vessels with bordered pits, associated with thick-walled fibres with slit-shaped pits; lignified, moderately thick-walled and pitted parenchyma from the medullary rays of xylem; abundant thin-walled parenchymatous cells, some containing large cluster crystals or scattered crystals of calcium oxalate; fragments of brownish cork (1).

General identity tests

Macroscopic and microscopic examinations (1, 2), and thin-layer chromatography for scopoletin and phytosterols (2).

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 (12).

Foreign matter

Not more than 2% (1).

Total ash

Not more than 8% (2).

Acid-insoluble ash

Not more than 3.5% (1).

Water-soluble extractive

Not less than 15% (1).

Loss on drying

Not more than 12% (2).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (13). For other pesticides, see the European pharmacopoeia (13), and the WHO guidelines on quality control methods for medicinal plants (12), and pesticide residues (14).

Heavy metals

For maximum limits and analysis for heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (12).

Radioactive residues

Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (12) 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

In addition to thin-layer chromatography for qualitative analysis (2), enzymelinked immunosorbent assay and high-performance liquid chromatography methods have also been developed to determine the concentration of Urtica dioica agglutinin in Radix Urticae (15, 16). However, concentration limits need to be established.

Major chemical constituents

A large number of compounds of different polarity and belonging to various chemical classes, including fatty acids, terpenes, phenylpropanes, lignans, coumarins, triterpenes, ceramides, sterols and lectins, have been isolated from Radix Urticae. Among these are oxalic acid, linoleic acid, 14-octacosanol, 13- hydroxy-9-cis,11-trans-octadecadienoic acid, α-dimorphecolic acid (9-hydroxy-10-trans,12-cis-octadecadienoic acid), scopoletin, p-hydroxybenzaldehyde, homovanillyl alcohol, β-sitosterol, stigmasterol, 24-R-ethyl-5α-cholestan-3β,6α-diol, campesterol, daucosterol (and related glycosides), secoisolariciresinol-9-O-β-D-glucoside, neoolivil, oleanolic acid, ursolic acid, Urtica dioica agglutinin and polysaccharides RP1-RP5 (3-5, 10, 17-21). The structures of the representative constituents are presented below.

p-hydroxybenzaldehyde

scopoletin

homovanillyl alcohol

neoolivil and enantiomer

Glc = β-D-glucopyranosyl

oleanolic acid

Medicinal uses

Uses supported by clinical data

Symptomatic treatment of lower urinary tract disorders (nocturia, polyuria, urinary retention) resulting from BPH stages I and II, as defined by Alken, in cases where diagnosis of prostate cancer is negative (22-35).

Uses described in pharmacopoeias and traditional systems of medicine

As a diuretic and for the treatment of rheumatism and sciatica (6).

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

Treatment of asthma, coughs, dandruff, diabetes, diarrhoea, eczema, fever, gout, haemorrhoids, nose bleeds, scurvy, snakebites and tuberculosis (5, 6). The plant has also been used to stop uterine bleeding after childbirth, increase lactation and promote hair growth, and as a vermifuge (5, 6).

Pharmacology

Experimental pharmacology

Anti-inflammatory activity

An ethanol extract of Radix Urticae inhibited the activity of human leukocyte elastase and reduced the amount of the enzyme released by activated polymorphonuclear granulocytes during the inflammatory response. The extract also inhibited degradation of a peptide substrate in vitro by human leukocyte elastase (IC₅₀ 3.6 µg/ml) and bovine elastin (IC₅₀ 68 µg/ml) (36). Intragastric administration of a polysaccharide fraction isolated from Radix Urticae to rats (40mg/kg body weight) suppressed carrageenan-induced footpad oedema for up to 20h (21, 37). The activity of the polysaccharides was comparable to that of indometacin (10mg/kg body weight) (21, 37).

Lymphocyte proliferation

A lyophilized aqueous extract (10 µg/ml) and a 40% alcohol extract of the roots (100 µg/ml) stimulated human lymphocyte proliferation in vitro by 63% and 100%, respectively (21, 37). Polysaccharides isolated from an aqueous root extract induced human lymphocyte proliferation in vitro (10-100 µg/ml) (21, 37). An ethyl acetate extract of the roots induced cell differentiation in human promyelocytic leukaemia HL-60 cells in vitro (ED₅₀ 4 µg/ml) (38). Urtica dioica agglutinin (500 ng/ml), however, inhibited lymphocyte proliferation and the binding of epidermal growth factor to its receptor on A431 epidermoid cancer cells in vitro (39). The lectin also exhibited immunomodulatory effects on T-lymphocytes in a dose-dependent manner (21, 37). Urtica dioica agglutinin bound to the cell membrane of prostatic hyperplastic cells (40) and inhibited their proliferation (21).

Effect on benign prostatic hyperplasia

Effect on sex hormone-binding globulin

Sex hormone-binding globulin (SHBG) is a blood plasma protein that binds to circulating androgens and estrogens, thereby regulating their free concentration in plasma. The plasma membrane of the human prostate contains specific SHBG receptors, and SHBG appears to play a role in the development of BPH. A 10% hydroalcoholic extract of the root reduced the binding capacity of SHBG (isolated from human plasma) for 5α-dihydrotestosterone by 67% in vitro (41). An aqueous extract of the root (0.6-10.0mg/ml) inhibited the binding of ¹²⁵I-labelled SHBG to human prostate membranes in vitro (42). The lignan, secoisolariciresinol, and a mixture of the isomeric compounds 13-hydroxy-9- cis,11-trans-octadecadienoic acid and 9-hydroxy-10-trans,12-cis-octadecadienoic acid isolated from a methanol root extract, reduced the binding of SHBG to 5α-dihydrotestosterone (18). Secoisolariciresinol and its main intestinal transformation products, (-)-3,4-divanillyltetrahydrofuran and enterofuran, displaced the binding of 5α-dihydrotestosterone to SHBG in vitro by 60%, 95% and 73%, respectively (43).

Enzymatic activity

Intragastric administration of a 30% ethanol extract of the root to male mice inhibited the activities of 5α-reductase and aromatase (ED₅₀ 14.7 and 3.58mg/ml, respectively) (44). However, a hydroalcoholic extract of the root dissolved in dimethyl sulfoxide did not inhibit the activity of 5α-reductase from human prostate cells in vitro (up to 500 µg/ml) (45). A standardized hydroalcoholic extract of the roots (IC₅₀ 338 µg/ml) inhibited aromatase activity in vitro. A heptane-soluble fraction of the extract was the most effective inhibitor (IC₅₀ 9 µg/ml) (36). Both ursolic acid and 14-octacosanol isolated from a methanol extract of the roots inhibited the activity of aromatase in vitro (46). 9-Hydroxy-10-trans,12-cis-octadecadienoic acid isolated from the roots inhibited the activity of aromatase in vitro (19). Butanol, ether, ethyl acetate and hexane extracts of the roots inhibited the activity of sodium- and potassium-adenosine triphosphatase isolated from prostatic hyperplastic cells by 27.6-81.5% (47). In addition, steroidal components of the roots, stigmast-4-en-3-one, stigmasterol and campesterol (1 µmol/l to 1mmol/l), inhibited sodium- and potassium-adenosine triphosphatase activity by 23-67% (47).

Effect on prostate growth

Intragastric administration of a hexane extract of the roots (1.28 g daily) to castrated rats did not inhibit prostate growth stimulated by testosterone or dihydrotestosterone (45). Intraperitoneal administration of a hydroalcoholic extract of the roots (20mg/kg body weight) suppressed testosterone-stimulated increases in prostate weight and prostatic ornithine decarboxylase activity in castrated rats (48). Daily oral administration of a hydroalcoholic extract of the root to dogs with BPH (30mg/kg body weight) decreased prostate volume by 30% after 100 days of treatment (49).

The effect of various root extracts was assessed after implantation of the fetal urogenital sinus into the prostate gland of adult mice. Intragastric administration of a butanol, cyclohexane or ethyl acetate extract of the root (0.25 ml/daily for 3 weeks) had no effect on the development of BPH in mice. However, intragastric administration of the same dose of a 20% methanol extract of the root reduced the development of BPH by 51.4% (50).

Toxicology

The LD₅₀ of an aqueous extract or infusion of the roots after intravenous administration to rats was 1721 mg/kg body weight and 1929 mg/kg body weight, respectively. Oral administration of an infusion of the roots to rats was well tolerated at doses up to 1310mg/kg body weight (3).

Clinical pharmacology

Benign prostatic hyperplasia

Placebo-controlled clinical trials

Three double-blind, placebo-controlled clinical trials have assessed the efficacy of oral administration of Radix Urticae for the symptomatic treatment of lower urinary tract disorders resulting from BPH (24, 27, 35). One study assessed the efficacy of a 20% methanol extract of the roots in 50 men with BPH stages I and II (35). A significant increase in urine volume (by 43.7%; P = 0.027) and a significant decrease in serum levels of SHBG (P = 0.0005) was observed in patients treated with 600 mg extract daily for 9 weeks. A modest increase in maximum urinary flow of 8% was also observed in the treated group; however, it was not significant (35). Another study assessed the efficacy of a 20% methanol extract in 40 men with BPH. Treatment with 1200 mg extract daily for 6 weeks decreased the frequency of micturition and serum levels of SHBG (27). The third study assessed the efficacy of a methanol extract in the treatment of 32 men with BPH stage I (24). A 4-14% increase in average urinary flow and a 40-53% decrease in postvoid residual volume were observed in patients treated with 600 mg extract daily for 4-6 weeks (24).

Clinical trials without controls

Numerous clinical trials without controls have assessed the efficacy of oral administration of various Radix Urticae extracts (20% methanol or 30-45% ethanol) for the symptomatic treatment of lower urinary tract disorders (nocturia, polyuria, dysuria, urine retention) resulting from BPH (22, 23, 25, 26, 28-32, 34, 51, 52). One trial assessed the efficacy of a 40% ethanol extract of the roots in 67 men with BPH. Treatment with 5ml daily for 6 months decreased nocturia and postvoid residual volume, but did not reduce prostate enlargement (23). In another trial, a 20% methanol extract of the roots was assessed in 89 men with BPH. Treatment with 600mg daily decreased the postvoid residual volume in 75% of patients after 3-24 months (25). In a study of 26 men with BPH stage I or II, a decrease in prostate volume was observed in 54% of patients, and a decrease in postvoid residual volume was observed in 75% of patients, after treatment with 1200mg methanol extract daily for 3-24 weeks (26). Ten men with BPH were treated with 30-150 drops of a 45% ethanol extract of the root daily for 30 days. After treatment, the postvoid residual volume decreased by 66% (29). In a study of 39 men with BPH stages I-III, an improvement in urinary flow, and a reduction in postvoid residual volume, nocturia and polyuria were seen in 95% of patients after 6 months of treatment with a 20% methanol extract (600-1200mg daily) (51). Twenty-seven men with BPH stages I and II were treated with a 20% methanol extract of the roots for 3.5 months. Postvoid residual volume decreased significantly in 75% of patients (P < 0.001), and maximum urinary flow increased significantly in 50% of patients (P < 0.002) (52).

Three large-scale multicentre studies involving 14033 men with BPH assessed the efficacy of a 20% methanol extract (28, 31, 32). In one study, a decrease in nocturia and polyuria was seen in 91% of patients after 6 months of treatment (28). In another study, a 50% decrease in nocturia was observed in patients treated with 1200mg extract daily for 10 weeks (31). In the third study, significant improvements in both urinary flow and postvoid residual volume were observed in 4480 patients treated with 600-1200mg extract daily for 20 weeks (P < 0.01) (32).

Effects on prostate morphology

Three studies without controls examined the effect of various methanol extracts of Radix Urticae on prostate morphology. Prostate cells were obtained from patients with BPH by needle biopsy, and were analysed for morphological changes before and after treatment. In two of the studies, cells were taken from the patients at various intervals during treatment (53, 54). In the third study, cells were obtained once from the patients, and treatment with the extract was carried out in vitro (55). In the first study, 31 men with BPH stages I and II were treated orally with 1200mg of a 20% methanol root extract daily for 20 weeks. Prostate cells were analysed every 4 weeks by fluorescent microscopy. After 4-16 weeks of treatment, an increase in nuclear volume, as well as hydropic swelling and vacuolization of the cytoplasm, were observed (53). In the second study, prostate cells from four men with BPH stage I were examined by electron microscopy. After 6 months of oral treatment with a 20% methanol extract (1200mg daily), a reduction in the activity of smooth muscle cells and an increase in the secretory activity of glandular epithelial cells were observed (54). In the third study, prostate glandular epithelial cells from 33 patients with BPH were analysed by fluorescent microscopy following incubation of the cells in vitro with a 20% methanol extract of the root. Treatment with the extract caused an increase in nuclear volume, loosening of chromatin and hydropic swelling of the cytoplasm. In addition, the number of homogeneous secretory granules was reduced, indicating a reduction in the biological activity of these cells (55).

Contraindications

Radix Urticae is contraindicated in cases of known allergy to plants of the Urticaceae family. Owing to its effects on androgen and estrogen metabolism, the use of Radix Urticae during pregnancy and lactation and in children under the age of 12 years is contraindicated.

Warnings

Radix Urticae relieves the symptoms associated with BPH but does not have an effect on the size of the prostate. If symptoms worsen or do not improve, or in cases of blood in the urine or acute urinary retention, contact a physician.

Precautions

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; drug and laboratory test interactions; or carcinogenesis, mutagenesis and impairment of fertility.

Adverse reactions

Clinical studies have shown that extracts of Radix Urticae are well tolerated in humans. A few cases of minor transient gastrointestinal side-effects, such as diarrhoea, gastric pain and nausea (32, 35), and allergic skin reactions (32), have been reported.

Dosage forms

Crude drug for infusion; hydroalcoholic extracts (4, 56). Store in a well-closed container, protected from light and humidity (2, 13).

Posology

(Unless otherwise indicated)
Daily dosage: 4-6 g crude drug or equivalent preparations as an infusion (4, 56); 600-1200 mg dried 20% methanol extract (5: 1) (22, 25, 27, 31, 32); 1.5-7.5 ml 45% ethanol extract (1: 1) (29); 5 ml 40% ethanol extract (1: 5) (17, 23).

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