COMMUNITY HERBAL MONOGRAPH ON
SOLIDAGO VIRGAUREA
L., HERBA
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Solidago virgaurea
L., herba
(European goldenrod)
i) Herbal substance
Not applicable.
ii) Herbal preparations
-
Comminuted herbal substance
-
Liquid extract (1:1) prepared with
ethanol/water 25% v/v
-
Tincture (1:5 v/v) prepared with
ethanol/water 45% v/v
-
Dry extract (5-7:1) prepared with
ethanol/water 30 – 60% v/v
Well-established use
Traditional use
Herbal preparation in solid or liquid dosage forms
or herbal tea for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Ph. Eur. monograph (ref. 01/2006:1893).
2
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal quality guidance.
©
EMEA 2008
2/5
4.1.
Therapeutic indications
Well-established use
Traditional use
Traditional herbal medicinal product to increase
the amount of urine - as adjuvant in treatment of
minor urinary complaints.
The product is a traditional herbal medicinal
product for use in specified indications
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults and adolescents
Single dose
-
Comminuted herbal substance for preparation
of an infusion: 3-5 g, 2-4 times daily
-
Liquid extract: 0.5-2 ml, 3 times daily
-
Tincture: 0.5-2 ml, 3 times daily
-
Dry extract: 350-450 mg, 3 times daily
The use in children under 12 years of age is not
recommended (see also 4.4. ‘Special warnings
and precautions for use’).
Duration of use
The herbal substance is traditionally used over a
period of 2 up to 4 weeks.
If the symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Method of administration
Oral use.
For extracts, ensure appropriate fluid intake.
©
EMEA 2008
3/5
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance or to
plants of the
Asteraceae
(
Compositae
) family.
Conditions where a reduced fluid intake is
recommended, e.g. severe cardiac or renal
diseases.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use is not recommended in children under the
12 years of age because of the lack of available
experience.
If complaints of symptoms such as fever, dysuria,
spasms or blood in the urine occur during the use
of the medicinal product, a doctor or a qualified
health care professional should be consulted.
Concomitant treatment with synthetic diuretics is
not recommended.
For tinctures and extracts containing ethanol the
appropriate labelling for ethanol, taken from the
‘Guideline on excipients in the label and package
leaflet of medicinal products for human use’,
must be included.
4.5.
Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
©
EMEA 2008
4/5
4.8.
Undesirable effects
Well-established use
Traditional use
Hypersensitivity reactions or gastrointestinal
disorders may occur. The frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
Well-established use
Traditional use
Not applicable.
4 September 2008
©
EMEA 2008
5/5
Assessment Report
ASSESSMENT REPORT
FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS
THEREOF WITH TRADITIONAL USE
Solidago virgaurea
L., herba
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Herbal substance
Flowering aerial parts of
Solidago virgaurea
L.
Herbal preparation(s)
A)
Comminuted herbal substance
B)
Liquid extract (1:1), prepared with
ethanol/water 25% v/v
C)
Tincture (1:5 w/v)), prepared with
ethanol/water 45% v/v
D)
Dry extract (5-7:1) prepared with
ethanol/water 30 – 60% v/v
Pharmaceutical forms
Herbal preparation in solid or liquid dosage
forms or herbal tea for oral use.
Rapporteur
Dr Ewa Widy Tyszkiewicz
EMEA 2008
2/31
TABLE OF CONTENTS
I. REGULATORY STATUS OVERVIEW
3
II. ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
PREPARATION(S) OR COMBINATIONS THEREOF WITH WELL-ESTABLISHED
USE AND/OR TRADITIONAL USE
11
II.1 INTRODUCTION
11
II.2 CHEMICAL COMPOSITION
11
II.3 PHARMACOLOGY
13
II.3.1 NON-CLINICAL DATA
13
II.3.1.1 Pharmacodynamics
13
II.3.1.1.1 Antiinflammatory activity
13
II.3.1.1.2 Antioxidant activity
14
II.3.1.1.3 Analgesic activity
15
II.3.1.1.4 Spasmolytic activity
16
II.3.1.1.5 Antibacterial activity
17
II.3.1.1.6 Antifungal activity
18
II.3.1.1.7 Anticancer activity
18
II.3.1.1.8. Immunobiological activity
18
II.3.1.1.9 Diuretic activity
20
II. 3.2. Assessor’s overall conclusions on pharmacology
22
II. 3 .3. Pharmacokinetics
23
II. 3. 3 1. Assessor’s overall conclusions on pharmacokinetics
23
II. 3 .4. Toxicology
23
II. 3. 4. 1. Cytotoxicity
23
II. 3. 4. 2. Acute Toxicity
24
II. 3. 4. 3. Repeated dose toxicity
24
II. 3. 4. 4. Genotoxicity, Carcinogenicity
24
II. 3. 4. 5. Reproduction Toxicity
24
II. 3. 4. 5. Assessor’s overall conclusions on toxicology
24
II. 4. CLINICAL STUDIES
24
II. 4 .1. Clinical Pharmacology
24
II. 4. 1. 1. Clinical studies with Solidago virgaureae products
25
II. 4.1.2. Clinical studies with composition products
II. 4. 2. 1. Clinical studies in special populations (e.g. elderly and children)
25
II. 4. 2. 2. Assessor’s overall conclusions on clinical efficacy
30
II. 4. 3. Adverse events
30
II. 4. 4.Interactions
30
II. 4. 5. Assessor’s overall conclusions on clinical safety
30
II. 4. 6. Use in pregnancy and lactation
30
II. 4. 7. Overdose
30
II. 4. 8. Effects on ability to drive or operate machinery
30
II. 4. 9. Contraindications
II. 4. 10. Overall conclusions on safety
30
II. 5. ASSESOR'S OVERALL CONCLUSIONS
31
EMEA 2008
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I.
MA: Marketing Authorisation;
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:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
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
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify:
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:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
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 2008
4/31
Member state
Products
Status
Austria
Traditional use
: The herbal substance is only available in
combination products.
Main combination substances are other herbs with diuretic properties.
Average 2-3 substances are present in combinations
.
Traditional use
The combination product Phytodolor® (Populi cortex, Fraxini cortex,
Solidaginis herba) is authorized in indication of rheumatic complains.
Bulgaria
No authorized herbal medicinal products containing
Solidago
virgaurea
are on the market.
Czech
Republic
Traditional use
:
I. Comminuted herbal substance. Present on the market as authorized
product since 1998. The herbal substance is only available in
combination products. Pharmaceutical form: herbal tea. According to
Czech Pharmacopoeia (Česky Lékopis, 2005): single dose 2.0 g, daily
dose 10.0 to 20.0 g.
Czech name of the herbal substance: nať zlatobýlu obecného
Posology: for oral use; 1 tea spoon/250 ml boiling water several times
daily.
Indications: as an adjuvant therapy in inflammations of the urinary
tract, prevention of cysto- and nephrolithiasis.
Contraindications: contraindicated in cardiac and renal insufficiency.
Risk of allergic reactions.
Traditional use
II. Combination products. Average number of combination substances:
3-5 and >5.
1) Herbal tea – Filipendulae ulmariae herba, Salicis cortex, Violae
tricoloris herba, Harpagophyti radix, Equiseti herba,
Solidaginis
herba
, Callunae herba - on the market since 1999; for oral use;
indications - as an adjuvant for inflammatory and degenerative
diseases of locomotors apparatus (rheumatism, arthrosis, arthritis and
gout), adjuvant therapy in flu like symptoms
2) Herbal tea – Epilobii herba, Bucco folium,
Solidaginis herba
,
Calendulae flos cum calyce - on the market since 1999; for oral use;
indication- for adjuvant therapy in case of micturition difficulties (e.g.
associated with
diagnosed
benign prostate hyperplasia, prostatitis,
inflammations of the urinary tract; special warning: not recommended
for patients with chronic renal diseases, regular medical supervision is
required!
3) Herbal tea – Uvae ursi folium, Equiseti herba, Myrtilli herba,
Matricariae flos, Sambuci nigrae flos,
Solidaginis herba
, Thymi
herba; - on the market since 1989, for oral use; indications - as an
adjuvant therapy in acute and chronic infections and inflammations of
the urinary tract.
EMEA 2008
5/31
Member state
Products
Status
Denmark
Herbal substance present on the market as an authorized product.
Well
established use
Well established use
:
1) Solidaforce® (MAH Bioforce). 1 ml ethanolic extract of Solidago
virgaureae herba 320-468 mg, corresponding to 114 mg of dry herb.
Pharmaceutical form: oral drops. Posology: 30-40 drops 3-4 times
daily. Present on the market before 2000.
2) Solidamin 10®
Indication: Herbal medicinal product for slightly increasing the
diuresis, especially at irritation in the urinary tract. ATC code: C03
Traditional use
Traditional use:
1) A combination product: Salus tea nr. 23. Present on the market
between 1993-2007 as a herbal medicinal product. Pharmaceutical
form: herbal tea
Adverse effects: Known hypersensitivity to
Compositae
flowers
Pharmacovigilance actions were not taken on medicinal products
containing the herbal substance.
Finland
No authorized herbal medicinal products containing
Solidago
virgaurea
are on the market.
Germany
Well established use
Well
established use
There are 13 herbal medicinal products on the market:
1, 5, 12
) dry extract from Solidaginis virgaureae herba (5-7:1),
extraction solvent: ethanol 30% m/m;
2, 4
) dry extract from Solidaginis virgaureae herba (5-7:1),
extraction solvent: ethanol 60% V/V;
3, 13
) dry extract from Solidaginis virgaureae herba (5-7.1:1),
extraction solvent: ethanol 30% m/m
6)
dry extract from Solidaginis virgaureae herba (5-6:1), extraction
solvent: water
7
) powder from Solidaginis virgaureae herba
8, 11
)dry extract from Solidaginis virgaureae herba (5-6.1:1),
extraction solvent: ethanol 50% m/m
9
) dry extract from Solidaginis virgaureae herba (6-7:1), extraction
solvent: ethanol 60% V/V
10
) liquid extract from Solidaginis virgaureae herba (1:0.9-1.1),
extraction solvent: ethanol 35% V/V
Preparations 1, 2, 3, 11, 6, 7, 8, 9, 10, 11) are on the market
at least since 1976; preparations
5, 13) since 1996; preparation 12 since 2000
Pharmaceutical forms:
Preparations 1,7, 12 are film coated tablets.
Preparations 2, 9 are tablets; preparations 3,4,5,6 are hard capsules;
preparations 8, 10, 11 are oral liquid and preparation 13 is soft capsule
EMEA 2008
6/31
Member state
Products
Status
Germany
Posology:
All preparations are for oral use and
all for use in adults and adolescents over 12 years.
1, 12) three times daily 1 film-coated tablet containing 342 mg dry
extract
2) four-five times daily 1 tablet containing 342 mg dry extract
3, 5) three-four times daily 1 hard capsule containing 428.8 mg dry
extract
4) three times daily 1 hard capsule containing 360 mg dry extract
6) three times daily 2-3 hard capsules containing 250 mg dry extract
each
7) three times daily 4 film-coated tablets containing 500 mg powder
each three times daily 5 ml oral liquid
(100 g oral liquid = 93 ml contain 9 g dry extract)
9) two-three times daily 3 tablets containing 116.4 mg dry extract each
10) three-five times daily 50 drops (ca. 2 g) oral liquid
containing 100% liquid extract
11) three times daily 5 ml oral liquid
(100 g oral liquid = 92.8 ml contain 9 g dry extract)
13) three-four times daily 1 soft capsule containing 428.8 mg dry
extract
Well
established use
Indication:
As a purging in inflammatory diseases of the urinary tract collection
system, urolithiasis and renal gravel, preventive treatment in
urolithiasis and renal gravel.
Adverse effects:
Preparations 1 – 13) Gastrointestinal complaints (pain, cramps,
nausea)
Allergic reactions (itching, exanthema, swelling of the tongue, oral
and pharyngeal mucosa
Case reports in our data bank, Schätzle M
et al
. Allergic contact
dermatitis from goldenrod (Herba Solidaginis) after systemic
administration. Contact dermatitis 1998, 39: 272.
Pharmacovigilance actions were not taken on medicinal products
containing the herbal substance.
Well established use combination product: (1) contains Betulae folium
and Orthosyphonis folium besides Solidago virgaureae herba.
Traditional use
Herbal medicinal authorised product:
1
) liquid extract from fresh
Solidaginis virgaureae herba (1:1.9-3.2), extraction solvent: ethanol
57.3% m/m present on the market since 1976.
Traditional use
Pharmaceutical form: oral liquid
Posology: for oral use in adults and adolescents over 12 years 5 x daily
40 drops (1 ml = 32 drops) containing 100% extract
Indications: Traditional herbal medicinal producst to support the
elimination function of the kidney. The product is a traditional herbal
medicinal product for use in specified indications exclusively based on
long-standing use.
EMEA 2008
7/31
Ireland
No
authorized
herbal
medicinal
products
containing
Solidago
virgaurea
are on the market.
Latvia
No
authorized
herbal
medicinal
products
containing
Solidago
virgaurea
are on the market.
Poland
Traditional use
Present on the market as 3 authorized products since 1995.
Preparations: Comminuted herbal substance Solidaginis herba
prepared as herbal tea.
Infusion made of 3 - 4 g of dried herb in 100 ml of boiling water,
3 times daily.
Indications: Traditionally to increase the amount of urine, as adjuvant
in treatment of minor urinary complaints.
Adverse effects: not known
Pharmacovigilance actions were not taken on medicinal products
containing the herbal substance.
Combination products:
Most of products on Polish market are herbal teas (16 products) with
Solidaginis virgaureae herba being one of components. There are also
oral liquids (7 composed products); capsules containing pulverised
herbs (1 product); pastae (2 composed products); one herbal granulate;
drops (2 composed products); one product in form of tablets.
Traditional
use
Slovenia
No
authorized
herbal
medicinal
products
containing
Solidago
virgaurea
are on the market.
Spain
Traditional use.
Comminuted herbal substance. Present on the market as registered
product before 1980. Solidaginis herba prepared as herbal tea.
Infusion made of 6 - 10 g of dried herb, one cup 3 -4 times daily.
Indications: diuretic
Pharmacovigilance actions were not taken on medicinal products
containing the herbal substance.
Combination products
:
Combination products of diuretic herbal substances for use as a Herbal
tea
Average number of combination substances:
3-5 and >5 in the product.
Traditional
use
EMEA 2008
8/31
Sweden
Traditional use
Herbal medicinal authorised product present on the market since 1978
Traditional
use
1) Ethanol extract (1:8, 66 %) 910 mg.
1 ml contains 910 mg extract corresponding to 0.4 g fresh herb (or 0.1
g dried herb).
Pharmaceutical form: oral drops, solution.
Posology: Adults and adolescents: 1 ml in ½ glass of water, 3-5 times
daily. Not recommended to children.
Indications: Traditionally used for symptomatic relief of lower urinary
tract disorders of the type that may benefit from an increased flow
through the urinary tract, for example urinary tract irritation or light
pain caused by passing urinary stones or kidney gravel
Contraindications: Should not be used as a diuretic by oedema due to
heart or kidney insufficiency.
Allergy to
Compositae
.
Precautions should be taken with a lot of water.
If the symptoms persist more than 3 days or if symptoms such as blood
in the urine, fever or low backpain occur the underlying condition
should be investigated in order to exclude urinary tract infection or
other serious condition.
Pharmacovigilance actions were not taken on medicinal products
containing the herbal substance.
The product is approved as a natural remedy.
United
Kingdom
No authorized herbal medicinal products containing
Solidago
virgaurea
are on the market.
EMEA 2008
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II.
ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
PREPARATION(S) OR COMBINATIONS THEREOF WITH WELL-
ESTABLISHED USE AND/OR TRADITIONAL USE
II.1
INTRODUCTION
Solidago virgaurea
L. (synonyms:
Amphiraphis leiocarpa
,
Amphiraphis pubescens, Dectis decurrens,
Doria virgaurea,
European golden rod) belongs to the family of
Asteraceae
(
Compositae
). The herbal
substance consists of the dried, flowering parts of the plant (
Solidaginis virgaureae herba
, British
Herbal Pharmacopoeia 1976; ESCOP Monographs 2003; Bader 1994; 1999; 2006; Goldenrod.
http://www.Herbalgram.org
;
Hoppe 1975; PDR for Herbal Medicines 2000; Pharmeuropa 2001;
http://www.pharmakobotanik.de/systematik/6droge-f/solida-v.htm
;
Pharmacopée Francaise 1989;
Verga D’Oro 2001).
Solidago has been used for treatment of different diseases in Europe since medieval times (Arnold
from Villanova (1240-1311),
Lonicerus
1564; Hieronimus Bock 1565 and
Tabernaemontanus
(1530-
1590). Its diuretic activity is mentioned in “
Thesaurus pharmacologicus
” Schroeder’s, 1669 (Bader
1999); in Madaus “Lehrbuch der Biologischen Heilmittel” (1938) and in Mayer Monograph of
Solidago
Virga aurea
L. (Mayer and Mayer 1950).
II.2
CHEMICAL COMPOSITION
European goldenrod contains miscellaneous flavonoids (1.5%) (quercetin, kaempferol and their
glycosides, astragalin and rutoside) and antocyanidins, derivatives of cyanidin. Other constituents
include triterpene saponins of the oleanane type (up to 2%), the bisdesmosidic phenol glycosides
leiocarposide (0.08-0.48%) and virgaureoside A, diterpenoid lactones of the cis-clerodane type,
phenolic acids (caffeic acid, chlorogenic acid (0.2-0.4%), ferulic acid, synapic and vanillin acids) and
small amount of essential oil (cadinene, α and β pinene, myrcene, limonene, sabinene and germacren
D) (Bader 1999; Bornschein 1987; ESCOP Monograph 2003; Fötsch and Pfeifer 1989; Fötsch
et al
.
1989; Gerlach 1972; Goswami
et al
. 1984; Hiller
et al
. 1975; Hiller and Gil Rjong 1980; Hiller and
Fötsch 1986; Hiller
et al
. 1991; Inose
et al
. 1991, 1992; Jiang
et al
. 2006; Kalemba 1998; Knütter and
Pohloudek-Fabini1969; Lück 2001 edoc.hu-berlin.de/dissertationen/lueck-lorna-2001-08-
03/HTML/lueck-bib.html; Poetsch 1999; Prosser at al. 2002; Radoias
et al
2004; Schilcher 1964,
1965). The polyphenolic compounds and terpenoids from
Solidago virgaurea
L
.
are presented in
Table 1 according to Wittig and Veit (1999).
EMEA 2008
10/31
Table 1. Chemical composition of
Solidago virgaurea
L (according to Wittig and Veit 1999
)
Salicylic acid
Kalemba 1992
p-Hydroxybenzoic acid
Kalemba 1992
Protocatechuic acid
Kalemba 1992
p-Coumaric acid
Kalemba 1992
Gentisic acid
Kalemba 1992
Ferulic acid
Kalemba 1992
Synapic acid
Kalemba 1992
Vanillic acid
Kalemba 1992
Caffeic acid
Björkman and Holmgren 1960;
Borkowski and
Skrzypczakowa 1
962; Kalemba 1992
Chlorogenic acid
Björkman and Holmgren 1960; Kalemba 1992;
Synapic acid
Kalemba 1992
Isorhamnetin
Wittig and Veit (1999)
Isorhamnetin 3-
O
-galactoside
Wittig and Veit (1999)
Isorhamnetin 3-
O-
glucoside
Wittig and Veit (1999)
Isorhamnetin 3-
O-
rhamno-glucoside
Wittig and Veit (1999)
Kaempferol
Wittig and Veit (1999)
Kaempferol 3-
O
-arabinoside
Wittig and Veit (1999)
Kaempferol-3-
O
-glucoside (Astragalin)
Skrzypczakowa 1962; Hiller
et al
. 1979 Wittig and
Veit (1999)
Kaempferol-3-
O
-rutinoside
Hiller
et al
. 1979; Kalemba
et al
. 1992
Kaempferol-3-
O
-galactoside
Wittig and Veit (1999)
Kaempferol-3-
O
- rhamno-glucoside
(Nicotiflorin)
Wittig and Veit (1999)
Kaempferol-3-
O
- rhamnoside (Afzelin)
Wittig and Veit (1999)
Kaempferol-3-
O
-robino-bioside
Wittig and Veit (1999)
Quercetin
Skrzypczakowa 1962; Wittig and Veit (1999)
Quercetin-D-glucoside
Hiller
et al
. 1979
Quercetin-3-
O
-arabino-pyranoside
Wittig and Veit (1999)
Quercetin-3-
O
-galactoside
(Hyperoside)
Wittig and Veit (1999)
Quercetin-3-
O
-glucoside (Isoquercitrin) Wittig and Veit (1999)
Quercetin-3-
O
-rhamno-glucoside
(Rutin)
Thiem and al. 2001; Wittig and Veit (1999)
Quercetin-3-
O
-rhamnoside (Quercitrin)
Skrzypczakowa 1962; Wittig and Veit (1999)
Quercetin-3-
O
-roibinoside
Wittig and Veit (1999)
Rhamnetin-3-
O
-rhamno-glucoside
Wittig and Veit (1999)
EMEA 2008
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Limonene
Fujita 1991Kalemba 1998
β-Caryophyllene
Kalemba 1998
β-Elemene
Fujita 1991
δ-Elemene
Fujita 1991
α-Humulene
Kalemba 1998
Germacrene B
Fujita 1991
Germacrene-D
Fujita 1991
δ-Cadinene
Fujita 1991
α-Muurolene
Kalemba 1998
Oleanolic acid
Tamas and Rosea 1988
Bayogenin
Tamas and Rosea 1988
Leiocarposide
Hiller
et al
. 1979; Bader
et al
. 1990a; 1998; Fötsch
et al
. 1988.
α-Pinene
Fujita 1991; Tucker and Maciarello 1999; Kalemba
1998
β-Pinene
Kalemba 1998
Sabibene
Kalemba 1998
β-Myrcene
Fujita 1991; Tucker and Maciarello 1999; Kalemba
1998
Virgaureasaponin 3
Bader
et al
. 1991; 1995
Virgaureoside A
Hiller
et al
. 1985
Solidagosaponins 21
Miyase
et al
. 1994
Solidagosaponins 22
Miyase
et al
. 1994
,
Solidagosaponins 23
Miyase
et al
. 1994
Solidagosaponins 24
Miyase
et al
. 1994
,
Solidagosaponins 25
Miyase
et al
. 1994
Solidagosaponins 26
Miyase
et al
. 1994
Solidagosaponins 27
Miyase
et al
. 1994
Solidagosaponins 28
Miyase
et al
. 1994
Solidagosaponins 29
Miyase
et al
. 1994
Solidagosaponins 30
Miyase
et al
. 1994
EMEA 2008
12/31
II.3
PHARMACOLOGY
The pharmacological and clinical effects of
Solidago virgaurea
has been described in several reviews
(Bader 1999; Hiller and Bader 1996; Laszig
et al
. 1999, Melzig 2004, Schilcher 1987; Schilcher 1999,
Schmitt 1996; Weiss 1980; Yarnell 2002).
A synergic action of several components of the
Solidago virgaurea
L. is proposed. Therefore, the
herbal substance or herbal preparations from Solidago must be considered as the active ingredient.
II.3.1 NON-CLINICAL DATA
II.3.1.1 Pharmacodynamics
II.3.1.1.1 Anti-inflammatory activity
Anti-inflammatory activity of saponins from
Solidago virgaurea
L. was tested in experimental oedema
model in rats. Pletysmographic estimation showed significant reduction of the volume of the oedema
after iv administration of 1.25mg – 2.5 mg/kg of triterpene saponin complex (Jacker
et al
. 1981).
Terpene fraction or its derivatives were shown to present antiulcer activity. Such activity was
described for a labdane diterpene from
Solidago chilensis
in HCl/ethanol induced gastric lesions in
mice (Schmeda-Hirschmann
et al
. 2002).
In experiment on rats the combined preparation of
Solidago virgaurea
,
Fraxinus excelsior
and
Populus tremula
(Phytodolor
®
) was tested for an anti-inflammatory, analgetic and antipyretic activity.
Activity was similar to that of reference substances salicyl alcohol and indomethacin. Each of the
individual extracts exhibited significant efficacy (Okpanyi
et al
. 1989).
Extracts of
Solidago virgaurea
(aqueous/alcoholic) were tested for anti-inflammatory activity in
carrageenen induced oedema and in adjuvant induced arthritis in rats. Both extracts of
Solidago
as
well as extracts of
Populus tremula
and
Fraxinus excelsior
(composition of Phytodolor
®
preparation)
significantly reduced the carrageenen oedema and reduced the volume of the arthritic paw
(El-Ghazaly
et al
. 1992).
Anti-inflammatory activity was also demonstrated with samples from Phytodolor
®
in
in vitro
experiments, where significant inhibition of expression of TNF-α and COX-2 activity was observed
(Schaser
et al
. 2006).
Anti-inflammatory influence of
Solidago virgaurea
extract from fixed composition Phytodolor
®
on the
activity of myeloperoxidase (MPO) liberated by activated granulocytes was estimated in
in vitro
experiments. Solidago extract did not inhibit myeloperoxidase activity at concentrations up to 1%
(Von Kruedener
et al
. 1995; 1996).
EMEA 2008
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Saponins, flavonoids and caffeic acid esters from
Solidago virgaurea
inhibited the activity of
leukocyte elastase, a protease involved in the progression of inflammation. The ester saponins
increased permeability of cells and stimulated the synthesis and release of glucocorticoids in the
adrenal glands (Melzig
et al
. 2000).
Anti-inflammatory activity of leiocarposide was tested in rats with carrageenen oedema test
(Table 2, Metzner
et al
. 1984).
Table 2. Anti-inflammatory activity of leiocarposide and phenylbutazone in rats (Metzner
et al
. 1984).
Oedema inhibition (%)
Dose
mg/kg
N=8
1 h
2 h
3 h
4 h
5 h
Leiocarposide
100
0
0
5
6
20
Leiocarposide
200
10
3
10
14
27
*
Phenylbutazone
50
15
53
55
*
66
*
54
*
The pharmacological activity and toxicology of phytotherapeutic Ariven
®
composed of aqueous
extract of
Solidago virgaureae
,
extr. Oleandris
, sparteine sulfate, pyridine-3-carbonic acid, pyridine-3-
carbonic acid amide, vitamin B
1
and vitamin B
6
. was estimated in several experiments testing
antioedemic effects. The Solidago extract significantly inhibited the inflammatory skin reaction
induced by X-ray radiation model in guinea pigs and examined with Trypan Blue method (Wagener
1966).
II.3.1.1.2 Antioxidant activity
Chlorogenic and caffeic acids have been reported to scavenge reactive species of oxygen and nitrogen
(Kono
et al
. 1997).
Mixture of the ethanolic extracts (35% aqueous ethanol) from dried
Solidago virgaurea
,
Potentilla
anserina
,
Radix Rubiae
tinctorum
,
Equisetum arvense
,
Oleum Juniperi
and
Petroselini
sativi
fructus
was used
in vitro
to estimate glucose consumption by rabbit brain slices. Swelling of brain slices
in
vitro
was significantly diminished with an increase of glucose consumption and the aerobic formation
of lactic acid (Dittmann 1973).
Antioxidant activity of ethanolic extract of
Solidago virgaurea
(0.52 mg/ml of rutin, 0.64 mg/ml of
flavonoids and ethanol 45.6% v/v) was tested
in vitro
as a component of the phytotherapeutic drug
Phytodolor
®
. The activity of xanthine oxidase (XOD), diaphorase (NAD-dia-juglone), lipooxygenase
(LOX) and the light activators, riboflavin and rose Bengal was studied. The results showed inhibition
of production of reactive oxygen species in above mentioned reactions by
Solidago virgaurea
L.
extract (Meyer and Elstner 1990; Meyer
et al
.; 1995).
Similar effects of Phytodolor
®
were described in another series of experiments (Germann
et al
. 2005).
EMEA 2008
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Compound tested
II.3.1.1.3 Analgesic activity
Analgesic activity of leiocarposide was shown in experiments performed on mice in hot plate and
withdrawal of a hind foot upon irradiation (the inhibition of a polysynaptic reflex)
tests. This activity
was compared with aminophenazone effects (Table 3, Metzner
et al
. 1984).
Table 3. Analgesic activity of leiocarposide and aminophenazone in mice (Metzner et al. 1984).
Analgesic effects (%)
Compound
tested
Dose
mg/kg
N=10
0.5 h
1 h
2 h
Inhibition of
polysynaptic
reflex
Leiocarposide
200
70
30
10
Aminophenazone
100
60
40
40
Hot plate
Leiocarposide
200
100
90
20
Aminophenazone
50
100
90
80
The analgesic potential of
Solidago virgaurea
was tested
in vitro
for affinity to three neuropeptide
receptors involved in the mediation of acute pain in mammals: bradykinin, expressed in Chinese
hamster ovary cells, neurokinin 1 expressed in astrocytoma cells and calcitonin gene related peptide.
The Solidago methanolic extract of the seeds of the plant produced significant inhibition of radio-
ligand binding for bradykinin receptors (Sampson
et al
. 2000).
II.3.1.1.4 Spasmolytic activity
In experiment performed
in vitro
on isolated smooth muscles of intestines of guinea pig
Solidago virgaurea
ethanolic extract induced spasmolytic activity in the range of 14.73% of papaverin
(Westendorf and Vahlensieck, 1981).
Presence of flavonoids (quercetin and kaempferol) in
Solidago virgaurea
preparations may contribute
to explain vascular smooth muscle relaxation. It can be concluded that vasodilatatory action depends
on the inhibition of protein kinase C, inhibition of cyclic nucleotide phosphodiesterase or decrease of
Ca
2+
uptake (Rácz
et al
. 1980; Duarte
et al
. 1993).
In other experiments performed
in vitro
in acetylcholine pretreated urinary bladder of the rat the
phytotherapeutic product Urol
®
) combined of
Extr Rad. Rubiae tinct. Spir, Extr. Sem Ammeos
visnagae
spir., Extr. Herb. Solidago virgaureae spir., Extr. Rad. Taraxaci
and aescin exhibited
spasmolytic activity. This effect was mainly due to the ingredient
Extr. Solidago virgaureae
Westendorf and Wahlensieck 1983).
Aqueous extract of leaves of
Solidago virgaurea
(aqueous extraction, evaporation of eluate to a
spissum extract and dilution with water) inhibited muscarinic M
2
and
M
3
receptor-mediated
contraction of rat and human bladder muscle strips. Low extract concentrations (0.01%) appeared to
EMEA 2008
15/31
Test
result from non-competitive muscarinic receptor antagonism, whereas higher (0.1%) concentrations
might have non-specific inhibitory effect. Relationship between
in vitro
concentrations and therapeutic
doses remained unclear due to unknown bioavailability of the active ingredients of the extract
(Borchert
et al
. 2004).
II.3.1.1.5 Antibacterial activity
Antibacterial activity of monovalent preparations (six extracts) and mixtures (ten preparations) of
Solidago virgaurea
were tested
in vitro
against urogenital bacterial pathogens (
Staphylococcus aureus,
Staphylococcus epidermidis
). Tested mixtures (
Solidago virgaurea
combined with
Cortex
Rhus
aromaticae
,
Fol. Uvae ursi
and
Hb. Taraxaci
) showed significantly stronger antibacterial activity than
monovalent preparations. The results indicate that
Solidago virgaurea
extracts exhibited antibacterial
effect against
Staphylococcus aureus
and
Staphylococcus epidermidis
. Moreover these extracts of
Solidago virgaurea
demonstrated activity against a larger range of microbes than extracts of
Solidago
gigantea
and
Solidago canadensis
(Brantner 1999).
Antimicrobial activity of ethanolic and methanolic extracts of
Solidago virgaurea
L. were tested
in vitro
by use of freeze-dried biomass from 4-week old callus cultures of the plant. The minimal
bactericidal concentrations of the ethanolic and methanolic extracts of
Solidago virgaurea
estimated
with the agar diffusion assay method showed a moderate activity and are presented in Table 4.
(Thiem and Goślińska 2002).
Table 4. Antimicrobial activity (MBC) of extracts from plant and callus of
Solidago virgaurea
L. from
in vitro
cultures (Thiem and Goślińska 2002).
Microorganism
Plant
Callus tissue
MeOH
MBC
EtOH
MBC
MeOH
MBC
Bacillus subtilis
1.8
3.9
31.2
Bacillus pumilis
15.6
31.2
62.5
Proteus mirabilis
3.9
7.8
62.5
Proteus vulgaris
31.2
62.5
-
Micrococcus luteus
7.8
15.6
31.2
Pseudomonas aeruginosa
31.2
62.5
-
Staphylococcus aureus
62.5
12.5
62.5
Staphylococcus epidermidis
31.2
31.2
12.5
Escherichia coli
31.2
62.5
-
Aspergillus niger
62.5
62.5
-
MBC – minimal bactericidal concentration (mg/ml); - no activity
Inhibition of dihydrofolate reductase activity, an enzyme modulating cytostatic and antibacterial
activity was found in
in vitro
experiments with water-soluble components of Phytodolor
®
phytotherapeutic composed of
Fraxinus excelsior
,
Populus tremula
and
Solidago
virgaurea
. The
Solidago virgaurea
ethanolic extract (rutin 0.52 mg/ml, flavonoids 0.64 mg/ml, ethanol 45.6% v/v,
Steigerwald Arzneimittelwerk) induced inhibition of the activity of dihydrofolate reductase
EMEA 2008
16/31
(I
50
=0.013% v/v). However, the overall effect of the combination was more pronounced. The single
component as the combined extracts exhibited activity in the range of effective NSAID’s
(Strehl
et al
. 1995).
II.3.1.1.6 Antifungal activity
In the course of screening for new antifungal agents Bader
et al
. (1987) showed that deacylated
triterpenoid saponins of
Solidago virgaurea
, isolated after mild alkaline hydrolysis of the mixture of
genuine ester saponins, showed higher activity against several
Candida
species (
Candida albicans,
Candida tropicalis, Candida krusei, Candida parapsilosis, Candida pseudotropicalis, Candida
guilliermondi, Candida glabrata
and
Cryptococcus neoformans
), than the mixture of ester saponins.
These deacylated saponins (bisdesmosidic glycosides of polygalacic acid) virgaureasaponins 1, 2 and
3 (Bader
et al
. 1992) demonstrated higher antifungal activity than that of the corresponding
prosapogenins (monodesmosides) (Bader
et al
1990b).
In other experiments Pepeljnjak
et al
. (1998) showed antimycotic activity of
Solidago virgaurea
ethanolic extract against dermatophytes, especially against
Trichophyton mentagrophytes,
Microsporum gypseum
and
Microsporum canis
. Antifungal activity against
Candida albicans
was
very low.
II.3.1.1.7 Anticancer activity
Significant tumour inhibitory action of Virgaurea saponin E (1 mg/kg/day) was found
in vivo
in mice
in allogenic sarcoma-180 model and in syngenic sarcoma model (Bader
et al
. 1996; 1998b). In another
series of experiments the antitumour effects of polysaccharides were demonstrated.
In an SCID mouse model antineoplastic activity of
Solidago virgaurea
on prostatic tumour cells was
tested and cytotoxic activity on various tumour cell lines was demonstrated (human prostate, breast,
melanoma and small lung carcinoma). The active fraction of the extract corresponding to a molecular
weight of 40,000 (G-100) was administered
i.p
. or s.c. every 3 days for 25 days in experimental
tumour model in mice. The growth of the tumours was inhibited at 5 mg/kg (Gross
et al
. 2002).
II.3.1.1.8 Immunobiological activity
Immunomodulatory (induction of macrophages and activation of NK-cells) and antitumour activity of
triterpene saponins (Virgaurea saponin E
1
)
were shown in
in vitro
experiments (Plohman et al. 1997,
1999).
Further chromatographic separation demonstrated the presence of five benzylbenzoates from the
hexane soluble fraction of the methanolic extract of the aerial parts of
Solidago virgaurea
var.
gigantea
. By using
in vitro
mouse peritoneal macrophages two compounds (2-methoxybenzyl-2-
hydroxybenzoate and benzyl-2-hydroxy-6-methoxybenzoate) exhibited stimulation macrophage
EMEA 2008
17/31
function (range of 1-100 μg/ml), suggesting potential use in the treatment of infectious diseases and
tumours (Choi
et al
. 2005).
II.3.1.1.9 Diuretic activity
The diuretic properties of
Solidago spp.
are in prevalence based on studies performed on the European
goldenrod (
S. virgaurea
L
.
). Leiocarposide (2’-hydroxybenzyl-2,4-dihydroxy-3-methoxybenzoate
2’.4-diglucoside) was isolated for the first time from
Solidago virgaurea var. Leiocarpa
(Benth/Gray)
(Hiller
et al
. 1979) and was found in
Solidago virgaurea L
(Chodera
et al
. 1985a, 1985b;
Budzianowski 1999). Leiocarposide is completely absent in
Solidago canadensis
L. and
Solidago
gigantea
Ait. Acute toxicity (LD
50
)
of leiocarposide in rats was 1.55 g/kg. The compound was shown
to exhibit diuretic activity in rats, only 75% lower than furosemide (Table 5,
Chodera
et al
. 1985a).
The action of leiocarposide was 30% higher after
i.p
. than
per os
administration. The diuretic action
was delayed and started after 5 hours after administration and lasted up to 24 hours (Table 6, Chodera
et al
. 1985b).
The leiocarpic acid (3,6-dihydroxy-2-methoxybenzoic acid), part of the leiocarposide molecule,
showed no diuretic activity at the dose 25 mg/kg
i.p
. (Budzianowski 1999).
Table 5. Diuretic activity of leiocarposide and furosemide in rats (Chodera
et al
. 1985a, b).
Groups
N
Urine
volume/rat/day
(ml)
% Increase
of urine volume
after 24 h
Control
10
7.8 ± 0.5
-
Furosemide 6 mg/kg
i.p.
10
17.3 ± 0.5
*
125
Leiocarposide 25 mg/kg
i.p
..
10
13.3 ±
*
70
*
p<0.05 vs. control
Table 6.Diuretic activity of leiocarposide after intraperitoneal (
i.p
.) and oral (
per os)
administration
(Chodera
et al
. 1985 b).
Groups (N=10)
Urine volume/rat/day (ml)
% Increase of
urine volume
after 24 h
5 h
6 h
12 h
24 h
Control
per os
1.0±0.1
1.7±0.1
2.7±0.2
4.7±0.3
i.p
0.5±0.1
1.5±0.1
2.7±0.3
4.5±0.4
Leiocarposide 25 mg/kg
1.3±0.1
2.4±0.2
3.0±0.2
8.4±0.3
*
80
per os
i.p.
0.9±0.1
1.1±0.1
3.6±0.2
9.4±0.5
*
110
*
p<0.05
EMEA 2008
18/31
Table 7. Elimination of sodium, potassium and calcium ions in urine of the control, leiocarposide and
furosemide treated rats (Chodera
et al
1985b).
N
Na
+
mMol/l
K
+
mMol/l
Ca
+
mMol/l
Control
10
32.41 ± 3.04
2.93 ± 0.21
0.51 ± 0.09
Leiocarposide
25 mg/kg
i.p
.
10
25.34 ± 3.12
1.76 ± 0.14
0.31 ± 0.06
Furosemide
i.p.
10
54,43 ± 5.15
*
1.74 ± 0.12
0.31 ± 0.06
The flavonoid fraction of
Solidago virgaurea
L. administered to rats showed an increase of diuresis
(88% after 24
h
). Decrease of an overnight excretion of potassium and sodium and increase of excretion
of calcium ions was observed (Table 8, Chodera
et al
. 1991).
Table 8. Diuretic and saluretic activity of the flavonoid fractions of
Solidago virgaurea
(Chodera
et al
.
1991).
N
Na
+
mmol/dm
3
K
+
mmol/dm
3
Ca
+
mmol/dm
3
Increase of
diuresis after 24
h
Control
NaCl,
5 ml
per os
10
31.83±1.91
87.82±6.12
1.35±0.22
Solidago Virgaureae
flavonoid fraction
25 mg/kg
per os
10
17.82±1.33
*
68.04±4.31
*
4.08±0.29
*
88
Interestingly, it was also demonstrated, that leiocarposide diuretic activity was reduced by the
presence of flavonoids and saponins. In contrary, some researchers suggest that diuretic activity of
goldenrod is exerted by the mixture of flavonoids and saponins, but the others demonstrated in animal
studies relative inactivity of flavonoid mixture (Schilcher
et al
. 1989).
In experimentally induced renal calculi model in rats it was shown, that after 6 weeks of
administration of leiocarposide (25 mg/kg) the growth of the renal calculi was significantly decreased
(Chodera
et al
. 1988).
Significant increase of diuresis in rats together with an increased elimination of sodium, potassium and
chloride ions was observed after oral administration of infusion of
Solidago virgaurea
(0.3% of
flavonoids, 4.64 ml/kg and 10.0 ml/kg). The lower dose was more efficient (Schilcher and Rau 1988).
Acylated triterpenoid saponins (especially virgaureasaponin B) present in
Solidago virgaurea
could
transiently change the cell membrane permeability and induced alterations in ionic homeostasis with
enhanced permeability between the intracellular and extracellular compartments. These effects could
be the result of the structural similarity of acyl groups with fatty acids as constituents of the biological
membranes (Melzig
et al
. 2001).
EMEA 2008
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Comparison of diuretic activity of different fractions of
Solidago virgaurea
extracts (methanol/water,
70:30) on Sprague Dawley rats (N=12–16 per experimental group) showed significant diuretic and
saluretic activity of some fractions of the extract.
The hydroxycinnamic acid fraction (100 mg/kg p.os) significantly increased sodium and potassium
excretion in urine. This activity did not differ from furosemide efficacy 10 mg/kg/. There was no
influence on calcium ion excretion, both in hydroxycinnamic acid and furosemide groups.
The flavonoid fraction (100 mg/kg) did not elevate urine volume or ion secretion. The significant
increase of urine volume and saluretic activity for sodium and potassium ions was demonstrated for
the saponin fraction (25 mg/kg – 100 mg/kg). These effects were comparable to those of furosemide
(10 mg/kg
per os
) (Kaspers
et al
. 1998).
Active flavonoides of
Solidago virgaurea
(especially quercetin) inhibit NEP and angiotensin-
converting enzyme (ACE) activity (Schilcher and Rau 1988; Melzig
et al
. 2001a; Melzig and Major
2000; Table 9, Major 2001
http://edoc.hu-berlin.de/dissertationen/major-hedd
a
).
Table 9. Influence of the methanol extracts of
Solidago virgaurea
and their fractions on activity of
neutral endopeptidase (NEP) (Major 2001,
http://edoc.hu-berlin.de/dissertationen/major-hedd
a
)
Tested compounds
Concentration
μg/ml
NEP
Inhibition
%
Saponin mixture
200
100
-
-
Flavonoids and phenolic acids
200
100
26
26
Flavonoids mixture with rutin
750
500
200
28
17
-
Solidago virgaurea
extract (80%MeOH)
750
500
38
29
Solidago virgaurea
extract (96%MeOH)
750
500
41
33
The mechanism of beneficial renal and cardiovascular activity of
Solidago virgaurea
can depend on
modulation of neutral endopeptidase activity (NEP). By blocking the hydrolysis of the vasoactive
peptides, Solidago treatment can regulate water and sodium balance and cardiovascular homeostasis
by increasing water and sodium excretion and arterial and venous vasodilatation (Melzig and Major
2000).
EMEA 2008
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II.3.2 Assessor’s overall conclusions on pharmacology
Non-clinical data show diuretic, anti-inflammatory, antioxidant, analgesic and spasmolytic,
antibacterial, antifungal, anticancer and immunomodulatory activity of
Solidago virgaurea
. However,
as no single ingredient is responsible for these effects, the whole herbal preparation of
Solidago
inflorescences must be considered as the active ingredient.
II.3.3 Pharmacokinetics
A selection of several herbal medicinal products was analysed for their modulatory influence on
expression of cytochrome P-450 enzymes CYP1A2, CYP3A4 and the transporter protein MDR1. The
experiments were performed
in vitro
on cultures of LS180 cells. The
Solidago virgaurea
product
Solidanin
®
(Bioforce, Roggwill, Switzerland) was resolved in DMSO and then diluted to final
concentration of 100 μg/ml. Solidanin
®
solution did not influence CYP1A2 and MDR1 expression,
however it induced 1.9±0.2 fold CYP3A4 genes. The activation of the nuclear receptor PXR is
believed to be responsible for modulation CYP3A4 expression (Brandin
et al
. 2007).
II.3.3.1 Assessor’s overall conclusions on pharmacokinetics
There are no specific data on pharmacokinetics of
Solidago virgaurea
. However, some interactions are
possible due to influence on CYP3A4 genes expression.
II.3.4 Toxicology
II.3.4.1 Cytotoxicity
Constituents of the aerial parts of the plant
Solidago virgaurea var. gigantea
used as stomachic and
diuretic in Korea were identified by chemical and spectroscopic methods. Six terpenoids and four
phenolics were isolated from the hexane-soluble fraction of the total MeOH extract. Compounds:
ent
-
germacra-4(15),5,10,(14)-trien-1β-ol, β-dictyopterol and 3,5-di-
O-
caffeoylquinic acid showed
in vitro
cytotoxicity against cultured lines of human tumour cells (A549-non small cell lung adenocarcinoma,
SK-OV-3-ovarian, SK-MEL-2 – skin melanoma, XF498 – CNS and HCT15 –colon. The ED
50
values
ranged from 1.52-18.57 μg/ml (Table 10, Choi
et al
. 2004).
Table 10. Cytotoxic effects of
Solidago virgaurea
constituents (Choi
et al
. 2004).
EC
50
values (concentration (μM) that caused 50% inhibition of cell growth
in vitro
.
Compound
A549
SK-OV-3
SK-MEL-2 XF498 HCT15
ent
-germacra-4(15),5,10,(14)-trien-
1β-ol
14.21
17.06
12.30
14.34
14.17
β-dictyopterol
18.57
17.97
5.91
1.52
9.11
3,5-di-
O-
caffeoylquinic acid
>30
>30.0
>30.0
>30.0
>30.0
EMEA 2008
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Other investigations on the constituents
Solidago virgaurea var. gigantea
revealed isolation of three
cytotoxic compounds: erythrodiol-3-acetate, α-tocopherol-quinone and trans-phytol from the hexane
soluble fraction (Sung
et al
. 1999).
II.3.4.2 Acute Toxicity
No data available. Acute toxicity of the leiocarposide in rats was reported: LD
50
(oral) as 1.55 g/kg
b.w. (Chodera 1985a).
II.3.4.3 Repeated dose toxicity
No data available.
II.3.4.4 Genotoxicity, Carcinogenicity
No information on genotoxicity and carcinogenicity is available.
II.3.4.5 Reproduction Toxicity
No data are available on reproductive or developmental toxicity.
II.3.4.5 Assessor’s overall conclusions on toxicology
No relevant data are available on toxicology of
Solidago virgaurea
except of acute toxicity of
leiocarposide. Because of the lack of data concerning mutagenicity and genotoxicity, the inclusion of
Solidago virgaurea
L. to the Community List cannot be considered.
II.4
CLINICAL STUDIES
II.4.1
Clinical Pharmacology
II. 4. 1. 1
Clinical studies with
Solidago virgaurea
products (Table 11)
In an open post marketing crossover study with placebo in 22 healthy patients (age 17 – 61 years), an
ethanolic extract made from fresh plant
Solidago virgaurea
L. was tested. The patients received 100
(5x20) drops/day of the ethanolic extract (64 % V/V, Goldruten Tropfen
®
) for 2 days. In Solidago
treated groups the significant increase of daily volume of urine (27%) was observed (p<0.01)
(Klinisch-Experimentelle Studie Nr 23223. P 1. 1992).
In an open multicentre postmarketing study the ethanolic extract of
Solidago virgaurea
L. made from
fresh plant (64 Vol%, Goldruten Tropfen
®
) was tested in 53 patients (45 female, 8 male, age: 6 – 83
years) with symptoms of urinary tract inflammation: dysuria, pollakisuria, tenesmus. The treatments
lasted 1 year, but time of the treatment of individual patient differed, depending on the physician´s
decision. The patients with renal stones, renal carcinoma, gonorrhoea, syphilis, AIDS and marked
prostate hyperplasia were excluded, as patients with bacterial counts in urine over 10
4
. Adult patients
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received 100 drops (5x20) of Solidago extract. Patients younger than 12 years received 55 drops/day.
After treatment in 65.4% treated patients the significant clinical improvement was observed with
significant reduction of dysuria, pollakisuria and tenesmus (Klinisch-Experimentelle Studie Nr.
23223.P2. 1992).
The efficacy of the dry extract of
Solidago virgaurea
(5.4:1, Stromic
®
) was tested in an open
multicentre study performed by 289 physicians in 745 female patients (age: 12-94 years) with dysuria
of different origin. After 14 days of treatment with Solidago extract (three times 380 mg/day) in 69.2%
patients micturition frequency was decreased as the other symptoms of cystitis (Schmitt 1996).
In the postmarketing study performed on 1487 patients with several urinary tract diseases (irritable
bladder, urinary tract infections, renal calculi/gravel) the efficacy of an extract from
Solidago
virgaurea
(5.0-7.1:1, ethanol 30% m/m) was estimated. Patients were treated in average for 4 weeks
(Cystinol Long
Kapseln
®
, 3x424.8 mg/day). Global improvement (in CGI scale) was evaluated by
physicians and in 79% of patients reached significance (Laszig
et al
. 1999).
In an open multicentre (308 physicians) study performed on 1487 patients with chronic recurrent
irritable bladder condition the subgroup of 512 patients (age: 13 – 96 years, 77% female) was treated
for five weeks. The patients received
Solidago virgaurea
L. dry extract (5.0-7.1:1, 424.8 mg, 3x/day).
In result, 96% of the patients treated showed improvement registered in CGI scale, and in 80.1% of
patient´s estimation of effectiveness was good or very good. Side effects were not registered (Melzig
et al
. 2001b; Pfannkuch and Stammwitz 2002).
The case report of patients treated with
Solidago virgaurea
dry extract for 4 weeks after extracorporeal
shock wave lithotripsy resulted with spasmolytic effects, and lack of additional spasmolytic treatment
needed (Laszig
et al
. 1999).
II.4.1.2 Clinical studies with composition products
An open outpatient study was performed in 20 patients with renal calculi/gravel (age: 7 – 60 years) to
test therapeutical efficacy of phytomedicine Fitolizyna
®
(Solidago extract as one of the components)
for 2 weeks – 3 months (1 teaspoon of paste, three times daily). Significant diuretic effect was noted in
all tested patients with very good tolerance of treatment (Krzeski 1960).
In patients with different subtypes of rheumatic diseases the anti-inflammatory and analgesic efficacy
of the fixed combination of
Populus tremula
,
Solidago virgaurea
and
Fraxinus excelsior
(Phytodolor
®
) have shown a similar efficacy compared to NSAID treatment (Chrubasik and Pollak
2003; Ernst 2004; Jorken and Okpanyi 1996; Klein-Galczinsky 1999)
However, the relevant participation of
Solidago virgaurea
in clinical efficacy of composition products
is not known.
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Table 11. Presentation of the non–randomized open clinical studies with
Solidago virgaurea
products.
Reference
Quality of the
study
Indication
Baseline
conditions
Preparation
Daily dose
Mode of administration
Duration of treatment
Patients
Number (N)
Age
Statistics
Adverse
events
Toxicity
Final results
Efficacy
Comment
Klinisch-
Experimentell
e Studie Nr
23223.P 1.
1992
Open,
postmarketing,
crossover,
non-randomized
with placebo group
Healthy volunteers
Test phase:
Goldruten Tropfen
®
ethanolic extract of
Solidago virgaureae
fresh (64 Vol%).
N = 22
Student t-
Test
No data
Increased urine
volume during
treatment of
Goldruten
Tropfen
●
compared to
placebo effects
(1.3 dl – 27%),
p<0.01
Significant
diuretic
activity in
healthy
volunteers
Age: 17 – 61
years
Good
tolerance of
treatment.
Male: 8
Female: 14
Daily dose
:
20 drops x 5/day
Duration
: 2 days
Time between
20.00
h
p.m. and
1-st miction
episode related
do urine volume
was significantly
shortened
compared to
placebo effects
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Reference
Quality of the
study
Indication
Baseline
conditions
Preparation
Daily dose
Mode of administration
Duration of treatment
Patients
Number (N)
Age
Statistics
Adverse
events
Toxicity
Final results
Efficacy
Comment
Klinisch-
Experimentell
e Studie Nr
23223.P 2.
1992
Open, prospective,
multicenter study
(16 physicians),
postmarketing,
non-randomized
with placebo group
Inclusion criteria
:
Inflammation of
urinary tract.
Symptoms:
dysuria,
pollakisuria,
tenesmus,
gorączka,
bacteriuria.
Goldruten Tropfen
®
ethanolic extract of
Solidago virgaureae
fresh (64 Vol%)
N = 53
No
statistical
data.
Mild side
effects in
2% of
patients.
Gastro-
esophageal
reflux
symptoms.
Clinically
relevant
improvement
according to the
opinion of
physicians
reduction of:
dysuria in 86.0%,
pollakisuria in
86.4%,
tenesmus in
72.7%
was found in
75.5% of
patients:
(in 64.2% good,
and in 11.3%
moderate efects).
Significant
diuretic and
antiin-
flammatory
activity in
patients
with
inflammati
on of
urinary
tract.
8 patients
excluded from
trial
For
calculations
SAS
(Statistical
Analysis
System)
Datasets,
Version
6.04) was
used.
Daily dose
:
20 drops x 5/day
Age:
6 – 83
(45.5 ± 20.1)
Years
Duration
: 1 year
General
good
tolerance of
treatment
Exclusion
criteria:
Bladder stones,
bladder carcinoma,
gonorrhea,
syphilis, marked
prostate
hyperplasia,
bacteriuria 10
4
Children <12
years: 3
Male: 8
Female: 45
Significant
reduction of
ascending
infections of
urinary tract in
90.0% of
patients.
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Reference
Quality of the
study
Indication
Baseline
conditions
Preparation
Daily dose
Mode of administration
Duration of treatment
Patients
Number (N)
Age
Statistics
Adverse
events
Toxicity
Final results
Efficacy
Comment
Schmitt
1996
Open, prospective,
multicenter study
(289 physicians),
postmarketing,
non-randomized
Dysuria of
different origin:
hyperactive
bladder with urine
incontinence
Stromic
®
(dry extract
of
Solidago virgaurea
,
5.4:1)
N = 745
No data
In 12
patients
(0.3%) side
effects
were noted:
gastrointe
stinal
disorders
and allergic
reactions.
After 14 days of
treatment in
69.2% of patients
micturition
frequency was
significantly
decreased.
Successful
reduction
of
symptoms
of irritable
bladder.
Age:
12 – 94 years
Mean: 47
years
Daily dose
:
380 mg x 3/day
Inclusion criteria:
pollakisuria:
>5x/day
Female : 745
Lack of
statistical
data.
Duration
: 14 days
According to
opinion of
physicians in
98.5% of patients
effects of
treatment were
“very good or
good”.
According to
personal opinion
of patients such
results were
observed in
97.5% of treated
persons.
Exclusion
criteria:
pollakisuria:
≤5x/day,
bacteriuria,
genital organs
infections, heart
and kidney
insufficiency,
others diuretics
use, allergy to the
Solidago spp
.
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Reference
Quality of the
study
Indication
Baseline
conditions
Preparation
Daily dose
Mode of administration
Duration of treatment
Patients
Number (N)
Age
Statistics
Adverse
events
Toxicity
Final results
Efficacy
Comment
Laszig
et al
.
1999
Open, prospective,
postmarketing,
multicenter study
(289 physicians),
postmarketing,
non-randomized
Cystinol Long Kapseln
®
(dry extract, 5.0-7.1 : 1,
ethanol 30% m/m)
N = 1487
No data
No data
1 group
Improvement was
noted in 71% of
patients.
Significant
therapeutic
efficacy in
infections
of urinary
tract,
irritable
bladder and
in
urolithiasis.
Subgroups:
1 group
N = 555
1 group:
Infections of
urinary tract
Daily dose
:
424.8 mg x 3/day
2 group
N = 512
2 group
Improvement was
observed in 71%
of patients.
2 group:
Irritable bladder
Duration
: 4 weeks
CGI arbitrary scale
3 group
N = 427
3 group:
Urolithiasis
Renal calculi,
Renal and bladder
gravel
3 group
Significant
improvement was
observed after 4
weeks of
treatment in 79%
of treated patients
(evaluation by
physicians by use
of CGI scale)
In 99% of patient
opinion results
were estimated as
good/very good.
Age:
mean =
54 years
Lack of
statistical
data.
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Reference
Quality of the
study
Indication
Baseline
conditions
Preparation
Daily dose
Mode of administration
Duration of treatment
Patients
Number (N)
Age
Statistics
Adverse
events
Toxicity
Final results
Efficacy
Comment
Pfannkuch
and
Stammwitz
2002
Open, prospective,
postmarketing,
multicenter study.
Subgroups:
Cystinol Long Kapseln
®
(dry extract, 5.0-7.1 : 1,
ethanol 30% m/m)
N = 1487
Wilcoxon-
Test
Side
effects
observed in
0.07% of
patients.
In result of 5
weeks therapy
96% of the 512
patients treated
showed
improvement
after 35 days,
registered in CGI
scale
(p<0.0001).
Successful
reduction
of
symptoms
of irritable
bladder.
Urolithiasis
renal calculi, renal
and bladder gravel,
irritable bladder.
infections of
urinary tract.
Female : 77%
(308 physicians),
non-randomized
Daily dose
:
424.8 mg three times/day
1 group
(Active)
N = 512
Female
N = 463
Male
N = 49
General
good
tolerance of
treatment.
CGI arbitrary scale
Used by physicians
and patients
Duration
: 5 weeks
Descriptive
statistics
included.
1 group:
Irritable bladder
with urine
incontinence
95% of patients
estimated results
as ” very good”.
2 group
2 group:
Urolithiasis
renal calculi, renal
and bladder gravel,
3 group
N = 427
Age:
13 – 96 years
3 group
Infections of
urinary tract
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II.4.2.1
Clinical studies in special populations (e.g. elderly and children)
No relevant data available.
No special studies for children and elderly were performed. The number of
children included into studies is to small for further assessment. Products containing
Solidago
virgaurea
L. cannot be recommended for use in children below the age of 12 years.
II.4.2.2
Assessor’s overall conclusions on clinical efficacy
Solidago virgaurea
products were used in 5 non-controlled, non-randomized open trials. The number
of participants varied between the trials from 22 to 1487.
On the basis of published results of these
clinical trials, the quality of the available studies cannot be evaluated. The protocols with sample
calculation are missing. Statistical methods are not shown in all protocols, characteristics of the
patients are incomplete, in most trials inclusion and exclusion criteria are not given and no
comparators (control groups) included. There is no information about dropping out cases. No specific
questionnaires on the quality of life are given. The relevance of non-clinical studies has not been
confirmed by clinical trials.
Overall, in the presence of missing information, assessing and interpreting treatment effects of
Solidago virgaurea
can be limited only to traditional use.
II.4.3 Adverse events
Hypersensitivity reactions and mild gastrointestinal disorders (in 0.07%-0.3% patients tested) were the
only adverse reactions registered in connection with
Solidago virgaurea
L. intake.
Patients suffering from allergic contact dermatitis due to
Compositae
species are requested to avoid
contacts with
Solidago virgaurea
(De Jong
et al
. 1998; Lundh
et al
. 2006; Myers and Wohlmuth 2005;
Schätzle
et al
. 1998, Stingeni
et al
. 1999, Zeller
et al
. 1985).
II.4.4 Interactions
No data available.
II.4.5 Assessor’s overall conclusions on clinical safety
No case reports on adverse reactions or other signals of safety concern in connection with
Solidago
virgaurea
L., inflorescences were identified, except in patients allergic to
Compositae
species. As
there is no information on reproductive and developmental toxicity the use during pregnancy and
lactation cannot be recommended.
II.4.6 Use in pregnancy and lactation
No data available.
II.4.7
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No data available.
II.4.8 Effects on ability to drive or operate machinery
No data available.
II.4.9 Contraindications
Known hypersensitivity or allergy to
Compositae
(
Asteraceae
) or
Solidago
spp
.
II.4.10 Overall conclusions on safety
As there is no information on reproductive and developmental toxicity the use during pregnancy and
lactation cannot be recommended.
The traditional medicinal use of
Solidago virgaurea
L. has been documented within the Community.
No specific clinical data of
Solidago virgaurea
L. adverse effects have been identified under normal
conditions of use. Two post-marketing studies demonstrated good tolerability in 97 – 98% of patients
(N=745 and 1487) treated for 2-4 weeks. Only one case of a minor adverse effect was noted
(heartburn) (Schmitt 1996; Laszig
et al
. 1999).
As no data on use in children are available, products containing
Solidago virgaurea
L. cannot be
recommended for use in children below the age of 12 years.
II.5
ASSESSOR’S OVERALL CONCLUSIONS
The traditional use of
Solidago virgaurea
L. is well documented. However, because of absence
of sufficient clinical data, the quality of the available studies cannot be evaluated. The results of
clinical trials cannot support a well-established indication of use.
Several non-clinical experiments indicate on diuretic, spasmolytic, anti-inflammatory, analgesic
and antibacterial effects of the
Solidago virgaurea
. However, the relevance of non-clinical
studies has not been confirmed by clinical trials.
Although this phytotherapeutic treatment in urinary tract diseases is extremely popular, there is
no detailed reasonable scientific explanation on effects and the exact mechanism of diuretic
action.
No isolated compound which has been isolated from
Solidago virgaurea
is recognized as
responsible for its diuretic action, thus the complex mixture of constituents contributed to this
effect.
Indication of an increase of volume of urine, especially in cases of inflammation and renal
calculi/gravel is well documented, both in monographs and textbooks, as in data regarding
longstanding use.
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The therapeutic dose is 3.0-5.0 g dried herbal substance for preparation of an infusion,
equivalent to 0.5-2.0 ml of liquid extract or to 0.5-2.0 ml of tincture, 2-4 times daily.
There is almost no information on the toxicity, genotoxicity, carcinogenicity and reproductive
and developmental toxicology. Therefore the use in pregnancy and lactation is not
recommended.
The use in children under 12 years of age is not recommended, as no data are available on safety
of treatment.
Products containing
Solidago virgaurea
L. are available in many Member States of the EU.
Thus, the requirement of medicinal use for at least 30 years (15 years within the Community),
Directive 2004/24/EC is fulfilled.
Because of lack of data concerning mutagenicity, the inclusion of
Solidago virgaurea
L., herba
to the Community list of herbal substances, preparations and combinations thereof for use in
traditional herbal medicinal products cannot be considered.
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Source: European Medicines Agency
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