Urticae radixNettle Root

MonographsThe Scientific Foundation for Herbal Medicinal Products

2015

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The Scientific Foundation for Herbal Medicinal Products

URTICAE RADIXNettle Root

2015

ESCOP Monographs were first published in loose-leaf form progressively from 1996 to 1999 as Fascicules 1-6, each of 10 monographs

© ESCOP 1996, 1997, 1999

Second Edition, completely revised and expanded© ESCOP 2003

Second Edition, Supplement 2009© ESCOP 2009

ONLINE SERIESISBN 978-1-901964-40-0

Urticae radix - Nettle Root

© ESCOP 2015

Published by the European Scientific Cooperative on Phytotherapy (ESCOP)Notaries House, Chapel Street, Exeter EX1 1EZ, United Kingdom

www.escop.com

All rights reservedExcept for the purposes of private study, research, criticism or review no part of this text

may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, without the written permission of the publisher.

Important Note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment may be required. In their efforts to provide information on the efficacy and safety of herbal drugs and herbal preparations, presented as a substantial overview together with summaries of relevant data, the authors of the material herein have consulted comprehensive sources believed to be reliable. However, in view of the possibility of human error by the authors or publisher of the work herein, or changes in medical knowledge, neither the authors nor the publisher, nor any other party involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for results obtained by the use of such information. Readers are advised to check the product information included in the package of each medicinal preparation they intend to use, to be certain that the information contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.

Edited by Simon Mills and Roberta HutchinsCover photographs by Simon Mills (Urtica dioica) and Martin Willoughby

Cover and text design by Martin WilloughbyTypeset in Optima by Roberta Hutchins

Plant illustrated on the cover: Urtica dioica

FOREWORD

It is a great pleasure for me to introduce the online era of ESCOP Monographs. Interest in herbal medicinal products continues to stimulate research on herbal substances and the body of knowledge in this field is steadily growing. ESCOP takes account of this by preparing new monographs and - as the only organisation in the field at the moment - particularly through regular revision of our published monographs. In order to provide readers and authorities with balanced compilations of scientific data as rapidly as possible, ESCOP Monographs will be published online from now on. This contemporary way of publishing adds further momentum to ESCOP’s endeavours in the harmonization of European standards for herbal medicinal products.

The Board of ESCOP wishes to express its sincere gratitude to the members of the Scientific Committee, external experts and supervising editors, and to Peter Bradley, the final editor of every monograph published up to March 2011. All have voluntarily contributed their time and scientific expertise to ensure the high standard of the monographs.

Liselotte KrennChair of the Board of ESCOP

PREFACE

Over the 15 years since ESCOP published its first monographs, initially as loose-leaf documents then as two hardback books, ESCOP Monographs have achieved a reputation for well-researched, comprehensive yet concise summaries of available scientific data pertaining to the efficacy and safety of herbal medicinal products. The Second Edition, published in 2003 with a Supplement in 2009, covered a total of 107 herbal substances.

The monograph texts are prepared in the demanding format of the Summary of Product Characteristics (SPC), a standard document required in every application to market a medicinal product for human use within the European Union and ultimately providing information for prescribers and users of individual products.

As a change in style, literature references are now denoted by the name of the first author and year of publication instead of reference numbers; consequently, citations at the end of a monograph are now in alphabetical order. This is intended to give the reader a little more information and perspective when reading the text.

Detailed work in studying the pertinent scientific literature and compiling draft monographs relies to a large extent on the knowledge, skills and dedication of individual project leaders within ESCOP Scientific Committee, as well as invited experts. After discussion and provisional acceptance by the Committee, draft monographs are appraised by an eminent Board of Supervising Editors and all comments are taken into account before final editing and approval. In this way a wide degree of consensus is achieved, but it is a time-consuming process.

To accelerate the publication of new and revised monographs ESCOP has therefore decided to publish them as an online series only, commencing in 2011. We trust that rapid online access will prove helpful and convenient to all users of ESCOP Monographs.

As always, ESCOP is indebted to the many contributors involved in the preparation of monographs, as well as to those who provide administrative assistance and hospitality to keep the enterprise running smoothly; our grateful thanks to them all.

NOTES FOR THE READER

From 2011 new and revised ESCOP Monographs are published as an online series only. Earlier monographs are available in two books, ESCOP Monographs Second Edition (2003) and the Second Edition Supplement 2009, but are not available online for copyright reasons.

After purchase of a single monograph, the specific items to be downloaded are:

Front cover Title page Verso Foreword and Preface Notes for the Reader Abbreviations The monograph text Back cover

Information on the member organizations and people involved in ESCOP’s activities can be found on the website (www.escop.com): Members of ESCOP Board of Supervising Editors ESCOP Scientific Committee Board of Directors of ESCOP

ABBREVIATIONS used in ESCOP monographs

AA arachidonic acidABTS 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)ACE angiotensin converting enzymeADP adenosine diphosphateALAT or ALT alanine aminotransferase (= SGPT or GPT)ALP alkaline phosphataseanti-IgE anti-immunoglobulin EASA acetylsalicylic acidASAT or AST aspartate aminotransferase (= SGOT or GOT)ATP adenosine triphosphateAUC area under the concentration-time curveBMI body mass indexBPH benign prostatic hyperplasiab.w. body weightcAMP cyclic adenosine monophosphateCI confidence intervalCmax maximum concentration of a substance in serumCNS central nervous systemCoA coenzyme ACOX cyclooxygenaseCSF colony stimulating factorCVI chronic venous insufficiencyCYP cytochrome P450d dayDER drug-to-extract ratioDHT dihydrotestosteroneDNA deoxyribonucleic acidDPPH diphenylpicrylhydrazylDSM Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association)ECG electrocardiogramED50 effective dose in 50% of casesEDTA ethylenediamine tetraacetateEEG electroencephalogramEMA European Medicines AgencyENT ear, nose and throatER oestrogen receptorERE oestrogen-responsive elementFSH follicle-stimulating hormoneGABA gamma-aminobutyric acidGal galactoseGFR glomerular filtration rateGGTP gamma-glutamyl transpeptidaseGOT glutamate oxalacetate transaminase (= SGOT)GPT glutamate pyruvate transaminase (= SGPT)GSH glutathione (reduced)GSSG glutathione (oxidised)HAMA Hamilton Anxiety Scale12-HETE 12-hydroxy-5,8,10,14-eicosatetraenoic acidHDL high density lipoproteinHIV human immunodeficiency virusHMPC Committee on Herbal Medicinal Products (of the EMA)HPLC high-performance liquid chromatography 5-HT 5-hydroxytryptamine (= serotonin)IC50 concentration leading to 50% inhibitionICD-10 International Statistical Classification of Diseases and Related Health Problems, Tenth RevisionICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human UseICSD International Classification of Sleep DisordersIFN interferonIL interleukini.m. intramusculariNOS inducible nitric oxide synthaseINR International Normalized Ratio, a measure of blood coagulation (clotting) tendency

i.p. intraperitonealIPSS International Prostate Symptom Scorei.v. intravenouskD kiloDaltonKM Index Kuppermann Menopausal IndexkPa kiloPascalLC-MS liquid chromatography-mass spectrometryLD50 the dose lethal to 50% of animals tested LDH lactate dehydrogenaseLDL low density lipoproteinLH luteinizing hormone5-LOX 5-lipoxygenaseLPS lipopolysaccharideLTB4 leukotriene B4M molar (concentration)MAO monoamine oxidaseMBC minimum bactericidal concentrationMDA malondialdehydeMFC minimum fungicidal concentrationMIC minimum inhibitory concentrationMr molecularMRS Menopause Rating ScaleMRSA methicillin-resistant Staphylococcus aureusMTD maximum tolerated doseMTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideMW molecular weightNBT nitro blue tetrazoliumNF-kB necrosis factor kappa-BNO nitric oxide NOS nitric oxide synthasen.s. not significantNSAID non-steroidal anti-inflammatory drugovx ovariectomy or ovariectomizedORAC oxygen radical absorbance capacityPA pyrrolizidine alkaloidPAF platelet activating factorPCR polymerase chain reactionPEG polyethylene glycolPGE prostaglandin EPHA phythaemagglutininp.o. per osPOMS profile of mood statesPVPP polyvinylpolypyrrolidoneRANKL receptor activator of nuclear factor kappa-B ligandRNA ribonucleic acidRT-PCR reverse transcription polymerase chain reactions.c. subcutaneousSCI spinal cord injury SERM selective oestrogen receptor modulatorSGOT or GOT serum glutamate oxalacetate transaminase (= ASAT or AST)SGPT or GPT serum glutamate pyruvate transaminase (= ALAT or ALT)SHBG sex hormone binding globulinSOD superoxide dismutaseSSRI selective serotonin reuptake inhibitorSTAI state-trait anxiety inventoryt1/2 elimination half-lifeTBARS thiobarbituric acid reactive substancesTGF-b transforming growth factor-betaTNF tumour necrosis factorTPA 12-O-tetradecanoylphorbol-13-acetateURT upper respiratory tractURTI upper respiratory tract infectionUTI urinary tract infectionVAS visual analogue scaleVLDL very low density lipoprotein

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Nettle Root

DEFINITION

Nettle root consists of the whole, or fragmented, underground parts of Urtica dioica L., Urtica urens L., their hybrids or mixtures of these.

The material complies with the European Pharmacopoeia [Nettle Root].

CONSTITUENTS

Approx. 0.1% agglutinin (UDA), a lectin which can be separated into 11 isolectins and which contains 86 amino acid residues [Peumans 1984; Van Damme 1988; Broekaert 1989; Willer 1991, 1992; Balzarini 1992; Beintema 1992; Lerner 1992, Wagner 1994a; Frank 1998; Ganzéra 2005]; a mixture of polysaccharides, basically 2 glucans, 2 rhamnogalacturonans and 1 arabinogalactan [Willer 1992; Wagner 1992, 1994b; Frank 1998]; scopoletin, b-sitosterol, b-sitosterol glucoside and other sterols and sterol glucosides [Schilcher 1986; Chaurasia 1986a, 1987a,b; Frank 1998]; phenylpropanes (homovanillyl alcohol and its glucoside) as well as lignans such as (+)-neo-olivil and its derivatives, (-)-secoisolariciresinol, (-)-isolariciresinol and dehydrodiconiferyl alcohol, and lignan glucosides [Chaurasia 1986b, 1987a; Kraus 1990a,b; Ganßer 1995a,b; Schöttner 1997a,b; Orčić 2015]; ceramides [Kraus 1991a]; hydroxy fatty acids including (10E,12Z)-9-hydroxy-10,12-octadecadienoic acid [Kraus 1991b] and the isomeric 9,10,13-trihydroxy-11-octadecenoic and 9,12,13-trihydroxy-10-octadecenoic acids [Ganßer 1995a,b]; monoterpene diols and their glucosides [Kraus 1991c].

CLINICAL PARTICULARS

Therapeutic indicationsSymptomatic treatment of micturition disorders (dysuria, pollakisuria, nocturia, urine retention) in benign prostatic hyperplasia (BPH) [Djulepa 1982; Tosch 1983; Schilcher 1988a,b, 1989, 1992; Stahl 1984; Vontobel 1985; Vahlensieck 1986, 1996; Vandierendounck 1986; Dathe 1987; Maar 1987; Bauer 1988; Feiber 1988; Friesen 1988; Goetz 1989; Jaspersen-Schib 1989; Belaiche 1991; Fischer 1992; Kaldewey 1995; Brom 1996; Engelmann 1996; Bracher 1997; Veit 1998; Chrubasik 2007; Pagano 2014] at stages I and II as defined by Alken [Alken 1973] or stages II and III as defined by Vahlensieck [Vahlensieck1996].

Posology and method of administration

Dosage

Daily dose: 4-6 g of the drug as an infusion [Schilcher 1992; Jaspersen-Schib 1989]; 300-600 mg of dried native extract (7-14:1, 20% V/V methanol) [Djulepa 1982; Tosch 1983; Stahl 1984; Vontobel 1985; Vandierendounck 1986; Dathe1987; Maar 1987; Bauer 1988; Feiber 1988; Friesen 1988; Fischer 1992; Brom 1996; Bracher 1997; Veit 1998; Pagano 2014] or 378-756 mg of dried native extract (12-16:1, 70% V/V ethanol) [Kaldewey 1995]; 4.5-7.5 mL of fluid extract (1:1, 45% ethanol) [Goetz 1989] or 15 mL of fluid extract (1:5, 40% ethanol) [Belaiche 1991]; comparable extracts at equivalent dosages.

Method of administrationFor oral administration.

Duration of administrationNo restriction.

Contra-indicationsNone known.

Special warnings and special precautions for useAll cases of difficulty in micturition require clarification by a physician and regular medical checks in order to rule out the need for other treatment, e.g.

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surgical intervention. Consultation with a physician is particularly necessary in cases of blood in the urine or acute urine retention.

Interaction with other medicaments and other forms of interactionNone reported.

Pregnancy and lactationNot applicable.

Effects on ability to drive and use machinesNone known.

Undesirable effectsGastrointestinal complaints [Djulepa 1982; Stahl 1984; Vontobel 1985; Kaldewey 1995; Engelmann 1996; Pagano 2014]. Rare cases of allergic skin reactions [Tosch 1983, Pagano 2014].

OverdoseNo toxic effects reported.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

In vitro experimentsSignificant suppression (average 67%) of SHBG binding cap-acity by a 10% solution of a 20% methanolic extract of nettle root has been demonstrated. It appears that the binding of 5a-dihydrotestosterone to proteins can be influenced by the

extract [Schmidt 1983]. An aqueous extract of nettle root dose-dependently inhibited the binding of SHBG to solubilized receptors from human prostatic tissue; in the same experiment neither a 70% ethanolic extract of nettle root nor Urtica dioica agglutinin were effective [Hryb 1995].

The lignan secoisolariciresinol and a mixture of isomeric (11E)-9,10,13-trihydroxy-11-octadecenoic and (10E)-9,12,13-trihydroxy-10-octadecenoic acids isolated from nettle root reduced the binding activity of human SHBG; methylation of the mixed hydroxy acids increased their activity by about 10-fold [Ganßer 1995a].

(10E,12Z)-9-hydroxy-10,12-octadecadienoic acid isolated from an aqueous-methanolic extract of nettle root inhibited aromatase activity [Kraus1991b; Bartsch 1992]. On the other hand, aromatase inhibition by five other compounds isolated from a methanolic extract of nettle root was only weak (less than 1% compared to 4-hydroxy-androst-4-ene-3,17-dione) [Ganßer 1995b].

A polysaccharide fraction from an aqueous extract of nettle root showed activity in the lymphocyte transformation test. Isolated polysaccharides produced significant, concentration-dependent reduction of haemolysis (95% reduction at 1 mg/mL) in classical and alternative complement tests. From these results anti-inflammatory and immunomodulating activities were deduced [Wagner 1989; Willer 1990,1992]. Lectin fractions from Urtica dioica agglutinin stimulated the proliferation of human lymphocytes in the lymphocyte transformation test [Wagner 1989; Willer 1992].

Stages of Benign Prostatic Hyperplasiaas defined by Alken

Stage IDysuria, pollakisuria, possibly nocturia, reduction in projection of the urine stream, no residual urine (stage of compensation of the bladder musculature).

Stage IISame symptomatic as under I, except with residual urine (incipient decompensation of the bladder musculature).

Stage IIIComplete stoppage or overflow of the bladder (decompensation of the bladder musculature).

Stages of Benign Prostatic Hyperplasiaas defined by Vahlensieck

Stage INo micturition problemsMore or less marked BPHUrine stream: greater than 15 mL/s maximal flowNo residual urineNo bladder trabeculation

Stage IIIntermittent micturition problems(frequency, calibre of urine stream)More or less marked BPHUrine stream: between 10 and 15 mL/s maximal flowNo or low (≤ 50 mL) residual urineNo or incipient bladder trabeculation

Stage IIIPermanent micturition problems(frequency, calibre of urine stream)More or less marked BPHUrine stream: less than 10 mL/s maximal flowResidual urine more than 50 mL Trabeculated bladder

Stage IVPermanent micturition problems(frequency, calibre of urine stream)More or less marked BPH Urine stream: less than 10 mL/s maximal flowResidual urine more than 100 mLOverflowing bladderStoppage of the upper urinary tract

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Organic solvent extracts of nettle root inhibited Na+, K+-ATPase activity of human BPH tissue cells by 28-82% at 0.1 mg/mL. Steroidal compounds from nettle root, such as stigmast-4-en-3-one, stigmasterol and campesterol, inhibited the enzyme activity by 23.0-67.0% at concentrations from 10-3 to 10-6 M. These results suggest that some hydrophobic constituents such as steroids inhibit the membrane Na+, K+-ATPase activity of the prostate, which may subsequently suppress prostate-cell metabolism and growth [Hirano 1994].

A lectin fraction from Urtica dioica agglutinin inhibited by 53% the binding of epidermal growth factor (EGF) to EGF receptors in cells cultured from human prostatic tissue [Willer 1992]. The growth of cells cultured from human BPH tissue was significantly inhibited by 5 different fractions from a 20% methanolic extract of nettle root [Enderle-Schmidt 1988]. Urtica dioica agglutinin at 500 ng/mL to 100 µg/mL dose-dependently inhibited the binding of 125I-labelled EGF to its receptor on human A431 epidermoid cancer cells [Wagner 1994].

Lignans present in polar extracts of nettle root, (+)-neo-olivil, (-)-secoisolariciresinol, dehydrodiconiferyl alcohol, isolarici-resinol and (-)-3,4-divanillyltetrahydrofuran, as well as the main intestinal metabolites of plant lignans in humans (enterodiol, enterolactone and enterofuran), showed binding affinity to human SHBG. Outstandingly high affinity was exhibited by (-)-3,4-divanillyltetrahydrofuran, which is present only in traces in nettle root [Schöttner 1997b].

A 20% methanolic extract of nettle root significantly (p<0.05), and time- and concentration-dependently, inhibited the proliferation of human prostatic epithelial LNCaP (lymph node carcinoma of the prostate) cells; maximum growth reduction of 30% was obtained on day 5 at a concentration of 10-6 mg/mL. In contrast, the extract had no antiproliferative effect on human prostatic stromal cells. Comparable inhibition (p<0.05) of proliferation of human epithelial LNCaP cells by a polysaccharide-rich fraction (POLY M) of the same extract was observed over a 7-day period. Again, the inhibition was time- and concentration-dependent, with maximum suppression of 50% on day 6 at concentrations of 10-9 and 10-11 mg/mL. No cytotoxic effects of the extract or the fraction POLY-M on cell proliferation were observed [Lichius 1999a; Konrad 2000]. Nettle root extract inhibited cell proliferation in cultures of prostate tissue taken from BPH patients [Rausch 1992].

It has been shown that Urtica dioica agglutinin binds to the cell membrane of prostatic adenoma cells from BPH patients [Sinowatz 1994] and can inhibit the action of growth factors involved in the regulation of prostate growth [Wagner 1992].

An ethanolic and a petroleum ether extract inhibited 5a-reductase with an IC50 of 120 µg and 190 µg, respectively, compared to 1.06 µg by finasteride [Nahata 2012].

In vivo experimentsTen dogs suffering from BPH, treated daily for 100 days with 90 mg/kg b.w. of a nettle root extract (3.5-7:1, 20% V/V methanol), showed an average decrease of 30% in prostate volume [Daube 1988]. The same extract did not inhibit testosterone and dihydrotestosterone stimulated growth of the prostate in castrated rats [Rhodes 1993].

A crude aqueous fraction from nettle root containing 4 different polysaccharides, administered orally at 40 mg/kg, significantly inhibited carrageenan-induced rat paw oedema by 36.8% after 5 hours (p<0.01) and 63.6% after 22 hours (p<0.005). This anti-inflammatory activity was comparable after 5 hours,

and markedly superior after 22 hours, to that exhibited by indometacin at 10 mg/kg (42.1% and 27.3% inhibition respectively) [Wagner 1989, 1992, 1994c]. In a BPH model involving implantation of mouse fetal urogenital sinus tissue into the ventral prostate glands of adult male mice, a 20% methanolic extract of nettle root administered orally for 28 days reduced experimentally-induced prostate growth by 51.3%, compared to 26.5% by an aqueous extract [Lichius 1997]. In the same model, a polysaccharide-rich fraction (POLY-M) from the 20% methanolic extract reduced prostate growth by 33.8% whereas Urtica dioica agglutinin increased prostate growth by 20.1% and secoisolariciresinol by 37.2% [Lichius 1999b].

An ethanolic and a petroleum ether extract were administered orally to rats with testosterone-induced increased prostatic weight. At 50 mg/kg b.w. the nettle extracts reduced this weight increase by 70% and 73% respectively. At 10 mg/kg b.w the respective reductions were close to 30%, compared to 50% for b-Sitosterol at this level. The positive control finasteride at 1 mg/kg b.w reduced the weight increase by 80%. In the negative control group, administered only subcutaneous testosterone, urine output was reduced by 77% after 4 weeks. Treatment with the extracts reduced the urinary obstruction to 2 and 5%, b-Sitosterol to 11% and finasteride to 1% (at the above mentioned concentrations) [Nahata 2012].

Pharmacological studies in humans31 men aged between 58 and 82 years with BPH at stages I to II were treated daily for 20 weeks with 1200 mg of a dried nettle root extract preparation (3.5-7:1; 20% V/V methanol). From fine needle aspiration biopsies of the prostate at 4-weekly intervals, morphologically significant changes in prostatic adenoma cells were detected that may relate to competitive inhibition of SHBG binding capacity by the extract [Ziegler 1982].

Prostatic cells taken by needle biopsy from 33 BPH patients treated with nettle root extract for about 6 months were investi-gated by fluorescence microscopy. Compared with normal prostatic cells, a decrease in homogenous granules was detected in hyperplastic cells from the BPH patients, indicating that biological activity in these cells had decreased [Ziegler 1983]. The presence of nettle root constituents or their metabolites in prostate tissue obtained (through prostatectomy) from BPH patients treated with nettle root extract was demonstrated by fluorescence microscopy. The granular fluorescence was not observed in prostate tissue from patients not treated with nettle root extract, but could be simulated to some extent by in vitro incubation of this tissue with nettle root extract [Dunzendorfer 1984].

Morphological examination of prostate tissue obtained by needle biopsy from BPH patients before and 6 months after therapy with nettle root extract confirmed ultrastructural changes in the smooth muscle cells and epithelial cells of the prostate [Oberholzer 1987].

Clinical studies

Clinical studies performed with dried native extract of nettle root (7-14:1, 20% V/V methanol) in a preparation containing an equal amount of diluent. As in the published reference papers where mg amounts are stated, the following dosages relate to the extract preparation, of which only 50% was native extract (7-14:1).

A review of 34 clinical trials including 40,000 patients concluded that there is evidence of efficacy for the methanolic extract in

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the improvement of BPH related complaints [Chrubasik 2007].

In a randomized, double-blind, placebo-controlled study with 40 BPH II patients (1200 mg of extract preparation per day, n = 20; placebo, n = 20), statistically significant (p<0.05) decreases in micturition frequency and SHBG levels were observed in the verum group after 6 months [Fischer 1992].

Significant improvements of 14% in average urinary flow rate and 40-53% in residual urine volume were observed in BPH patients (n = 32) who received 600 mg of extract preparation daily for 4-6 weeks in a randomized, placebo-controlled (n = 35), double-blind study [Dathe 1987].

Fifty BPH stage I-II patients enrolled in a double-blind, controlled study were treated daily for 9 weeks with 600 mg of extract preparation (n = 25) or placebo (n = 25). A significant increase of 44% in micturition volume (p<0.05) and a highly significant decrease in serum levels of SHBG (p = 0.0005) were observed. The latter effect was probably due to the SHBG binding cap-acity of the extract [Vontobel 1985].

In an open, multicentre study with 5492 patients receiving 600-1200 mg of extract preparation per day for 3-4 months, significant improvements in nycturia and daytime micturition frequency were observed [Tosch 1983]. A 50% decrease in nycturia was reported in an open, multicentre study with 4051 BPH patients who received 1200 mg of extract preparation per day for 10 weeks [29]. In another open, multicentre study, with 4480 BPH patients receiving 600-1200 mg of extract preparation per day for 20 weeks, significant improvements (p<0.01) in urinary flow and residual urine volume were observed [Friesen 1988].

111 BPH patients with nycturia received 1200 mg of extract preparation per day for 10 weeks in an open study. Noct-urnal micturition frequency decreased in 55% of cases [Vandierendounck 1986]. 37 out of 39 BPH I-III patients experienced improvements in urinary flow, residual urine, nycturia and pollakisuria after a 6-month treatment with 600-1200 mg of extract preparation per day [Maar 1987]. In another open study, residual urine decreased in 67 out of 89 BPH patients receiving 600 mg of extract preparation per day for 3-24 months [Djulepa 1982].

Significant decreases (p<0.05) in prostate volume and residual urine volume as well as in serum SHBG, oestradiol and oestrone levels were observed in an open study with 253 BPH patients who received 1200 mg of extract preparation per day for 12 weeks [Bauer 1988]. Decreases in prostate volume in 54% of cases and residual urine in 75% of cases were observed in an open study with 26 BPH patients who received 1200 mg of extract preparation per day for 4-24 weeks [Feiber 1988].

A one-year double-blind, randomized, placebo-controlled, multicentre study involving 124 patients (mean age 64 ±0.6) treated with 459 mg nettle root dry extract once a day demonstrated a significant (p=0.0233) difference in decrease of the International Prostate Symptom Score (IPSS) in favour of the verum group, by 5.7 points (from 18.7 ±0.3 to 13.0 ±0.5) compared to 4.7 points (from 18.5 ±0.3 to 13.8 ±0.5) in the placebo group (122 patients; mean age 63). The secondary objective variables showed positive but non-significant results in favour of the verum group: maximal urinary flow was increased by 3mL/s while residual urinary volume was lowered by 5 mL, compared to 2.9 mL/s and 4 mL respectively for placebo. Analysis showed better results for quality of life improvement in the verum group (65%) than in the placebo group (62%) (p=0.69) [Schneider 2004].

Clinical studies performed with other nettle root preparationsIn a double-blind, multicentre study, 41 BPH patients were treated daily for 3 months with either 2 x 3 mL of an aqueous extract preparation equivalent to 4.68 g of a fluid extract (1:1, 16% ethanol) (n = 20) or placebo (n = 21). A decrease in residual urinary volume of 19.2 mL in the verum group compared to 10.7 mL in the placebo group, and an increase in maximal urinary flow of 7.1 mL/s in the verum group compared to 4.4 mL/s in the placebo group, were observed. A significantly greater improvement (p = 0.002) in the IPSS was also reported in the verum group [Engelmann 1996].

Daily treatment for 60 days with 90-150 drops of a fluid extract (1:1, 45% ethanol; Ph. Fr.) led to a 66% decrease in residual urine in an open study with 10 BPH patients [Goetz 1989].

In an open study with 67 BPH patients, a reduction in nocturnal micturition frequency was observed after 6 months of daily treatment with 3 x 5 mL of a fluid extract (1:5, 40% ethanol) [Belaiche 1991].

In an open multicentre study involving 1319 patients with BPH and/or prostatitis, daily treatment for 6 months with 378-756 mg of a native extract of nettle root (12-16:1, 70% V/V ethanol) led to substantial improvements in dysuria, nycturia, pollakisuria, urinary flow and residual urine volume. 79.9% of the patients reported an improvement in their quality of life [Kaldewey 1995].

In a double blind, randomized, placebo-controlled, partial crossover study, 620 patients with lower urinary tract symptoms (LUTS) secondary to BPH, aged between 55 and 72 (mean age 63), were treated for 6 months with a preparation of Urtica dioica fluid extract (120 mg per dose; not further specified) (n = 305) or placebo (n = 315) three times daily with meals. Unblinding was carried out after completion of the six month trial, and for an 18 month follow-up period patients were allowed to continue with Urtica dioica treatment or to crossover if they had previously been on placebo. Patients with a follow up >16 months after participation in the trial were included in the analysis. After the initial 6 months, verum treatment demonstrated a significantly greater (p<0.001) reduction in residual urinary volume than placebo, from 73 mL ± 32.6 to 36 mL ± 25.5 in the verum group compared with 74 mL ± 29.6 to 71 mL ± 24.4 in the placebo group, and a significantly greater increase in maximal urinary flow (p<0.05) for verum (8.2 mL/s) compared to placebo (3.4 mL/s). Crossing over to Urtica dioica resulted in a reduction in urinary retention to a volume of 38 mL ± 25.5 and an increase of the maximal urinary flow by 7.4 mL/s. The size of the prostate was measured by transrectal ultrasonography (TRUS) and showed a significant reduction (p<0.001) of the prostate volume in the verum group from 40.1 cc ± 6.8 to 36.3cc ± 4.2, this increased again to 39.5 cc ± 6 in those patients who discontinued the medication during the follow up, while the volume stayed decreased in those patients who continued the medication during follow-up. There was also a significantly greater improvement to the IPSS in the verum group compared to placebo (p<0.002) [Safarinejad 2005].

In an open, prospective phase IV multicentre trial, 100 patients with LUTS received four capsules each containing 240 mg of a dry extract (5.4-6.6:1; ethanol 20% V/V) daily for 24 weeks. Treatment with the preparation resulted in a significant (p<0.0001) reduction in the IPSS from 19.5 ± 4.8 to 13 ± 5, a significant (p<0.0001) increase in the maximal urinary flow rate from 9.7 mL/s ± 2.2 to 13.2 mL/s ± 3.8 and a non-significant reduction of the residual urinary volume by 24.8 mL (±150). Digital measurement (n=48) showed no reduction in prostate volume after 24 weeks [Klein-Bischoff 2007].

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Pharmacokinetic propertiesAfter oral administration of 20 mg of purified Urtica dioica agglutinin (UDA) to patients and healthy volunteers, 30-50% was excreted unchanged in the faeces. The concentration in urine was in the 1-10 ng/mL range and the total amount of UDA in urine was less than 1% of the administered dose. These data confirmed the extreme stability of UDA in the digestive tract and its partial uptake and renal clearance [Samtleben 1996].

Preclinical safety dataNo data available.

Clinical safety dataOver 16,000 patients were treated with nettle root extracts in clinical studies [Djulepa 1982; Tosch 1983; Stahl 1984; Vontobel 1985; Vandierendounck 1986; Dathe 1987; Maar 1987; Bauer 1988; Feiber 1988; Friesen 1988; Goetz 1989; Belaiche 1991; Fischer 1992; Kaldewey 1995; Engelmann 1996] and have taken daily doses of up to 756 mg of hydroalcoholic dry native extract for periods of up to 6 months or, in a few cases, 300 mg of dry native extract for 24 months. The incidence of adverse events was generally under 5%. No serious adverse effects have been reported, the majority of complaints being mild gastrointestinal upsets. In a large open study involving 1319 patients, the incidence of adverse events probably or possibly related to treatment with nettle root extract was 1.0% [Kaldewey 1995].

According to a review, the majority of 40,000 patients participating in clinical trials were treated with an extract prepared with 20% methanol. As adverse effects were only reported as occurring in 2% of all cases, and these were of minor concern, treatment with this particular extract was suggested to be safe [Chrubasik 2007]. REFERENCES

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LIQUIRITIAE RADIX Liquorice Root Second Edition, 2003LUPULI FLOS Hop Strobile Second Edition, 2003MALVAE FLOS Mallow Flower Supplement 2009MARRUBII HERBA White horehound Online Series, 2013MATRICARIAE FLOS Matricaria Flower Second Edition, 2003MELALEUCAE AETHEROLEUM Tea Tree Oil Supplement 2009MELILOTI HERBA Melilot Second Edition, 2003MELISSAE FOLIUM Melissa Leaf Online Series, 2013MENTHAE PIPERITAE AETHEROLEUM Peppermint Oil Second Edition, 2003MENTHAE PIPERITAE FOLIUM Peppermint Leaf Second Edition, 2003MENYANTHIDIS TRIFOLIATAE FOLIUM Bogbean Leaf Online Series, 2013MILLEFOLII HERBA Yarrow Supplement 2009MYRRHA Myrrh Online Series, 2014MYRTILLI FRUCTUS Bilberry Fruit Online Series, 2014OLIBANUM INDICUM Indian Frankincense Supplement 2009ONONIDIS RADIX Restharrow Root Online Series, 2015ORTHOSIPHONIS FOLIUM Java Tea Online Series, 2014PASSIFLORAE HERBA Passion Flower Second Edition, 2003PAULLINIAE SEMEN Guarana Seed Supplement 2009PELARGONII RADIX Pelargonium Root Online Series, 2015PIPERIS METHYSTICI RHIZOMA Kava-Kava Second Edition, 2003PLANTAGINIS LANCEOLATAE FOLIUM/HERBA Ribwort Plantain Leaf/Herb Online Series, 2013PLANTAGINIS OVATAE SEMEN Ispaghula Seed Second Edition, 2003PLANTAGINIS OVATAE TESTA Ispaghula Husk Second Edition, 2003POLYGALAE RADIX Senega Root Second Edition, 2003PRIMULAE RADIX Primula Root Second Edition, 2003PRUNI AFRICANAE CORTEX Pygeum Bark Supplement 2009PSYLLII SEMEN Psyllium Seed Second Edition, 2003RATANHIAE RADIX Rhatany Root Supplement 2009RHAMNI PURSHIANI CORTEX Cascara Online Series, 2015RHEI RADIX Rhubarb Second Edition, 2003RIBIS NIGRI FOLIUM Blackcurrant Leaf Second Edition, 2003ROSAE PSEUDO-FRUCTUS Dog Rose Hip Supplement 2009ROSMARINI FOLIUM Rosemary Leaf Second Edition, 2003RUSCI RHIZOMA Butcher’s Broom Second Edition, 2003SALICIS CORTEX Willow Bark Second Edition, 2003SAMBUCI FLOS Elder flower Online Series, 2013SALVIAE OFFICINALIS FOLIUM Sage Leaf Second Edition, 2003SALVIA TRILOBAE FOLIUM Sage Leaf, Three-lobed Online Series, 2014SENNAE FOLIUM Senna Leaf Second Edition, 2003SENNAE FRUCTUS ACUTIFOLIAE Alexandrian Senna Pods Second Edition, 2003SENNAE FRUCTUS ANGUSTIFOLIAE Tinnevelly Senna Pods Second Edition, 2003SERENOAE REPENTIS FRUCTUS (SABAL FRUCTUS) Saw Palmetto Fruit Second Edition, 2003SERPYLLI HERBA Wild Thyme Online Series, 2014SOLIDAGINIS VIRGAUREAE HERBA European Golden Rod Second Edition, 2003SILYBI MARIANI FRUCTUS Milk Thistle Fruit Supplement 2009SYMPHYTI RADIX Comfrey Root Online Series, 2012TANACETI PARTHENII HERBA Feverfew Online Series, 2014TARAXACI FOLIUM Dandelion Leaf Second Edition, 2003TARAXACI RADIX Dandelion Root Second Edition, 2003THYMI HERBA Thyme Second Edition, 2003TORMENTILLAE RHIZOMA Tormentil Online Series, 2013TRIGONELLAE FOENUGRAECI SEMEN Fenugreek Second Edition, 2003URTICAE FOLIUM/HERBA Nettle Leaf/Herb Second Edition, 2003URTICAE RADIX Nettle Root Online Series, 2015UVAE URSI FOLIUM Bearberry Leaf Online Series, 2012VACCINII MACROCARPI FRUCTUS Cranberry Supplement 2009VALERIANAE RADIX Valerian Root Supplement 2009VERBASCI FLOS Mullein Flower Online Series, 2014VIOLAE HERBA CUM FLORE Wild Pansy Online Series, 2015VITIS VINIFERAE FOLIUM Red Vine Leaf Supplement 2009ZINGIBERIS RHIZOMA Ginger Supplement 2009

10

The second edition of ESCOP Monographs, published as a hardback book in 2003 with a Supplement in 2009, has been widely acclaimed for its authoritative information on the therapeutic uses of herbal medicines. Monographs covering a total of 107 herbal substances include extensive summaries of pharmacological, clinical and toxicological data, and copious references to scientific literature form an important part of each text.

Although publication in the form of books was convenient in the past, ESCOP recognizes that online publication now offers a number of advantages, not least in facilitating rapid publication of individual monographs as soon as all stages of preparation have been completed. Commencing from 2011, therefore, new and revised monographs will be published online only.

The European legislative framework for herbal medicines has advanced considerably over the past decade. Directive 2004/24/EC introduced a simplified registration procedure for traditional herbal medicinal products in EU member states and imposed a 2011 deadline for the registration of certain products on the market. The Committee on Herbal Medicinal Products (HMPC), established in 2004 as part of the European Medicines Agency, has made substantial progress in the preparation of Community Herbal Monographs and associated documentation to provide a more harmonized approach to the scientific assessment of herbal medicinal products throughout the European Community

Whether the evaluation of a herbal medicine is based on evidence of clinical efficacy (well-established use) or on experience and historical use of that product (traditional use) those involved at all levels of the regulatory process need access to detailed, reliable and structured summaries of the available efficacy and safety data. ESCOP monographs meet that requirement and offer an invaluable source of scientific information on herbal medicines to regulators, manufacturers, academics, researchers, health professionals and numerous others.

MonographsThe Scientific Foundation for Herbal Medicinal Products

www.escop.com ISBN 978-1-901964-40-0

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