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A comprehensive review on the stinging nettle effect and efficacy profiles. Part II: Urticae radix.

Abstract

Nettle root is recommended for complaints associated with benign prostatic hyperplasia (BPH). We therefore conducted a comprehensive review of the literature to summarise the pharmacological and clinical effects of this plant material. Only a few components of the active principle have been identified and the mechanism of action is still unclear. It seems likely that sex hormone binding globulin (SHBG), aromatase, epidermal growth factor and prostate steroid membrane receptors are involved in the anti-prostatic effect, but less likely that 5[alpha]-reductase or androgen receptors are involved. Extract and a polysaccharide fraction were shown to exert anti-inflammatory activity. A proprietary methanolic nettle root extract and particular fractions inhibited cell proliferation. Isolated lectins (UDA) were shown to be promising immunomodulatory agents, having also anti-viral and fungistatic effects. However, despite these in vitro studies it is unclear whether the in-vitro or animal data are a surrogate for clinical effects.

The clinical evidence of effectiveness for nettle root in the treatment of BPH is based on many open studies. A small number of randomised controlled studies indicate that a proprietary methanolic extract is effective in improving BPH complaints. However, the significance and magnitude of the effect remains to be established in further confirmatory studies before nettle root treatment may be accepted in the guidelines for BPH treatment. The risk for adverse events during nettle root treatment is very low, as is its toxicity. Pre-clinical safety data remain to be completed.

[c] 2007 Elsevier GmbH. All rights reserved.

Keywords: Urticae radix; Stinging nettle root; Pharmacology; Efficacy profiles

Introduction

Preparations from nettle root are recommended for symptomatic treatment of micturition disorders (dysuria, pollakisuria, nocturia, urine retention) in benign prostatic hyperplasia (BPH) at stages I and II (as defined by Alken, 1973) or stages II and III (as defined by Vahlensieck and Fabricius, 1996; Anonymous, 2003). Empirical studies use daily doses of 4-6g as an infusion, 300-600 mg or 378-756 mg for dried native nettle extracts (DER 7-14:1, solvent 20% methanol or DER 12-16:1, solvent 70% ethanol, respectively) or 4.5-7.5 ml or 15 ml for fluid extracts (DER 1:1, solvent 45% ethanol or 1:5, solvent ethanol 40%) or equivalent doses. Phytosterols, lignans, polysaccharides and the lectin UDA are considered to be among the active principles (Anonymous, 2003, Table 1). Phytosterol components are thought to be the least important since their content in nettle products is very low (<0.01%). Some of the components are probably not absorbed at all and others only minimally, e.g. [beta]-sitosterol (Ritschel et al., 1990). The aim of this systematic review was to summarise data on the effects and efficacy of nettle root.

Methods

Systematic literature searches were conducted on Medline (via Pubmed). The database was searched from its inception until the end of July 2006 to identify studies investigating nettle root preparations. Additionally, experts were contacted to identify further studies. Hand searches were performed by searching the authors' own files and the bibliographies of all located papers. No restrictions regarding the language of publication were imposed. Controlled and uncontrolled clinical studies and pre-clinical studies were eligible for inclusion. Studies with plant mixtures (e.g. sabal or pygeum) were excluded from this review.

Pharmacological properties: in vitro experiments

Interaction with sex hormone binding globulin (SHBG)

An aqueous but not a 70% ethanol nettle root extract (1) inhibited in a dose-related manner the binding of radioactively labelled SHBG to receptors on human prostatic membranes. Isolated UDA, a lectin, and stigmasta-4-en-3-one, were without any effect (Hryb et al., 1995). Nettle root extracts contain at least 18 phenolic compounds and 8 lignans (Kraus and Spiteller, 1990). Isolated polar lignans, e.g. secoisolariciresinol, were shown to interfere with the SHBG binding towards steroids. Methylation of the isomeric mixture increased its activity about 10 fold (Gansser and Spiteller, 1995a). Competitive inhibition seemed likely (Schottner et al., 1997a). Other nettle lignans with a high affinity to SHBG included neoolivil, dehydrodiconiferyl alcohol, and isolariciresinol, 3,4-divanillyltetrahydrofuran and metabolites, such as enterodiol and enterolactone (Schottner et al., 1997b). A low polarity in the aliphatic part and a 3-methoxy-4-hydroxy substitution pattern in the aromatic part resulted in higher binding affinity for SHBG (Schottner and Spiteller, 1998). A two-fold mechanism of action has been suggested: (i) interaction with blood levels of free (active) steroid hormones by displacing them from their SHBG binding sites and (ii) prevention of the interaction of prostate receptors with SHGB (Schmidt, 1983). It remains to be established which components are responsible for the various actions.

Interaction with aromatase

There is strong evidence that nettle extract interferes with the conversion of testosterone into oestrogens. The ethanolic nettle root extract WS1031 (DER 8-13:1, solvent 60% ethanol) inhibited aromatisation of androstenedione in vitro ([IC.sub.50] 338 [micro]g/ml). This effect was increased by adding saw palmetto extract (Koch, 1995). The active principle was found in an heptane fraction, suggesting that lipophilic compounds are responsible for the action (Koch, 1995). The heptane fraction was more effective than a single component--9-hydroxy-10,12-octadecadienoic acid. Semimaximal inhibitory concentrations were higher than those of Sabal extracts (solvents ethanol 90%, hexane) but the combination of Sabal and Urtica extracts showed a clear additive effect. In a similar test procedure, a comparable aromatase inhibition of ethanolic nettle extract LI 166 (60% ethanol, DER 8 12:1) and a synthetic aromatase inhibitor was achieved, however at a concentration 250 fold higher than that of the synthetic (Morgenstern and Ziska, 1999). Likewise, the dose-dependent inhibitory effect of a methanolic extract (DER 10:1, solvent 30% methanol) on aromatase was increased by concomittant administration of a Pygeum extract (Hartmann et al., 1996).

Besides common fatty acids, (10E,12Z)-9-hydroxy-10,12-octadecadienoic acid was identified as co-active component (Kraus et al., 1991). Later, other lignans, e.g. secoisolariciresinol, oleanolic and ursolic acid, (9Z,11E)-13-hydroxy-9,11-octadecadienoic acid and 14-octacosanol, were identified as weak to moderate inhibitors of the aromatase (Gansser and Spiteller, 1995b). Nettle root extracts of various producers were found to inhibit the aromatase, as did isolated 9-hydroxy-10-trans-12-cis-ocadecadienoic acid or its derivative 9-oxo-10-trans-12-cis-ocadecadienoic acid (Bartsch and Kuhne, 1992). However, nettle root contains only low quantities of these components and the active principle for a clinical relevant aromatase inhibition needs still to be defined. However, the aqueous nettle extract BNO 1250 (DER 10:1, 0.75 and 7.5 mg/ml) also inhibited oestradiol formation in a time and dose-dependent manner (a cytotoxic effect could be excluded). Jarry et al. (1999) suggested that besides the inhibition of the enzyme activity, inhibition of aromatase gene expression may be involved in the nettle root effect.

Interaction with androgen receptor binding

There is no evidence that the nettle root extract BAZ (DER 5:1, solvent 20% methanol) interacts with the binding of radioactively labelled DHT to rat prostatic androgen receptors (Rhodes et al., 1993) nor that this nettle root extract affected microsomal 5[alpha]-reductase activity (Rausch et al., 1992).

Interaction with 5[alpha]-reductase

Only high doses of a methanolic extract (DER 10:1, solvent 30% methanol) inhibited 5[alpha]-reductase ([ED.sub.50] 14.7mg/ml; Hartmann et al., 1996). The effect was very low when compared with the synthetic 5[alpha]-reductase inhibitor finasteride (Rhodes et al., 1993). Likewise, the ethanolic extract WS1031 had no impact on the conversion of testosterone into DHT (Koch and Biber, 1994).

Anti-inflammatory effect

The inhibition of human leukocyte elastase reflects anti-inflammatory activity. Ethanolic nettle root extract WS1031 inhibited bovine leukocyte elastase ([IC.sub.50] 68 [micro]g/ml (Koch et al., 1995). The methanolic extract BAZ was shown to inhibit the alternative pathway of complement activation which involves various serine proteinases (Wagner et al., 1994). Complement activation was also inhibited by a polysaccharide fraction and isolated polysaccharides, e.g. rhamnogalacturanes, a type II arabinogalactane (Willer, 1992). Since the commercially available Bazoto[n.sup.R] contains 1.7% polysaccharides this component may well exert anti-inflammatory activities (Wagner et al., 1994).

Effect on prostate cell growth

Prostate growth factor (PGF) activity was found in extracts of benign prostatic hypertrophy stimulating the proliferations of mouse 3T3 and human BUD-8 fibroblasts. However, Jinno et al. (1986) found no correlation between PGF contents and tissue weight of BPH or histological differences (fibromuscular or glandular type). Although rats do not suffer BPH, invitro cultured fibroblasts from the rat ventral prostate may be appropriate for screening of prostatotropic substances. Incubation of prostatic stromal fibroblasts with 0.01% nettle root extract BAZ reduced cell proliferation by 50%. The proliferation rate was affected by DHT. High extract doses were even toxic, probably due to osmotic conditions (Schmitt, 1987). Enderle-Schmitt et al. (1988) cultivated human hyperplastic prostate cells from biopsy samples. Fractions of the methanolic extract BAZ inhibited cell growth in vitro to various degrees. Electronmicroscopic examination did not reveal specific changes and testosterone metabolism remained unaffected. EGF receptor concentrations were reduced when particular fractions were employed but the effect on receptor expression did not correlate with ultrastructural changes. Rausch et al. (1992) used a similar method to incubate fibroblastic and epithelial cells. Already low concentrations of the methanolic extract BAZ (dose range tested: 10ng-100 [micro]g/ml) inhibited cell growth by about 20%. Higher concentrations were not more effective. Since microsomal 5[alpha]-reductase activity was not affected, an androgen-independent mechanism was suggested. However, Konrad et al. (2000) observed a concentration-dependent and significant anti-proliferative effect of this extract only on epithelial cells, whereas stromal cell growth remained unaltered. The inhibition was time dependent, with a maximum growth reduction of 30% at a concentration of 1.0[E.sup.-6]mg/ml on day 5 compared to the untreated control. No cytotoxic effect was observed. A particular polysaccharide fraction of the methanolic extract was identified to account for this effect (Lichius et al., 1999a). The group of Ziegler (1983) incubated cells from normal and BPH biopsies with different concentrations of the methanolic extract BAZ. Prostate metabolism remained unaffected, but homogenous granules showed a relevant decrease in nettle root extract-treated cells. UDA inhibited the binding of EGF/bFGF (basic fibroblast growth factor) to HeLa cells, binding of EGF to membranes of A431 cells, and EGF receptor tyrosine kinase activity (Wagner et al., 1994). Using the human epidermoid cancer cell line A431 with its high expression of EGF receptors at the cell surface, UDA was found to inhibit the binding of [.sup.125.I]-labelled EGF to the receptor. The effect was more pronounced than with wheat germ agglutinin, which possesses the same sugar specificity and the mannose-specific agglutinin Conconavalin A. The inhibitory effect of UDA could be antagonised by chitotriose, an oligosaccharide with affinity for the EGF receptor site (Wagner et al., 1995). A membrane [Na.sup.+], [K.sup.+] -ATPase fraction was prepared from a patient with BPH. Nettle root extracts (2) prepared with hexane, ether, ethyl acetate and butanol caused inhibition of the enzyme activity at concentrations of 0.1 mg/ml, as did isolated steroidal compounds, such as stigmast-4-en-3-one, stigmasterol, and campesterol at concentrations ranging from [10.sup.-3] to [10.sup.-6]M (Hirano et al., 1994), indicating that nettle root extracts may suppress prostate cell metabolism and growth by interaction with prostate steroid membrane receptors.

Thus, the impact of nettle root extract on cell growth in vitro is not yet conclusive and requires further elucidation.

The data on the in vitro immunomodulatory, antiviral, fungistatic, chemopreventive and cardiovascular activities are summarised on the webpage: www.uniklinikfreiburg.de/rechtsmedizin/live/forschung/phytomedicine/originalartikel.html.

Pharmacological properties: in vivo experiments

Anti-inflammatory effect

The effect oral nettle root extract LI166 (DER 8-12:1, solvent ethanol 60%; 250-750 mg/kg, Morgenstern and Ziska, 1999) and of root components (40mg/kg of a particular polysaccharide fraction, which consisted of four different polysaccharides administered orally or a mixture of two polysaccharides intravenously) (Willer, 1992) were investigated in the carrageenan-induced rat paw oedema test and indicated an anti-inflammatory potential. However, it needs to be shown if this effect contributes to the anti-prostatic nettle root effect.

Effect on prostate cell growth

In dogs, treatment with 3 x 300 mg/10 kg nettle root extract BAZ over 100 days decreased the size of the prostate and serum testosterone levels (Daube, 1988). In a later study over 100 days, Daube (1992) showed that hecogenin acetate is a co-active constituent. Doses 0.5 and 5mg/10kg resulted in sonographic prostate volume reductions of 14% and 29%, respectively.

Studies in castrated rats with testosterone-stimulated prostate growth (Scapanini and Friesen, 1992, Rhodes et al., 1993) or fetal urogenital sinus implantation (Lichius and Muth, 1997) do not reflect the situation in humans, since rats do not develop prostate hyperplasia per se. However, such studies may provide useful information when comparing different extracts or in searching for the co-active components. For example, a particular polysaccharide fraction inhibited prostate growth whilst UDA and secoisolariciresinol did not (Lichius et al., 1999b).

Effect on muscle contractility

Izzo et al. (1996) studied the spasmolytic effect of a root extract (3) on isolated guinea pig ileum. In concentrations of 100-800 [micro]g/ml, the extract did not affect circular muscle spontaneous contractions or longitudinal muscle contractions induced by acetylcholine and barium chloride.

Human pharmacological studies

Effect of sex hormones

In two double-blind studies a decrease in SHBG was observed during treatment with nettle root extract BAZ 1200mg/day compared to treatment with placebo. Whereas Fischer and Wilbert (1992) found a 10% increase in the concentrations of testosterone, 5[alpha]-DHT and estradiol in the course of a 7 months treatment (phosphatases, blood count and urine analysis remained uninfluenced), no difference for testosterone, androstandiol and acid phosphatase between groups was found by Vontobel et al. (1985) (study duration 9 weeks, BAZ dose 600mg/day). In open uncontrolled studies, findings on nettle extract induced changes on serum sex hormones (SHBG, DHT, testosterone, prolactin) were not uniform, suggesting that estradiol and estron rather than DHT and testosterone are involved in the mechanism of the nettle root effect. The extracts investigated included up to 1200 mg BAZ/day (Frick and Aulitzky, 1987; Bauer et al., 1988; Huber et al., 1992) and a diethyl ether extract 20:1 in a dose of 360mg/day (Safarinejad, 2005). Further studies are needed to elucidate the effect of nettle extract on sex hormones.

Effect on cell growth

Histological prostate cell changes were observed by various groups after treatment with BAZ 600 mg/day. After 9 weeks, the changes were interpreted as treatment-induced glandular cell death and reactive inflammation (Streber, 1986). After 20 weeks of treatment with 1200 mg BAZ/day, the changes were interpreted as reduced cell metabolism (Ziegler, 1982). After 6 months treatment with 1200 mg BAZ/day the volume density of cytoplasmatic secretion granula had increased and those of lysosomes had decreased, which might reflect decreasing autophagy and increased secretion of the glandular cells (Oberholzer et al., 1986). An increase in the proportion of large-volume nuclei was also seen by Schubert (1988). Lower zink levels were found by Romics and Bach (1990) in prostate tissue of BPH patients compared to controls after a 7 day intake of 1800mg BAZ/day. After 12 months of treatment with various doses, intensive accumulated fluorescence representing nettle root constituents or metabolites was detectable in the glandular cells compared to controls. Incubation of BPH tissue with the extract did not result in fluorescence changes (Dunzendorfer, 1984). Further studies are required to draw definitive conclusions on the interaction of nettle root and cell growth.

Clinical studies

Open studies are presented according to their publication dates. A first case report on the beneficial effect of nettle root tea dates back to Ruckle (1950). A diuretic effect was observed as a side effect. So far, a total of about 40,000 men suffering from BPH have been treated with various nettle root preparations (Table 2) in 34 clinical studies (Tables 3 and 4). Most studies were open and uncontrolled (n = 24), two studies open controlled. Only one of 6 randomised controlled studies versus placebo tested a hypothesis, thus being confirmatory. All studies evaluated methanolic nettle root extracts. One of them compared 2 nettle root preparations. One double-blind study compared different nettle root treatment regimens. Only 2 of the double-blind studies (Engelmann et al., 1996; Vontobel et al., 1985) were included in a systematic review considering ICH quality items (Wilt et al., 2000).

Taken together, there is some evidence of effectiveness of methanolic nettle root extracts in improving BPH complaints in the short term, however, in order to calculate the effect size, more rigorous data are necessary which should better consider the suggestions of the WHO International Consultation on BPH (Khoury et al., 2000) and the consensus index (International Prostate Symptom Score, IPSS) (Barry et al., 1992). This is necessary before nettle root extract may be considered in the BPH treatment guidelines. However, recently pure nettle root extracts have decreased importance due to the fact that nettle root-saw palmetto mixtures were found to be more effective than pure nettle root extracts (Wilt et al., 2000).

Better characterisation of the nettle root products is also required. Although the active principle has not yet been identified, some of the constituents may be useful markers in order to guarantee the conformity of batches (Beck, 1989; Chaurasia and Wichtl, 1986; Schilcher and Effenberger, 1986; Willer et al., 1991).

The number of adverse events has not been stated in all studies. Thus the real number of adverse events may be higher than the 699 reported (estimated 2%). Most common complaints were urogenital, specifically impotence and decreased libido. Since the majority of patients were treated with an extract prepared with 20% methanol, treatment with this particular proprietary extract seems to be safe in the short term. Only few data are available for longer treatment periods and more long-term studies are needed to confirm the safety of nettle root products.

Toxicology

Acute toxicity

In rats, the BAZ oral [LD.sub.50] was suggested to be greater than 30 g/kg, and the BAZ intraperitoneal [LD.sub.50] to be greater than 3 g/kg (data unpublished, property of Kanoldt Manufacturer; Frick and Aulitzky, 1987). Acute toxicity seems to be very low (Bock, 1988; Sabo et al., 1996).

Reproduction and chronic toxicity

No data available.

Mutagenic potential

An extract (not characterized) of radix urticae was tested using two Salmonella typhimurium strains (TA98 and TA100) using the plate incorporation test and extract doses up to 5000 [micro]g/plate. None of the tester strains showed increased reversion to prototrophy either in the absence or presence of rat liver metabolic activation system. Significant increases in the number of revertant colonies were induced by the known mutagens and carcinogens sodium azide, 2-nitrofluorene, 2-aminoanthracene when tested under the same conditions (Meester and Leonard, 1988).

Carcinogenic potential

Aqueous extract (4) did not affect cell viability, thus demonstrating no cytotoxic effect (Harput et al., 2005).

Appendix A. Supplementary Materials

The online version of this article contains additional supplementary data. Please visit doi:10.1016/j.phymed.2007.03.014.

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Julia E. Chrubasik (a), Basil D. Roufogalis (b), Hildebert Wagner (c), Sigrun Chrubasik (a,b,*)

(a) Department of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany

(b) Herbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia

(c) Department of Pharmacy--Zentrum fur Pharmaforschung- Haus B, University of Munich, Butenandtstrasse 5-13, D-81377 Munchen, Germany

*Corresponding author. Institut fur Rechtsmedizin. Universitat Freiburg, 79104 Freiburg, Germany. Tel.: +49 761 2036853; fax: +49 761 203 6851.

E-mail address: sigrun.chrubasik@klinikum.uni-freiburg.de (S. Chrubasik).

(1) Extract prepared by exhaustive percolation with water 80 [degrees]C of 1 cm cubes of air-dried root (amount taken not stated) or with ethanol 70%.Yields of 10% and 8.5% were achieved, respectively.

(2) Nettle root (600g) were cut into pieces and extracted with 3 x 41 methanol for 24 h. The solvent was removed in vacuo and the residue suspended in 11 water. The mixture was extracted with 4 x 500 ml cyclohexane. The combined cyclohexane layers were washed with 200 ml water and dried over [Na.sub.2]S[O.sub.4] and evaporated to dryness in vacuo. The water which was used to wash the organic layer was combined with the original water suspension. Following the same procedure, the water suspension was extracted successively with 4 x 500ml diethyl ether, 4 x 500 ml ethyl acetate, and 4 x 500 ml n-butanol. Extraction yields: methanol-raw extract 11.9%, cyclohexane extract 0.38%, ether extract 0.25%, ethyl acetate extract 0.17%, n-butanol extract 1.0%. and residual water 10.1%. All extracts were dried and redissolved in ethanol.

(3) Finely dried ground dried material (100g) was extracted with 500 ml of methanol water (50:50 v/v) at room temperature for 24h. The extract was evaporated until a thick residue was obtained. For bioassay, the residues were dissolved in Krebs solution.

(4) Air-dried aerial parts (10g) of U. dioica were boiled with water for 1 h, filtrated and evaporated under reduced pressure at 40 [degrees]C. After freeze-drying and solvent elimination, the yield was 2.4g of powdery, crude aqueous extract (24% w/w).
Table 1. Main constituents of Urticae dioicae radix

* Isolectin mixture (a,b) (UDA = Urtica dioica agglutinine) (0.2-0.6%)
* Polysaccharides (b) (2 glucans, 2 glucogalacturonans, acidic
 arabinogalactan)
* Sterols (c) (3-[beta]-sitosterol, hydroxy-sitosterol and their
 glucosides)
* Scopoletin (d) (cumarin)
* Dimeric phenylpropane-lignans (d) (e.g. neo-olivil,
 secoisolariciresinol and their acetyl- and glucosides)
* Phenylpropanes (e) (homovanillylalcohol and its 4'-O-glucoside)
* Phenols (e) (e.g. p-hydroxy-benzaldehyde)
* Ceramides (e)
* Triterpenoic acids (e)
* Monoterpendiols and their glucosides (e)

(a) Peumans et al., 1983.
(b) Wagner et al., 1994.
(c) Chaurasia and Wichtl, 1986a.
(d) Chaurasia and Wichtl, 1987.
(e) Wichtl, 2002.

Table 2. Nettle root products used in clinical and preclinical trials

Product name
(abbreviation) Dosage form Recommended daily dosage (mg)

Urtica plus Capsules 600 or 300 bid
Urtica plus N Capsules 540 bid (270 = 189 native)
Bazoton (BAZ) Capsules 600 bid (300 bid after 3 mos)
Bazoton Liquidum Liquid 3 ml bid
Bazoton N Capsules 300 (native) bid
Bazoton uno Tablets 459
Prostaherb N Dragees 161 mg (native) tid
ZY15095 (b) Capsules 600 bid
UU (c) Liquid 5 mL tid
UDL (e) Liquid 30-150 drops
Urtica-APS Tablets 250 bid
Prostamon Capsules 300 bid
Winar (LI 166) Tablets 459
Prosta-Truw Capsules 240 tid
Urtidin Liquid 120 in 18 drops (f) tid
Prostatin Tablets 300 tid + A. uva ursi (g)
Prostaherb Tablets 230 tid mg

Product name
(abbreviation) Characterization: DER/solvent Manufacturer

Urtica plus 9:1/70% ethanol Osterholz/Schwarzpharma
Urtica plus N 12-16:1/70% ethanol Osterholz/Schwarzpharma
Bazoton (BAZ) 5:1/20% methanol Kanoldt/Abbott
Bazoton Liquidum 100g (a), 16% ethanol Kanoldt
Bazoton N 7-14:1/20% methanol Kanoldt
Bazoton uno 7-14:1/20% methanol Kanoldt
Prostaherb N 7-14:1/20% methanol Cesra
ZY15095 (b) 5:1/20% methanol Zyma/Novartis
UU (c) 1:1/40% ethanol (d) Study medication
UDL (e) 1:1/45% ethanol Study medication
Urtica-APS 7-9:1/60% ethanol Zyma/Novartis
Prostamon No information No longer available
Winar (LI 166) 8-13:1/60% ethanol Lichtwer
Prosta-Truw 7-8: 1/20% ethanol Truw
Urtidin 20:1 (f)/diethyl ether (f) Study medication
Prostatin 5:1/20% carbinol Abbott
Prostaherb 7:1/20% ethanol Cesra

DER = drug-to-extract ratio.
(a) Contains 78g aqueous extract from 84g crude drug.
(b) Standardized on 8 [micro]g scopoletin.
(c) Urtica dioica and Urtica urens (ratio not fixed).
(d) Diluted 1:5 with ethanol.
(e) Mother tincture made according to the French Pharmacopoeia.
(f) Information from the author Reza Safarinejad M (100 mg/ml were
standardized on 35 ppm scopoletin).
(g) Arctostaphylos uva ursi = 700 mg dried extract of A. uva ursi leaf;
standardized on 20% arbutin.

Table 3. Studies of nettle root preparations for BPH

 Number of
 patients
 Medication prepared for Nettle (N)
 the study or brand of Control (C)
Study First author (date) nettle product Placebo (P)

 1 Barsom and Bettermann Prostati[n.sup.R] 30 N
 (1979)
 2 Hallwachs (1981) Bazoto[n.sup.R] 54 N
 3 Schonefeld et al. (1982) Prostamo[n.sup.R] 30 N
 4 Djulepa (1982) Bazoto[n.sup.R] 105 N
 5 Djulepa (1983) Bazoto[n.sup.R] 12 N
 6 Tosch and Mussiggang Bazoto[n.sup.R] ? of 5620 N
 (1983)
 Bazoto[n.sup.R] ? of 5620 N
 7 Stahl (1984) Bazoto[n.sup.R] 4051 N
 8 Vontobel (1985) Bazoto[n.sup.R] 25 N, 25 P
 9 Vandierendounck and Simi[c.sup.R] 111 N
 Burkhardt (1986) (= Bazoto[n.sup.R])
10 Dathe and Schmid (1987) Bazoto[n.sup.R] 35 N, 37 P
11 Brandstadter (1987) Urtica plu[s.sup.R] 149 N
12 Maar (1987) Bazoto[n.sup.R] 39 N
13 Romics (1987) Bazoto[n.sup.R] 27 N
 Bazoto[n.sup.R] 23 N
14 Sonnenschein (1987) Urtica plu[s.sup.R] 4551 N (a)
15 Bauer (1988) Bazoto[n.sup.R] 253 N
16 Frick (1987) Bazoto[n.sup.R] 8 N
17 Friesen (1988) Bazoto[n.sup.R] 4480 N
18 Feiber (1992) Bazoto[n.sup.R] 26 N, 16 C
19 Goetz (1989) Study medication 10 N
20 Belaiche and Lievoux Study medication 67 N
 (1991)
21 Kanoldt (1991) Bazoto[n.sup.R] 6165 N
22 Kanoldt (1992) Bazoto[n.sup.R] 6254 N
23 Fischer (1992) Bazoto[n.sup.R] 20 N, 20 P
24 Romics (1992) Bazoton [N.sup.R] 27 N (dose
 splitted)
 Bazoton [N.sup.R] 23 N once
 daily)
25 von Thiel and Grosskurth Bazoton un[o.sup.R] 5097 N
 (1994)
26 Kaldewey (1995) Urtica plus [N.sup.R] 1319 N
27 Engelmann (1996a) Bazoton un[o.sup.R] 47 N, 47 P
28 Engelmann (1996b) Bazoton un[o.sup.R] 58 N
 Bazoton [N.sup.R] 61 N
29 Engelmann (1996a, b) Bazoton Liquidu[m.sup.R] 20 N, 21 P
30 Nennstiel (1996) Urtica AP[S.sup.R] 462 N
31 Radavicus (1996) Prostaherb [N.sup.R] 52 N
32 Wegener (2004) Prosta Tru[w.sup.R] 525 N
33 Schneider and Rubben Bazoton un[o.sup.R] 124 N, 122 P
 (2004)
34 Safarinejad (2005) Urtidi[n.sup.R] 287 N, 271 P
 NR

Study First author (date) Main outcome measure

 1 Barsom and Bettermann Sonographic residual volume, etc
 (1979)
 2 Hallwachs (1981) Residual volume, urinary flow
 3 Schonefeld et al. (1982) Residual volume, nycturia
 4 Djulepa (1982) Residual volume etc.
 5 Djulepa (1983) Residual volume etc.
 6 Tosch and Mussiggang Residual volume etc.
 (1983)
 Residual volume etc.
 7 Stahl (1984) Nycturia, micturition frequency
 8 Vontobel (1985) Miction volume, maximum urinary flow
 9 Vandierendounck and Nycturia, micturition frequency
 Burkhardt (1986)
10 Dathe and Schmid (1987) Maximum urinary flow, residual volume
11 Brandstadter (1987) Urinary flow, residual volume
12 Maar (1987) Urinary flow, residual volume, etc
13 Romics (1987) Mean urinary flow, residual volume,
 etc
 Mean urinary flow, residual volume,
 etc
14 Sonnenschein (1987) Subjective complaints, urinary flow
 etc.
15 Bauer (1988) Residual volume, prostate size
16 Frick (1987) Clinical symptoms, prostate size
17 Friesen (1988) Clinical symptoms, urinary flow etc
18 Feiber (1992) Prostate size, residual volume etc
19 Goetz (1989) Prostate size, residual volume etc
20 Belaiche and Lievoux Nycturia, residual volume etc
 (1991)
21 Kanoldt (1991) Maximim urinary flow, residual volume
22 Kanoldt (1992) Prostate size, residual volume etc
23 Fischer (1992) Clinical symptoms, mean urinary flow
 etc
24 Romics (1992) Residual volume, mean urinary flow etc
 Residual volume, prostate size etc
25 von Thiel and Grosskurth IPSS, maximum urinary flow, etc
 (1994)
26 Kaldewey (1995) Clinical symptoms, urinary flow etc
27 Engelmann (1996a) IPSS, maximum urinary flow, etc
28 Engelmann (1996b) IPSS, maximum urinary flow, etc
 IPSS, maximum urinary flow, etc
29 Engelmann (1996a, b) IPSS, maximum urinary flow, etc
30 Nennstiel (1996) Max. urinary flow, residual volume etc
31 Radavicus (1996) Clinical symptoms, residual volume
 etc.
32 Wegener (2004) IPSS, residual volume, etc
33 Schneider and Rubben IPSS, maximum urinary flow, etc
 (2004)
34 Safarinejad (2005) Nr
 IPSS, maximum urinary flow, etc

Study First author (date) Suggested outcome

 1 Barsom and Bettermann Improvement over time
 (1979)
 2 Hallwachs (1981) No improvement over time
 3 Schonefeld et al. (1982) No improvement over time
 4 Djulepa (1982) Improvement over time
 5 Djulepa (1983) Improvement over time
 6 Tosch and Mussiggang Improvement over time
 (1983)
 Improvement over time
 7 Stahl (1984) Improvement over time
 8 Vontobel (1985) N superior to P
 9 Vandierendounck and Improvement over time
 Burkhardt (1986)
10 Dathe and Schmid (1987) Improvement over time
11 Brandstadter (1987) Improvement over time
12 Maar (1987) Improvement over time
13 Romics (1987) Improvement over time
 Improvement over time
14 Sonnenschein (1987) Improvement over time
15 Bauer (1988) Improvement over time
16 Frick (1987) Improvement over time
17 Friesen (1988) Improvement over time
18 Feiber (1992) N superior to C
19 Goetz (1989) Improvement over time
20 Belaiche and Lievoux Improvement over time
 (1991)
21 Kanoldt (1991) Improvement over time
22 Kanoldt (1992) Improvement over time
23 Fischer (1992) N superior to P
24 Romics (1992) No difference
 Between groups
25 von Thiel and Grosskurth Improvement over time
 (1994)
26 Kaldewey (1995) Improvement over time
27 Engelmann (1996a) N superior to P
28 Engelmann (1996b) No difference
 Between groups
29 Engelmann (1996a, b) N superior to P
30 Nennstiel (1996) Improvement over time
31 Radavicus (1996) Improvement over time
32 Wegener (2004)
33 Schneider and Rubben N superior to P
 (2004)
34 Safarinejad (2005) Improvement over time
 N superior to P

Bazoto[n.sup.R]: 1200 mg initially, after 3 months dose reductopn to
600 mg/day; population, (a) BPH, prostatitis or BPH and prostatitis or
no diagnosis stated.

Table 4. Internal and external validity items in chronologically listed
studies on nettle root products (methods in Chrubasik et al., 2003)

 Internal validity Blinding and Attrition number of
 Randomisation masking of dropouts and intention-
Study number and/or allowance outcome to-treat and/or
from Table 1 for confounding assessment sensitivity analyses

 1 N N N 3 N N
 2 N N N 0 Y N
 3 N N N # N N
 4 N N N # N N
 5 N N N 0 Y N
 6 N N N 128 N N
 7 N N N 106 N N
 8 Y N Y 6 N/3 P N N
 9 N N N 28 N N
10 Y N N 7 (N + P) N N
11 N N N 5 N N
12 N N N # N N
13 N N N 0 Y N
14 N N N 473 N N
15 N N N # N N
16 N N N 0 Y N
17 N N N 84 N N
18 N N N 0 Y N
19 N N N 0 Y N
20 N N N 0 Y N
21 N N N # N N
22 N N N # N N
23 Y N Y 1N + 6P N N
24 N N N 2N + 1 N N N
25 N N N # N N
26 N N N # N N
27 Y Y Y 9N + 10P Y N
28 Y Y Y 7 N Y N
29 Y Y Y 2N + 1P Y N
30 N N N # N N
31 N N N 5 N N
32 N N N # N N
33 Y Y Y NR Y N
35 Y Y Y 18N + 34P Y N
31 N N N NR N N

 External validity
 Appropriate tests of Inclusion and
 null & alternative exclusion criteria Treatment
 hypotheses in pre- and/or baseline type &
 specified POM and/or description of availability of
Study number MV testing patients and their additional
from Table 1 Null Alt complaints treatments

 1 N N Y N N
 2 N N Y N N
 3 N N Y N N
 4 N N Y N N
 5 N N Y N N
 6 N N Y N N
 7 N N Y N N
 8 N N Y N N
 9 N N Y N N
10 N N Y N N
11 N N Y N N
12 N N Y N N
13 N N Y N N
14 N N Y N Y
15 N N Y N N
16 N N Y N N
17 N N Y N N
18 N N Y N N
19 N N Y N N
20 N N Y N N
21 N N Y N N
22 N N Y N N
23 N N Y N N
24 N N Y N N
25 N N Y N N
26 N N Y N N
27 Y N Y Y Y
28 N N Y N N
29 N N Y N N
30 N N Y N N
31 N N Y N N
32 N N Y N N
33 Y N Y N
35 N N Y N N
31 N N Y N N

 Validated Duration of study
 Setting outcome (w weeks) Documentation of
Study number (number of measures (m months) N (adverse
from Table 1 centres) included (ys years) events)

 1 1 Y 3 w Y (3)
 2 1 Y up to 5 m NR
 3 1 Y 12 w NR
 4 1 Y 3 m-2 ys NR
 5 1 Y up to 4 ys NR
 6 NR Y 3-4 m Y (216)
 7 580 N 10 w NR
 8 1 Y 9 w Y (3)
 9 1 Y 10 w Y (7)
10 1 Y 6-8 w zero
11 1 Y 10 w Y (2)
12 1 Y up to 6 m NR
13 1 Y 3.5 m NR
14 371 Y 12 w Y (44)
15 NR Y 12 w NR
16 1 N 12 w NR
17 1 Y 24 w Y (49)
18 1 Y 4;24 w NR
19 1 Y 2 m zero
20 1 Y 6 m zero
21 NR Y 6 m Y (128)
22 NR Y 3 6 m Y (128)
23 1 Y 7 m Y (1)
24 1 Y 16 w Y (3)
25 NR Y 3 m Y (46)
26 279 Y Up to 6 m Y (13)
27 17 Y 24 w Y (5)
28 NR Y 3 m Y (10)
29 1 Y 3 m Y (1)
30 42 Y 12 w Y (8)
31 1 Y Up to 24 w Y (1)
32 49 Y 12 w Y (2)
33 27 Y 1 y Y (29)
35 NR Y 6 m Zero
31 NR NR 12 m Zero

NR, not reported; POM, principal outcome measure; N, no; Y, yes; MV,
multivariate.
#Probably per protocol population.
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Author:Chrubasik, Julia E.; Roufogalis, Basil D.; Wagner, Hildebert; Chrubasik, Sigrun
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:1USA
Date:Aug 1, 2007
Words:8296
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