COMMUNITY HERBAL MONOGRAPH ON
ECHINACEA PALLIDA
(NUTT.) NUTT.,
RADIX
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
Echinacea pallida
(Nutt.) Nutt., radix, (pale
coneflower root)
i)
Herbal substance
Not applicable.
ii)
Herbal preparations
- dry extract (4-8:1), extraction solvent: ethanol
50% (v/v)
- tincture (1:5), extraction solvent: ethanol
50% (v/v)
Well-established use
Traditional use
Herbal preparations in solid or liquid dosage
forms for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the European Pharmacopoeia monograph (ref.: 01/2008:1822)
2
The declaration of the active substance(s) for an individual finished product should be in accordance with
relevant herbal quality guidance.
EMEA 2009
2/6
4.1.
Therapeutic indications
Well-established use
Traditional use
Traditional herbal medicinal product for
supportive treatment of common cold.
The product is a traditional herbal medicinal
product for use in the specified indication
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adolescents, adults, elderly
1) 3 times daily 1 tablet containing 30 mg dry
extract (4-8:1)
2) 4 times daily 2 tablets containing 12 mg dry
extract (4-8:1)
3) 5 times daily 25 drops containing 100%
tincture (1:5)
The use in children under 12 years of age is
contraindicated
(see
section
4.3.
‘Contraindications’).
Duration of use
The therapy should start at first signs of common
cold.
If the symptoms persist longer than 10 days
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Oral use.
EMEA 2009
3/6
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance or to
plants of the Asteraceae (Compositae) family.
Echinacea
must not be used in cases of
progressive systemic diseases such as:
tuberculosis, diseases of the white blood cells
system, collagenoses, multiple sclerosis, AIDS,
HIV infections, and other immune diseases.
Children under 12 years of age.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
If the symptoms worsen or high fever occurs
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
There is a possible risk of allergic reactions in
sensitive individuals. Those patients should
consult their doctor before using
Echinacea
.
There is a possible risk of anaphylactic reactions
in atopic patients. Atopic patients should consult
their doctor before using
Echinacea
.
For tinctures 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
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
EMEA 2009
4/6
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effects on the ability to drive
and use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
Hypersensitive reactions (skin reactions). 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.
EMEA 2009
5/6
Well-established use
Traditional use
Not applicable.
16 July 2009
EMEA 2009
6/6
Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW
........................................................................................ 4
II.
ASSESSMENT REPORT
................................................................................................................. 6
II.1
I
NTRODUCTION
II.1.1
............................................................................................................................... 7
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
...... 7
II.1.1.1
Herbal substance(s):
......................................................................................................... 7
II.1.1.2
Herbal preparation(s)
3
II.1.1.3
Combinations of herbal substance(s) and/or herbal preparation(s)
................................. 7
II.1.1.4
Vitamin(s)
.......................................................................................................................... 7
II.1.1.5
Mineral(s)
5
Information on period of medicinal use in the Community regarding the specified
indication
II.1.2.1
............................................................................................................................................... 8
Specified products on the market in the European Union Member States
........................ 8
II.1.2.2
Specified strength/posology/route of administration of use for relevant preparations and
indications
II.1.2.3
9
Bibliographic/expert evidence on the medicinal use
II.1.2.3.1
....................................................... 10
Evidence regarding the indication/traditional use
.................................................... 10
II.1.2.3.2
Evidence regarding the specified posology
.............................................................. 11
II.2
II.2.1
.................................................................................................................. 11
Pharmacology
..................................................................................................................... 11
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
II.2.1.1.1
............................................................................................................... 11
Immunomodulatory activity
..................................................................................... 11
II.2.1.1.2
Antimicrobial activity
............................................................................................... 12
II.2.1.1.3
Antiviral activity
....................................................................................................... 13
II.2.1.1.4
Anti-inflammatory activity
....................................................................................... 13
II.2.1.1.5
Antioxidant activity
.................................................................................................. 14
II.2.1.1.6
Other activities
......................................................................................................... 15
II.2.1.2
Assessor’s overall conclusions on pharmacology
........................................................... 16
II.2.2
Pharmacokinetics
................................................................................................................ 16
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
II.2.2.2
............................................................................................................... 16
Assessor’s overall conclusions on pharmacokinetics
...................................................... 16
II.2.3
Toxicology
........................................................................................................................... 17
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
II.2.3.2
.............................................................................................................................. 17
Assessor’s overall conclusions on toxicology
................................................................. 17
II.3
........................................................................................................................... 17
Clinical Pharmacology
........................................................................................................ 17
II.3.1.1
Pharmacodynamics
II.3.1.1.1
......................................................................................................... 17
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
II.3.1.1.2
................................................. 17
Assessor’s overall conclusions on Pharmacodynamics
............................................ 17
II.3.1.2
Pharmacokinetics
II.3.1.2.1
............................................................................................................ 17
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
II.3.1.2.2
................................................. 17
Assessor’s overall conclusions on pharmacokinetics
............................................... 17
II.3.2
Clinical Efficacy
.................................................................................................................. 17
II.3.2.1
Dose response studies
...................................................................................................... 17
II.3.2.2
Clinical studies (case studies and clinical trials)
............................................................ 18
EMEA 2009
2/21
II.1.2
II.2.1.1
II.2.2.1
II.2.3.1
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
................................. 18
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
......................................................... 19
II.3.3
Clinical Safety/Pharmacovigilance
..................................................................................... 19
II.3.3.1
Patient exposure
.............................................................................................................. 19
II.3.3.2
Adverse events
................................................................................................................. 19
II.3.3.3
Serious adverse events and deaths
.................................................................................. 19
II.3.3.4
Laboratory findings
......................................................................................................... 19
II.3.3.5
Safety in special populations and situations
II.3.3.5.1
.................................................................... 19
Intrinsic (including elderly and children) /extrinsic factors
..................................... 19
II.3.3.5.2
Drug interactions
...................................................................................................... 20
II.3.3.5.3
Use in pregnancy and lactation
................................................................................. 20
II.3.3.5.4
Overdose
................................................................................................................... 20
II.3.3.5.5
Drug abuse
................................................................................................................ 20
II.3.3.5.6
Withdrawal and rebound
.......................................................................................... 20
II.3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
... 20
II.3.3.6
Assessor’s overall conclusions on clinical safety
............................................................ 20
II.4
......................................................................................... 21
ANNEXES
III.1
....................................................................................................................................... 21
................ 21
III.2
........................................................................................................... 21
EMEA 2009
3/21
III.
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:
No answer.
Belgium
MA
TRAD
Other TRAD
Other Specify:
No products.
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
No products.
Cyprus
MA
TRAD
Other TRAD
Other Specify:
No answer.
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
No products.
Denmark
MA
TRAD
Other TRAD
Other Specify:
No products.
Estonia
MA
TRAD
Other TRAD
Other Specify:
Food supplements.
Finland
MA
TRAD
Other TRAD
Other Specify:
Comb. product (1).
France
MA
TRAD
Other TRAD
Other Specify:
No products.
Germany
MA
TRAD
Other TRAD
Other Specify:
Also comb. prod. (1).
Greece
MA
TRAD
Other TRAD
Other Specify:
No answer.
Hungary
MA
TRAD
Other TRAD
Other Specify:
Also comb. prod. (4).
Iceland
MA
TRAD
Other TRAD
Other Specify:
No products.
Ireland
MA
TRAD
Other TRAD
Other Specify:
No products.
Italy
MA
TRAD
Other TRAD
Other Specify:
No products.
Latvia
MA
TRAD
Other TRAD
Other Specify:
No products.
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
No answer.
Lithuania
MA
TRAD
Other TRAD
Other Specify:
No answer.
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
No answer.
Malta
MA
TRAD
Other TRAD
Other Specify:
No answer.
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
No products.
Norway
MA
TRAD
Other TRAD
Other Specify:
No products.
Poland
MA
TRAD
Other TRAD
Other Specify:
No answer.
Portugal
MA
TRAD
Other TRAD
Other Specify:
No products.
Romania
MA
TRAD
Other TRAD
Other Specify:
No products.
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
No products.
Slovenia
MA
TRAD
Other TRAD
Other Specify:
No products.
Spain
MA
TRAD
Other TRAD
Other Specify:
No products.
Sweden
MA
TRAD
Other TRAD
Other Specify:
Comb. products.
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
4/21
Member State
Regulatory Status
Comments
2
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
No answer.
EMEA 2009
5/21
II.
ASSESSMENT REPORT
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)
Cut, dried underground parts of
Echinacea pallida
(Nutt.) Nutt.
Herbal preparation(s)
- dry extract (4-8:1; ethanol 50% (v/v))
- tincture (1:5; ethanol 50% (v/v))
Pharmaceutical forms
Herbal preparations in solid or liquid dosage
forms for oral use.
Rapporteur
Damjan Janeš
EMEA 2009
6/21
II.1
I
NTRODUCTION
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Because of confusion regarding the identification of
Echinacea
species, much of the early research
conducted particularly on European
Echinacea angustifolia
was probably conducted on
Echinacea pallida
(Bauer
et al.
1988a).
Echinaceae pallidae radix
(Ph. Eur.)
Echinaceae pallidae radix consists of the whole or cut, dried underground parts of
Echinacea pallida
(Nutt.) Nutt. It contains not less than 0.2% of echinacoside in the dried drug.
Constituents
(Barnes
et al.
2005, Barnes
et al.
2007, Bauer & Remiger 1989, Bradley 2006, ESCOP
2003, Liersch & Bauer 1993, WHO 1999, Willuhn 2002, Wolters Kluwer Health 2004):
Alkamides: mainly absent (0.001%).
Phenylpropanoids: caffeic acid glycosides (echinacoside as the major component, 0.5-1.0%),
caffeic acid esters of quinic acid (chlorogenic acid, isochlorogenic acid, cynarin), caffeic acid
glycosides of tartaric acid (caftaric acid, cichoric acid).
Polysaccharides and glycoproteins.
Volatile oils (0.2-2.0%): mainly polyenes and polyacetylenes (pentadeca-1,8
Z
-diene), ketoalkenes
(pentadeca-8
Z
-en-2-one) and ketoalkenynes (pentadeca-8
Z
,13
Z
-diene-11-yne-2-one, tetradeca-8
Z
-
ene-11,13-diyne-2-one). These alkenes are unstable and readily oxidise to 8-hydroxy derivatives.
Other constituents: phytomelanin.
II.1.1.2
Herbal preparation(s):
A)
Dry extract (4-8:1), extraction solvent: ethanol 50% (v/v).
B)
Tincture (1:5), extraction solvent: ethanol 50% (v/v).
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)
4
According to the ‘Guideline on the clinical assessment of fixed combinations of herbal substances/herbal
preparations’ (EMEA/HMPC/166326/2005)
5
Only applicable to traditional use
EMEA 2009
7/21
Caffeic ac id derivatives
with tartaric ac id
Polyenes, ketoalkenes and ketoalkenynes
cichoric acid
caftaric acid
pentadeca-1,8Z-diene
O
with q uinic a c id
c ynarine
pentadeca-8Z-en-2-one
O
with sugar
pentadeca-8Z,13Z-diene-11-yne-2one
ec hinac oside
O
tetradeca-8Z-ene-11,13-diyne-2-one
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
II.1.2.1
Specified products on the market in the European Union Member States
Dry extracts
Germany:
Preparations
:
1) dry extract (5-7:1), extraction solvent: methanol 30% (v/v)
2, 3) dry extract (4-8:1), extraction solvent: ethanol 50% (v/v)
Preparation are on the market
:
1) since 1997
2, 3) at least since 1976
coated tablet
2)
lozenge
EMEA 2009
8/21
3)
tablet
Liquid extracts
Germany
Preparations
:
1) tincture (1:5), extraction solvent: ethanol 50% (v/v)
Preparation are on the market
:
1) at least since 1976
Hungary
Preparations
:
1) liquid extract (1:6.3-7.0), solvent: ethanol 96% (v/v): wine 16% (v/v), (1:1,5)
Preparation are on the market
:
1) since 2002
II.1.2.2
Specified strength/posology/route of administration of use for relevant preparations and
indications
Dry extracts
All for oral use and all for use in adults and adolescents over 12 years.
1) dry extract (5-7:1), extraction solvent: methanol 30% (v/v): 3 x daily 1 coated tablet containing 100 mg
dry extract
2) dry extract (4-8:1), extraction solvent: ethanol 50% (v/v): 3 x daily 1 tablet containing 30 mg dry
extract or 4 x daily 2 tablets containing 12 mg dry extract
Indications
:
1, 2) Herbal medicinal product for the supportive treatment of common cold.
Risks
:
1, 2) Hypersensitive reactions (rash, urticaria, angioedema of the skin, bronchospasm with obstruction and
anaphylactic reactions) may occur.
A list of the same adverse drug effects as in the draft monograph of E. purpurea herba is proposed:
Hypersensitive reactions (rash, urticaria, Stevens-Johnson Syndrome, angioedema of the skin, Quincke
edema, bronchospasm with obstruction, asthma and anaphylactic shock) may occur.
Echinacea
can trigger allergic reactions in atopic patients. Association with autoimmune diseases
(encephalitis disseminata, erythema nodosum, immunothrombocytopenia, Evans Syndrome, Sjögren
syndrome with renal tubular dysfunction) has been reported.
EMEA 2009
9/21
Liquid extracts
1) Tincture (1:5), extraction solvent: ethanol 50% (v/v): 5 x daily 25 drops containing 100% liquid extract
Indications
:
1) Herbal medicinal product for the supportive treatment of common cold.
Risks
:
1) Hypersensitive reactions (rash, urticaria, angioedema of the skin, bronchospasm with obstruction and
anaphylactic reactions) may occur.
A list of the same adverse drug effects as in the draft monograph of E. purpurea herba is proposed:
Hypersensitive reactions (rash, urticaria, Stevens-Johnson Syndrome, angioedema of the skin, Quincke
edema, bronchospasm with obstruction, asthma and anaphylactic shock) may occur.
Echinacea
can trigger allergic reactions in atopic patients. Association with autoimmune diseases
(encephalitis disseminata, erythema nodosum, immunothrombocytopenia, Evans Syndrome, Sjögren
syndrome with renal tubular dysfunction) has been reported.
2) Liquid extract (1:6.3-7.0), solvent: ethanol 96% (v/v): wine 16% (v/v), (1:1,5): Prevention: 3 x 20 drops
daily. Treatment: 3 x 50 drops daily
Indications
:
2) To increase the resistance of the body to prevent of recurrent infections of upper respiratory tract
(common cold) and adjuvant therapy of them.
Risks
:
2) Very rarely hypersensitivity reactions, e.g. cutaneous eruption, pruritus, oedema of the face, dyspnoea,
dizziness, and blood pressure drop. It is not recommended for pregnant women and during lactation,
children below 6 years of age.
CI: hypersensitivity, progressive systemic disease (e.g. tuberculosis, multiple sclerosis, leukosis,
collagenosis, AIDS, HIV infection, and other auto-immune disorders.)
Duration: Not more than 8 weeks. If the symptoms persist for more than 4-5 days or adverse effects occur,
stop taking the preparation and see your physician.
II.1.2.3
Bibliographic/expert evidence on the medicinal use
II.1.2.3.1
Evidence regarding the indication/traditional use
Traditional indications for oral use of liquid extracts
Indication
References
Adjuvant therapy and prophylaxis of
recurrent infections of the upper
respiratory tract (common cold).
ESCOP 2003, Bräunig & Knick 1993, WHO 1999, Willuhn
2002
EMEA 2009
10/21
II.1.2.3.2
Evidence regarding the specified posology
Oral administration
Herbal preparations:
Liquid extract: 0.25-1.0 ml (1:1 in 45% ethanol) three times daily.
Tincture: 0.5-1.0 ml (1:5 in 45% ethanol) or 2-5 ml (1:5 in 45% ethanol) three times daily. (Barnes
et al.
2007, ESCOP 2003).
The duration of treatement should not exceed eight weeks (Barnes
et al.
2007, ESCOP 2003, German
Commission E Monographs 1999).
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
Immunomodulatory activity
Alcohol extracts from roots of three widely used
Echinacea
species,
Echinacea angustifolia
,
Echinacea
pallida
, and
Echinacea purpurea
, were investigated for immunomodulating properties. The three
Echinacea
species demonstrated a broad difference in concentrations of individual lipophilic amides and
hydrophilic caffeic acid derivatives. Mice were gavaged once a day (for 7 days) with one of the
Echinacea
extracts (130 mg/kg) or vehicle and immunized with sheep red blood cells (sRBC) 4 days prior to
collection of immune cells for multiple immunological assays. The three herb extracts induced similar, but
differential, changes in the percentage of immune cell populations and their biological functions, including
increased percentages of CD49
+
and CD19
+
lymphocytes in spleen and natural killer cell cytotoxicity.
Antibody response to sRBC was significantly increased equally by extracts of all three
Echinacea
species.
Concanavalin A-stimulated splenocytes from
E. angustifolia
- and
E. pallida
-treated mice demonstrated
significantly higher T-cell proliferation. In addition, the
Echinacea
treatment significantly altered the
cytokine production by mitogen-stimulated splenic cells. The three herbal extracts significantly increased
interferon (IFN)-alpha production, but inhibited the release of tumor necrosis factor (TNF)-gamma and
interleukin (IL)-1beta. Only
E. angustifolia
- and
E. pallida
-treated mice demonstrated significantly higher
production of IL-4 and increased IL-10 production. Taken together, these findings demonstrated that
Echinacea
is a wide-spectrum immunomodulator that modulates both innate and adaptive immune
responses. In particular,
E. angustifolia
or
E. pallida
may have more anti-inflammatory potential (Zhai
et
al.
2007a).
The influences of different arabinogalactan-proteins (AGPs) on proliferation and immunoglobulin (Ig)M-
production of mouse lymphocytes as well as nitrite- and IL6-production of mouse macrophages were
investigated
in vitro
. AGPs have been isolated and purified from roots of
Baptisia tinctoria
and
Echinacea
pallida
and suspension culture of
Echinacea purpurea
. Comparing the AGPs, there are differences with
regard to fine structure as well as to activities. AGPs from roots of
B. tinctoria
and
E. pallida
show high
activity in all test systems. AGP from cell culture of
E. purpurea
shows no influence on proliferation of
mouse lymphocytes, only weak influence on the IgM-production of mouse lymphocytes and weak
stimulation of nitrite- and IL6-production in alveolar mouse macrophage culture (Classen
et al.
2006).
The effects of long-term (>1 year) dry storage on the capabilities of
Echinacea
spp. roots from mature
individuals to modulate cytokine production are unknown. Using an older human adult model of influenza
vaccination, peripheral blood mononuclear cells were collected from subjects 6 months post-vaccination
EMEA 2009
11/21
and stimulated them
in vitro
with the two Type A influenza viruses contained in the trivalent 2004-2005
vaccine with a 50% alcohol tincture prepared from the roots of one of seven
Echinacea
species:
E.
angustifolia
,
E. pallida
,
E. paradoxa
,
E. purpurea
,
E. sanguinea
,
E. simulata
, and
E. tennesseensis
. Before
being processed into extracts, all roots had been stored under dry conditions for sixteen months. Cells
were cultured for 48 hours; following incubation, supernatants were collected and assayed for IL-2, IL-10,
and INF-gamma production, cytokines important in the immune response to viral infection. Four species
(
E. angustifolia
,
E. purpurea
,
E. simulata
,
E. tennesseensis
) augmented IL-10 production, diminished IL-2
production, and had no effect on IFN-gamma production.
Echinacea pallida
suppressed production of all
cytokines;
E. paradoxa
and
E. sanguinea
behaved similarly, although to a lesser extent. The results from
these
in vitro
bioactivity assays indicate that dried
Echinacea
roots stored for sixteen months maintain
cytokine-modulating capacities. The data support and extend previous research and indicate that tinctures
from different
Echinacea
species have different patterns of immune modulation; further, they indicate that
certain species may be efficacious in the immune response to viral infection (Senchina
et al.
2006).
Chemical investigation of the roots of
Echinacea angustifolia
,
E. purpurea
, and
E. pallida
yielded two
new alkamides, identified by analysis of spectroscopic data and comparison with reported alkamides. The
new compounds were dodeca-2
Z
,4
E
,10
Z
-trien-8-ynoic acid isobutylamide from
E. angustifolia
and
dodeca-2
Z
,4
E
-diene-8,10-diynoic acid isobutylamide from
E. purpurea
and
E. pallida
. These two
components, as well as previously identified alkamides, exerted inhibition on Lipopolysaccharide (LPS)-
mediated activation of a murine macrophage line, RAW264.7. These data suggest that these alkamides
may have antiinflammatory activity (Chen
et al.
2005).
A 90% ethanolic extract (1:10) of pale coneflower root at concentration of 10
-2
m/ml enhanced the
phagocytosis index of human granulocytes by 23%; no effect was observed at concentations of 10
-6
mg/ml
or lower. The chloroform soluble fraction from the ethanolic extract increased phagocytosis by 39% at 10
-
4
mg/ml, while the water-soluble fraction stimulated phagocytosis by a maximum of only at 10
-3
mg/ml
(Bauer
et al.
1988b).
A high molecular weight fraction (M
r
> 10000 D) containing polysaccharides and glycoproteins from pale
coneflower root enhanced the proliferation of mouse spleen cells, and stimulated the production of IFN-
/ and IgM as well as the number of antibody-producing cells in spleen cell cultures. It also increased
the production of cytokines and nitric oxide in mouse macrophage cultures (Beuscher
et al.
1995, Bodinet
1999). Incubation of this fraction with human monocytes enhanced the production of IL-1, IL-6 and TNF
(Bodinet 1999).
In the carbon clearence test in mice, oral administration of a 90%-ethanolic extract (1:10) of pale
coneflower root daily for 2 days at 0.5 ml/kg body weight increased phagocytosis 2.2-fold. When
chloroform and water soluble fractions of the ethanol extract were administered separately at
concentrations corresponding to their content in the original extract, the lipophilic fraction (2.6-fold
increase) proved more ative than the hydrophilic (1.3-fold increase) (Bauer
et al.
1988b).
Intravenous injection of 50, 100 or 500 l of a high molecular weight fraction (M
r
> 10000 D) containing
polysaccharides and glycoproteins from pale coneflower root significantly increased the concentration of
the cytokine IL-1 in the serum of mice (p<0.05) (Beuscher
et al.
1995). A single oral administration of
this fraction to mice at 3.7 mg per animal significantly enhanced antibody production in Peyer’s plaque
cells (Bodinet 1999).
II.2.1.1.2
Antimicrobial activity
The antibacterial activity of echinacoside (8 × 10
-3
M) against
Staphylococcus aureus
corresponds to
approx. 10 Oxford units of penicillin (Stoll
et al.
1950).
EMEA 2009
12/21
Extracts of pale coneflower root exhibited near UV-mediated phototoxic and antifungal activity, measured
by inhibition of the growth of
Candida shehata
: the activity was attributed primarily to ketoalkenes and
ketoalkynes (Binns
et al.
2000).
Antifungal activity was tested against
Cryptococcus neoformans
, two
Candida albicans
isolates (D10 and
CN1A),
Trychophyton tonsurans
,
T. mentagrophytes
,
Mycrosporum gypseum
and
Pseudallescheria
boydii
. Root extracts of eight
Echinacea
taxa, including
Echinacea pallida
var. angustifolia
and
E. pallida
var. pallida
showed antifungal activity against most of the pathogenic fungi (Merali
et al.
2003).
II.2.1.1.3
Antiviral activity
Extracts of 8 taxa of the genus
Echinacea
were found to have antiviral activity against
Herpes simplex
virus (HSV) Type I
in vitro
when exposed to visible and UV-A light.
n
-Hexane extracts of roots
containing alkenes and amides were more active in general than ethyl acetate extracts containing caffeic
acids. The most potent inhibitors of HSV were
E. pallida var. sanguinea
crude (70% ethanol)
inflorescence extract (MIC = 0.026 mg/ml), cichoric acid (MIC = 0.045 mg/ml) and
Echinacea purpurea
n-hexane root extract (MIC = 0.12 mg/ml) (Binns
et al.
2002).
A high molecular weight fraction (M
r
> 10000 D) containing polysaccharides and glycoproteins from pale
coneflower root exhibited antiviral activity against HSV type 1 in a plaque-reduction assay (Beuscher
et
al.
1995). Antiviral activity of ecinacoside against vesicular stomatitis virus in L-929 mouse cells was
demonstrated in a plaque reduction assay (Cheminat
et al.
1988).
II.2.1.1.4
Anti-inflammatory activity
Inhibition of prostaglandin E
2
(PGE
2
) production in LPS-stimulated RAW264.7 mouse macrophage cells
was assessed with an enzyme immunoassay following treatments with
Echinacea
extracts or synthesized
alkamides. Results indicated that ethanol extracts diluted in media to a concentration of 15 g/ml from
E.
angustifolia
,
E. pallida
,
E. simulata
, and
E. sanguinea
significantly inhibited PGE
2
production. In further
studies, PGE
2
production was significantly reduced by all synthesized alkamides assayed at 50 M, by
Bauer alkamide 8, Bauer alkamide 12A analogue, and Bauer alkamide 14, Chen alkamide 2, and Chen
alkamide 2 analogue at 25 M and by Bauer alkamide 14 at 10 M. Cytotoxicity did not play a role in the
noted reduction of PGE
2
production in either the
Echinacea
extracts or synthesized alkamides. High-
performance liquid chromatography analysis identified individual alkamides present at concentrations
below 2.8 M in the extracts from the six
Echinacea
species (15 g/ml crude extract). Because active
extracts contained <2.8 M of specific alkamide and the results showed that synthetic alkamides must
have a minimum concentration of 10 M to inhibit PGE
2
, it is likely that alkamides may contribute
toward the anti-inflammatory activity of
Echinacea
in a synergistic or additive manner (LaLone
et al.
007).
It has been suggested that
Echinacea
has anti-inflammatory activity
in vivo
. Nitric oxide (NO), TNF-
alpha, and IL-1beta are important mediators in the inflammatory response. The effect of alcohol extracts
from roots of
E. angustifolia
(EA),
E. pallida
(EPA) and
E. purpurea
(EP) on the production of these
inflammatory mediators in both LPS-stimulated RAW 264.7 macrophages
in vitro
and murine peritoneal
exudate cells (PECs)
in vivo
were investigated. As macrophages produce these inflammatory mediators in
response to pathogenic infection, parallel cultures of macrophages were studied for phagocytosis and
intracellular killing of
Salmonella enterica
. EPA and EP
in vitro
inhibited NO production and TNF-alpha
release in a dose-dependent manner. RAW 264.7 cells treated with EA or EP showed decreased killing
over 24 h, although EA enhanced bacterial phagocytosis. Upon bacterial infection, RAW 264.7 cells
produce high levels of NO; however, an
Echinacea
-mediated decrease in NO production was observed.
Echinacea
alcohol extracts administered orally at 130 mg/kg per day for seven days had a weak effect on
EMEA 2009
13/21
2
NO production and phagocytosis by LPS-stimulated PECs. The results indicated that all
Echinacea
species significantly decreased inflammatory mediators
in vitro
, however, only EA and EP reduced
bacterial killing. Oral administration of
Echinacea
alcohol extracts did not adversely affect the
development and anti-bacterial function of inflammatory PECs
in vivo
; however, NO production was
ecreased during bacterial infection of PECs (Zhai 2007b).
5-lipoxygenase (5-LOX)-inhibiting activity of extracts of five wild and three commercially used species of
the genus
Echinacea
were investigated to characterise anti-inflammatory activity of
Echinacea
. The
inhibition of the 5-LOX enzyme of the arachadonic acid pathway was determined by HPLC detection of a
direct metabolic product (LTB4) of 5-LOX derived from stimulated rat basophilic cells. Root extracts of
the three commercial species of
Echinacea
(
E. purpurea
p
, E. pallida var. angustifolia, E. pallida var.
allida
) inhibited the 5-LOX enzyme (Merali
et al.
2003).
The anti-inflammatory and wound healing activities of echinacoside, compared with the ones of the total
dry ethanolic root extract of
Echinacea purpurea
and
E. angustifolia
, were examined in rats, after topical
application of gel containing 100 mg/ml of the extract. The tissues of the treated animals were evaluated
after 24, 48 and 72 h treatment and excised for histological observation at the end of the experiment.
Results confirm the good anti-inflammatory and wound healing properties of
E. pallida
and of its
constituent echinacoside, with respect to
E. purpurea
and contr
a
ntihyaluronidase activity of echinacoside (Speroni
et al.
2002).
ol. This activity probably resides in the
II.2.1.1.5
Antioxidant activity
The radical scavenging activity of
Echinacea
methanolic extracts was evaluated
in vitro
with a
spectrophotometric method based on the reduction of an alcoholic 2,2-diphenyl-1-picrylhydrazyl (DPPH)
radical solution at 517 nm in the presence of a hydrogen donating antioxidant. As for pure compounds,
echinacoside had the highest capacity to quench DPPH radicals (EC50 = 6.6 M), while caftaric acid had
the lowest (EC50 = 20.5 M). The average EC
50
values for
Echinacea purpurea
,
E. pallida
and
E.
angustifolia
were 134, 167 and 231 g/ml, respectively. The radical scavenging activity of
Echinacea
root
extracts reflected their phenolic composition. The results indicate that
Echinacea
roots and derivatives are
a good source of natu
(P
ellati
et al.
2004).
ral antioxidants and could be used to prevent free-radical-induced deleterious effects
Alcoholic extracts of the roots and leaves of three
Echinacea
species (
E. purpurea
,
E. angustifolia
and E
.
pallida
) were found to have antioxida
p
nt properties in a free radical scavenging assay and in a lipid
eroxidation assay (Sloley
et al.
2001).
Methanol extracts of freeze-dried
Echinacea
(
E. angustifolia
,
E. pallida
, and
E. purpurea
) roots were
examined for free radical scavenging capacities and antioxidant activities. Root extracts of
E. angustifolia
,
E. pallida
, and
E. purpurea
were capable of scavenging hydroxyl radical. Similar scavenging activities for
each variety were found for both 1,1-diphenyl-2-picrylhydrazyl radical and ABTS radical. Meanwhile,
antioxidant activities of all three varieties of
Echinacea
were found to delay the formation of conjugated
diene hydroperoxide induced by the thermal decomposition of 2,2'-azobis(2-amidinopropane)
dihydrochloride and extend the lag phase of peroxidation of soybean liposomes.
Echinacea
root extracts
suppressed the oxidation of human low-density lipoprotein, as evaluated by reduced agarose
electrophoretic mobility following oxidative modification by Cu
2+
. The mechanisms of antioxidant
activity of extracts derived fr
c
om
Echinacea
roots included free radical scavenging and transition metal
helating (Hu & Kitts 2000).
The protective effect of caffeoyl derivatives (echinacoside, chlorogenic acid, chicoric acid, cynarine, and
caffeic acid, typical constituents of
Echinacea
species) on the free radical-induced degradation of Type III
collagen has been investigated. The macromolecule was exposed to a flux of oxygen radicals (superoxide
EMEA 2009
14/21
d
anion and hydroxyl radical) generated by the xanthine/xanthine oxidase/Fe2+/EDTA system and its
degradation assessed qualitatively by SDS-PAGE and quantitatively as the amount of soluble peptides
(according to the 4-hydroxyproline method) released from native collagen after oxidative stress. The SDS-
PAGE pattern of native collagen is markedly modified by free radical attack, with formation of a great
number of peptide fragments with molecular masses below 97 kDa: in the presence of µM concentrations
of echinacoside, there is a complete recovery of the native profile. Collagen degradation was, in fact,
dose-dependently inhibited by all the compounds, with the following order of potency: echinacoside
approximately chicoric acid > cynarine approximately caffeic acid > chlorogenic acid, with IC
50
ranging
from 15 to 90 µM. These results indicate that this representative class of polyphenols of
Echinacea
species protects collagen from free radical damage through a scavenging effect on reactive oxygen species
and/or C-, N-, S-centered secondary radicals, and provide an indication for the topical use of extracts from
Echinacea
species for the prevention/treatment of photodamage of the skin by UVA/UVB radiation, in
hich oxidative stress plays a crucial role (Maffei Facino
et al.
1995).
II.2.1.1.6
Other activities
The
n
-hexane root extracts from
Echinacea pallida
,
Echinacea angustifolia
and
Echinacea purpurea
were
evaluated for inhibition of the multidrug transporter P-glycoprotein (Pgp) activity, the product of the
ABCB1 gene, involved in cancer multidrug resistance (MDR) and in herb-drug or drug-drug interactions.
The biological assay was performed using the human proximal tubule HK-2 cell line that constitutively
expresses ABCB1. The
n
-hexane extracts of all three species reduced the efflux of the Pgp probe calcein-
AM from HK-2 cells two-fold in a concentration-dependent manner, and
E. pallida
was found to be the
most active species. For the first time, two polyacetylenes and three polyenes, isolated from the
n
-hexane
extract of
E. pallida
roots by a bioassay-guided fractionation, were found to be able to reduce Pgp activity.
Pentadeca-(8
Z
,13
Z
)-dien-11-yn-2-one was the most efficient compound, being able to dec
c
rease the
alcein-AM efflux about three-fold with respect to the control at 30 g/ml (Romiti
et al.
2008).
The
n
-hexane extracts of the roots of three medicinally used
Echinacea
species exhibited cytotoxic
activity on human cancer cell lines, with
Echinacea pallida
found to be the most cytotoxic. Acetylenes are
present in
E. pallida
lipophilic extracts but essentially absent in extracts from the other two species. In the
present study, the cytotoxic effects of five compounds, two polyacetylenes (namely, 8-hydroxy-pentadeca-
(9
E
)-ene-11,13-diyn-2-one (1) and pentadeca-(9
E
)-ene-11,13-diyne-2,8-dione (3)) and three polyenes
(namely, 8-hydroxy-pentadeca-(9
E
,13
Z
)-dien-11-yn-2-one (2), pentadeca-(9
E
,13
Z
)-dien-11-yne-2,8-dione
(4) and pentadeca-(8
Z
,13
Z
)-dien-11-yn-2-one (5)), isolated from the
n
-hexane extract of
E. pallida
roots
by bioassay-guided fractionation, were investigated and the potential bioavailability of these compounds
in the extract was studied. Cytotoxic effects were assessed on human pancreatic MIA PaCa-2 and colonic
COLO320 cancer cell lines. Cell viability was evaluated by the WST-1 assay and apoptotic cell death by
the cytosolic internucleosomal DNA enrichment and the caspase 3/7 activity tests. Caco-2 cell monolayers
were used to assess the potential bioavailability of the acetylenes. The five compounds exhibited
concentration-dependent cytotoxicity in both cell types, with a greater potency in the colonic cancer cells.
Apoptotic cell death was found to be involved in the cytotoxic effect of the most active, compound 5.
Compounds 2 and 5 were found to cross the Caco-2 monolayer with apparent permeabilities above
10 × 10
-6
cms
-1
. Compounds isolated from
n
-hexane extracts of
E. pallida
roots have a direct cytotoxicit
o
y
n cancer cells and good potential for absorption in humans when taken orally (Chicca
et al.
2008).
Bioassay-guided fractionation of
n
-hexane extracts of
Echinacea pallida
(Asteraceae) roots led to the
isolation and structure elucidation of two polyacetylenes (1, 3) and three polyenes (2, 4, 5). Two of them
are known hydroxylated compounds, namely 8-hydroxy-pentadeca-(9E)-ene-11,13-diyn-2-one (1) and 8-
hydroxy-pentadeca-(9E,13Z)-dien-11-yn-2-one (2). Two dicarbonylic constituents, namely pentadeca-
(9E)-ene-11,13-diyne-2,8-dione (3) and pentadeca-(9E,13Z)-dien-11-yne-2,8-dione (4), were isolated and
characterized for the first time. Furthermore, the structure elucidation of pentadeca-(8Z,13Z)-dien-11-yn-
2-one (5) is described. The structure of the compounds isolated was determined on the basis of UV, IR,
EMEA 2009
15/21
w
NMR (including 1D and 2D NMR experiments, such as
1
H-
1
H gCOSY, gHSQC-DEPT, gHMBC,
gNOESY) and MS spectroscopic data. The cytotoxic activity of the isolated constituents against MIA
PaCa-2 human pancreatic adenocarcinoma cells was evaluated in the concentration range 1-100 g/ml.
Results show that the hydroxylated compounds (1, 2) have low cytotoxicity, while the more hydrophobic
olyacetylenes (3) and polyenes (4, 5) displayed moderate activity (Pellati
et al.
2007).
Intake of
Echinacea
preparations is common among patients with advanced malignancies enrolled onto
phase I chemotherapy trials; however, no data are available regarding the possible direct effect of
Echinacea
species on human cancer cells. The purpose of the study was to investigate potential
in vitro
cytotoxic and pro-apoptotic properties of hexanic root extract of the three medicinal
Echinacea
(Asteraceae) species (
Echinacea pallida
(Nutt.) Nutt.,
Echinacea angustifolia
DC.
var. angustifolia
,
Echinacea purpurea
(L.) Moench.) on the human pancreatic cancer MIA PaCa-2 and colon cancer
COLO320 cell lines. It was demonstrated, for the first time, that all the three species reduced cell viability
in a concentration- and time-dependent manner;
Echinacea pallida
was the most active species with IC
50
s
of 46.41+/-0.87 and 10.55+/-0.70 g/ml in MIA PaCa-2 and COLO320 cells, respectively.
Echinacea
pallida
extract was able to induce apoptosis by increasing significantly caspase 3/7 activity and promoting
nuclear DNA fragmentation. These results represent the starting point to establish viab
e
vidence on the possible role of
Echinacea
species in medical oncology (Chicca
et al.
2007).
le scientific
The effect of ten phytotherapeutic products on CCl
4
intoxicated liver in albino male Wistar rats was
investigated. Biochemical parameters, including serum transaminase activity (GPT and GOT),
histoenzymological measurements (lactate dehydrogenase, succinate dehydrogenase, cytochromoxidase,
Mg
2+
-dependent adenosine triphosphatase) and histochemical (Sudan black) and histological examinations
(haematoxylin-eosin staining) of the liver were investigated. Some positive effects such as the reduction of
hepatocytolysis and steatosis, and a return to normal values of the activity of some enzymes in the
following plants:
Chrysanthemum balsam
a
velana
were obtained (Rusu
et al.
2005).
ita
,
Echinacea pallida
,
Calendula officinalis
and
Corylus
A constituent of the root oil of
Echinacea angustifolia
DC. and
E. pallida
(Nutt.) Nutt. Britt. inhibitory to
Walker carcinosarcoma 256 and P-388 lymphocytic leukemia was isolated and identified as (
Z
)-l,8-
pentadecadiene. This compound occurs in these oils to the extent of approximately 44% and appears to be
the first diene olefin reported to sh
a
ctive (Voaden & Jacobson 1972).
ow
in vivo
antitumor activity. The corresponding
trans
isomer is less
II.2.1.2
Assessor’s overall conclusions on pharmacology
For the extracts of pale coneflower root, immunomodulatory, antimicrobial, anti-inflammatory,
antioxidant and antitumor effects were proven in several
in vitro
and
in vivo
tests. In comparison to other
Echinacea
species,
E. pallida
s
was frequently the most active; however the pharmacological mechanisms
till remain to be elucidated.
II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data reg
releva
nt constituents thereof
arding the herbal substance(s), herbal preparation(s) and
N
o data available.
II.2.2.2
Assessor’s overall conclus
ions on pharmacokinetics
N
o conclusions due to absence of data.
EMEA 2009
16/21
p
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
No data available for
Echinacea pallida
. In general, animal studies with different preparations and
fractions of other
Echinacea
species have indicated low toxicity (Barnes
et al.
2007). Tests on
reproductive toxicity, genotoxicity and carcinogenicity have not been performed with
Echinacea pallida
or preparations thereof.
II.2.3.2
Assessor’s overall conclusions on toxicology
Toxicological data are only available for
Echinacea purpurea
; however a certain level of safety could be
expected due to the long-time use of
Echinacea pallida
preparations with no serious side effects reported.
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.
No data available.
II.3.1.1.2
Assessor’s overall conclusions on Pharmacodynamics
No conclusions due to absence of data.
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.
No data available.
II.3.1.2.2
Assessor’s overall conclusions on pharmacokinetics
No conclusions due to absence of data.
II.3.2
II.3.2.1
Dose response studies
No data available.
6
In case of traditional use the long-standing use and experience should be assessed.
EMEA 2009
17/21
II.3.2.2
Clinical studies (case studies and clinical trials)
Echinacea pallida
as a single ingredient
In a randomized, placebo controlled, double-blind study, 160 patients with influnza-like infections of the
upper respiratory tract were treated for 8-20 days with either a hydroalcoholic liquid extract of pale
coneflower root at a daily dose corresponding to 900 mg of dried root (n = 80) or placebo (n = 80). Further
specifications for the extract were not given. Significant improvements in four major symptoms, common
cold, weakness, pain in arm and legs, and headache (p<0.0001), and in the overall symptom score
(p<0.0004), were observed in the verum group compared to the placebo group. Also, the duration of
illness was significantly shorter in verum patients (p<0.0001): in those with putative bacterial infections,
9.8 days compared to 13.0 with placebo; in those with putative viral infections, 9.1 days compared to 12.9
with placebo (Bräunig & Knick 1993).
A double-blind randomized placebo controlled trial was performed to evaluate the use of
Echinaceae
pallidae
radix in flu-like upper respiratory symptoms in 160 patients. Liquid extract of pale coneflower
root was administered for 8 to 10 days at a daily dose corresponding to 900 mg of dried root. Further
specifications for the extract were not given. Study demonstrated a highly significant result for the herbal
remedy
Echinaceae
, as compared to placebo. The length of illness (P < 0.0001), overall symptom scores
(P < 0.0004) and whole clinical scores (P < 0.001) all demonstrates a significant result for real treatment
as compared to placebo. Side effects were not reported (Dorn
et al.
1997, Wolters Kluwer Health 2004).
Echinacea pallida
in combination with other herbal drugs
A double-blind randomized placebo controlled trial was performed on 263 patients to evaluate the use of
commercially available fixed combination herbal remedy containing ethanolic-aqueous extracts of Herba
thujae occidentalis, Radix echinaceae (purpurae + pallidae = 1 +1) and Radix baptisiae, 2, 7.5 and 10 mg
per tablet, respectively. Three tablets of study medication were applied three times daily for 7 to 9 days.
The therapeutic benefit of the herbal remedy had already occurred on day 2 and reached significance (p <
0.05) on day 4, and continued until the end of the treatment in the total score of symptoms, bronchitis
score and rhinitis score, as well as in the patients' overall rating of the cold intensity. In the subgroup of
patients who started therapy at an early phase of their cold, the efficacy of the herbal remedy was most
prominent. Serious adverse events did not occur. This study shows that the herbal remedy is effective and
safe. The therapeutic benefit consists of a rapid onset of improvement of cold symptoms (Henneicke-von
Zepelin H
et al.
1999, Wolters Kluwer Health 2004).
A randomized, double-blind placebo-controlled parallel group clinical trial was performed to investigate
the therapeutic effect of Kanjang mixture containing
Echinacea pallida
root (10g/100ml) in combination
with 4 other active ingredients for the treatment of uncomplicated upper respiratory tract infections
(common cold) in 66 patients. Medication was taken three times daily for a minimum of 5 days or a
maximum of 10 days in a daily dose of 15 ml. The improvement in symptoms following treatment with
Kanjang mixture was significantly better on the day 2 and 4 assessments compared with placebo, while
the day 10 scores were not significantly different. Tolerability of both treatments was excellent and no
side-effects were reported in either of the two groups. Treatment with the herbal mixture Kangjang
significantly eased the symptoms related to uncomplicated upper respiratory tract infections. Side effects
were not reported (Thom
et al.
1997, Wolters Kluwer Health 2004).
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
For the treatement in children only studies with combination products are available (Linde
et al.
2006,
Barnes
et al.
2007).
EMEA 2009
18/21
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
The efficacy of pale coneflower root preparations in improving the symptoms of common cold and
shortening the time of disease was reported in two randomized, placebo controlled, double-blind studies,
however, specifications for the extracts are not given. The treatment with
Echinacea pallida
preparations
should start at the first signs of cold. There are no data on effectiveness of
Echinacea pallida
for the
prevention of infections. The effectiveness of combination with other herbal drugs was reported. Despite
reported effectiveness of
Echinacea pallida
as a single ingredient, well established use can not be
supported, due to highly insufficient data on preparation and composition of the extracts used in clinical
studies.
The available published controlled clinical studies indicate that medicines containing
Echinacea pallida
may be effective immunomodulators. However, for clear therapeutic recommendations as to which
preparation to use and which dose to apply, the evidence is not yet sufficient.
Clinical efficacy of
Echinacea pallida
in children is not certain, because only data on combination
products are available.
Since
Echinacea
-containing medicinal products can have different contents of active constituents
depending on the plant material used, the method of preparation or the addition of other components - an
extrapolation of results from one preparation to another is not possible without proof of the chemical-
pharmaceutical equivalence. For future investigations it should therefore be required that the preparation
is chemically defined and standardised with regard to the composition of the main components. (Melchart
et al.
1994).
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
No data available.
II.3.3.2
Adverse events
In rare cases hypersensitivity reactions e.g. skin reactions may occur (Liersch & Bauer 1993). Individuals
with allergic tendecies, particulary those with known allergy to other members of the Asteraceae family
should be advised to avoid
Echinacea
(Barnes
et al.
2007).
II.3.3.3
Serious adverse events and deaths
None reported.
II.3.3.4
Laboratory findings
No data available.
II.3.3.5
Safety in special populations and situations
II.3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors
As with all imunostimulants not recommended in progressive systemic diseases such as: tuberculosis,
diseases of the white blood cells system, collagenoses, multiple sclerosis, AIDS, HIV infections, and
other immune diseases (Barnes
et al.
2007, German Commission E Monographs 1999, Liersch & Bauer.
1993).
EMEA 2009
19/21
II.3.3.5.2
Drug interactions
None reported.
II.3.3.5.3
Use in pregnancy and lactation
A review on safety of
Echinacea
during pregnancy and lactation was published recently (Perri
et al.
2006). There is no specification which species of
Echinacea
was evaluated. They searched 7 electronic
databases and compiled data according to the grade of evidence found. They found good scientific
evidence from a prospective cohort study that oral consumption of
Echinacea
during the first trimester
does not increase the risk for major malformations. Low-level evidence based on expert opinion shows
that oral consumption of
Echinacea
in recommended doses is safe for use during pregnancy and lactation.
They concluded that
Echinacea
is non-teratogenic when used during pregnancy. Using
Echinacea
during
lactation is not recommended until further high quality human studies can determine its safety.
Pregnancy outcome in women that used
Echinacea
during pregnancy was studied to evaluate the safety of
Echinacea
. There is no specification which species of
Echinacea
was evaluated. Since at least half of all
pregnancies are unplanned, many women inadvertently use
Echinacea
in their first trimester. The study
group consisted of 206 women who were prospectively followed up after contacting the Motherisk
Program regarding the gestational use of
Echinacea
, 112 women used the herb in the first trimester. This
cohort was disease-matched to women exposed to non-teratogenic agents by maternal age, alcohol, and
cigarette use. Rates of major and minor malformations between the groups were compared. There were a
total of 195 live births, including 3 sets of twins, 13 spontaneous abortions, and 1 therapeutic abortion in
Echinacea
group. Six major malformations were reported, including 1 chromosomal abnormality, and 4 of
these malformations occurred with
Echinacea
exposure in the first trimester. In the control group, there
were 206 women with 198 live births, 7 spontaneous abortions, and 1 therapeutic abortion. Seven major
malformations were reported. There were no statistical differences between the study and control groups
for any of the end points analysed. The authors concluded that gestational use of
Echinacea
during
organogenesis is not associated with an increased risk for major malformations (Gallo
et al.
2000).
II.3.3.5.5
Drug abuse
No case of drug abuse has been reported.
II.3.3.5.6
Withdrawal and rebound
No data available.
II.3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
II.3.3.6
Assessor’s overall conclusions on clinical safety
Hypersensitivity reactions e.g. skin reactions were observed in rare cases; therefore individuals with
allergic tendencies particularly those with known allergy to other members of the Asteraceae family
should avoid
Echinacea pallida
preparations.
There are no data on safety of pale coneflower preparations in children; therefore the use of herbal drug
and preparations is not recommended.
EMEA 2009
20/21
Echinacea pallida
should not be used in progressive systemic diseases such as: tuberculosis, diseases of
the white blood cells system, collagenoses, multiple sclerosis, AIDS, HIV infections, and other immune
diseases.
Due to the uncertainty which
Echinacea
was evalueted in studies, administration during pregnancy and
lactation is not generally recommended in accordance with general medical practice.
The duration of use should be restricted to 10 days according to the clinical studies and usual duration of
common cold.
II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
Immunomodulatory effects of
Echinacea pallida
preparations on cells of human immune system were
demonstrated
in vitro
, but there are no data on clinical pharmacology. Specifications for herbal
preparations used in clinical studies are not given. The available published controlled clinical studies
indicate that medicines containing
Echinacea pallida
may be effective immunomodulators; however they
lack sufficient data on preparation and composition of the extracts used. According to these studies,
common cold was treated as a viral or a bacterial infection. There are no data on clinical efficacy in
children. Nothing is known about the toxicity of pale conflower preparations (no data on acute toxicity,
genotoxicity and carcinogenicity) although pale coneflower has been used for decades. However, a certain
level of safety could be expected, because no serious side effects have been reported.
Echinacea pallida
was often confused with
Echinacea angustifolia
and it is not always clear which species was used for
evaluation.
Despite reported effectiveness of
Echinacea pallida
as a single ingredient,
well-established
use
of
Echinacea pallida
for the supportive treatment of common cold
is
not possible,
because there are highly
insufficient data on preparation and composition of the extracts used in clinical studies.
Traditional use
of
Echinacea pallida
in this indication is
possible
, although toxicological data are not
available. However, a certain level of safety can be assumed due to the long-time use of
Echinacea
pallida
preparations with no serious side effects reported.
III.
ANNEXES
III.1
C
OMMUNITY
H
ERBAL
M
ONOGRAPH ON
E
CHINACEA PALLIDA
(N
UTT
.)
N
UTT
.,
RADIX
III.2
L
ITERATURE
R
EFERENCES
EMEA 2009
21/21
Source: European Medicines Agency
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