TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW
........................................................................................ 3
OR THEIR MIXTURES, RADIX
............................................................................................................
. 6
. 7
. 7
II.1
INTRODUCTION
........................................................................................................................
II.1.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
...........
Information on period of medicinal use in the Community regarding the specified
indication
II.2
II.1.2
..............................................................................................................................................
. 8
. 11
. 11
II.2.1
.................................................................................................................
Pharmacology
....................................................................................................................
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
II.2.1.2
.......................................................................................................................
. 11
. 16
. 16
Assessor’s overall conclusions on pharmacology
..................................................................
II.2.2
Pharmacokinetics
...............................................................................................................
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
II.2.2.2
.......................................................................................................................
. 16
. 16
. 16
Assessor’s overall conclusions on pharmacokinetics
.............................................................
II.2.3
Toxicology
..........................................................................................................................
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
II.2.3.2
....................................................................................................................................
. 16
. 16
. 16
. 16
. 16
. 17
. 17
. 17
. 17
. 21
. 21
. 23
. 23
. 23
. 23
. 23
. 23
. 24
. 24
. 40
. 40
Assessor’s overall conclusions on toxicology
........................................................................
II.3
..........................................................................................................................
Clinical Pharmacology
.......................................................................................................
II.3.1.1
Pharmacodynamics
.................................................................................................................
II.3.1.2
Pharmacokinetics
....................................................................................................................
II.3.2
Clinical Efficacy
.................................................................................................................
II.3.2.1
Dose response studies
.............................................................................................................
II.3.2.2
Clinical studies (case studies and clinical trials)
....................................................................
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
.........................................
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
...............................................................
II.3.3
Clinical Safety/Pharmacovigilance
....................................................................................
II.3.3.1
Patient exposure
.....................................................................................................................
II.3.3.2
Adverse events
.......................................................................................................................
II.3.3.3
Serious adverse events and deaths
..........................................................................................
II.3.3.4
Laboratory findings
................................................................................................................
II.3.3.5
Safety in special populations and situations
...........................................................................
II.3.3.6
Assessor’s overall conclusions on clinical safety
...................................................................
II.4
........................................................................................
III.
ANNEXES
III.1
......................................................................................................................................
..........................................................................................................
EMEA 2009
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II.
II.2.1.1
II.2.2.1
II.2.3.1
MA: Marketing Authorization;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ’Not Known’
Member State
Regulatory Status
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify: Only in combination
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: Only in combination
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
32 db
MA
TRAD
Other TRAD
Other Specify: 5 authorized
combination product
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify: Only in combination
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: No products
Italy
MA
TRAD
Other TRAD
Other Specify: Food-supplement
Latvia
MA 1
TRAD
Other TRAD
Other Specify: + in combination
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify: Food-supplement
Poland
MA
TRAD
Other TRAD
Other Specify: + in combination
Portugal
MA
TRAD
Other TRAD
Other Specify: No products
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify: Only in combination
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
1
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in
the MSs concerned.
2
Not mandatory field
EMEA 2009
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Table 1
Products on the market
Active substance
Indication
Posology
Legal status
(MA since)
Urticae radix
herbal tea
Symptomatic
treatment of benign
prostatic hyperplasia
at stages I and II as
defined by Alken or
stages II and III as
defined by
Vahlensieck.
for use in adults and adolescents
over 16 years 2-3 x daily 1
sachet of 2.3 g containing 2.068g
Urticae radix n 150 ml of boiling
water, let 10 min extract and
drink
1992
liquid extract from Urticae
radix (1:1), extraction
solvent: ethanol 30% V/V
oral liquid
3 x daily 40 drops or 4 x daily 30
drops oral liquid containing
100% liquid extract
at least since
1976,
1 x daily 5 ml oral liquid
containing 100% liquid extract
at least 1990
dry extract from Urticae radix
(7-14:1),
extraction solvent: methanol
20% V/V
film-coated tablet, coated
tablet, hard capsules,
1 x daily 1 film-coated tablet
containing 460 mg dry extract
1991, 2000
2 x daily 1 coated tablet
containing 250 mg dry extract
3 x daily 1 hard capsule
containing 150 mg dry extract
At the begin of treatment for the
first 3 month and in stage II
2 x daily 2 hard capsules
1991
dry extract from Urticae radix
(7.1-14.3:1), extraction
solvent: methanol 20% V/V
coated tablet, film-coated
tablet,
3 x daily 1 coated tablet
containing 161 mg dry extract
at least since
1976
1 x daily 1 film-coated tablet
containing 459 mg dry extract
dry extract from Urticae radix
(6-11:1), extraction solvent:
methanol 20% V/V
film-coated tablet
1 x daily 1 film-coated tablet
containing 600.1 mg dry extract
2001, 2003
dry extract from Urticae radix
(12-16:1), extraction solvent:
ethanol 70% V/V
coated tablet
hard capsule
2 x daily 1 coated tablet
containing 150.5 mg dry extract
at least since
1976
2 x daily 1 hard capsule
containing 189 mg dry extract
EMEA 2009
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Table 2
Products on the market (continued)
Active substance
Indication
Posology
Legal status
(MA since)
dry extract from Urticae radix
(15-20:1), extraction solvent:
ethanol 80% (V/V)
film-coated tablet
Symptomatic
treatment of benign
prostatic hyperplasia
at stages I and II as
defined by Alken or
stages II and III as
defined by
Vahlensieck.
1 x daily 1 film-coated tablet
containing 285 mg dry extract
2001
dry extract from Urticae radix
(5.4-6.6:1), extraction solvent:
ethanol 80% (V/V)
hard capsules
3 x daily 1 hard capsule
containing 240 mg dry extract
At the begin of treatment 2 x
daily 2 hard capsules
1993,1994
3 x daily 1 hard capsule
containing 240 mg dry extract
dry extract from Urticae radix
(6.7-8.3:1), extraction solvent:
ethanol 20% V/V
soft capsule
3 x daily 1 soft capsule
containing 240 mg dry extract
at least since
1976, 1996,
1997,
dry extract from Urticae radix
(7-9:1), extraction solvent:
ethanol 60% V/V
film-coated tablet
2 x daily 2 film-coated tablets
containing 125 mg dry extract
each
1992
dry extract from Urticae radix
(8-12:1), extraction solvent:
ethanol 60% m/m
coated tablet
1 x daily 1 coated tablet
containing 475 mg dry extract
1998, 1999
dry extract from Urticae radix
(15.75-19.25:1),
extraction solvent: ethanol
80% (V/V)
hard capsule
At the begin of treatment
3 x daily 1 hard capsule
containing 115 mg dry extract
After amelioration of discomfort
and for long-term treatment 2 x
daily 1 hard capsule
1991
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II.
ASSESSMENT REPORT ON
URTICA DIOICA
L.,
URTICA URENS
L., THEIR HIBRIDS OR THEIR MIXTURES,
RADIX
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
(WELL-ESTABLISHED USE)
BASED ON ARTICLE 16D (1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
(TRADITIONAL USE)
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Whole, cut or powdered dried root and rhizomes
of Urtica dioica
L.
Urtica urens
L, their hybrids
or mixtures of these.
Herbal preparation(s)
Liquid extract, extraction solvent water
Liquid extract, extraction solvent ethanol
Dry extract, extraction solvent methanol
Dry extract, extraction solvent ethanol
Pharmaceutical forms
Herbal substance or herbal preparation in solid or
liquid dosage forms or as an herbal tea for oral
use.
Rapporteur
Dr. Susanna Biro-Sándor
Assessor(s)
Dr. Susanna Biro-Sándor
Dr. Dezső Csupor
EMEA 2009
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II.1
INTRODUCTION
This assessment report reviews the available scientific data for nettle root until the end of December 2008
(PubMed).
II.1.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Definition of the herbal substance:
ESCOP monographs (ESCOP 1996, 2003), WHO monograph (WHO 2002)
:
Nettle root consists of the whole, cut or powdered dried root and rhizomes
of
Urtica dioica
L.
Urtica urens
L., their hybrids or mixtures of these.
The material complies with the German Pharmacopoeia (DAB 10).
British Herbal Pharmacopoeia (BHP) (BHP 1996), British Herbal Compendium (Bradley 2006)
:
Nettle root consist of the dried rhizomes and roots of
Urtica dioica
L.
Phytotherapy in der Urologie (Schilcher
&
Wülker 1992)
:
Plant sources: Mainly
Urtica dioica
L
.,
common nettle,
but occasionally also
U. urens
L., small nettle
and/or their hybrids. Plant part: the whole subterranean part (rhizome and radix).
Description of the herbal substance:
German Pharmacopoeia (Deutches Arzneibuch - DAB 10, 1993)
British Herbal Pharmacopoeia (BHP 1996)
Phytotherapy in der Urologie (Schilcher & Wülker 1992)
Hagers Handbuch
(Blaschek et al. 1998)
WHO monographs (WHO 2002)
Herbal preparation(s):
Herbal tea
Comminuted herbal substance (products on the market since 1992)
3
According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2) and the ‘Procedure for the preparation of Community
monographs for herbal medicinal products with well-established medicinal use (
EMEA/HMPC/182352/2005
Rev.2)
EMEA 2009
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A)
Liquid extract from Urticae radix (1:1), extraction solvent: water (Blaschek et al. 1998)
B)
Liquid extract from Urticae radix (1:1), extraction solvent 16% ethanol
(ESCOP 2003, Engelmann et al. 1996)
C)
Liquid extract from Urticae radix (1:1), extraction solvent: ethanol 30% V/V
(product on the market at least since 1976)
D)
Liquid extract from Urticae radix (1:5), extraction solvent: ethanol 40% (ESCOP 1996, 2003)
E)
Liquid extract from Urticae radix (1:1), extraction solvent: ethanol 45% V/V, prepared according
to PF X) (ESCOP 1996, 2003; Blaschek et al. 1998 and Goetz 1989)
F)
Dry extract from Urticae radix (7-14:1), extraction solvent: methanol 20% V/V
(Blaschek et al. 1998; ESCOP 2003) (products on the market since 1991/2000)
G)
Dry extract from Urticae radix (7.1-14.3:1), extraction solvent: methanol 20% V/V
(product on the market at least since 1976)
H)
Dry extract from Urticae radix (6-11:1), extraction solvent: methanol 20% V/V
(product on the market since 2001/2003)
I)
Dry extract from Urticae radix (6.7-8.3:1), extraction solvent: ethanol 20% V/V
(product on the market since at least 1976)
J)
Dry extract from Urticae radix (7-9:1), extraction solvent: ethanol 60% V/V
(product on the market since 1992)
K)
Dry extract from Urticae radix (8-12:1), extraction solvent: ethanol 60% m/m
(product on the market since 1998/1999)
L)
Dry extract from Urticae radix (8.3-12.5:1), extraction solvent: ethanol 60% m/m
(Blaschek et al. 1998)
M)
Dry extract from Urticae radix (12-16:1), extraction solvent: ethanol 70% V/V
(product on the market at least since 1976)
N)
Dry extract from Urticae radix (15-20:1), extraction solvent: ethanol 80% (V/V)
(product on the market since 2001)
O)
Dry extract from Urticae radix (5.4-6.6:1), extraction solvent: ethanol 80% (V/V)
(product on the market since 1993/1994)
P)
Dry extract from Urticae radix (15.75-19.25:1), extraction solvent: ethanol 80% (V/V)
(product on the market since 1991)
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
Evidence regarding the indication/traditional use
Nettle roots were mentioned as herbal medicines first by Paracelsus and Matthiolus (Madaus 1938).
In folk medicine, nettle herb and leaves were of higher importance than nettle roots. In the Russian folk
medicine, the powder of the roots and seeds was used against dropsy, diarrhoea and worms. In the
Lithuanian folk medicine, the infusion of the aerial parts and roots was applied to treat atrophy (Madaus
1938). The Eclectics used leaf and root as blood purifier, styptic, stimulating tonic and diuretic to treat
diarrhoea, dysentery, discharges, chronic diseases of the colon and chronic skin eruptions (Mills 2003).
EMEA 2009
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Extracts
A syrup made from the juice of root or leaves was said to relieve bronchial and asthmatic troubles (Mills,
2003). In African medicine, nettle root is used to treat diarrhoea and as an anthelmintic to expel intestinal
worms (Blumenthal 1998).
Nettle root was first used in urinary tract disorders in the 1950s. Today it is used mainly in the
symptomatic treatment of early stages of benign prostatic hyperplasia (BPH) (Bradley 2006). The
Commission E approved the use of nettle root for difficulty in urination in BPH stages I and II
(Blumenthal 1998). ESCOP indicates its use for symptomatic treatment of micturition disorders (nocturia,
pollakisuria, dysuria, urine retention) in BPH at stages I and II as defined by Alken or stages II and III as
defined by Vahlensieck (ESCOP 2003). The British Herbal Pharmacopoeia reported prostatic action (BHP
1996). According to the wording of the British Herbal Compendium, nettle root is suitable for the
symptomatic treatment of micturition dysorders in the early stages of BPH (Bradley 2006). The French
Herbal Remedies Notice to Applicants for Marketing Authorization allows two uses of nettle root: as an
adjunctive treatment for the bladder outlet obstruction symptoms of prostatic origin, and to enhance the
renal elimination of water (Bruneton 1999). In the USA, it is used similarly, although as a dietary
supplement its indications for use are limited to non-therapeutic “structure and function” claims
(Blumenthal 1998).
Other use in the folk medicine:
Hagers Handbuch (Blaschek et al. 1998). In folk medicine as a component in ‘blood-purifying’
combination-preparations, against dropsy, for prostatitis, rheuma, gout similar to nettle herb.
Lutomsky J. and Speichert
(1983): against renal calculus
Jaspersen-Schib R.
(1989): mild diuretic
Herbal Drugs and Phytopharmaceuticals (Bisset 1994): In folk medicine like nettle herb, e.g. as diuretic,
but also because of its tannin content as an adstringent and gargle.
Healing plants (Rápóti & Romvári 1974): Decoction of the root is taken orally against enteritis
(diarhoeae), externally as shampoo against loss of hair and dandruff formation.
Evidence regarding the specified posology
Herbal substance:
Daily dose: 4-6 g of the drug as an infusion (ESCOP 1996, 2003; Schilcher & Wülker 1992; Bisset 1994;
Blaschek et al. 1998)
Herbal preparation(s):
Infusion: „Making tea: 1.5g of the coarsely powdered drug is put into cold water, heated to boiling for ca.
1 min, then covered and allowed to stand for 10 min, and finally strained. 1 Teaspoon=ca. 1.3 g.”
(Bisset 1994; Blaschek et al. 1998)
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Extracts
Liquid extracts:
A)
Liquid extract from Urticae radix (1:1), extraction solvent: water, daily dose: 6 ml
(Blaschek et al. 1998)
B)
Liquid extract from Urticae radix (1:1), extraction solvent: 16% ethanol, 2x3 ml daily
(equivalent to 4.68 g of the fluid extract) (ESCOP 2003; Engelmann et al. 1996)
C)
Liquid extract from Urticae radix (1:1), extraction solvent: ethanol 30% V/V,
3 x daily 40 drops or 4 x daily 30 drops (product on the market at least since 1976)
1 x daily 5 ml (product on the market at least since 1990)
D)
Liquid extract from Urticae radix (1:5), extraction solvent: ethanol 40% (ESCOP 1996), 5 ml daily
E)
Liquid extract from Urticae radix (1:1), extraction solvent: ethanol 45% V/V, prepared according to
PF X (Blaschek et al. 1998) At the beginning 30 drops daily, later in most of the cases the dose
increased to 150 drops daily (ESCOP 2003; Goetz 1989)
Dry extracts:
F)
Dry extract from Urticae radix (7-14:1), extraction solvent: methanol 20% V/V
1 x daily 1 film-coated tablet containing 460 mg dry extract, corresponding to 4830mg drug
(products on the market since 2000)
2 x daily 1 coated tablet containing 250 mg dry extract, corresponding to 5250 mg drug
(products on the market since 2000).
3 x daily 1 hard capsule containing 150 mg dry extract, corresponding to 4725 mg drug daily, at the
beginning of treatment for the first 3 months and in stage II, 2 x daily 2 hard capsules,
corresponding to 6300 mg drug daily (products on the market since 1991).
G)
Dry extract from Urticae radix (7.1-14.3:1), extraction solvent: methanol 20% V/V,
3 x daily 1 coated tablet containing 161 mg dry extract, corresponding to 5168 mg
(products on the market at least since 1976)
1 x daily 1 film-coated tablet containing 459 mg dry extract, corresponding to 4911 mg
(products on the market at least since 1976)
H)
Dry extract from Urticae radix (6-11:1), extraction solvent: methanol 20% V/V,
1 x daily 1 film-coated tablet containing 600 mg dry extract, corresponding to 5100 mg drug
daily (products on the market since 2001/2003)
I)
Dry extract from Urticae radix (6.7-8.3:1), extraction solvent: ethanol 20% V/V,
3 x daily 1 soft capsule containing 240 mg dry extract corresponding to 5400 mg drug daily
(products on the market at least since 1976/1996/1997)
J)
Dry extract from Urticae radix (7-9:1), extraction solvent: ethanol 60% V/V,
2 x daily 2 film-coated tablets containing 125 mg dry extract corresponding to 4000 mg drug daily
(products on the market since 1992)
K)
Dry extract from Urticae radix (8-12:1), extraction solvent: ethanol 60% m/m,
1 x daily 1 coated tablet containing 475 mg dry extract, corresponding to 4750 mg drug daily
(products on the market since 1998/1999)
EMEA 2009
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2 x 300 mg daily corresponding to 6300 mg drug daily (ESCOP 2003; Blaschek et al. 1998)
L)
Dry extract from Urticae radix (8.3-12.5:1), extraction solvent: ethanol 60% m/m,
2 x 120 mg daily corresponding to 2496 mg drug daily (Blaschek et al. 1998)
M)
Dry extract from Urticae radix (12-16:1), extraction solvent: ethanol 70% V/V,
2 x daily 1 coated tablet containing 150.5 mg dry extract, corresponding to 4214 mg drug daily
(products on the market at least since 1976)
2 x daily 1 hard capsule containing 189 mg dry extract, corresponding to 5292 mg drug daily
(products on the market at least since 1976)
N)
Dry extract from Urticae radix (15-20:1), extraction solvent: ethanol 80% (V/V),
1 x daily 1 film-coated tablet containing 285 mg dry extract, corresponding to 4988 mg drug daily
(product on the market since 2001)
O)
Dry extract from Urticae radix (5.4-6.6:1), extraction solvent: ethanol 80% (V/V),
3 x daily 1 hard capsule containing 240 mg dry extract, corresponding to 4320 mg drug daily.
At the beginning of treatment 2 x daily 2 hard capsules corresponding 5760 mg drug daily
(product on the market since 1993)
3 x daily 1 hard capsule containing 240 mg dry extract, corresponding to 4320 mg drug daily
(product on the market since 1994)
P)
Dry extract from Urticae radix (15.75-19.25:1), extraction solvent: ethanol 80% (V/V),
at the beginning of treatment 3 x daily 1 hard capsule containing 115 mg dry extract, corresponding
to 6038 mg drug daily. After amelioration of discomfort and for long-term treatment, 2 x daily
1 hard capsule, corresponding to 4025 mg drug daily (product on the market since 1991)
II.2
N
ON
-C
LINICAL
D
ATA
II.2.1
Pharmacology
II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
II.2.1.1.1
Constituents
Based on Blaschek 1998; ESCOP 2003; Mills 2003; Blumenthal 1998; Bruneton 1999; Wichtl 2002;
Bradley 2006.
Lectins:
0.05-0.6%
Urtica dioica
agglutinin (UDA). UDA is a small monomeric protein with a molecular
weight of 8.5 kDa, consisting of 89 amino acid residues including two 43-amino acid, glycine- and
cysteine-rich domains. UDA is a mixture of at least 6 similar isolectins.
Polysaccharides:
Approximately 0.85%. Five polysaccharides have been isolated (RP1-RP5), of which
two are glucans with [1→4]-linked glucose units but differing in MW (15 and 50 kDa), degree of
branching and acidity; two are rhamnogalacturonans of MW 18 and 210 kDa; and the fifth is an acidic
arabinogalactan of MW 70 kDa consisting of a [1→3]-linked galactan chain with arabinose side chains.
Lignans:
1,4-Butandiol-type lignans: 0.004% secoisolariciresinol-9-O-β-D-glucoside; 8.O.4'-Arylether-
type lignans: 0.002% 7'(
E
)-7-O-β-D-glucopyranosyl-4,4',7,9,9'-pentahydroxy-3,3'-dimethoxy-8.O.4'-
lignan, 0.001% 7'(
E
)-4,4',7,9,9'-pentahydroxy-3,3'-dimethoxy-8.O.4'-lignan Monoepoxylignans: 0.003%
neo-olivil, 0.004% neo-olivil-4-O-β-D-glucoside, 0.001% 9-acetyl-neo-olivil , 0.006% 9-acetyl-neo-olivil-
4-O-β-D-glucoside, 0.006% 9'-acetyl-neo-olivil-4-O-β-D-glucoside, 0.007% 9,9'-bisacetyl-neo-olivil,
0.01% 9,9'-bisacetyl-neo-olivil-glucosid.
Urtica dioica
roots contain lignans in higher amount than
Urtica
urens
roots.
EMEA 2009
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Sterols:
0.2-1% β-sitosterol, 0.032-0.2% β-sitosterol-3-O-β-glucoside (in
Urtica dioica
roots the ratio of
the former two compounds is between 2:1 and 1:1, in case of
Urtica urens
roots the ratio is 4:1), 0.003%
(6'-O-palmitoyl)-sitosterol-3-O-β-D-glucoside, 0.001% 7β –hydroxysitosterol, 0.001%
7α-hydroxysitosterol, 0.0005% 7β -hydroxysitosterol-β-D-glucoside, 0.0005% 7α-hydroxysitosterol-β-
glucoside, 0.0015% 24
R
-ethyl-5α-cholestane-3β,6α-diol, stigmasterol, campesterol, stigmast-4-en-3-on,
hecogenin.
Phenyl propanes:
0.002% Homovanillyl alcohol and its 4’-glucoside (0.003%).
Ceramides:
Two groups of ceramides, consisting of a sphingoid base (2-amino-1,3,4-trihydroxy-8-
octadecene) with an amido link from the amino group to an unbranched C
20
-C
25
fatty acid or
corresponding 2-hydroxy fatty acid, have been identified.
Hydroxy fatty acids:
(10
E
,12
Z
)-9-hydroxy-10-12-octadecadienoic acid, (9
Z
,11
E
)-13-hydroxy-9,11-
octadecadienoic acid and the isomeric 9,10,13-trihydroxy-11-octadecenoic and 9,12,13-trihydroxy-10-
octadecenoic acids.
Fatty alcohol:
14-Octacosanol.
Monoterpenes:
Three monoterpene diols and their monoglucosides.
Triterpenes:
0.002% Oleanolic acid and ursolic acid.
Phenols:
p-hydroxy-benzaldehyde.
Tannins
Coumarins:
0.0001-0.01% scopoletin in
Urtica dioica
roots, 0.0001% scopoletin in
Urtica urens
roots.
Monosaccharides, oligosaccharides:
Fructose, galactinol, galactose, glucose, myo-inositol, maltose,
raffinose, stachyose.
Amino acids:
Alanine, β-alanine, arginine, asparagine, asparaginic acid, glutamine, glutaminic acid,
glycine, histidine, isoleucine, leucine, lysine, methionine, methylhistidine, phenylalanine, serine,
threonine, tyrosine, valine (0.05%). In
Urtica dioica
roots, the free amino acid fraction contains
10% gamma-aminobutyric acid.
Silicic acid:
0.3-0.6%.
Adenosine:
0.002%.
II.2.1.1.2
Pharmacodynamics
Aromatase inhibition
A potential role of estrogens in the development of BPH has been emphasized by animal studies
(Habenicht 1991). The biological action of estrogens may be blocked either by estrogen receptor
antagonists or by suppressing estrogen synthesis, e.g. by inhibition of aromatase.
An extract from Urticae radix (DER 10:1, 30% methanol) inhibited concentration dependently (ED
50
=
3.58 mg/ml) the aromatase enzyme, which converts testosterone into estradiol (Hartmann 1996).
The nettle root extract WS1031 (DER 8–13:1, 60% ethanol) inhibited aromatisation of androstenedione
in
vitro
(IC
50
338 μg/ml). The active principle was found in a heptane fraction, suggesting that lipophilic
compounds are responsible for the action (Chrubasik 2007). (10
E
, 12
Z
)-9-hydroxy-10,12-octadecadienoic
acid isolated from an aqueous-methanolic root extract and its derivative (10
E
,12
Z
)-9-oxo-10,
12-octadecadienoic acid inhibited aromatase activity
in vitro
, however the heptane fraction was more
effective than the single component (Bartsch 1992; ESCOP 2003; Kraus 1991). In a human placenta
microsomal
in vitro
model, the EC
50
values of the fractions of an (DER 8.3-12.5:1, 60% ethanol) extract
were determined as follows: Urticae radix extract 338 μg/ml, heptane soluble fraction of the extract
9 μg/ml, ethylacetate soluble fraction of the extract 41 μg/ml, buthanol soluble fraction of the extract
109 μg/ml, water soluble fraction of the extract >200 μg/ml (Blaschek 1998). In this extract, besides
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common fatty acids, 9-hydroxy-10,12-octadecadienoic acid was identified as a major active constituent.
This compound is possibly only formed during or after extract preparation by the oxydation of linoleic
acid. The EC
50
values of γ-linolenic acid and 9-hydroxy-10,12-octadecadienoic acid were 10 μg/ml and
11 μg/ml, respectively (Koch 2001; Blaschek 1998). A comparable aromatase inhibition of the ethanolic
nettle extract LI166 (DER 8–12:1, 60% ethanol) and a synthetic aromatase inhibitor was achieved,
however at a concentration 250 fold higher than that of the synthetic one (Chrubasik 2007). On the other
hand, aromatase inhibition by 5 other compounds isolated from methanol extract of nettle root
(secoisolariciresinol, oleanolic and ursolic acid, (9
Z
,11
E
)-13-hydroxy-9,11-octadecadienoic acid, and
14-octacosanol) was only weak (Ganßer 1995a). The aqueous nettle extract BNO1250 (DER 10:1,
30% methanol; 0.75 and 7.5 mg/ml) inhibited estradiol 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
(Chrubasik 2007).
Different nettle root extracts were found to inhibit the aromatase, as did some isolated compounds.
However, nettle root contains only low quantities of these components and the active principle for a
clinically relevant aromatase inhibition needs still to be defined (Chrubasik 2007). Although nettle
extracts are weak inhibitors of aromatase compared to synthetic preparations, a pharmacological effect
might be expected from the lipophilic compounds accumulated in fatty tissues where androgens are
aromatized (Mills 2003).
Interaction with 5-α-reductase and androgen receptor binding
Increased plasma level of dihydrotestosterone (DHT) is associated with the development of BPH. Thus,
the inhibitors of 5-α-reductase, the enzyme which converts testosterone to DHT, and inhibitors of
androgen receptor binding are viable alternatives in the treatment of BPH.
Methanolic Urticae radix extract (UR102, DER 10:1, 30% methanol) inhibited 5α-reductase only at high
concentrations (≥ 12 mg/ml, ED
50
14.7 mg/ml) (Hartmann 1996). The ethanolic extract WS1031
(DER 8–13:1, 60% ethanol) had no impact on the conversion of testosterone into DHT (Chrubasik 2007).
An ethanolic extract of nettle roots (DER 7-14:1, 20% methanol) did not inhibit the binding of DHT to the
rat androgen receptor (Blaschek 1998). In human prostate adenoma cells, the 5α-reductase inhibitory
IC
50
value of this methanol nettle root extract (DER 7-14:1, 20% methanol) was >500 000 ng/ml,
compared with the 1 ng/ml IC
50
value of finasterid (Rhodes 1993). Urticae radix extract BAZ
(DER 5:1, 20% methanol) at a concentration up to 0.5 mg/ml did not inhibit 5-α-reductase
in vitro
or the
binding of radioactively labelled dihydrotestosterone to the rat prostatic androgen receptor, and also did
not inhibit testosterone- or dihydrotestosterone-stimulated prostate growth in castrated rats in doses
276 and 1380 mg extract/day (Rhodes 1993). This extract mildly inhibited DHT binding to cytosolic
androgen receptors in the prostate (ESCOP 1996; Mills 2003),
but did not affect microsomal 5α-reductase
activity (Chrubasik 2007).
Effect on the SHBG (sex hormone binding globulin) binding capacity and sex hormones
SHBG is a plasma transport protein which binds androgens and estrogens. In the blood only about 2% of
testosterone is circulating free, while approximately 44% and 54% are bound to SHBG and other plasma
proteins, respectively (Koch 2001). Advancing age is accompanied by the change of the androgen:
estrogen equilibrium and increased SHBG level. Increased binding capacity of SHBG to testosterone and
dihydrotestosterone results in hyperplasia, as a compensation for the decrease in hormones and increase in
5-α-reductase activity (ESCOP 2003). Two possibilities have been suggested to compensate these
changes: (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 (Chrubasik
2007).
Already in 1983 it was reported that an ethanol-water nettle root extract inhibited the binding of [
3
H]-DHT
to SHBG (Koch 2001). Since then, several extracts, fractions and compounds were tested for their
activities on SHBG. A significant (average 67%) suppression of the SHBG binding capacity in the
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presence of an Urtica root extract preparation (DER 5:1, 20% methanol) was shown
in vitro
after
preincubation in human serum (ESCOP 1996; Mills 2003). An aqueous extract (extraction at 80
o
C) of
Urticae radix inhibited dose-dependently (0.6-10 mg/ml) binding of radioactively labelled SHBG to
solubilized receptors from human prostatic tissue, however an 70% ethanol Urticae radix extract; isolated
U. dioica
agglutinin, and stigmasta-4-en-3-one were not active (Hryb 1995). The lignan
secoisolariciresinol, as well as a mixture of isomeric (11
E
)-9,10,13-trihydroxy-11-octadecenoic acid and
(10
E
)-9,12,13-trihydroxy-10-octadecenoic acids reduced binding activity of human SHBG. So did the
mixture of the latter two compounds after methylation, moreover, methylation increased activity about
10-fold (Ganßer 1995b). The affinity to human SHBG of the lignans (+)-neoolivil, (-)-secoisolariciresinol,
dehydrodiconiferyl alcohol, isolariciresinol, pinoresinol, and 3,4-divanillyltetrahydrofuran identified in
nettle roots was tested in an
in vitro
assay. In addition, the main intestinal transformation products of plant
lignans in humans, enterodiol and enterolactone, together with enterofuran were checked for their activity.
All lignans except (-)-pinoresinol developed a binding affinity to SHBG in the assay. The affinity of
(-)-3,4-divanillyltetrahydrofuran was outstandingly high. The metabolite of (-)-3,4-
divanillyltetrahydrofuran (enterofuran) showed higher binding affinity to SHBG than the metabolite of
secoisolariciresinol (enterodiol, enterolactone) ( Schöttner 1997).
Anti-inflammatory and immunomodulating activity
Although the aetiology of non-bacterial chronic prostatitis is poorly understood, it is well recognized that
this condition is frequently associated with BPH and may even be a causative factor in the pathogenesis of
this ailment (Koch 2001). Immunohistological analysis of lymphocyte subpopulations revealed marked
qualitative and quantitative differences between normal and BPH tissue. Cytokines released from
leukocytes not only possess pro-inflammatory properties but may also induce cell proliferation (Koch
2001). Therefore, anti-inflammatory and immunological interventions may provide approaches for the
treatment of BPH.
A polysaccharide fraction obtained from an aqueous extract of nettle root was shown to be active in the
lymphocyte transformation test. This fraction was found to be active in the carrageenan rat paw oedema
model as well (ESCOP 1996). The methanolic extract BAZ (DER 5:1, 20% methanol) was shown to
inhibit the alternative pathway of complement activation which involves various serine proteinases
(Wagner 1994). Isolated polysaccharides (e.g. rhamnogalacturanes, a type II arabinogalactane) produced a
dose-dependent reduction of haemolysis in the classical and alternative complement test. From these
results an anti-inflammatory and immunomodulating effect was deduced (ESCOP 1996; Chrubasik 2007).
Isolated
Urtica dioica
lectins were found to stimulate the proliferation of human lymphocytes in the
lymphocyte transformation test (ESCOP 1996). The 1T fraction of UDA stimulated the proliferation of
lymphocytes by 543%, UDA 2T by 341% (Blaschek 1998). UDA stimulated concentration dependently
the interferon secretion of human lymphocytes (Peumans 1984). The presence of human leukocyte
elastase in the seminal plasma has been demonstrated to be a biochemical marker of clinically silent
prostatitis (Wolff 1991). This enzyme catalyzes the degradation of many extracellular matrix and plasma
proteins. Ethanolic nettle root extract WS1031 (DER 8–13:1, 60% ethanol) inhibited bovine leukocyte
elastase (IC
50
68 μg/ml), which reflects anti-inflammatory activity (Chrubasik 2007). During a
pharmacological screening programme for human leukocyte elastase inhibitors, the nettle root extract
WS1031 (DER 8–13:1, 60% ethanol) was found to potently suppress enzyme activity with a calculated
IC
50
value of 3.6 μg/ml (Koch 2001).
A crude extract from nettle root containing 4 different polysaccharides was shown to possess anti-
inflammatory activity comparable to indomethacin in the rat paw oedema test 5 hours after oral
administration (Wagner 1994). The effect oral nettle root extract LI166 (DER 8–12:1, ethanol 60%;
250–750 mg/kg) and of root components (40 mg/kg of a particular polysaccharide fraction, which
consisted of four different polysaccharides administered orally or a mixture of two polysaccharides
intravenously) were investigated in the carrageenan-induced rat paw oedema test and indicated an anti-
inflammatory potential (Chrubasik 2007).
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Effect on muscle contractility
In concentrations of 100–800 μg/ml, a methanol extract (DER unknown, 50% methanol) did not affect
circular muscle spontaneous contractions or longitudinal muscle contractions on isolated guinea pig ileum
induced by acetylcholine and barium chloride (Chrubasik 2007).
Effect on growth of BPH-tissue cells
Different growth factors and their receptors and some enzymes (besides aromatase and 5-α-reductase)
may be involved in the pathogenesis of BPH. The inhibition of these receptors and enzymes may be a
therapeutic approach of BPH.
According to Farnsworth's hypothesis biological effects of androgens on the prostate are mediated not
only through binding to steroid receptors in the nucleus, but also through interaction with receptors on the
plasma membrane of target cells; as one of these sites Na/K-ATPase has been recognized (Koch 2001).
Organic solvent extracts of
Urtica dioica
root (0.1 mg/ml) gave 28-82% inhibition of Na/K-ATPase
activity of human BPH-tissue cells. Steroidal compounds of the root, such as stigmast-4-en-3-one,
stigmasterol, and campesterol, inhibited the enzyme activity by 23-67% at concentrations ranging 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; Mills 2003).
Five subfractions from the 20% methanolic extract of Urticae radix gave a statistically significant
proliferation inhibition of cultured BPH-tissue cells in concentrations ranging from 10 to 1500 μg/ml
(ESCOP 1996; Mills 2003). The lectin fraction UDA 1T gave 53% inhibition of the binding of epidermal
growth factor (EGF) to EGF-receptors in cultivated cells from human prostatic tissue (ESCOP 1996;
Blaschek 1998). UDA from an
Urtica dioica
root extract showed a dose-dependent inhibition of
EGF-binding to human A431 epidermal cancer cell membranes (ESCOP 1996.). Incubation of prostatic
stromal fibroblasts with 0.01% nettle root extract BAZ (DER 5:1, 20% methanol) reduced cell
proliferation by 50%. The proliferation rate was affected by DHT. High extract doses were even toxic,
probably due to osmotic conditions (Chrubasik 2007). Fractions of the methanolic extract BAZ
(DER 5:1, 20% methanol) inhibited cell growth of cultivated human hyperplastic prostate cells from
biopsy samples
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 (Chrubasik 2007). Already low concentrations of the methanolic extract BAZ
(DER 5:1, 20% methanol) (dose range tested: 10 ng–100 μg/ml) inhibited cell growth of incubated
fibroblastic and epithelial cells by about 20%. Higher concentrations were not more effective. Since
microsomal
5α-reductase activity was not affected, an androgen-independent mechanism was suggested
(Chrubasik 2007). A concentration-dependent and significant anti-proliferative effect of BAZ extract
(DER 5:1, 20% methanol) was documented only on epithelial cancer cells (LNCaP), whereas stromal cell
growth remained unaltered. The inhibition was time dependent, with a maximum growth reduction of 30%
at a concentration of 1.0E−6 mg/ml on day 5 compared to the untreated control. No cytotoxic effect was
observed (Konrad 2000). Chemical analysis of this extract revealed a carbohydrate content about 21%.
Therefore, a polysaccharide-enriched subfraction was prepared which suppressed growth of LNCap cells
maximally by about 50% at concentrations of 10-1000 fg/ml. The authors report that this fraction even at a
concentration of 10
-16
mg/ml caused a significant reduction of proliferation when compared with controls
(Lichius 1999). Cells from normal and BPH biopsies were incubated with different concentrations of the
methanol extract BAZ (DER 5:1, 20% methanol). Prostate metabolism remained unaffected, but
homogenous granules showed a relevant decrease in nettle root extract-treated cells (Chrubasik 2007).
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 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
125
I-labelled EGF to the receptor. The effect was more pronounced than
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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 1995).
An average decrease of 30% of prostate volume and decrease of serum testosterone levels after a 100-day
treatment with 900 mg of a BAZ extract (DER 5:1, 20% methanol) per kg body weight was shown in
10 dogs suffering from BPH (ESCOP 1996). In a later study over 100 days, it was confirmed that
hecogenin acetate is a co-active constituent. Doses 0.5 and 5 mg/10 kg resulted in sonographic prostate
volume reductions of 14% and 29%, respectively (Chrubasik 2007.). The same extract did not inhibit
testosterone and dihydrotestosterone stimulated growth of the prostate in castrated rats (Rhodes 1993).
In a BPH-model (directly implanting an urogenital sinus (UGS) into the ventral prostate gland of an adult
mouse) five differently prepared stinging nettle root extracts were. The 20% methanolic extract was the
most effective with a 51.4% inhibition of induced growth. The aqueous extract also inhibited growth,
although not significantly (26.5%). There was no correlation between the amounts of sitosterin and
scopoletin with the growth-inhibiting effect, however, a correlation was assumed with the UDA, lectin and
saccharyde content of the extract. (Lichius 1997; Blaschek 1998).
II.2.1.2
Assessor’s overall conclusions on pharmacology
The reputed beneficial effect of nettle root on BPH is supported by
in vitro
and
in vivo
pharmacological
studies, however, the active substances for the pharmacologic actions are unknown, which makes quality
control and chemical standardization of extracts difficult (Blumenthal 1998).
II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
No studies.
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
No studies.
II.2.3.2
Assessor’s overall conclusions on toxicology
No studies.
II.3
C
LINICAL
D
ATA
II.3.1
Clinical Pharmacology
II.3.1.1
Pharmacodynamics
II.3.1.1.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Thirty-one men aged between 58 and 62 years with BPH at stages I and II were treated daily for 20 weeks
with 1200 mg of dried nettle root extract preparation (DER:3.5-7:1; 20% V/V methanol). From fine needle
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aspiration biopsies of 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 investigated by fluorescence microscopy. Compared with normal prostatic cells, a decrease
in homogenous granules was detected in hyperplasic 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 extracts 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 stimulated 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
month after therapy with nettle root extract confirmed ultrastructural changes in the smooth muscle cells
and epithelial cells of prostate (Oberholzer et al. 1987.
II.3.1.1.2
Assessor’s overall conclusions on pharmacodynamics
It can be concluded from the pharmacodynamic studies that nettle root extract can cause some
morphological changes on prostatic cells.
II.3.1.2
Pharmacokinetics
II.3.1.2.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
After 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 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 et al. 1996).
II.3.1.2.2
Assessor’s overall conclusions on pharmacokinetics
The therapeutically active components of nettle root are not known, therefore no conclusion can be drawn.
II.3.2
II.3.2.1
Dose response studies
There are no studies.
II.3.2.2
Clinical studies (case studies and clinical trials)
II.3.2.2.1
Placebo controlled studies
In spite of the fact that in BPH the placebo effect is considerable, only six randomised, double blind,
placebo controlled clinical studies can be found in the literature: Dathe & Schmid 1987; Engelmann et al.
1996; Fischer & Wilbert 1992; Safarinejad 2005; Schneither & Rübben 1996; Vontobel et al. 1985.
Placebo controlled studies with dried native extract of nettle root (DER: 7-14:1; extraction solvent
methanol 20% V/V) in a preparation containing an equal amount of diluent:
4
In case of traditional use the long-standing use and experience should be assessed.
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(Similarly to the published references the following dosages (in mg) relate to the extract preparation, of
which only 50% was native extract (7-14:1))
Fisher & Wilbert (1992)
: In a randomized, double blind, placebo controlled study 40 BPH II patients
(1200mg extract preparation per day (2x2 caps) n= 20; placebo n=20), statistically significant (p<0.05)
decreases in micturition frequency (from 7.4 to 6.1, during 24 hours) and SHBG level was observed in the
verum group after 6 months. The subjective symptoms score, which consists of hesitancy, intermittency,
terminal dribbling, desire to urinate, decrease in force and size of the urinary stream, dysuria, and
sensations of incomplete emptying, improved considerably. The objective parameters (prostate volume,
urinary flow, residual urine volume) did not change in the nettle root extract group but worsened in the
placebo group. (See also Appendix I - tables of placebo controlled studies).
Dathe & Schmid (1987):
In double blind, placebo controlled study patients in stadium I of BPH were
randomized to 600 mg of nettle root extract (2 x 1 caps.) (n=35 or to matching placebo (n= 37). After
6-8 weeks of treatment in the verum group significant improvements of 14% in average urinary flow rate
(ml/s), 13% in micturation duration (second), 12% in maximum urinary flow (ml/s) and 40% in residual
urine volume (ml) were observed. There was no remarkable difference between the two groups in
subjective symptoms. (See also Appendix I.)
Vontobel et al. (1985)
: 50 BPH 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 (ml) (p<0.05) and a highly significant decrease in serum levels of SHBG
(p=0.0005) were observed. Maximum urinary flow (ml/s) improved with 8.6% in the treated group, but
decreased in the same degree in the placebo group (p=0.062). There was no remarkable difference
between the two groups in subjective symptoms. (See also Appendix I.)
Schneider & Rübben (2004)
: The authors performed a randomized, double-blind , placebo controlled
multi-center study for 1 year wit Bazoton
®
-uno, 459 mg dry extract of stinging nettle roots, [(7.1-14.3:1),
extraction solvent methanol 20% V/V, from Rote Liste] with 246 patients. The IPSS decreased on
average from 18.7± 0.3 to 13.0±0.5 with a statistically significant difference compared to placebo
(18.5±0.3 to 13.8±0.5; p=0.0233). The median Qmax increased by 3.0±0.4 ml/s in comparison to 2.9±0.4
ml/s (placebo) thus not a statistically significantly different, as well as the median volume of residual
urine, which changed from 35.5±3.4 ml before therapy to 20±2.8ml and from 40.0 ±4.0 ml to 21.0±2.9ml
under placebo application. The number of adverse events (29/38) as well as urinary infections etc. (3/10
events) was smaller under Bazoton
®
-uno therapy compared to placebo. (See also Appendix I.)
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‘Figure.from
Schneider & Rübben (2004)
Placebo controlled studies with other preparations:
Engelmann et al. (1996):
In a double blind, multi-centric study, 41 BPH patients were treated for 3
months with either 2x3ml of an aqueous extract preparation equivalent to 4.68 g of fluid extract (Bazoton
Liquidum 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 placebo group, were observed. A significantly greater
improvement (p=0.002) in International Prostate Symptoms Score* in the verum group was also reported.
Safarinejad (2005):
A 6 month, double blind, placebo controlled, randomized, partial crossover,
comparative trial of
Urtica dioica
with placebo in 620 patients was conducted. Patients were evaluated
using International Prostate Symptoms Score* (IPSS), the maximum urinary flow rate (Qmax), postvoid
residual urine volume (PVR), Serum Prostatic-Specific Antigen (PSA), testosterone levels, and prostate
size. At the end of the 6 month trial, unblinding revealed that patients who initially received the placebo
were switched to
Urtica dioica
. Both groups continued the medication up to 18 months. Five-hundred
fifty-eight patients (90%) completed the study (287/305, 91% in the
Urtica dioica
group, and 271/315,
86% in the placebo group). The unpaired t-test was used to assess differences between all the variables in
the original double-blind trial protocol. By intention-to-treat analysis, at the end of 6-month trial, 232
(81%) of 287 patients in the
Urtica dioica
group reported improved lower urinary tract symptoms
(LUTS) compared with 43(16%) of 271 patients in the placebo group (p<0.001). Both IPSS and Qmax
showed greater improvement with drugs than with placebo. The IPSS went for 19.8 down to 11.8 with
Urtica dioica
and from 19.2 to 17.7 with placebo (p=0.002). Peak flow rates improved by 3.4 ml/s for
placebo recipients and by 8.2 ml/s for treated patients (p<0.05.) In
Urtica dioica
group, PVR decreased
from an initial value of 73 to 36 ml (P < 0.05). No appreciable change was seen in the placebo group.
Serum PSA and testosterone levels were unchanged in both groups. A modest decrease in prostate size as
measured by transrectal ultrasonography (TRUS) was seen in
Urtica dioica
group (from 40.1 cc initially
to 36.3 cc; P < 0.001). There was no change in the prostate volume at the end of study with placebo.
At 18-month follow-up, only patients who continued therapy had a favorable treatment variables value,
with all values remaining stable from the end of the double-blind study to the 18-month follow-up. There
was no additional effect from the longer treatment period. No side effects were identified in either group.
CONCLUSION: In the present study,
Urtica dioica
has beneficial effects in the treatment of symptomatic
BPH. Further clinical trials should be conducted to confirm these results before concluding that
Urtica
dioica
is effective.
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* International Prostate Symptoms Score (=IPSS, scale: 0-5, items: micturition frequency, nocturia
frequency, hesitancy, decreased urinary stream, residual urine, urge to urine) according to the suggestion
of the American Urological Association.Grades: 0-7 point = slight-grade, 8-19 point = middle-grade,
20-35 = great-grade
II.3.2.2.2
Open clinical studies
Open studies with dried native extract of nettle root (DER: 7-14:1; extraction solvent methanol
20% V/V):
Other 7 open studies were conducted with the above preparation, Bazoton
®
whereof 4 were multi-centric,
prospective observational studies with 14,408 patients altogether (Tosch & Müssiggang 1983; Stahl 1984;
Friesen 1988; Vandierendounck & Burkhardt 1986; Maar 1987; Djulepa 1982; Bauer et al. 1988; Feiber
1988). Detailed data from three multi-centric studies can be seen in Appendix II. of the nettle root
assessment report (Tables of open clinical studies: Tosch & Müssiggang 1983; Stahl 1984; Friesen 1988)
In most studies the indication was the benign prostatic hyperplasia (BPH), only in one study the
preparation was also used for treatment of prostatitis (Djulepa 1982). The patients were mostly in stadium
I-II of the disease.
The evaluation criteria were the change in the subjective symptoms (micturition frequency, nocturia
frequency), and objective parameters were also measured (prostate volume, maximum urinary flow rate,
residual urine volume).
The dosage was 600-1200 mg of extract preparation per day in the open studies and duration of treatment
was 10 weeks - 24 moths. In every open study the subjective symptoms improved significantly. Objective
parameters as urinary flow and residual urine volume also decreased (Friesen 1988; Maar 1987; Djulepa
1982; Feiber 1988). Even in one study decrease in the prostate volume in 54% of cases were observed
(Feiber 1988).
Open studies with other preparations:
Goetz (1989):
Daily treatment for 60 days with 90-50 drops of a fluid extract (1:1, 45% ethanol; Ph Fr.)
led to 66% decrease in residual urine in an open study with 10 BPH patients. (See Appendix II.)
Belaiche et al. (1991):
67 BPH patients were treated with 3x 5 ml of a fluid extract (1:5, 40% ethanol).
After 6 months a reduction in nocturnal micturition frequency was observed (See Appendix II.)
Kaldewey (1995):
In an open multi-centre 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 (See Appendix II.).
II.3.2.2.3
Changes in serum parameters in clinical studies
In 3 studies SHBG, testosterone, 5-alfa-DHT, estradiol and oestron serum levels were also measured
(Fischer & Wilbert 1992; Vontobel et al. 1985; Bauer et al. 1988). In the study published by Safarinejad
(2005), prostate volume, serum PSA and testosterone levels were documented.
SHBG levels decreased significantly in the three studies. Sexual hormone parameters did not change
significantly (Fischer & Wilbert 1992; Vontobel et al. 1985). Serum PSA and testosterone levels were
unchanged after 6-month therapy (Safarinejad 2005).
In the study conducted by Bauer et al. (1988) a significant difference (p<0.05) was found between the
values of PSA, oestradiol, oestron and SHBG at the beginning of the therapy
(
2x2 Bazoton capsules
)
and
after 12 weeks.
EMEA 2009
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Figure from
Bauer et al. (1988)
Results of the ERU study. (n=253) GES: Total-testosterone, FREI: free testosterone, %=percent of free
testosterone, OSTDL: oestradiol; OTRN= oestron; RH: residual urine, PV: prostate volume; FAI=quotient
of testosterone/SHBG. Significance < 0.05 in OSTDL; OTRN; PSA; RH; PV (Basiswert=baseline value
Wochen=weeks):
Assessor’s comment: Since the recent study of Safarinejad (2005) is placebo-controlled and of longer
duration than previous studies, the Committee appreciated the results of this study. The fact that the value
of PSA did not change during a 6 month-long placebo-controlled study is mentioned in the monograph.
Bauer et al. (1988) did not publish any numeric data (only a figure) and the article was part of a promotion
work from one of the authors, therefore the significance of this publication is questionable.
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
Most of the patients were over 60 years. This disease generally appears in men over 50 years due to
ageing.
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
In spite of the fact that in BPH the placebo effect is considerable, only six randomised, double-blind,
placebo-controlled clinical studies can be found in the literature. In three of them the patients number was
very low, and in two of them the treatment period is very short (Dathe & Schmid 1987: 72 patients,
6-8 weeks; Engelmann et al. 1996: 41 patients, 3 months; Fisher & Wilbert 1992: 40 patients, 6 months).
Three studies used the International Prostate Symptoms Score (IPSS) for the evaluation (Engelmann et al.
1996;
Schneider & Rübben 2004; Safarinejad 2005).
Only Engelmann et al. (1996) mentioned they
followed the rules of GCP, but from the
date of the issue of the two other articles it can be presumed that
they were conducted under GCP circumstances as well.
Since in this disease the placebo effect is considerable, only long-term (at least 6-12 moths) studies can be
accepted. Only three studies met this requirement.
Fisher & Wilbert (1992):
It is a randomized, double blind, placebo controlled study but only with
40 BPH II patients. The preparation is a dry extract (DER: 7-14:1, extraction solvent: 20% v/v methanol).
The dosage is 1200 mg extract preparation per day. Duration of treatment is 6 months. The baseline
parameters in the two groups are not mentioned in the articles. Standard deviation values can not be found
as well. They found statistically significant (p<0.05) but clinically not relevant decrease in micturition
frequency (from 7.4 to 6.1, during 24 hours) in the verum group after 6 months, the data in the placebo
group were not given. Significant decrease SHBG level was observed as well. The subjective symptoms
EMEA 2009
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score, which consist of hesitancy, intermittency, terminal dribbling, desire to urinate, decrease in force and
size of the urinary stream, dysuria, and sensations of incomplete emptying, improved considerably. The
objective parameters (prostate volume, urinary flow, residual urine volume) did not change in the nettle
root extract group but worsened in the placebo group. It can be concluded, that this article does not give
relevant data for evaluation of the efficacy.
Schneider & Rübben (2004):
Although in this study the IPSS decreased on average from 18.7±.0.3 to
13.0±0.5 with a statistically significant difference compared to placebo p=0.0233, the
„repeated
measures model”
as used for statistical evaluation seems not to be persuasive.
‘Figure from
Schneider & Rübben (2004)
The median Qmax increased by +3.0±0.4 ml/s in comparison to +2.9±.0.4 ml/s (placebo), the median
volume of residual urine, which changed from 35.5±.3.4 ml before therapy to 20.0±.2.8 ml and from
40.0±.4.0 ml to 21.0±.2.9 ml under placebo application. They are not statistically significant different.
[The dosage was 459 mg of extract (7.1-14.3:1, extraction solvent: methanol 20% V/V).]
Safarinejad (2005):
In this study significant improvement of subjective symptoms and objective
parameters was reported. The study was well designed, with a duration of 6 months (followed by an
18-month follow-up) and 620 patients were involved. However, it is hard/impossible to identify the herbal
preparation.
In summary, the effectiveness of nettle root is not proven sufficiently. One properly conducted placebo-
controlled study was too short (with duration of only three months) (Engelmann et al/ 1996). The study
published by Schneider & Rübben (2004) was long enough, but the result was not persuasive. In the
article by Safarinejad (2005) it is impossible to identify the herbal preparation.
None of these studies give
answers for questions concerning the percentage of the responders, what they consider clinically relevant
changes in the objective parameters before the treatment.
The large open multi-centre studies can serve only as positive signals.
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II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
II.3.3.2
Adverse events
Over 16,000 patients have been treated with nettle root extracts in clinical studies and have taken daily
doses of up to 756 mg of hydro-alcoholic 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 the most recent large open study, involving 1319 patients, the incidence of adverse events
probably related to treatment with nettle root extract was 1.0% (Kaldewey 1995).
The tolerability of the preparations was excellent. Only few, not serious adverse effects occurred. Mainly
gastro-intestinal complaints and in some cases allergic reactions occurred.
In the Schneider & Rübben (2004) study the number of adverse events (29/38) as well as urinary infection
etc. (3/10 events) was smaller under Bazoton ®-uno therapy compared to placebo. Only very few gastro-
intestinal and one allergic side-effects (urticaria) occurred.
Frequency data of adverse effects from the SPC of Bazoton preparations:
According to MedDRA system organ class and frequency convention:
Gastrointestinal disorders:
Gastro-intestinal complaints (nausea, heartburn, feeling of repletion,
flatulentia, diarrhoea) may occur commonly (>1/100, <1/10).
Immune system disorders:
Allergic reactions i.e. pruritus, rash, urticaria may occur uncommonly
(>1/1,000, <1/100).
II.3.3.3
Serious adverse events and deaths
There were no serious adverse events reported.
II.3.3.4
Laboratory findings
The value of PSA did not change during an 18-month long study. (Safarinejad 2005))
II.3.3.5
Safety in special populations and situations
II.3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors
II.3.3.5.2
Contraindication
Hypersensitivity to the active substance(s).
II.3.3.5.3
Warnings
If urinary tract complaints worsen and symptoms such as fever, spasm, blood in the urine, retention of
urine occur during the use of medicinal product, a doctor should be consulted.
In order to minimise cancer risk, regular medical checks of the prostate are recommended, because
symptoms may improve without decrease of the size of the prostate.
II.3.3.5.4
Drug interactions
Not reported.
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II.3.3.5.5
Use in pregnancy and lactation
Not relevant.
II.3.3.5.7
Drug abuse
Not reported.
II.3.3.5.8
Withdrawal and rebound
In the Safararinejad (2005) study, patients, who discontinued the treatment after 6 months, had a relapse at
the 18- month follow-up.
II.3.3.5.9
Effects on ability to drive or operate machinery or impairment of mental ability
No studies on effect on the ability to drive and to use machines have been performed.
II.3.3.5.10
Assessor’s overall conclusions on clinical safety
The tolerability of the preparations was excellent. Only a few, not serious adverse effects occurred.
II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
The effectiveness of the nettle root is not proven sufficiently in BPH. There are only three properly
conducted placebo controlled studies. One of these studies was too short (only three months), the other
two were long enough. However, one of those is not persuasive and in the other study the products can not
be identified.
The studies did not provide satisfactory answers to some important questions: the percentage
of the responsive patients and what they considered clinically relevant changes in the objective parameters
before the treatment.
The large open multi-centre studies can serve as positive signals only.
The Committee concluded that the effectiveness of nettle root in BPH is not proven properly. Since BPH
is a disease which can not be treated without medical control, a traditional indication can not be accepted.
Consequently, a positive monograph can not be prepared for nettle root, neither for well-established use
nor for traditional use.
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APPENDICES
1.
TABLES OF PLACEBO CONTROLLED STUDIES
Name of author:
Dathe G, Schmid H.
Reference /Year
Urologe [B] 1987; 27:223-6 [26]
Name of the product:
Bazoton
®
300mg
Producer:
KANOLDT Arzneimittel GmbH
Active substance
300mg Extractum Radicis Urticae (ERU)
DER:
7-14:1
Extraction solvent:
20% V/V methanol
Type
Randomised, double blind, placebo controlled
Patient number:
Verum: 35 Placebo: 37 Age: 54-83 years
Indication:
BPH I
Duration Dosage/day
Time:
6-8 weeks
Dosage/day:
2x1caps. (600mg)
Evaluation criteria:
Results
Verum
Placebo
Before
After
Difference
Before
After
Difference
282
292
+10
291
289
- 2
micturition volume (ml
micturition duration ( s)
31
27
-4
(13%)
significant
31.6
31.3
- 0.3
average urinary flow rate (ml/s)
9.4
10.7
+1.3
(14%)
significant
9.3
9.5
+ 0.2
maximum urinary flow (ml/s)
13.8
15.4
+ 1.6
(12°%)
significant
13.9
13.2
- 0.7
flow rising time (s)
6.1
5.2
- 0.9
(15%)
significant
6.2
6.1
- 0.1.
residual urine volume (ml)
measured with catheter
94
56
38
(40%)
significant
75
69
- 6
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Name of author:
Dathe G, Schmid H. (continued)
Evaluation criteria:
Results
Verum
Placebo
Before
After
Difference
Before
After
Difference
residual urine volume (ml)
measured by Sonographie
95
72
- 15
(24%)
85
113
+ 28
Residual volume under 100ml
62
29
- 32
(53%)
35
30
-5
subjective symptoms:
(micturition frequency, nocturia
frequency, difficulty in initiating
urination, quality of the urinary
stream, terminal dribbling)
no remarkable difference between the two groups
Adverse effect
No
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Name of author:
Engelmann U. et al.
Reference /Year
Urologe [B] 1996; 36: 287-91 [40]
Name of the product:
Bazoton
®
solution
Producer:
KANOLDT Arzneimittel GmbH
Active substance
Liquid extract from Urticae radix
DER:
1:1
Extraction solvent:
16 % (V/V) ethanol, 20% methanol ?
Type
Randomised, double blind, placebo controlled,
GCP
Patient number:
Verum: 20 Placebo: 21
Age: 67 (49-84) Age: 63(51-84)
Indication:
BPH; Max. Urine. flow <15ml/s, Micturition volume >100ml
residual urine volume > 30ml
Duration Dosage/day
Time:
3 months
Dosage/day:
2x3ml= 4,68g fluid extr.
Results
Evaluation criteria:
Verum
Placebo
Significance
Before After Differ. Before After Differ.
18.2
8.7
9.5
17.7
12.9
4.7
p=0.002
95% CI:
1.995-7.541
International Prostate
symptoms score**
micturition volume (ml)
225
247
+22
232
262
+ 30
micturition duration ( s)
36.6
27
- 9.6
32.5
26.4
- 6
maximum urinary flow (ml/s)
10.9
18.1
+ 7.1
12.3
16.8
+4.4
Significant
(2.7 ml/s)
residual urine volume (ml)
47.8
28.6
-19.2 40.8
30.1
-10.7
Prostate volume
(Sonograph) (cm)
34.4
33.3
1.1
38.3
35
3.3
3.4
1.6
1.7
3.2
2.5
0.7
95% CI:
0.4-1.6
Quality of life
Adverse effects
1 dizziness
1 heartburn
*This value is for Alfuzosin 1.5ml/s, for Tamsulosin 1.0ml/s, Finasterid 1.4ml/s in comparison with
placebo.
** International Prostate Symptoms score (1-5, micturition frequency, nocturia frequency, hesitancy,
decreased urinary stream, residual urine, urge to urine) according to the suggestion of the American
Urological Association. 0-7 point = slight-grade, 8-19 point = middle-grade, 20-35 = great-grade
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Name of author:
Fischer M & Wilbert D.
Reference /Year
Fischer M, Wilbert D. Wirkprüfung eines Phytopharmakons zur
Behandlung der benignen Prostata hyperplasie (BPH). In
Rutishauser G, Editor. Benigne Prostatahyperplasie III. Klinische
und experimentelle Urologie 22. München-Bern-New York:
Zuckschwert, 1992:79-84
Name of the product:
1200mg Extractum Radicis Urticae (ERU)
Bazoton
®
300mg
Producer:
KANOLDT Arzneimittel GmbH
Active substance
300mg Extractum Radicis Urticae (ERU)
DER:
7-14:1
Extraction solvent:
20% V/V methanol
Type
Randomised, double blind, placebo controlled
Patient number:
Verum: 20 Placebo: 20 Age: 54-83 years
Indication:
BPH II.
Duration Dosage/day
Time:
1 month placebo therapy
6 months placebo or verum
Dosage/day:
2x2 caps.
Results
Evaluation criteria:
Verum
Placebo
Micturition frequency (during 24
hours)
from 7.4 to 6.1
decreased (p<0.05)
No change
nocturia frequency
considerable
improvement
Subjective symptoms
-score:
hesitancy, intermittency, terminal
dribbling, desire to urinate,
decrease in force and size of the
urinary stream, dysuria, sensations
of incomplete emptying
from 4.8 to 3.63
decreased, significant
improvement
from 3,29 to 3,3 no change
Objective parameters (prostate
volume, urinary flow, residual urine
volume )
did not change
worsening
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Name of author:
Fischer M &Wilbert D. (continued)
Results
Evaluation criteria:
Verum
Placebo
Endocrine parameters:
SHBG levels
decreased significantly
5α-DHT concentration difference
free and bounded testosterons conc.
free and bounded oestradiol conc.
+3,7 ng/100ml, slight
increasing tendency
+ 0.4
slight rose
decrease
slight rose
decrease
Adverse effect
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Name of author:
Schneider T & Rübben H.
Reference /Year
Urologe [B] 1996; 36: 287-91 [40]
Name of the product:
Bazoton
®
-uno filmtablets
Producer:
Active substance
459 mg dry extract from Urticae radix
DER:
7.1-14.3:1
Extraction solvent:
methanol 20% (V/V)
Type
Randomised, double blind, multi-centric (27), placebo controlled, Phase 4,
Patient number:
Verum: ITT 124 , 114 Placebo: ITT 122, 112
Age: 64±0..6 Age: 63±0..6
Indication:
BPH I-II;
Exclusion criteria: IPPS ≥ 13 Max. Urine. flow ≤15ml/s, Micturition volume ≥
150ml, residual urine volume <200 ml
Duration Dosage/day
Time:
1 week placebo-run-in Phase
52 weeks
Dosage/day:
1 film tablet
Results
Evaluation criteria:
Verum
Placebo
Before
After
Differ.
Before
After
Differ. Significance
International Prostate
symptoms score**
(±SEM)
18.7
±.0.3
13.0
±0.5
- 5.7
±0.5
(31%)
18.5
±0.3
13.8
±0.5
- 4.7
±0.5
(25%)
p= 0.0233
„repeated
measures
model”
maximum urinary flow
(ml/s±SEMD)
11.0
±.0.2
13.8
±0.5
+ 3.0
±0.4
10.7
±0.3
12.3
±0.5
+2.9
±.0.4
p=0.49
Wilcoxon-
Test
residual urine volume
(ml±SEMD)
35.5
±.3.4
20.0
±.2.8
- 0.5
±.2.1
40.0
±.4.0
21.0
±.2.9
- 4
±.1.6
p=0.67
Wilcoxon-
Test
Quality of life
Better 63%,
Worse 8%
No change: 27%
Better 62%,
Worse 7%
No change: 31%
p=0.69
Wilcoxon-
Test
Adverse effects
29
(3 infections of the urinary
tract, haematuria, dysuria,
Gastro-intestinal, allergic
38
(10 infections of the urinary
tract, haematuria, dysuria)
** International Prostate Symptoms score (1-5, micturition frequency, nocturia frequency, hesitancy,
decreased urinary stream, residual urine, urge to urine) according to the suggestion of the American
Urological Association. 0-7 point = slight-grade, 8-19 point = middle-grade, 20-35 = great-grade
EMEA 2009
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Figure from
Schneider T &Rübben H. 1996 (continued)
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Name of author:
Vontobel HP
et al
Reference /Year
Urologe [A] 1985; 24: 49-51 [27]
Name of the product:
Bazoton
®
300mg
Producer:
KANOLDT Arzneimittel GmbH
Active substance
300mg Extractum Radicis Urticae (ERU)
DER:
7-14.1
Extraction solvent:
20% V/V methanol
Type
Randomised, double blind, placebo controlled
Patient number:
Verum:19 Placebo: 22
Age: 67.9 Age: 66
Indication:
BPH I-II
(Patients over 150 ml residual volume were excluded)
Duration Dosage/day
Time: 9 weeks
Dosage/day: 2x1caps. (600mg)
Results
Evaluation criteria:
Verum
Placebo
Difference
Increased 43.7%
decreased 9%
p=0.027
micturition volume (ml)
average urinary flow rate (ml/s)
slight increase
no significant
maximum urinary flow (ml/s)
improved 8.6%
similar decrease
p=0.062
residual urine volume (ml)
measured by Sonograph
no significant.
SHBG serum levels
with average 2.43
nmol/litre decreased
increased
p=0.0005
testosterons serum levels
no signif.
5α-DHTserum levels
no signif.
Subjective symptoms: (micturition
frequency, nocturia frequency,
difficulty in initiating urination,
quality of the urinary stream,
terminal dribbling)
significant
improvement
significant
improvement
no remarkable
Adverse effects
Obstipation
Diarrhoea, gastro-
intestinal complaints
Feeling of perineales
pressure
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Name of author:
Safarinejad M, Z
Reference /Year
Journal of Herbal Pharmacotherapy 2005
Name of the product:
Producer:
Active substance
Fluid extract
100 mg of
Urtica dioica
root
extract in 1 ml
DER:
Extraction solvent:
Type
6 months placebo controlled study
+ 18 months follow-up period with active treatment
Patient number:
Verum: 305 Placebo: 315
Age: 64 (57-71) Age: 62(53-73)
Indication:
Lower urinary tract symptoms due to BPH;
Duration Dosage/day
Time:
6 months placebo controlled
study
340 patients + 18 months
with active treatment
Dosage/day:
3x120mg
Results after 6 months
Evaluation criteria:
Verum
Placebo
Significance
Before
After
Before
After
19.8±4.9
11.8±4
(-40%)
19.2±4.6
17.7±3.1
(-9%)
p=0.002
International Prostate
symptoms score**
maximum urinary flow (ml/s)
10.7±2.4
18.9 ±4.7
( + 8.2)
10.8±2.8
14.2 ±3.7
(+3.4)
p<0.05
Postvoid residual urine volume
(ml)
73±32.6
36 ± 25.5 74±29.6
71 ± 24.4
p<0.05
Prostate size
(transrectal ultrasonograph)
(cc)
40.1±6.8
36.3 ± 4.2 40.8±6.2
40.6 ± 5.1
Adverse effects
No
No
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2.
TABLES OF SOME OPEN STUDIES
Belaiche P & Lievoux O. 1991
Year
Type
Indication
Patient
number
Duration
Dosage/day
Evaluation criteria
Results
Adverse
effect
BHP
6 month
Patient’ number
Before
treatment
After treatment
open
67
3 x 5 ml
fluid extract
(DER1:5, 40%
Ethanol)
no need to get
up
≤ 2
no
improvement
Micturition frequency /night
12
27
28
Group A ≤ 2
Group B ≤ 3
Group C > 3
10
13
7
2
10
17
4
4
Prostate volume
unaffected
Residual bladder volume
post micturition
decreased
EMEA 2009
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Friesen A. 1988
Type
indication
patient
number
Duration
Evaluation criteria
Results
Adverse
effects
Dosage /day
Open
Multi-
centric
BHP
Six months
Percent of patients who thought their
status improved
1. month
3. month
77 %
6. month
31 %
0.7%
gastro-
intestinal
complaints
4480
600-1200mg
ERU (Bazoton
®
)
89.8%
The grade of the improvement
No
complain
19.6%
improvement
23.8%
Consider.
improv.
47.5%
no
improvement
8.8%
(DER: 7-14:1, 20%
V/V methanol)
Percent of patients
At the begining.
2x2 caps.
1 month later 2x1 cap.
without nocturia
> 3
At the beginning
4.2%
48.1%
At the end of the
study
Difference
37.8%
6.3%
12.6%
Significant
Significant
Pollakisuria /
percent of patients
73%
high signif.
0. month
3. month
6. month
Difference
Average urinary flow ml/s
13.26
15.94
17.69
P<0.01
Residual urine volume
Percent of the patients %
At the beginning
At the end
0 ml
7.4
25.5
>0-50
>50-100
>100-200
>200
22.7
53.9
45.7
17.2
16.9
3.1
2.2
0.4
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Nocturia frequency
/ percent of
patients
Goetz P. 1989
Type
Indication
patient
number
Duration
dosage /day
Evaluation criteria
Results
Adverse
effects
open
BHP
2 months
Subjective symptoms (problems in
emptying of the bladder, decreased
urinary stream)
Satisfying improvement an all cases
no
complain
10
90-150 drops
4.5-7.5ml fluid extract
(DER: 1:1, 45%
ethanol
nocturia frequency/night
Patient’s number before treatment
after treatment
0-2
3-4
> 5
1
4
5
10
0-50 ml
50-100 ml
>
100ml
Residual urine volumen
decreased with 66%
Patient’s number before treatment
after treatment
3
9
7
1
prostate size
in 5 cases decreased, in 4 cases not changed, in
1case increased
decreasing is 14.8 cm on average
EMEA 2009
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Kaldewey W. 1995
Type Indication patient
number
Duration
dosage /day
Evaluation criteria
Results
Adverse
effects
open
BHP
1074
(
81.4%)
StadiumI :
233 (16.9%)
Stadium II:
766 (58.1%)
Stadium III:
226 (17.1%)
Stadium IV:
6 (0.5%)
Prostatitis
70 (5.3%)
Prost.+BHP
172 (13%)
6 months
Overall evaluation of effectiveness
by physicians
by patients as change in life quality
72,2 % very good or good
79.9 % improved, 14.6% not changed, 2.7%
worsened
improved in 71.6% of the patients increase
4 ml/s on average
increased with 26 ml on average
decreased with 5 seconds on average
13 cases
(1%)
minor
gastro-
intestinal
complain
540-1080 mg
ERU
multi
centr.
average urinary flow rate
(Urtica Plus N
®
270mg)
at the beginning
73.3% of patients
2x2 caps.
12.4% 2x1
5.4% 3x1
8 weeks later
60% of
patients
2x1 caps.
micturition volume
duration of micturition
symptoms
percent of patients
3 patients
(0.2%)
stopped
the
treatment
because of
adverse
effects
improved
at the beginning
at the end
nocturia frequency by nights
0-1
>4
60.3%
15.5%
22.7%
27.5%
56%
61.1%
2%
2.7%
11.4%
policusuria /day >8
dysurie
76.9%
difficulty in initiating urination
no hesitancy
70.3%
6.7%
22.4%
56.9%
residual urine volumen
0
>100ml
11.7%
8.6%
29%
1.1%
EMEA 2009
37/40
Stahl HP. 1984
Type
Indication
and
patient
number
Duration
Evaluation criteria
Results
Adverse
effects
Dosage /
day
1
st
week
(mean value)
10
th
week
(mean value)
improvement
%
No
effect
%
BHP
10 weeks
NOCTURIA FREQUENCY
Open
Multi-
centric
31
4051
2X2 caps.
1. group weekly 0-7 ( n = 384)
5.5
3.8
32
1200mg ERU
(
DER: 7-14:1, 20%
V/V methanol
)
2. group weekly
8-21
( n = 2464)
14.7
7.3
50
p<0.0001
55
p<0.0001
57
p<0.0001
9.7
(Simic
®
)
3. group weekly
22-35
( n = 961)
26.3
11.9
4.4
3. group weekly
>36
( n = 136)
42.9
18.6
5.9
can not be evaluated ( n=106)
EMEA 2009
38/40
Tosch U. Müssiggang H. 1983
Type
Indication and
patient’s number
Duration
Dosage /day
Evaluation criteria
Results
Adverse
effects
open
multi-
centric
Stadium I:
2194
Stadium II: 2928
Stadium III: 370
3-4 months
Evaluation by the doctor
Stadium I
83,2% of the
patients
improved
Stadium II
Stadium III
84 patients
stopped the
treatment
because of
adverse eff.:
gastric
comp.
nausea,
heartburn,
diarrhoea
86 further
adverse
effects: 54
gastric
comp.
12 diarrhoea
others:
allergy,
itching,
palpitation,
impotence,
dizziness,
lower leg
oedema,
urge to
urination
600-1200mg ERU
(DER: 7-14:1,
20% v/v methanol)
(simic
®
)
80,4% of the
patients
improved
61% of the
patients
improved
All: 5492
Subjective symptoms
High significant improvement
Age < 50 51-60 61-70
at the beginning
2x2,
1 month later 2x1
caps.
improvement score 1-3
micturition frequency
nocturia frequency
2.5 1.7 1.5
2.5 1.0 1.5
Objective parameters:
average urinary flow rate
improvement in ml/sec.
3.2 2.5 2.4
residual urine volume (measured
with catheter or x-ray or
Sonograph) improvement
score 1-4
improvement: 1 score in general
The effectiveness of the therapy
in the age of 50-69 and in the stadium I-II was very significant, but it decreased in advanced age and advanced
stadium.
EMEA 2009
39/40
Source: European Medicines Agency
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