Community herbal monograph on
Echinacea purpurea
(L.)
Moench, 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 purpurea
(L.) Moench, radix (purple
coneflower root)
i) Herbal substance
Not applicable.
ii) Herbal preparations
a)
dry extract (5.5-7.5:1), extraction solvent
ethanol 45% (v/v).
Well-established use
Traditional use
Herbal preparations in solid dosage forms for oral
and oromucosal use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Traditional herbal medicinal product for supportive
treatment of common cold.
1
The material complies with the Ph. Eur. monograph (ref.: 01/2008:1824).
2
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
Community herbal monograph on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577784/2008
Page 2/5
Well-established use
Traditional use
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 and elderly
a) 1 chewing tablet containing 40 mg of extract
every second hour (maximum 9 tablets a day).
The use in children under 12 years of age is not
recommended (see section 4.4 ‘Special warnings
and precautions for use’).
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 and oromucosal use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance or to
plants of the Asteraceae (Compositae) family.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
Not recommended in cases of progressive
systemic diseases such as tuberculosis, diseases
of the white blood cell system, collagenoses,
multiple sclerosis, AIDS, HIV infections and other
immune diseases.
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
Community herbal monograph on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577784/2008
Page 3/5
Well-established use
Traditional use
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
.
The use in children under 12 years of age has not
been established due to lack of adequate data.
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.
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.
4.8.
Undesirable effects
Well-established use
Traditional use
Hypersensitivity reactions (skin reactions) 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.
Community herbal monograph on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577784/2008
Page 4/5
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.
11 March 2010
Community herbal monograph on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577784/2008
Page 5/5
Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.3. Search and assessment methodology....................................................................
6
2. Historical data on medicinal use ........................................................................................ 6
2.1. Information on period of medicinal use in the Community ........................................
6
preparations and indications.......................................................................................
7
3. Non-Clinical Data ............................................................................................................... 7
preparation(s) and relevant constituents thereof ...........................................................
7
preparation(s) and relevant constituents thereof ......................................................... 2
0
preparation(s) and constituents thereof ..................................................................... 2
1
3.4. Overall conclusions on non-clinical data......................
Error! Bookmark not defined.
4. Clinical Data ..................................................................................................................... 22
4.1. Clinical Pharmacology ....................................................................................... 2
2
including data on relevant constituents ...................................................................... 2
2
including data on relevant constituents ...................................................................... 2
3
4.2. Clinical Efficacy ................................................................................................ 2
4
4.2.1. Dose response studies.................................................................................... 2
4
4.2.2. Clinical studies (case studies and clinical trials).................................................. 2
4
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 2
7
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 2
7
5. Clinical Safety/Pharmacovigilance................................................................................... 27
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 2
7
5.2. Patient exposure .............................................................................................. 2
7
5.3. Adverse events and serious adverse events and deaths ......................................... 2
8
5.4. Laboratory findings .......................................................................................... 2
8
5.5. Safety in special populations and situations ......................................................... 2
8
5.6. Overall conclusions on clinical safety ................................................................... 3
0
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 2/31
1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Echinaceae purpureae radix (European Pharmacopoeia monograph reference 01/2008: 1824)
Echinaceae purpureae radix consists of the whole or cut, dried underground parts of
Echinacea
purpurea
(L.) Moench. It contains not less than 0.5 % for the sum of caftaric acid (C
13
H
12
O
9
; M
r
312.2) and cichoric acid (C
22
H
18
O
12
; M
r
474.3) in dried drug.
Constituents (Barnes
et al.
2005, Barnes
et al.
2007, Bauer and Remiger 1989, Bradley 2006, ESCOP
2003 and 2009,
Bauer and Liersch 1993, Mazza and Cottrell 1999, Wolters Kluwer Health 2004, PDR
2007):
Alkamides (0.01-0.7%): mainly isobutylamides of straight-chain fatty-acids with olefinic and/or
acetylenic bonds e.g. isomeric dodeca-2
E
,4
E
,8
Z
,10
E
/
Z
-tetraenoic isobutylamide. Undeca-
2
Z
,4
E
-diene-8,10-diynoic acid isobutylamide is also prominent. Isobutylamides contain mainly
2,4-dienoic units.
Caffeic acid derivatives (2.0-2.8%): principally cichoric acid (2,3-
O
-dicaffeoyltartaric acid, 1.7-
2.4%) and caftaric acid (2-
O
-caffeoyltartaric acid, ca. 0.2-0.8%) also echinacoside,
verbascoside, caffeoylechinacoside, chlorogenic and isochlorogenic acids.
Polysaccharides and glycoproteins: arabinogalactans, and an arabinogalactan-containing
glycoprotein with a sugar component consisting of arabinose (64-84%), galactose (2-5%) and
galactosamine (6%).
Volatile oil (0.1%): caryophyllene, caryophyllene oxide, humulene,
-phellandrene, limonene,
camphene, aldehydes and dimethyl sulphide.
Other constituents: small amounts of polyacetylenic compounds polyynes (0.01 mg/%
including trideca-1-en-3,5,7,9,11-pentaine, trideca-1,11-dien-3,5,7,9,-tetraine, trideca-
8,10,12-triene-2,4,6-triine)
Effective pyrrolizidine alkaloids: tussilagine, isotussilagine (PDR 2007).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 3/31
Caffeic acid
derivatives
with tartaric acid
cichor ic ac id
caftaric acid
with quinic
acid
cynar ine
with sugar
echinacoside
Herbal preparation(s)
Comminuted herbal substance for decoctions and galenic preparations (PDR 2007, Blumenthal
et al.
2000, ESCOP 2009)
Dry extract (6.5:1), extraction solvent: ethanol 45% (V/V).
Dry extract (5.5-7.5:1), extraction solvent: ethanol 45% (V/V)
Tincture (1:5), extraction solvent: ethanol 55% (V/V) (ESCOP 2009, Blumenthal
et al.
2000, Bräunig
et al.
1992, Barrett
et al.
1999, Melchart
et al.
1994).
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
Not applicable.
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 4/31
1.2.
Information about products on the market in the Member States
Dry extracts
Spain
Preparations
:
1) Dry extract (5.5-7.5:1) ethanol 45% V/V. 30 mg of extract/tablet, equivalent to 200 mg of the
herbal substance.
1)
tablet
Sweden
Preparations
:
1) Ethanol extract (6.5:1), ethanol 45% V/V. 1 chewable tablet contains 40 mg extract
corresponding to 260 mg radix.
1)
chewable tablet
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: No answer.
Belgium
MA
TRAD
Other TRAD
Other Specify: Comb. product (1).
Bulgaria
MA
TRAD
Other TRAD
Other Specify: No products.
Cyprus
MA
TRAD
Other TRAD
Other Specify:
No products.
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No products.
Denmark
MA
TRAD
Other TRAD
Other Specify: Comb. product (1).
Estonia
MA
TRAD
Other TRAD
Other Specify: Food supplements.
Finland
MA
TRAD
Other TRAD
Other Specify:
Comb. prod. (3).
France
MA
TRAD
Other TRAD
Other Specify: No products.
Germany
MA
TRAD
Other TRAD
Other Specify: Comb. products.
Greece
MA
TRAD
Other TRAD
Other Specify: No products.
Hungary
MA
TRAD
Other TRAD
Other Specify:
Comb. prod. (4).
Iceland
MA
TRAD
Other TRAD
Other Specify: Food supplements.
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 products.
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 5/31
Member State Regulatory Status
Comments (not
mandatory field)
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: Food supplements.
Poland
MA
TRAD
Other TRAD
Other Specify: No products.
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: Comb. prod. (2).
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No answer.
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’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3.
Search and assessment methodology
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
Spain
The dry extract (5.5-7.5:1) ethanol 45% V/V has been on the market since 2002.
Sweden
The ethanol extract (6.5:1), ethanol 45% V/V) has been on the market since 1978.
2.2.
Information on traditional/current indications and specified
substances/preparations
Traditional indications for oral use of herbal teas and tincture.
Indication
References
Adjuvant therapy and prophylaxis of
recurrent infections of the upper
respiratory tract (common cold).
ESCOP 2003 and 2009, Barnes
et al.
2005, Barnes
et al.
2007,
Bradley 2006, Bauer and Liersch 1993, Blumenthal
et al.
2000,
Bräunig
et al.
1992, Barrett
et al.
1999, Melchart
et al.
1994)
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 6/31
Herbal substance
Not applicable.
Herbal preparations:
0.9 g comminuted or powdered dried roots as infusion several times daily between meals (Bauer and
Liersch 1993, PDR 2007, Blumenthal
et al.
2000, ESCOP 2009).
Infusion: Steep 0.9 g dried root in 150 ml boiled water for 10 min (Blumenthal
et al.
2000).
Tincture: 60 drops (1:5 in ethanol 55%) three times daily, corresponding to three times 300 mg of
dried root (Barnes
et al.
2007, ESCOP 2003 and 2009, Blumenthal
et al.
2000, Bräunig
et al.
1992,
Barrett
et al.
1999, Melchart
et al.
1994).
The duration of treatment should not exceed eight (8) weeks (Barnes
et al.
2007, ESCOP 2003 and
2009).
There is no evidence of 30-year of medicinal use of the comminuted or powdered dried roots and of
the tincture (1:5 in ethanol 55%) in the EU. These preparations are therefore not included in the
monograph on Echinaceae purpureae radix.
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Dry extracts
1) dry extract (5.5-7.5:1) ethanol 45% V/V. 30 mg of extract / tablet, equivalent to 200 mg of the
herbal substance: 6-9 tablets a day.
2) dry extract (6.5:1) ethanol 45% V/V. Chewable tablet contains 40 mg extract corresponding to 260
mg radix: chewable tablet every second hour (maximum 9 tablets a day).
Indications
:
1) Herbal medicinal product for the treatment of early symptoms of common cold.
Risks
:
2)
Special warning and precaution for use
: Hypersensitivity reactions such as anaphylaxis and
angioedema may occur in persons treated with
Echinacea
products. The risk appears higher in
patients with atopic eczema. Treatment with
Echinacea
must be discontinued at first signs of
hypersensitivity.
Undesirable effects
: Hypersensitivity reactions such as skin reactions including urticaria may occur.
A few cases of severe hypersensitivity reactions such as angioedema, dyspnea/bronchospasm and
fall in blood pressure have been reported.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Immunomodulatory activity
In vitro
experiments
Purified polysaccharides (EPS) prepared from the herb and root of
Echinacea purpurea
are shown to
strongly activate macrophages. Macrophages activated with these substances develop pronounced
extracellular cytotoxicity against tumour targets. The activation is brought about by EPS alone and is
independent of any cooperative effect with lymphocytes. Also the production and secretion of oxygen
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 7/31
radicals and interleukin-1 (IL-1) by macrophages is increased after activation with EPS. Cells of the
macrophages lineage seem to be the main target for the action of these polysaccharides. EPS has no
effect on T lymphocytes. B lymphocytes show a comparatively modest proliferation after incubation
with
E. purpurea
EPS. Thus, these compounds, which are at least in tissue culture completely nontoxic,
may be suited to activate
in vivo
cells of the macrophage system to cytotoxicity. They may therefore
be of relevance in tumour and infectious systems (Stimpel
et al.
1984).
From the water or alcaline-water extracts of
Echinacea purpurea
(L.) Moench and -
angustifolia
DC.,
Eupatorium cannabinum
L. and
-perfoliatum
L.,
Chamomilla recutita
(L.) (Rauscher),
Calendula
officinalis
L.,
Baptisia tinctoria
(L.) R.B.,
Achyrocline satureoides
DC.,
Arnica montana
L.,
Sabal
serrulata
Roem et Schult. and
Eleutherococcus senticosus
Maxim. polysaccharide fractions with
molecular weights in the range of 25 000 to 500 000 and higher have been isolated, which, according
to the granulocytes- and carbon clearance tests, showed significant immunostimulating activities. They
stimulated the activity of mouse macrophages; this activation included enhanced secretion of
interleukin-1 (IL-1). The isolated compounds belong to the group of water-soluble, acidic
heteroglycanes. The linkages in the different polysaccharides do not represent a uniform structure type
(Wagner
et al.
1984, Beuscher
et al.
1990).
An ethanolic extract of purple coneflower root enhanced phagocytosis by 33% in the granulocyte
smear test at a concentration of 10
-4
mg/ml. Aqueous and lipophilic fractions from the ethanolic extract
showed immunostimulatory activity (Bauer
et al.
1989).
Extracts of
Echinacea purpurea
and
Panax ginseng
were evaluated for their capacity to stimulate
cellular immune function by peripheral blood mononuclear cells (PBMC) from normal individuals and
patients with either the chronic fatigue syndrome or the acquired immunodeficiency syndrome. PBMC
isolated on a Ficoll-hypaque density gradient were tested in the presence or absence of varying
concentrations of each extract for natural killer (NK) cell activity versus K562 cells and antibody-
dependent cellular cytotoxicity (ADCC) against human herpes virus 6 infected H9 cells. Both
Echinacea
and
Ginseng
, at concentrations > or = 0.1 or 10
g/kg, respectively, significantly enhanced NK-
function of all groups. Similarly, the addition of either herb significantly increased ADCC of PBMC from
all subject groups. Thus, extracts of
Echinacea purpurea
and
Panax ginseng
enhance cellular immune
function of PBMC both from normal individuals and patients with depressed cellular immunity (See
et
al.
1997).
A high molecular weight fraction (M
r
>10,000 D) containing polysaccharides and glycoproteins from
purple coneflower root enhanced the proliferation of mouse spleen cells; stimulated the production of
cytokines such as interferon (IFN
/
) in spleen cell cultures, and IL-1, interleukin-6 (IL-6) and tumour
necrosis factor-
(TNF-
) in mouse macrophage cultures; increased immunoglobulin M production and
the number of antibody-producing cells, and increased nitric oxide (NO) production of macrophages
(Beuscher
et al.
1995, Bodinet 1999). Incubation of this fraction with human monocytes also enhanced
the production of IL-1, IL-6 and TNF-
(Bodinet 1999).
Purple coneflower root powders and various extracts showed a macrophage activating capacity.
Extracts standardised to 4% of phenolic compounds (such as chlorogenic and cichoric acid) or to
alkylamides were inactive with respect to induction of macrophage cytokine production (Rininger
et al
.
2000).
Isolated alkamides dodeca-2
Z
,4
E
,10
Z
-trien-8-ynoic acid isobutylamide from
E. angustifolia
roots and
dodeca-2
Z
,4
E
-diene-8,10-diynoic acid isobutylamide from
E. purpurea
roots and
E. pallida
roots
exerted inhibition on lipopolysaccharide (LPS)-mediated activation of a murine macrophage line,
RAW264.7. These data suggest that these alkamides may have anti-inflammatory activity (Chen
et al.
2005).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 8/31
With the increasing popularity of herbal medicines, many people make their own
Echinacea
extracts at
home and storing them at refrigerator (4°C) temperatures. An hypothesis is that
Echinacea
extracts
made using homemade methods change in immunomodulatory efficacy with storage at 4°C over a 4-
day period. Three extract types (50% ethanol tincture, cold water infusion, hot water infusion) from 5
different species (
E. angustifolia
,
E. pallida
,
E. purpurea
,
E. sanguinea
,
E. tennesseensis
) were
prepared. Four
in vitro
immune assays (monocyte secretion of TNF-
, IL-10, and IL-12 and PBMC
proliferation) using human blood were used to test extract efficacy at days 1 and 4 post-extraction.
Two statistical analyses, traditional ANOVA and several statistical models that account for endotoxin
effects were used. Endotoxin was found to significantly impact immune outcomes only in 4-day old cold
water infusions and not in all assays. Extracts showed the greatest stimulation in TNF-
assays. By
extract type, 50% ethanol tinctures produced the most immune stimulation. By species, extracts from
E. angustifolia
extracts were the most efficacious in the assays; extracts from
E. sanguinea
showed the
least activity overall (Senchina
et al.
2005).
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 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 IFN-
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-
production.
E. 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 authors concluded that 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).
Extracts of
Echinacea purpurea
aerial parts (E1 – expressed juice) and roots (E2 – 50% alcoholic
tincture, 1:9 w/v) were tested for immunomodulation in rhinovirus-infected and uninfected epithelial
cells. Since immune modulation has been reported for similar extracts, cytokine antibody arrays were
used to investigate the changes in the pro-inflammatory cytokines and chemokines released from a
cultured line of human bronchial epithelial cells exposed to rhinovirus 14 and two different chemically
characterized
Echinacea
extracts. Virus infection stimulated the release of at least 31 cytokine-related
molecules, including several important chemokines known to attract inflammatory cells. Most of these
effects were reversed by simultaneous exposure to either of the two
Echinacea
extracts, although the
patterns of response were different for the two extracts. These results could explain the anti-
inflammatory properties of
Echinacea
extracts. Furthermore, a number of these cytokines were
stimulated by the same
Echinacea
preparations in uninfected cells. The authors concluded that these
observations therefore provide support for the alleged beneficial uses of
Echinacea
extracts (Sharma
et
al.
2006).
The immunomodulatory properties of
Echinacea
tinctures from seven species after being stored at -
20°C for 2 years were tested.
Two experimental techniques were employed using human PBMCs.
In
the first set of experiments, PBMCs were stimulated
in vitro
with tinctures alone and assayed for
proliferation and production of IL-10, IL-12, and TNF-
.
In the second set of experiments, subjects
were immunized with influenza vaccine.
PBMCs from vaccinated individuals were stimulated
in vitro
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 9/31
with
Echinacea
tinctures and influenza virus; cytokine production (IL-2, IL-10, and IFN-
was
compared prevaccination and postvaccination.
In the first experiments, (1) tinctures from
E.
angustifolia
,
E. pallida
,
E. paradoxa
, and
E. tennesseensis
stimulated proliferation and tended to
increase IL-10, (2)
E. sanguinea
and
E. simulata
stimulated only proliferation, (3)
E. purpurea
stimulated only IL-10, and (4) none of the extracts influenced IL-12 or TNF-
. In the second
experiments, (1) tinctures from
E. pallida
,
E. paradoxa
,
E. sanguinea
, and
E. simulata
diminished
influenza-specific IL-2, and (2) none of the extracts influenced influenza-specific IL-10 or IFN-
. For
in
vitro
models using
Echinacea
, immune response may vary based on stimulus (
Echinacea
alone vs.
Echinacea
+ recall stimulation with virus) (McCann
et al.
2007).
The effects of
Echinacea
and several of its phytochemical components on NFκB expression by Jurkat
cells (a human T-cell line) were investigated
in vitro
. In the absence of stimulation,
Echinacea
and its
components exerted no significant effect on basal NFκB expression levels. In the presence of endotoxin
(LPS), NFκB expression was decreased. However, this decrease was significantly reversed by treatment
with cichoric acid, an
Echinacea
root extract (prepared from both
Echinacea angustifolia
and
Echinacea
purpurea
; 1:2 extraction solvent ethanol 60%) and the alkylamide fraction derived from this
combination. For the phorbol myristate acetate stimulation of Jurkat cells, effects on NFκB expression
were mixed. Depending on the concentration, cichoric acid and a 2,4-diene alkylamide significantly
induced NFκB levels, whereas a 2-ene alkylamide caused a significant inhibition. In contrast, both the
Echinacea
and the mixed alkylamide fraction exerted no effect. The alkylamide results indicate that the
two basic forms of these compounds present in
Echinacea
may have opposing effects. These opposing
effects demonstrate the importance of knowledge, not only of the phytochemical make-up of a herbal
preparation, but also of the actions of each component and the consequences of differing relative
amounts in the preparation being investigated (Matthias
et al.
2008).
Standardized tincture Echinaforce® (made from aerial parts and roots of
E. purpurea
) was analysed
and found that it induced de novo synthesis of TNF-
mRNA in primary human
monocytes/macrophages, but not TNF-
protein. Moreover, LPS-stimulated TNF-
protein was potently
inhibited in the early phase but prolonged in the late phase. A study of the main constituents of the
extract showed that the alkylamides dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides, trienoic
and dienoic acid derivatives are responsible for this effect. The upregulation of TNF-
mRNA was found
to be mediated by CB2 receptors, increased cAMP, p38/MAPK and JNK signalling, as well as NF-jB and
ATF-2/CREB-1 activation. The authors concluded that this study is the first to report a possible
molecular mechanism of action of
Echinacea
, highlighting the role of alkylamides as potent
immunomodulators and potential ligands for CB2 receptors (Gertsch
et al.
2004).
Similarities and differences in immune response among
Echinacea
species, which are commonly used
to treat upper respiratory infections were compared and investigated. The investigation involved two
components: acquisition of immunomodulatory data reported for the first time according to the
authors, and combined phenetic analysis of these data along with previous reports. Experimental data
were obtained by stimulating human PBMC
in vitro
with extracts from
Echinacea
spp. and assaying
production of three cytokines (IL-1
, IL-2, and TNF-
). Phenetic analyses were employed to compare
responses across the entire data set, including UPGMA (Unweighted Pair Group Method with Arithmetic
Mean) and neighbor-joining methods. In the immune experiments conducted for this investigation,
E.
angustifolia
,
E. paradoxa
,
E. purpurea
,
E. simulata
, and
E. tennesseensis
extracts significantly
augmented IL-1
and TNF-
production, whereas no extracts significantly modulated IL-2. All phenetic
methods produced similar dendrograms, revealing two species pairs (
E. angustifolia
+
E. simulata
and
E. pallida
+
E. sanguinea
) where both species cluster tightly and have similar immune-response
profiles. These two species-pairs are maximally dissimilar from each other. The remaining species (
E.
paradoxa
,
E. purpurea
, and
E. tennesseensis
) occupy intermediate positions in the dendrogram. The
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 10/31
authors concluded that the results suggest that
Echinacea
spp. act heterogeneously on immune
function (Senchina
et al.
2008).
In vivo
experiments
A 3-fold increase in phagocytosis was demonstrated in the carbon clearance test in mice after oral
administration of 10 ml/kg of a solution containing ca. 5 mg of an ethanolic extract of pale coneflower
root (1:10, 90% ethanol V/V) in 30 ml of physiological saline, three times daily for 2 days. When
chloroform and aqueous fractions of this extract were administered separately, the lipophilic fraction
proved more active than the hydrophilic. However, the hydrophilic fraction showed considerably more
activity than a hydrophilic fraction from
Echinacea pallida
root (Bauer
et al.
1989, Bauer
et al.
1988).
Production of the cytokines IL-1 and IL-6 in mice was enhanced by intravenous doses (50, 100 and
500 µg/animal) of a purified high molecular weight fraction containing glycoproteins and
polysaccharides from purple coneflower root (Bodinet and Beuscher 1991, Beuscher
et al.
1995). Oral
administration of this fraction to mice significantly enhanced antibody production in Peyer’splaque cells
(Bodinet 1999).
The combination preparation, comprising aqueous ethanolic extracts of
Echinacea purpurea
and
E.
pallida
root,
Baptisia tinctoria
root and
Thuja occidentalis
herb, administered orally via the diet or
drinking water to mice for 7 days enhanced the antibody response to sheep red blood cells (sRBC)
(Bodinet and Freudenstein
1999).
In contrast with the extensive body of research supporting the immunostimulatory effect of Echinacea
preparations, some recent
work has reported a lack of effect. No evidence of NK cell activity or
antibody formation was found in studies involving rats fed various preparations of
Echinacea
, including
an alcoholic extract of
E. purpurea
root and an alcoholic extract of the roots of
E. angustifolia
and
E.
pallida
in their diet (South and Exon 2001).
Oral administration of 0.45 mg/day of commercial purple coneflower root extract (Phyto Adrien
Gagnon, La Prairie, QC, Canada) to 7-week-old mice for 2 weeks resulted in a doubling of the number
of NK cells and monocytes in the bone marrow, and in the spleen (Sun
et al.
1999). Oral
administration of the same amount of root extract to ageing mice (15-16 months old, with an average
life span of 21 months) stimulated the production of new NK cells, leading to 30% increase in the
absolute number of NK cells and a 20% increase in the total functional activity of NK cells in the spleen
as measured by the lysis of lymphoma cells
in vitro
(Currier and Miller 2000). Moreover, oral
administration of the powdered root to mice injected with leukaemia cells increased their survival time
compared to controls (Currier and Miller 2001). Powdered root also exhibited strong adjuvant effect on
vaccination with inactivated leukaemia cells (Currier and Miller 2002).
Using male Sprague-Dawley rats (425–475 g), an
in vivo
study was conducted to examine the
immunomodulatory effects of preparations of Echinacea containing its components cichoric acid,
polysaccharides and alkylamides in different concentrations. The rats were gavaged orally with these
preparations two times daily for 4 days. Phagocytic activity of alveolar macrophage was increased with
increasing concentrations of the Echinacea components. A trend of increase in TNF-
and NO release
by the alveolar macrophages following an in vitro stimulation with LPS was also evident. An enhanced
release of cytokines (such as TNF-
and IFN-
) in response to Echinacea components, was also
apparent in rat’s spleen macrophage, but at higher concentrations. Among the components,
alkylamides at the dose level of 12 mg/kg body weight/day significantly increased the phagocytic
activity as well as phagocytic index of the alveolar macrophages. None of the components at any
concentration had any effect on the release of TNF-
, IFN-
and IL-2 by the splenocytes. These results
suggest that the
Echinacea
preparations containing optimal concentrations of cichoric acid,
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 11/31
polysaccharides and alkylamides are potentially effective in stimulating an
in vivo
, non-specific immune
response in normal rats and that the alkylamides at a dose level of approximately 12 mg/kg body
weight/day effectively stimulate alveolar macrophage function in healthy rats. The immunomodulatory
effects of alkylamides appear to be more pronounced in lungs than in spleen (Goel
et al
. 2002a, Goel
et al.
2002b).
A phytopharmaceutical containing an extract of Echinacea purpurea and Glycyrrhiza glabra root
(Revitonil
®
tablets) was investigated for its suggested immunostimulating potential, using several
in
vitro
tests and the
in vivo
carbon-clearance model in mice. In the
in vitro
phagocytosis test with
human granulocytes, Revitonil
®
showed a 44-53% stimulating effect at a concentration of 100 µg/ml.
Whereas in the chemoluminescence test at a concentration of 1.25 µg/ml, Revitonil
®
tablets exhibited
a moderate enhancing effect only, a remarkable stimulating activity (30-50%) was observed in the T-
lymphocyte CD69 bioassay at a concentration of 100 µg - 1 µg/ml. The highest immunological efficacy
could be assigned to Revitonil
®
as revealed by the
in vivo
carbon clearance model in mice. With
RCt/RCc-values of 2.0, Revitonil
®
exhibited a very high carbon elimination rate at oral administration.
Because the Echinacea and Glycyrrhiza monoextracts alone showed lower RCt/RCc-values (1.3-1.7)
than Revitonil
®
, a potentiating synergistic effect of the extract mixture in Revitonil
®
can be postulated
(Wagner
and Jurcic 2002).
Echinacea purpurea
dry root powder (containing 1.5% total polyphenols, calculated as chlorogenic
acid) increased the resistance of splenic lymphocytes to apoptosis; splenic lymphocytes were obtained
from mice administered the
Echinacea
preparation orally at dosages of 30 or 100 mg/kg daily for 14
days (Di Carlo
et al.
2003).
The debate is still on-going with respect to the efficacy of ingesting
Echinacea purpurea
preparation
intermittently, continuously, or only at the beginning of an affliction. It was sought, therefore, to find
out if mice, receiving dietary
Echinacea
daily (commercial purple coneflower root extract; Phyto Adrien
Gagnon, La Prairie, QC, Canada), throughout life, from youth until late middle-age, demonstrated any
longevity/survival differences, and/or any differences in their various populations of
immune/hemopoietic cells. Sustained and/or high levels of these cells are crucial for longevity. Some
mice were maintained on a regular chow diet to which was added
Echinacea purpurea
daily (2
mg/mouse), from puberty (7 week) until just beyond 13 months of age (late middle-age in mice).
Control mice, identically housed and maintained, received identical chow without the herbal
preparation. Mice consuming untreated diet had a 79% survival by 10 months of age, while those
consuming
Echinacea
daily in the diet were still 100% alive by 10 months. At approximately 13 months
of age, mice consuming untreated diet had a 46% survival rate while those consuming
Echinacea
, were
74% alive at this time. Moreover, the key immune cells, acting as the first line of defence against
developing neoplasms in mice and humans, i.e., NK cells, were significantly elevated in absolute
number both in their bone marrow production site, as well as in the major organ to which they traffic
and function, i.e. the spleen. The cells of the myeloid/granulocyte lineages remained steadfastly at
control levels in both the bone marrow and spleen in Echinacea-consuming mice. Thus, the authors
concluded that it appears that regular intake of
Echinacea
may indeed be beneficial/prophylactic, if
only for the reason that it maintains in an elevated state, NK cells, prime elements in
immunosurveillance against spontaneous-developing tumours, a phenomenon which increases in
frequency with progressive aging (Brousseau and Miller 2005).
In vitro
antimicrobial activity
Antibacterial activity against
Escherichia coli
,
Proteus mirabilis
,
Pseudomonas aeruginosa
and
Staphylococcus aureus
has been demonstrated for a multi-herbal preparation containing
Echinacea
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 12/31
purpurea
root extract, although it was stated that the observed antibacterial effects were most likely
attributable to one of the ingredients, extract of onion (Westendorf 1982).
Extracts of purple coneflower root exhibited near UV-mediated phototoxic and antifungal activity,
measured by inhibition of the growth of
Candida
spp. and
Saccharomyces cerevisiae
; 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
E. purpurea
showed antifungal activity against
most of the pathogenic fungi (Merali
et al.
2003).
In vitro
antiviral activity
Using mouse fibroblasts it was demonstrated that incubation with methanolic and aqueous extract of
Echinacea purpurea
root resulted in resistance to influenza A2, herpes, and vesicular stomatitis virus
infection for 24 hours (Wacker and Hilbig 1978).
A high molecular weight fraction (Mr >10,000 D) containing polysaccharides and glycoproteins from
purple coneflower root exhibited antiviral activity against
Herpes simplex
virus (HSV) and influenza
virus (Beuscher
et al.
1995).
A decoction and a 30% ethanolic extract of purple coneflower root inhibited the propagation of ECHO9
Hill virus in monkey kidney cell cultures (Skwarek
et al.
1996).
Extracts of 8 taxa of the genus
Echinacea
were found to have antiviral activity against 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
E. purpurea
n-hexane root extract (MIC
= 0.12 mg/ml) (Binns
et al.
2002).
In vivo
anti-inflammatory activity
Polyunsaturated isobutylamides have been shown to exert anti-inflammatory activity in the 5-
lipoxygenase assay (Wagner
et al.
1989, Müller-Jakic
et al
. 1994). A fraction from purple coneflower
root consisting of ten polyunsaturated isobutylamides had an inhibitory effect on 5-lipoxygenase of
92.5% at 60 µM (calculated for a mean relative molecular mass of 220) (Wagner
et al.
1989).
Echinacea purpurea
(L.) Moench (dry root powder) and
Hypericum perforatum
L. were evaluated for
their anti-inflammatory activity against carrageenan-induced paw oedema in mice. Each drug was
administered orally to mice at 30 and 100 mg/kg, twice daily. Only the higher dose significantly
inhibited, time dependently, the formation of oedema, evaluated as area under the curve (
Echinacea
P
< 0.01;
Hypericum
P < 0.05). Western blot analysis showed that
in vivo
treatment with these extracts
could modulate lipopolysaccharide (LPS) and IFN-
induced cyclooxygenase-2 (COX-2) and inducible
nitric oxide synthase (iNOS) expression in peritoneal macrophages. In particular, treatment with 100
mg/kg
Hypericum
inhibited both iNOS and COX-2 expression, whereas treatment with 100 mg/kg
Echinacea
down-regulated only COX-2 expression. The present study suggests that the anti-
inflammatory effect of these extracts could be in part related to their modulation of COX-2 expression
(Raso
et al.
2002). Further exploration suggested that the observed effect may be due to down-
regulation of COX-2 expression by the
Echinacea
preparation.
In vitro
inhibition of COX-1 and, to
lesser extent, COX-2 has been described to alkamides isolated from
E. purpurea
roots (Clifford
et al.
2002).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 13/31
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. pallida
, 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 hours 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 control (
E. purpurea
was more
effective over the first 24 hours but inferior at 48-72 hours). This activity probably resides in the
antihyaluronidase activity of echinacoside (Speroni
et al.
2002).
5-lipoxygenase-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-lipoxygenase (5-LOX) enzyme of the arachadonic acid pathway was determined by
high-performance liquid chromatography (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
,
E. pallida
var.
angustifolia
,
E. pallida
var.
pallida
) inhibited the 5-LOX enzyme
(Merali
et al.
2003).
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
µg/ml from
E. angustifolia
,
E. pallida
,
E. simulata
, and
E. sanguinea
significantly inhibited PGE2
production. In further studies, PGE2 production was significantly reduced by all synthesized alkamides
assayed at 50 µM, by Bauer alkamides 8, 12A analogue, and 14, Chen alkamide 2, and Chen alkamide
2 analogue at 25 µM and by Bauer alkamide 14 at 10 µM. Cytotoxicity did not play a role in the noted
reduction of PGE2 production in either the
Echinacea
extracts or synthesized alkamides. HPLC analysis
identified individual alkamides present at concentrations below 2.8 µM in the extracts from the six
Echinacea
species (15 µg/ml crude extract). Because active extracts contained <2.8 µM of specific
alkamide and the results showed that synthetic alkamides must have a minimum concentration of 10
µM to inhibit PGE2, it is likely that alkamides may contribute toward the anti-inflammatory activity of
Echinacea
in a synergistic or additive manner (LaLone
et al.
2007).
Alcohol extracts from three widely used
Echinacea
species,
E. angustifolia
,
E. pallida
, and
E. 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 sRBC 4 days prior to collection of immune cells for multiple
immunological assays. The three 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 NK 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 IFN-
production,
but inhibited the release of TNF-
and IL-1
. 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).
It has been suggested that
Echinacea
has anti-inflammatory activity
in vivo
. Nitric oxide (NO), TNF-
and IL-1
are important mediators in the inflammatory response. The effect of alcohol extracts of
E.
angustifolia
(EA),
E. pallida
(EPA) and
E. purpurea
(EP) on the production of these inflammatory
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 14/31
mediators in both LPS-stimulated RAW264.7 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-
release in a dose-dependent manner. RAW264.7 cells treated with EA or EP showed decreased killing
over 24 h, although EA enhanced bacterial phagocytosis. Upon bacterial infection, RAW264.7 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 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
decreased during bacterial infection of PECs (Zhai
et al.
2007b).
In vitro
antioxidant activity
The protective effect of caffeoyl derivatives (echinacoside, chlorogenic acid, cichoric 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 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 microM 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 cichoric acid > cynarine approximately caffeic acid >
chlorogenic acid, with IC
50
ranging from 15 to 90 microM. 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 provides 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 which oxidative stress
plays a crucial role (Maffei Facino
et al.
1995).
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 (DPPH) 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 Cu2+. The
mechanisms of antioxidant activity of extracts derived from
Echinacea
roots included free radical
scavenging and transition metal chelating (Hu and Kitts 2000).
Alcoholic extracts of the roots and leaves of three
Echinacea
species (
E. purpurea
,
E. angustifolia
and
E. pallida
) were found to have antioxidant properties in a free radical scavenging assay and in a lipid
peroxidation assay. Cichoric acid and verbascoside predominated in extracts of
E. purpurea
(Sloley
et
al.
2001).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 15/31
The radical scavenging activity of
Echinacea
methanolic extracts was evaluated
in vitro
with a
spectrophotometric method based on the reduction of an alcoholic 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 (EC
50
= 6.6 µM), while caftaric acid had the lowest (EC
50
= 20.5
µM). The average EC
50
values for
E. purpurea
,
E. pallida
and
E. angustifolia
were 134, 167 and 231
µg/ml, respectively. The radical scavenging activity of
Echinacea
root extracts reflected their ph
composition. The results indicate that
Echinacea
roots and derivatives are a good source of natural
antioxidants and could be used to prevent free radical-induced deleterious effects (Pellati
et al.
2004).
enolic
After extraction, fractionation, and isolation, the antioxidant activity of three extracts, one alkamide
fraction, four polysaccharide-containing fractions, and three caffeic acid derivatives from
Echinacea
purpurea
root was evaluated by measuring their inhibition of
in vitro
Cu(II)-catalyzed oxidation of
human low-density lipoprotein. The antioxidant activities of the isolated caffeic acid derivatives were
compared to those of echinacoside, caffeic acid, and rosmarinic acid for reference. The order of
antioxidant activity of the tested substances was cichoric acid > echinacoside > derivative II > caffeic
acid > rosmarinic acid > derivative I. Among the extracts the 80% aqueous ethanolic extract exhibited
a 10 times longer lag phase prolongation (LPP) than the 50% ethanolic extract, which in turn exhibited
a longer LPP than the water extract. Following ion-exchange chromatography of the water extract, the
majority of its antioxidant activity was found in the latest eluted fraction (H2O-acidic 3). The
antioxidant activity of the tested
Echinacea
extracts, fractions, and isolated compounds was dose-
dependent. Synergistic antioxidant effects of
Echinacea
constituents were found when cichoric acid
(major caffeic acid derivative in
E. purpurea
) or echinacoside (major caffeic acid derivative in
E. pallida
and
E. angustifolia
) were combined with a natural mixture of alkamides and/or a water extract
containing the high molecular weight compounds. This contributes to the hypothesis that the
physiologically beneficial effects of
Echinacea
are exerted by the multitude of constituents present in
the preparations (Dalby-Brown
et al.
2005).
The antioxidant activity of extracts of the stems, leaves, and roots of
Echinacea purpurea
was
compared with the antioxidant activity of purified cichoric acid and alkamides, both constituents of
E.
purpurea
. The extracts were quantified by HPLC. The antioxidant activity was determined using
different methods: effect on oxygen consumption rate of a peroxidating lipid emulsion, and scavenging
of radicals, i.e. DPPH, measured by two different techniques. The efficacy of the extracts in the
reaction with DPPH correlated well with the amount of cichoric acid present in the various extracts. The
alkamides alone showed no antioxidant activity in any of the tests. Alkamides present in the extract
increased, however, the antioxidative effect of cichoric acid in the peroxidating lipid emulsion. The
activity was further compared with that of rosmarinic acid, a well-characterised antioxidant, and the
extracts as well as cichoric acid were found to be efficient scavengers of radicals with an activity
comparable to that of rosmarinic acid. Cichoric acid was found to have a stoichiometric factor of 4.0 in
scavenging DPPH and to react in a second-order reaction with DPPH with a rate constant of 40 L/mol/s
at 25°C in methanol (Thygesen
et al.
2007).
Other activities
Fibroblast-populated collagen lattice was used to study the influence of purple coneflower extracts on
the collagen contracting ability of C3H10T1/2 mouse fibroblasts. An ethanolic extract (65% V/V) of
purple coneflower root showed a dose-dependent inhibition of collagen gel contraction when added at
the time of preparation of the gel. A corresponding amount of ethanol showed no influence. With
increase of elapsed time between gel preparation and addition of extract, there was less inhibition of
elongation of fibroblasts and of the processes leading to collagen linking. No effect was observed when
the extract was added one hour after gel preparation (Zoutewelle
and Van Wijk 1990).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 16/31
Serial dilutions of 21 commercial ethanolic herbal extracts and tinctures, and 13 related pure plant
compounds have been analyzed for their
in vitro
cytochrome P450 3A4 (CYP3A4) inhibitory capability
via a fluorometric microtitre plate assay. Roughly 75% of the commercial products and 50% of the
pure compounds showed significant inhibition of CYP3A4 metabolite formation. For each herbal product
and pure compound exhibiting dose-dependency, the inhibition values were used to generate median
inhibitory concentration (IC
50
) curves using linear regression. Among the commercial extracts,
Hydrastis canadensis
(goldenseal),
Hypericum perforatum
(St. John's wort), and
Uncaria tomentosa
(cat's claw) had the lowest IC
50
values at < 1% full strength, followed by
Echinacea angustifolia
roots,
Trifolium pratense
(wild cherry),
Matricaria chamomilla
(chamomile), and
Glycyrrhiza glabra
(licorice),
which had IC
50
values ranging from 1%-2% of full strength.
Echinacea purpurea
root extract showed
moderate inhibitory activity (IC
50
> 5% and < 10% full strength. Dillapiol, hypericin, and naringenin
had the lowest IC
50
values among the pure plant compounds at < 0.5 mM; dillapiol was the most
potent inhibitor at 23.3 times the concentration of the positive CYP3A4 inhibitor ketoconazole
(Budzinski
et al.
2000).
The effect of
Echinacea purpurea
root extract (prepared with 50% aqueous ethanol, DER was not
given) on the weight of prostates in rats as well as on alterations of histological structure and separate
blood cells was studied. Experiments were carried out with 3-month old male Wistar rats, divided by 6
into 3 different groups. The first group was the control one. The rats of the second group were fed for
30 days with the usual food ration plus 50 mg/kg of
Echinacea
extract. The third group was fed for 60
days in the same way as the second one. After weighing the rats their prostates were removed and
weighed. The weight of prostates in the first group of rats was 412.0±14.93 mg, in the second group
403.0±13.33 mg, and in the third group it was 388.0±14.66 mg. Having calculated the proportion
between prostates of rats and their body weight it was estimated that in the first group it made
0.125±0.009%, in the second group 0.105±0.005%, and in the third group 0.091±0.007%. The
percentage of lymphocytes in the first group was 72±1.41; in the second group 73±0.81; in the third
group 79±1.86. The percentage of segmented neutrophils in the first group was 23±3.31; in the
second group 23±2.25; in the third group 18±2.33. Having conducted analysis of the experimental
results, a significantly important decrease of prostate weight of investigated rats, an increase in the
number of lymphocytes as well as the alterations of histological structures after using
Echinacea
extract for 8 weeks were observed (Skaudickas
et al.
2003).
The effect of
Echinacea purpurea
extract (prepared with 50% aqueous ethanol, DER was not given) on
a rat testicle and epididymis was examined, the mass of these organs was determined, the proportion
between the mass of the organ and the mass of a body was calculated, the changes in histological
structures were evaluated in this study. Experiments with the Wistar line 3-month old male rats were
carried out. There were 3 experimental groups of rats. The first one was control group. The rats of the
second group were fed on the usual food enriched with the
Echinacea
extract additive with the
proportion of 50 mg/kg for 4 weeks. The rats in the third group were fed equally to the second one for
8 weeks. The rats were weighed, the testicles and epididymis were eliminated, and pathohistological
examinations were carried out. Calculations of the relative quantity between the mass of the organs
and the body weight were made and it was estimated that the testicles of the rats in the first group
made up 0.496±0.399% of a body mass, in the second one 0.459±0.419%, and in the third one
0.429±0.410%. The epididymis in the control group made up 0.189±0.332% of a body mass; in the
second one 0.1733±0.328%, and in the third one 0.1723±0.198%. The histological structural changes
were traced after 4 weeks of using the preparation; however they became more obvious after 8 weeks.
Results of the study enabled to determine statistically significant reduction in the percentage of a
testicle and the body mass, as well as changes in histological structures after 8 weeks of consuming
extract of
E. purpurea
(Skaudickas
et al.
2004).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 17/31
It was shown that the alkylamides dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (A1) and
dodeca-2E,4E-dienoic acid isobutylamide (A2) bind to the CB2 receptor more strongly than the
endogenous cannabinoids. The Ki values of A1 and A2 (CB2~60 nM; CB1>1500 nM) were determined
by displacement of the synthetic high affinity cannabinoid ligand [3H]CP-55,940. Molecular modelling
suggests that alkylamides bind in the solvent-accessible cavity in CB2, directed by H-bonding and
-
interactions. In a screen with 49 other pharmacologically relevant receptors, it could be shown that A1
and A2 specifically bind to CB2 and CB1. A1 and A2 elevated total intracellular Ca2+ inCB2-positive but
not in CB2-negative promyelocytic HL60 cells, an effect that was inhibited by the CB2 antagonist
SR144528. At 50 nM A1, A2, and the endogenous cannabinoid anandamide (CB2 Ki >200 nM) up-
regulated constitutive IL-6 expression in human whole blood in a seemingly CB2-dependent manner.
A1, A2, anandamide, the CB2 antagonist SR144528 (Ki <10 nM), and also the non-CB2-binding
alkylamide undeca-2E-ene-8,10-diynoic acid isobutylamide all significantly inhibited LPS-induced TNF-
, IL-1β, and IL-12p70 expression (5–500 nM) in a CB2-independent manner. Alkylamides and
anandamide also showed weak differential effects on anti-CD3- versus anti-CD28-stimulated cytokine
expression in human whole blood. Overall, alkylamides, anandamide, and SR144528 potently inhibited
LPS-induced inflammation in human whole blood and exerted modulatory effects on cytokine
expression, but these effects are not exclusively related to CB2 binding (Raduner
et al.
2006).
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 (
E. pallida
(Nutt.) Nutt.,
E. angustifolia
DC. var.
angustifolia
,
E. purpurea
(L.)
Moench) on the human pancreatic cancer MIA PaCa-2 and colon cancer COLO320 cell lines. The
authors concluded that it was demonstrated, for the first time, that all the three species reduced cell
viability in a concentration- and time-dependent manner. These results represent the starting point to
establish viable scientific evidence on the possible role of
Echinacea
species in medical oncology
(Chicca
et al.
2007).
The curative efficacy of an
Echinacea
extract (Echinacin®; Madaus AG, Germany) in γ-irradiated mice
is reported.
E. purpurea
was given to male mice that were divided into 5 groups (control, treated,
irradiated, treated before irradiation & treated after irradiation) at a dose of 30 mg/kg body weight for
2 weeks before and after irradiation with 3 Gy of γ-rays. The results reflected the detrimental reduction
effects of γ-rays on peripheral blood hemoglobin and the levels of red blood cells, differential white
blood cells, and bone marrow cells. The thiobarbituric acid-reactive substances (TBARs) level,
superoxide dismutase (SOD) and glutathione peroxidase (GSPx) activities and DNA fragmentation were
also investigated. FT-Raman spectroscopy was used to explore the structural changes in liver tissues.
Significant changes were observed in the microenvironment of the major constituents, including
tyrosine and protein secondary structures.
E. purpurea
administration significantly ameliorated all
estimated parameters. The radio-protection effectiveness was similar to the radio-recovery
curativeness in comparison to the control group in most of the tested parameters. The radio-protection
efficiency was greater than the radio-recovery in haemoglobin level during the first two weeks, in
lymphoid cell count and TBARs level at the fourth week and in SOD activity during the first two weeks,
as compared to the levels of these parameters in the control group (Abouelella et al. 2007).
Effect of Immunal forte® (containing dry ethanol-water extract of herb), Echinapur® (containing thick
extract of herb) and Esberitox® (combination product containing extracts of
Thuja occidentalis
,
Baptisia tinctoria
,
Echinacea purpurea
and
Echinacea pallida
) on mice fetuses was studied to establish
whether pharmaceuticals containing alcoholic extracts of
E. purpurea
given to pregnant mice influence
angiogenic activity and tissue VEGF and bFGF production of their fetuses. It was shown that angiogenic
activity of tissue homogenates was increased in Esberitox® group and diminished in case of Immunal
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 18/31
forte® as compared to standard diet group. In case of Echinapur® group no significant differences in
angiogenic activity were found. VEGF and bFGF concentration were lower in all groups compared to the
control. In the case of Echinapur® and Esberitox® number of fetuses in one litter were slightly lower
as compared to control group, but the difference is on the border of statistical significance. In
conclusion, there is some possibility that pharmaceuticals containing
E. purpurea
might influence fetal
development in human also, because they may interfere with embryonal angiogenesis , and should not
be recommended for pregnant women (Barcz
et al.
2007).
The six commonly used trade herbal products, St. John's wort, common valerian, common sage,
Ginkgo biloba,
Echinacea purpurea
and horse chestnut, and ethanol, were investigated for their
in vitro
inhibitory potential of cytochrome P450 2D6 (CYP2D6)-mediated metabolism. Herbal components were
extracted from commercially available products in a way that ensured the same composition of
constituents in the extract as in the original trade products. c-DNA baculovirus expressed CYP2D6 was
used with dextromethorphan as substrate. Quinidine was included as a positive control inhibitor. A
validated HPLC methodology was used to quantify the formation of dextrorphan (product of
dextromethorphan O-demethylation). Ethanol showed a biphasic effect on CYP2D6 metabolism,
increasing initially the CYP2D6 activity with 175% of control up to a concentration of 1.1%, where after
ethanol linearly inhibited the CYP2D6 activity. All the investigated herbs inhibited CYP2D6 activity to
some extent, but only St. John's wort, common sage and common valerian were considered possible
candidates for
in vivo
clinically significant effects. They showed IC
50
values of 0.07 +/- 7 x 10(-3)
mg/ml, 0.8 +/- 0.05 mg/ml and 1.6 +/- 0.2 mg/ml, respectively. St. John's wort inhibited CYP2D6-
mediated metabolism in an uncompetitive manner, while common valerian and common sage in a non-
competitive manner demonstrated interherb differences in inhibition patterns and differences when
compared to the more homogenous competitive inhibitor quinidine. Common valerian was the only
herb that showed a mechanistic inhibition of CYP2D6 activity and attention should be paid to a possible
toxicity of this herb (Hellum and Nilsen 2007).
The n-hexane root extracts from
Echinacea pallida
,
E. angustifolia
and
E. 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-(8Z,13Z)-dien-11-yn-2-one was the most efficient compound, being
able to decrease the calcein-AM efflux about three-fold with respect to the control at 30 µg/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. 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 (Chicca
et al.
2008).
Assessor’s overall conclusions on pharmacology
For the extracts, fractions and isolated compounds of purple coneflower root, immunomodulatory
(purified polysaccharides, glycoproteins, alkamides), antimicrobial, antiviral (fraction containing
polysaccharides and glycoproteins), anti-inflammatory (polyunsaturated isobutylamides, echinacoside),
antioxidant (caffeoyl derivatives), cytochrome enzyme inhibitory, antiandrogenic, cannabinoidomimetic
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 19/31
(alkylamides), radioprotective and antitumor effects (polyacetylenes, polyenes) were proven in several
in vitro
and
in vivo
tests. However, most of the pharmacological mechanisms and active compounds
responsible for the effects still remain to be elucidated. Regarding combination products, it is difficult
to say, which component is the active one, the pharmacological effects are probably achieved by
synergistic effect.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Studies of transport of alkamides trough a cultured monolayer of colonic cells were performed on
human adenocarcinoma colonic cell line Caco-2 (ATCC) as a model to assess the epithelial transport of
dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides. 30 minutes after apical loading of 25 µg/ml,
about 15% of these alkamides were detectable on the basolateral side. Close monitoring of the
transport during 6 hours revealed a nearly complete transport to the basolateral side after 4 hours and
no significant metabolism was observable. Transport experiments performed at 4oC showed only a
slight decrease in transport, which is a strong hint that dodeca-2E,4E,8Z,10E/Z-tetraenoic acid
isobutylamides cross biological membranes by passive diffusion. Nearly the same results were obtained
after preincubation of the Caco-2 cells with LPS or phorbol 12-myristate-13-acetate to mimic an
inflammatory status. These results support the assumption that the alkamides can be easily
transported from the intestine and hence may contribute to the
in vivo
effects of Echinacea
preparations (Jager
et al.
2002).
Transport of 12 alkamides and 5 caffeic acid conjugates from a proprietary preparation of
Echinacea
(Echinacea Premium® Liquid; MediHerb, Austria) which contains 60% ethanol/water extract of
E.
angustifolia
root (200 mg/ml) and
E. purpurea
root (300 mg/ml) was studied on Caco-2 monolayers.
Almost all of the caffeic acid conjugates permeated poorly through the Caco-2 monolayers: their
uptake was no better than that of control (mannitol). By contrast, both 2,4-diene and 2-ene alkamides
readily diffused through the monolayers. Theses findings suggest that alkamides would be bioavailable
following oral administration (Matthias
et al.
2004).
The metabolism by human liver microsomes of the alkylamide components from an
Echinacea
preparation as well as that of pure synthetic alkylamides was investigated. No significant degradation
of alkylamides was evident in cytosolic fractions. Time- and NADPH-dependent degradation of
alkylamides was observed in microsomal fractions suggesting they are metabolised by cytochrome
P450 (CYP450) enzymes in human liver. There was a difference in the susceptibility of 2-ene and 2,4-
diene pure synthetic alkylamides to microsomal degradation with (2E)-N-isobutylundeca-2-ene-8,10-
diynamide (1) metabolised to only a tenth the extent of (2E,4E,8Z,10Z)-N-isobutyldodeca-2,4,8,10-
tetraenamide (3) under identical incubation conditions. Markedly less degradation of 3 was evident in
the mixture of alkylamides present in an ethanolic
Echinacea
extract, suggesting that metabolism by
liver P450s was dependent both on their chemistry and the combination present in the incubation. Co-
incubation of 1 with 3 at equimolar concentrations resulted in a significant decrease in the metabolism
of 3 by liver microsomes. This inhibition by 1, which has a terminal alkyne moiety, was found to be
time- and concentration-dependent, and due to a mechanism-based inactivation of the P450s.
Alkylamide metabolites were detected and found to be the predicted epoxidation, hydroxylation and
dealkylation products. These findings suggest that
Echinacea
may affect the P450-mediated
metabolism of other concurrently ingested pharmaceuticals (Matthias
et al.
2005a).
Assessor’s overall conclusions on pharmacokinetics
In pharmacokinetic studies only alkamides and caffeic acid conjugates were investigated. It was shown
that alkamides (in contrast with caffeic acid conjugates) readily diffuse through the monolayers of
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 20/31
Caco-2 cells. This supports the assumption that the alkamides can be easily transported from the
intestine and hence may contribute to the
in vivo
effects of
Echinacea
preparations. Study of
metabolism suggests that alkamides of
Echinacea
are metabolised by cytochrome P450 and may affect
the CYP450-mediated metabolism of other concurrently ingested pharmaceuticals.
These data must be confronted with clinical data – see section ‘Drug interactions’ under 5.5.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
In general, animal studies with different preparation and fractions of
Echinacea
species have indicated
low toxicity (Barrett 2003).
Acute toxicity of
Echinacea purpurea
root extract was > 3000 mg/kg after p.o. application to NMRI
mice. Specifications for the extract are not available (Bauer and Liersch 1993).
Single oral or intravenous doses of the expressed juice of
Echinacea purpurea
(EP) proved virtually
non-toxic to rats and mice. After 4 weeks of oral administration in doses amounting to many times the
human therapeutic dose laboratory tests and necropsy findings gave no evidence of any toxic effects in
rats. Tests for mutagenicity carried out in microorganisms and mammalian cells
in vitro
and in mice all
gave negative results. In an
in vitro
carcinogenicity study EP did not produce malignant transformation
in hamster embryo cells (Mengs
et al.
1991).
Six major herbal references published from 1996 to 2000 were selected to evaluate the adequacy of
their toxicological information in light of published adverse events. To identify herbs most relevant to
toxicology, herbal-related calls to regional California Poison Control System, San Francisco division
(CPCS-SF) in 1998 were reviewed and 12 herbs were identified (defined as botanical dietary
supplements) most frequently involved in these CPCS-SF referrals. Medline was searched
(1966 to
2000) to identify published reports of adverse effects potentially related to these same 12 herbs. Each
herbal reference text was scored on the basis of information inclusiveness for the target 12 herbs, with
a maximal overall score of 3. The herbs, identified on the basis of CPCS-SF call frequency were: St
John's wort, ma huang, echinacea, guarana, ginkgo, ginseng, valerian, tea tree oil, goldenseal, arnica,
yohimbe and kava kava. The overall herbal reference scores ranged from 2.2 to 0.4 (median 1.1). The
Natural Medicines Comprehensive Database received the highest overall score and was the most
complete and useful reference source. All of the references, however, lacked sufficient information on
management of herbal medicine overdose, and several had incorrect overdose management guidelines
that could negatively impact patient care. Current herbal reference texts do not contain sufficient
information for the assessment and management of adverse health effects of botanical therapies
(Haller
et al.
2001).
Reports to poison control centers (PCCs) were characterised involving two widely used herbal dietary
supplements (HDSs),
Echinacea
, and St. John's wort (SJW). METHODS: Data were purchased from the
American Association of Poison Control Center's (AAPCC) toxic exposure surveillance system (TESS(R))
on reports made to PCCs in 2001 involving Echinacea or SJW. Analyses were limited to those cases in
which
Echinacea
or SJW were the only associated products, and in which these HDSs were deemed
primary to observed adverse effects. Descriptive statistics were generated for selected demographic
and exposure-related variables. During 2001, PCCs were contacted regarding 406 exposures involving
Echinacea
and 356 exposures involving SJW. Most of the reported exposures for both HDSs occurred
among children 5 years and younger, and the majority of exposures were coded as unintentional. For
both HDSs, exposures among patients >/=20 years old were more likely to be associated with adverse
effects. Intentional exposures accounted for 21% of SJW cases and 3% of
Echinacea
cases, with 13%
of SJW exposures reported as 'suspected suicidal'. TESS represents a potentially important means of
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 21/31
assessing and characterizing HDS-related adverse effects. Detailed studies validating the clinical
events and outcomes of a sample of exposures reported to TESS(R) might offer substantial insights
into adverse events that could be systematically studied with other, established
pharmacoepidemiological study designs (Gryzlak
et al.
2007).
Assessor’s overall conclusions on toxicology
In general, the toxicity of
Echinacea purpurea
is low. However, the data on purple coneflower root
toxicity are limited and findings are sometimes difficult to interpret since there is a lack of detail
regarding the tested preparation or the part of the plant of
E. purpurea
. Tests on reproductive toxicity,
genotoxicity and carcinogenicity have not been performed on the dry ethanolic extract included in the
Community herbal monograph.
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
Five placebo-controlled randomized studies investigating the immunomodulatory activity of
preparations containing extracts of
Echinacea
in healthy volunteers were studied. A total of 134 (18
female and 116 male) healthy volunteers between 18 and 40 years of age were studied. Two studies
(2 and 3a) tested oral alcoholic extracts of roots of
E. purpurea
, (2: ethanolic extract, corresponding to
333 mg of roots, 3a: 380 mg of dried extract made with 50% ethanol (V/V)) one study an extract of
E.
pallida
roots (study 3b), and one study an extract of
E. purpurea
herb (study 4). Test and placebo
preparations were applied for four (study 5) or five (studies 1-4) consecutive days. The primary
outcome measure for immunomodulatory activity was the relative phagocytic activity of
polymorphonuclear neutrophil granulocytes (PNG), measured in studies 1 and 2 with a microscopic
method and in studies 3, 4, and 5 with two different cytometric methods. The secondary outcome
measure was the number of leukocytes in peripheral venous blood. Safety was assessed by a
screening program of blood and other objective parameters as well as by documentation of all
subjective side effects. In studies 1 and 2 the phagocytic activity of PNG was significantly enhanced
compared with placebo [maximal stimulation 22.7% (95% confidence interval [CI] 17.5-27.9%) and
54.0% (8.4-99.6%), respectively], while in the other studies no significant effects were observed.
Analysis of intragroup differences revealed significant changes in phagocytic activity during the
observation periods in five test and three control groups. Leukocyte number was not influenced
significantly in any study. Side effects due to the test preparations could not be detected. The study
showed immunomodulatory activity of the
E. purpurea
radix extract tested in study 2. The negative
results of the other 3 studies are difficult to interpret due to the different methods for measuring
phagocytosis, the relevant changes in phagocytic activity within most placebo and treatment groups
during the observation period, and the small sample sizes. Further studies should be performed on
patients rather than healthy volunteers and use standardized or chemically defined monopreparations
of
Echinacea
(Melchart
et al.
1995).
In a double-blind study, 24 healthy male volunteers took three times 30 drops of an ethanolic extract
of purple coneflower root (detailed specifications of the extract are not given) or placebo daily for 5
days. By day 5 a significant increase in phagocytosis of 120% was observed in the verum group,
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 22/31
compared to 20% in the placebo group. The effect was transient and phagocytotic activity returned to
normal within 6 days (Jurcic
et al.
1989).
The effect of Echinacea Premium® tablets containing 675 mg of
E. purpurea
root extract and 600 mg
of
E. angustifolia
root extract, prepared by ethanol extraction (MediHerb, Warwick, Australia) on the
expression of leucocyte heat shock protein 70 (hsp70), erythrocyte haemolysis, plasma antioxidant
status, serum chemistry, haematological values and plasma alkylamide concentrations. Eleven healthy
individuals (26–61 years of age) were evaluated at baseline (day 1) and on day 15 after consuming
two commercially blended
Echinacea
tablets daily for 14 days.
Echinacea
supplementation enhanced
the fold increase in leucocyte hsp70 expression after a mild heat shock (P = 0.029). White cell counts
(WCC) were also increased (P = 0.043). A preventative effect against free radical induced erythrocyte
haemolysis (P = 0.006) indicative of an antioxidant effect was also observed. The pilot study suggests
that
Echinacea
may invoke an immune response through altered expression of hsp70 and increased
WCC (Agnew
et al.
2005).
Echinilin® (extract of herb and root of
Echinacea purpurea
) or placebo were administered to volunteers
at the onset of their cold for a period of 7 days, with 8 doses (5 ml/dose) on day 1 and 3 doses on
subsequent days. Fasting blood samples were obtained before and during their colds. The decrease in
total daily symptomatic score was more evident in the
Echinacea
group than in the placebo group.
These effects of
Echinacea
were associated with a significant and sustained increase in the number of
circulating total white blood cells, monocytes, neutrophils and NK cells. In the later part of the cold,
the
Echinacea
treatment suppressed the cold-related increase in superoxide production by the
neutrophils. These results suggested that Echinilin®, by enhancing the non-specific immune response
and eliciting free radical scavenging properties, may have led to a faster resolution of the cold
symptoms (Goel
et al.
2005).
Assessor’s overall conclusions on pharmacodynamics
Increased phagocytosis was observed in two studies on purple coneflower root extract as a single
ingredient, unfortunately detailed composition of extracts is not available. In other two studies
combination herbal products were investigated and it is difficult to interpret which plant or part of
E.
purpurea
plant was responsible for the effect (leucocyte hsp70 expression, increased WCC,
preventative effect against free radical induced erythrocyte haemolysis, antioxidant effect, suppressed
cold-related increase in superoxide production by the neutrophils).
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
Serial plasma samples from 9 healthy volunteers who ingested
Echinacea
tablets manufactured from
both ethanolic liquid extracts of
E. angustifolia
and
E. purpurea
immediately after a standard high fat
breakfast were examined. Caffeic acid conjugates could not be identified in any plasma sample at any
time after tablet ingestion. Alkamides were rapidly absorbed and were measurable in plasma 20 min
after tablet ingestion and remained detectable for up to 12 h. Concentration-time curves for 2,4-diene
and 2-ene alkamides were determined. The maximal concentrations for the sum of alkamides in
human plasma were reached within 2.3 hours post ingestion and averaged 336±31 ng eq/ml plasma.
No obvious differences were observed in the pharmacokinetics of individual or total alkamides in 2
additional fasted subjects who took the same dose of the
Echinacea
preparation. (Matthias
et al.
2005b).
The relative oral bioavailability of alkylamides from two different
Echinacea
dosage forms (liquid and
tablet) were compared in a small two-way crossover study in humans (n = 3). The liquid preparation
investigated contained a mixture of
E. purpurea
root (300 mg/ml) and
E. angustifolia
root (200 mg/ml)
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 23/31
extracted in 60% ethanol. The tablet preparation investigated was also a mixture of
E. purpurea
root
(675 mg/tablet) and
E. angustifolia
root (600 mg/tablet), but was prepared from the dried 60%
ethanolic extracts of these two
Echinacea
species. Alkylamides were found to be rapidly absorbed and
measurable in plasma from both preparations. No significant differences in the tetraene alkylamide
pharmacokinetic parameters for T
1/2
, AUCt-lin and C
max
in the two different preparations were found.
T
max
increased from 20 min for the liquid to 30 min for the tablet, which is not unexpected as the
tablet required time for disintegration before absorption could occur. These results suggested that
there was no significant difference in the bioavailability of alkylamides from the liquid and tablet
Echinacea
formulations. Furthermore, the results also indicated that the absorption site and any
alkylamide loss due to digestive processes were similar in both preparations (Matthias
et al.
2007).
Assessor’s overall conclusions on pharmacokinetics
Evidence were provided that alkamides are orally available from liquid extracts and tablets and that
their pharmacokinetics is in agreement with the daily regimen already recommended for
Echinacea
and
there was no significant difference in the bioavailability of alkylamides from the liquid and tablet
Echinacea
formulations. In contrast, caffeic acid conjugates could not be identified in any plasma
sample; therefore their oral bioavailability is questionable.
4.2.
Clinical Efficacy
Several papers have been published reviewing studies of the effects of
Echinacea purpurea
herbal
products (aerial parts, roots and combinations) in clinical trials (Barnes
et al.
2005, Barnes
et al.
2007,
Barrett 2003, Bradley 2006, ESCOP 2003 and 2009, PDR 2007, Blumenthal
et al.
2000, Bauer and
Liersch 1993, Linde
et al.
2006, Melchart
et al.
1994, Melchart
et al.
2004, Schoop
et al.
2006, Shah
et
al.
2007).
4.2.1.
Dose response studies
In a double-blind, placebo-controlled study, 180 patients (18-60 years old) with influenza, randomized
into three groups of 60, were given a tincture of purple coneflower root made with 55% ethanol (V/V)
at daily dosages corresponding to 459 mg or 900 mg of dried root, or placebo. After 3-4 days and 8-10
days, there was no statistical difference in symptoms between the group taking the 450 mg dose and
the placebo group. In contrast, the group taking the 900 mg dose showed a highly significant reduction
in symptom score at both time points (p < 0.0001). An effect from the higher dose was seen after 3 to
4 days, but the full effect was not seen for 8-10 days (Bräunig
et al.
1992). This trial is frequently
referred to as a plausible evidence of the efficacy of preparations of
E. purpurea
root, for the treatment
of symptoms associated with common cold (Blumenthal
et al.
2000, Melchart
et al.
1994, Barrett
et al.
1999).
4.2.2.
Clinical studies (case studies and clinical trials)
Echinacea purpurea
as a single ingredient
289 volunteers from four military establishments and one industrial plant participated in a double-
blind, placebo-controlled study to investigate the efficacy of
Echinacea
extracts in the prevention of
upper respiratory tract infections. Randomised groups were instructed to take twice daily for 12 weeks
50 drops (ca. 1 ml) of one of three trial preparations: ethanolic extract (1: 11, ethanol 30%) of purple
coneflower root (Group A, n = 99) or
E. angustifolia
root (Group B, n = 100), or an ethanolic placebo
solution (Group C, n = 99). 244 participants fully conformed with the protocol: 85, 84 and 75 in
Groups A, B and C, respectively. The average time until occurrence of first upper respiratory tract
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 24/31
infections was 69, 66 and 65 days, and 29%, 32% and 37% of participants had at least one upper
respiratory tract infection, in Groups A, B and C, respectively. Although perhaps suggesting a relative
reduction in risk of infection of 20% for purple coneflower root compared to placebo, the results were
not statistically significant (Melchart
et al.
1998).
In a randomized, double-blind, placebo-controlled study the efficacy and safety of different doses and
preparations of
Echinacea purpurea
in the treatment of common cold. 246 of 559 recruited healthy,
adult volunteers caught a common cold and took 3 times daily 2 tablets of either Echinaforce®
(
Echinacea purpurea
-preparation from 95% herba and 5% radix),
Echinacea purpurea
concentrate
(same preparation at 7 times higher concentration), special
Echinacea purpurea
radix preparation (dry
extract from root, 29.6 mg per tablet) or placebo until they felt healthy again but not longer than 7
days. The primary endpoint was the relative reduction of the complaint index defined by 12 symptoms
during common cold according to the doctor's record. Echinaforce® and its concentrated preparation
were significantly more effective than the special
Echinacea
extract or placebo. All treatments were
well tolerated. Among the
Echinacea
groups the frequency of adverse events was not significantly
higher than in the placebo group. Therefore,
Echinacea
concentrate as well as Echinaforce® represent
a low-risk and effective alternative to the standard symptomatic medicines in the acute treatment of
common cold (Brinkeborn
et al.
1999).
Echinacea purpurea
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
(
purpureae
+
pallidae
= 1 + 1) and
Radix baptisiae
, 2, 7.5
and 10 mg per tablet, respectively. The aim of the study was to verify clinical efficacy shown in recent
studies under (i) good clinical practice (GCP) quality assurance and (ii) common situations at family
doctors. Patients attending one of 15 study centres (practitioners) as a result of an acute common cold
were randomised to the double-blind placebo-controlled study. Three tablets of study medication were
applied t.i.d. for 7 to 9 days. Patients daily documented the intensity of 18 cold symptoms, as well as
the cold overall, using a 10-point scale and estimated their general well-being using the Welzel-Kohnen
colour scales. Additionally, the severity of illness was assessed by the physician on days 4 and 8 (CGI-
1). The main and confirmatory outcome measure was expressed as a total efficacy value. This was
gauged from the z-standardised AUC values of the primary endpoints (rhinitis score, bronchitis score,
CGI-1 and general well-being). Adverse events, overall tolerability, vital signs and laboratory
parameters were documented. For safety analysis, all patients were used. 259 patients were evaluable
for primary efficacy analysis (ITT). Results were confirmed analysing only the 238 valid cases (VCs).
The primary efficacy parameters showed the superiority of the herbal remedy over placebo (p < 0.05).
Effect size was 20.6% of the standard deviation (90% CI: 0.04-41.1%; ITT) and 23.1% (1.7-44.5%;
VC). In relation to the general well-being, the effect size was 33.9% of the standard deviation (12.5-
55.3%; VC). Patients who suffered from at least moderate symptom intensity at baseline showed
response rates (at least 50% improvement of the global score, day 5) of 55.3% in the herbal remedy
group and 27.3% in the placebo group (p = 0.017; NNT = 3.5). In the subgroup of patients who
started therapy at an early phase of their cold, the efficacy of the herbal remedy was most prominent
(p = 0.014 for the primary efficacy parameter). 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. At that time, equal levels of improvement were reached
three days earlier in the verum group than in the placebo group. In 26 patients receiving the herbal
remedy and 23 patients receiving placebo, adverse events were reported. Adverse drug reactions were
suspected in 2 patients in the verum group and in 4 patients in the placebo group. Serious adverse
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 25/31
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. If patients with colds are able to
start the application of the herbal remedy as soon as practical after the occurrence of the initial
symptoms, the benefit would be expected to increase (Henneicke-von Zepelin
et al.
1999).
The aim of this study was to determine the efficacy of an
Echinacea
compound herbal tea preparation
Echinacea Plus® (comprising
E. purpurea
herb and extract of
E. purpurea
root equivalent to 1275 mg
dried herb and root per tea bag) given at early onset of cold or flu symptoms in a random assignment
double-blind placebo-controlled study. A total of 95 subjects with early symptoms of cold or flu (runny
nose, scratchy throat, fever) were randomly assigned to receive Echinacea Plus® tea 5 to 6 cups per
day titrating to 1 over 5 days or placebo in a double-blind situation. Each participant completed a
questionnaire 14 days after beginning the program. The efficacy, number of days the symptoms lasted
and number of days for change were measured with a self scoring questionnaire. The study period was
90 days (1 January 1999 to 30 March 1999). There was a significant difference between the
experimental group (Echinacea Plus®) and control group (placebo) for all 3 questions measured: p <
0.001. There were no negative effects reported by any of the subjects in either group. Treatment with
Echinacea Plus® tea at early onset of cold or flu symptoms was effective for relieving these symptoms
in a shorter period of time than a placebo (Lindenmuth and Lindenmuth 2000).
The efficacy of dried, encapsulated, whole-plant
Echinacea
as early treatment for the common cold in a
randomised, double-blind, placebo-controlled community-based trial at the University of Wisconsin, on
148 students with common colds of recent onset was assessed. Each active capsule contained a dried
mixture of
E. angustifolia
root (50% [123 mg]),
E. purpurea
root (25% [62 mg]), and
E. purpurea
herb (25% [62 mg]).
Echinacea
capsules also contained thyme (49 mg) and peppermint (31 mg) to
disguise taste and flavour, as well as citric acid (3 mg) as a preservative. The placebo capsules
contained 333 mg of alfalfa. The patients took 4 capsules 6 times during the first 24 hours of the
study, and 4 capsules 3 times each day thereafter until symptoms resolved, for a maximum of 10
days. Severity and duration of self-reported symptoms of upper respiratory tract infection were
recorded. No statistically significant differences were detected between the
Echinacea
and placebo
groups for any of the measured outcomes. Trajectories of severity over time were nearly identical in
the 2 groups. Mean cold duration was 6.01 days in both groups as a whole, 5.75 days in the placebo
group, and 6.27 days in the
Echinacea
group (between-group difference, -0.52 day [95% CI, -1.09 to
0.22 days]). After controlling for severity and duration of symptoms before study entry, sex, date of
enrolment, and use of nonprotocol medications, researchers found no statistically significant treatment
effect (adjusted hazard ratio, 1.24 [CI, 0.86 to 1.78]). Multivariable regression models assessing
severity scores over time failed to detect statistically significant differences between the Echinacea and
placebo groups (Barrett
et al.
2002).
A formulation containing alkamides, cichoric acid, and polysaccharides at concentrations of 0.25, 2.5,
and 25 mg/ml, respectively, was prepared from freshly harvested
Echinacea purpurea
herb and root
(commercially available as Echinilin®, Natural Factors Nutritional Products, Inc., Vancouver, BC,
Canada). The objective of this study was to test the efficacy of this highly standardized formulation in
reducing the severity and duration of symptoms of a naturally acquired common cold. In a
randomized, double-blind, placebo-controlled trial, 282 subjects aged 18-65 years with a history of two
or more colds in the previous year, but otherwise in good health, were recruited. The subjects were
randomized to receive either
Echinacea
or placebo. They were instructed to start the Echinacea or
placebo at the onset of the first symptom related to a cold, consuming 10 doses the first day and 4
doses per day on subsequent days for 7 days. Severity of symptoms (10-point scale: 0, minimum; 9,
maximum) and dosing were recorded daily. A nurse examined the subjects on the mornings of days 3
and 8 of their cold. A total of 128 subjects contracted a common cold (59
Echinacea
, 69 placebo). The
total daily symptom scores were found to be 23.1% lower in the
Echinacea
group than in placebo in
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 26/31
those who followed all elements of the study protocol (P < 0.01). Throughout the treatment period, the
response rate to treatments was greater in the
Echinacea
group. A few adverse event profiles were
observed in both groups. Early intervention with a standardized formulation of
Echinacea
resulted in
reduced symptom severity in subjects with naturally acquired upper respiratory tract infection. Further
studies with larger patient populations appear to be warranted (Goel
et al.
2004).
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No data available.
4.3.
Overall conclusions on clinical pharmacology and efficacy
Purple coneflower root extract did not prove to be successful in preventing of upper respiratory tract
infection in one double-blind, placebo-controlled study, it also did not prove to be successful in the
treatment of common cold in other study. In only one double-blind, placebo-controlled study on
patients with influenza, a tincture of purple coneflower root (1:5, ethanol 55%) showed significant
reduction in symptom score at both time points (after 3-4 and 8-10 days) and the effect was dose-
dependent.
In 3 double-blind, placebo-controlled trials
Echinacea purpurea
root in combination with other herbal
drugs was reported to be successful in reducing the severity of symptoms of common cold or flu. There
was no significant difference between placebo and verum group in one double-blind, placebo-controlled
trial. The results are difficult to interpret, it is difficult to say which component is the active one, and
the pharmacological effects are probably achieved by synergistic effect.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
See below.
5.2.
Patient exposure
A systematic review, based on clinical studies, case reports and surveillance programmes of national
medicines regulatory authorities and WHO, concluded that
Echinacea
products have a good safety
profile when taken in the short term, while data on long-term use is not available. If adverse events
occur they tend to be transient and reversible, the most common being gastrointestinal or skin related
(Huntley
et al.
2005).
No adverse events were reported in a clinical study in which 180 patients randomised in 3 groups of 60
patients with influenza received oral treatment daily for 10 days with a tincture of purple coneflower
root made with ethanol 55% (V/V), equivalent to 450 mg or 900 mg of dried root; the preparation
was well tolerated (Bräunig
et al.
1992).
In a clinical study, 10 out 99 subjects who took 2 times 50 drops (2 times 1 ml) of a hydroethanolic
extract of purple coneflower root (detailed specifications of the extract are not given) daily for 12
weeks reported adverse effects, compared to 11 out of 90 subjects in the placebo group; none of the
adverse effects were serious or required therapeutic action (Melchart
et al.
1998).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 27/31
5.3.
Adverse events and serious adverse events and deaths
In rare cases hypersensitivity reactions e.g. skin reactions may occur (ESCOP 2003 and 2009, Bauer
and Liersch 1993, Blumenthal
et al.
2000, Mullins 1998). Individuals with allergic tendencies,
particularly those with known allergy to other members of the Asteraceae family should be advised to
avoid
Echinacea
(Barnes
et al.
2007, Bauer and Liersch 1993).
In an analysis of the Australian Adverse Drug Reactions Advisory Committtee’s database of events of
IgE-mediated hypersensitivity reactions, 51 reports were found to be related to
Echinacea
use. 26
reactions including urticaria, angio-oedema, asthma and anaphylaxis were confirmed to be IgE-
mediated reactions to
Echinacea
. More than half of the affected patients had a history of asthma,
allergic rhinitis or atopic dermatitis. Four persons required hospitalization due to their reactions and no
deaths occurred. In 94% of patients, the symptoms appeared within 24 hours of
Echinacea
ingestion.
80% of the patients included were female and the medium age was 32 years (PDR 2007, Mullins &
Heddle 2002).
Serious adverse events and deaths
None reported.
5.4.
Laboratory findings
No data available.
5.5.
Safety in special populations and situations
Intrinsic (including elderly and children)/extrinsic factors
As with all immunostimulants, use is 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.
2005, Barnes
et al.
2007, ESCOP 2003 and 2009,
Bauer and Liersch 1993, Blumenthal
et al.
2000).
In accordance with the ‘Guideline on the Summary of Product Characteristics’ dated September 2009,
the statement ‘Not recommended 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’ appears in the section ‘Warnings and precautions for use’ of the monograph on
Echinaceae purpureae radix
(not as a contraindication).
Atopic patients and those with asthma should be cautious since rare allergic reactions have been
reported (Barnes
et al.
2005, Barnes
et al.
2007, Huntley
et al.
2005).
Use in children
There are no sufficient data on safety of purple coneflower root preparations in children; therefore the
use of
Echinacea purpurea
root and preparations thereof is not recommended. This appears as a
warning in the monograph and not as a contraindication in accordance with the ‘Guideline on the
Summary of Product Characteristics’ dated September 2009.
Drug interactions
The effect of
Echinacea
(
Echinacea purpurea
root) on CYP activity
in vivo
was assessed by use of the
CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 28/31
midazolam (hepatic and intestinal CYP3A). Twelve healthy subjects (6 men) completed this 2-period,
open-label, fixed-schedule study. Caffeine, tolbutamide, dextromethorphan, and oral and intravenous
midazolam were administered before and after a short course of
Echinacea
(400 mg 4 times a day for
8 days) to determine
in vivo
CYP activities.
Echinacea
administration significantly increased the
systemic clearance of midazolam by 34%, from 32 +/- 7 L/h to 43 +/- 16 L/h (P =0.003; 90% CI,
116%-150%), and significantly reduced the midazolam area under the concentration-time curve by
23%, from 127 +/- 36 microg. h/L to 102 +/- 43 microg. h/L (P =0.024; 90% CI, 63%-88%). In
contrast, the oral clearance of midazolam was not significantly altered (P =0.655; 90% CI, 75%-
124%), 137 +/- 19 L/h compared with 146 +/- 71 L/h. The oral availability of midazolam after
Echinacea dosing was significantly increased (P =0.028; 90% CI, 108%-153%), from 0.23 +/- 0.06 to
0.33 +/- 0.13. Hepatic availability (0.72 +/- 0.08 versus 0.61 +/- 0.16; P =0.006; 90% CI, 73%-
90%) and intestinal availability (0.33 +/- 0.11 versus 0.61 +/- 0.38; P =0.015; 90% CI, 125%-203%)
were significantly altered in opposite directions. Echinacea dosing significantly reduced the oral
clearance of caffeine, from 6.6 +/- 3.8 L/h to 4.9 +/- 2.3 L/h (P =0.049; 90% CI, 58%-96%). The oral
clearance of tolbutamide was reduced by 11%, from 0.81 +/- 0.18 L/h to 0.72 +/- 0.19 L/h, but this
change was not considered to be clinically relevant because the 90% CIs were within the 80% to 125%
range. The oral clearance of dextromethorphan in 11 CYP2D6 extensive metabolizers was not affected
by
Echinacea
dosing (1289 +/- 414 L/h compared with 1281 +/- 483 L/h; P =0.732; 90% CI, 89%-
108%).
Echinacea
(
E. purpurea
root) reduced the oral clearance of substrates of CYP1A2 but not the
oral clearance of substrates of CYP2C9 and CYP2D6.
Echinacea
selectively modulates the catalytic
activity of CYP3A at hepatic and intestinal sites. The type of drug interaction observed between
Echinacea
and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic
and intestinal sites. Caution should be used when
Echinacea
is co-administered with drugs dependent
on CYP3A or CYP1A2 for their elimination (Gorski
et al.
2004).
An increasing number of cancer patients are using complementary and alternative medicines (CAM) in
combination with their conventional chemotherapeutic treatment. Considering the narrow therapeutic
window of oncolytic drugs, this CAM use increases the risk of clinically relevant herb-anticancer drug
interactions. Recently identified nuclear receptors, such as the pregnane X receptor, the constitutive
androstane receptor, and the vitamin D-binding receptor, play an important role in the induction of
metabolizing enzymes and drug transporters. This knowledge has already been an aid in the
identification of some CAM probably capable of causing interactions with anticancer drugs: kava-kava,
vitamin E, quercetin, ginseng, garlic, beta-carotene, and echinacea. Evidently, more research is
necessary to prevent therapeutic failure and toxicity in cancer patients and to establish guidelines for
CAM use (Meijerman
et al.
2006).
The review by Freeman and Spelman assessed the occurrence of drug interactions with one of the top
selling botanical remedies,
Echinacea
including
E. angustifolia
,
E. pallida
, and
E. purpurea
. Only eight
papers containing primary data relating to drug interactions were identified. Herbal remedies made
from
E. purpurea
appear to have a low potential to generate cytochrome P450 (CYP450) drug–herb
interactions including CYP 450 1A2 (CYP1A2) and CYP 450 3A4 (CYP3A4). Currently there are no
verifiable reports of drug–herb interactions with any
Echinacea
product. However, further
pharmacokinetic testing is necessary before conclusive statements can be made about
Echinacea
drug–
herb interactions. The authors concluded that given the findings, the estimated risk of taking
Echinacea
products (1 in 100 000), the number of
Echinacea
doses consumed yearly (> 10 million), the number
of adverse events (< 100) and that the majority of use is short term,
E. purpurea
products (roots
and/or aerial parts) do not appear to be a risk to consumers (Freeman and Spelman 2008).
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 29/31
Use in pregnancy and lactation
A review on safety of
Echinacea
during pregnancy and lactation was published recently (Perri
et al.
2006). 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 the
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 endpoints 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).
No case of overdose has been reported.
Drug abuse
No case of drug abuse has been reported.
Withdrawal and rebound
No data available.
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.6.
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 purpurea
preparations. Atopic patients and those with asthma should be
cautious since rare allergic reactions have been reported.
There are no sufficient data on safety of purple coneflower root preparations in children; therefore the
use of
Echinacea purpurea
root and preparations thereof is not recommended.
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 30/31
Echinacea purpurea
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 unreliable studies, administration during pregnancy and lactation is not generally recommended
in accordance with general medical practice.
Echinacea purpurea
preparations should not be used
during pregnancy or lactation without medical advice.
Herbal remedies made from
Echinacea purpurea
appear to have a low potential to generate
cytochrome P450 (CYP450) drug–herb interactions including CYP 450 1A2 (CYP1A2) and CYP 450 3A4
(CYP3A4). Currently there are no verifiable reports of drug–herb interactions with any
Echinacea
product. However, further pharmacokinetic testing is necessary before conclusive statements can be
made about
Echinacea
drug–herb interactions.
6.
Overall conclusions
The pharmacological effects of
Echinacea purpurea
root preparations on immune system of adults were
proved but the pharmacological mechanisms and active compounds still remain mainly unclear. So far
the only compounds for which the oral availability has been established are alkamides. Clinical efficacy
in children is not certain. The data about the toxicity of purple coneflower root preparations are very
limited although it has been used for decades.
Well-established use of
Echinacea purpurea
root for the preventive or supportive treatment of common
cold is not possible, due to insufficient clinical data.
Traditional use of
Echinacea purpurea
root in this indication is possible, although toxicological data are
limited; however a certain level of safety could be expected due to the long-standing use of
Echinacea
purpurea
root preparations with no serious side effects reported.
Annex
List of references
Assessment report on
Echinacea purpurea
(L.) Moench, radix
EMA/HMPC/577786/2008
Page 31/31
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/echinaceae_purpureae_radix_herbal.html
Copyright © 1995-2021 ITA all rights reserved.