MEDICINAL HERBS "ECHINACEA"
ECHINACEA
SUMMARY AND PHARMACEUTICAL COMMENT (Barnes., et al. 2007)
The chemistry of
echinacea is well documented (see Constituents). The three species are
chemically dissimilar. Echinacea purpurea and E. angustifolia both contain
alkamides as their major lipophilic constituents, but of differing structural
types. By contrast, the lipophilic fraction of E. pallida is characterised by
polyacetylenes and contains only very low concentrations, if any, of alkamides.
The alkene constituents are stated to be susceptible to auto-oxidation,
resulting in the formation of artefacts during storage.(G2)
Commercial echinacea
samples and marketed echinacea products may contain one or more of the three
echinacea species mentioned above. Analysis of commercial samples of raw
echinacea material and marketed echinacea products has shown that in some cases
the echinacea species assigned to the sample or product was incorrect, and that
the pharmaceutical quality and labelling of some finished products was
inadequate (see Constituents, Quality of plant material and commercial products).
Users and potential users of echinacea products should be made aware of the
possible differences between products and the implications of this for efficacy
and safety.
Evidence from in
vitro and animal studies supports some of the uses for echinacea, particularly
the reputed
immunostimulant properties,
although immunostimulant activity has been disputed following one series of
studies (see Pharmacological Actions, In vitro and animal studies, Immunomodulatory
activity). Reported pharmacological activities have been documented for the
polyene and high molecular weight polysaccharide constituents, as well as the alkamides
and caffeic acid derivatives.
Several, but not all,
clinical trials of echinacea preparations have reported effects superior to
those of placebo in the prevention and treatment of upper respiratory tract
infections (URTIs). However, evidence of efficacy is not definitive as studies
have included different patient groups and tested various different preparations
and dosage regimens of echinacea. As such, there is insufficient evidence to recommend
any specific echinacea products, or to advise on optimal dose and treatment
duration (see Clinical studies). Further well-designed clinical trials using
well-defined, standardised preparations are necessary in order to establish efficacy.
There is a lack of
clinical research on the anti-inflammatory and wound-healing properties of
echinacea preparations documented in vitro and in animal studies. Several other
areas of interest, related to the immunostimulant effects of echinacea, such as
prevention of recurrence of genital herpes and other infections, and reduction
of adverse effects associated with antineoplastic treatment, also require
further clinical investigation.
Another area that
requires further study is whether certain groups of constituents, such as the
polysaccharides, are active after oral administration and, if so, what is the
mechanism of action since polysaccharides usually would be broken down into
simple inactive sugars. There is a lack of data on the pharmacokinetics of
echinacea preparations, although very preliminary studies have reported
transportation of isobutylamides across Caco-2 cells, an in vitro model of intestinal
absorption, and detection of alkamides in blood taken from healthy volunteers
who ingested echinacea preparations (see Clinical studies, Pharmacokinetics).
On the basis of the
available (limited) safety data, whichcome mostly from short-term clinical
trials of echinacea preparations for the prevention and treatment of URTIs in otherwise
generally healthy individuals, echinacea appears to be well-tolerated. However,
firm conclusions cannot be drawn from these limited data, and further
investigation is required to establish the safety profile of different
echinacea preparations. At present, the main safety issues are the possibility
of allergic reactions, and concern about the use of echinacea by patients with
progressive systemic diseases, such as tuberculosis, leukaemia, collagen
disorders, multiple sclerosis and other autoimmune diseases (see Side-effects, Toxicity
and Contra-indications, Warnings). In view of the lack of toxicity data, excessive
use of echinacea should be avoided. In placebo-controlled trials of echinacea preparations
for the prophylaxis of URTIs, treatment was taken typically for 8–12 weeks.
As with other herbal medicines, the potential
for echinaceapreparations to interact with conventional medicinesshouldbe
considered. As E.
purpurea root can inhibit CYP1A2 and selectively modulate CYP3A, echinacea should
be used with caution in patients receiving therapeutic agents with a narrow therapeutic
range and which are substrates for these CYP enzymes.
BOTANICAL DESCRIPTION
A perennial herb of the
COMPOSITAE family that grows up to 45 cm.
The leaves are sparse, solitary, lanceolate to linear, opposite or
alternate with rough surface, 7.5 to 20 cm long, entire margined on slender
petioles. The dried rhizome is
grayishbrown, often twisted, longitudinally furrowed, up to about 1 cm in
diameter. The transverse section shows a
thin bark and a yellow ish porous wood fleck ed with black. The flower heads are large and solitary on
terminal peduncles with spreading ray florets.
The bracts are in a number of rows. The bracts are dry or leafy, rigid,
thorny tipped, and longer than the conical erect disc florets. The reddish or occasionally white
florets are conspicuous, usually sterile
lingual florets and 3 cm long.
Figure 1. Echinacea in Flowers and Lanceolate Upper Leaves
Figure 2. Close view of Flowers with Conic Discs
Figure 3. Flowers with Subglobose and Flattish Round Discs
(Reference Figure 1, 2 and 3 is a Lim, T.K. 2014)
SPECIES (FAMILY) (Barnes., et
al. 2007)
Ø
*Echinacea angustifolia DC.
(Asteraceae/Compositae)
Ø
†Echinacea pallida (Nutt.) Nutt.
Ø
‡Echinacea purpurea (L.) Moench
SYNONYM(S) (Barnes., et al.
2007)
Ø
Black Sampson, Coneflower
Ø
*E. angustifolia var. strigosa
Ø
†Rudbeckia pallida Nutt., Brauneria
pallida (Nutt.) Britton, E.angustifolia Hook. f.
Ø
‡Rudbeckia purpurea L., sp., R. serotina
(Nutt.) Sweet, R. hispida
Ø
Hoffm., E. intermedia Lindl., E.
purpurea (L.) Moench var.arkansana Stey., E. purpurea var. purpurea f.
Liggettii
OTHER COMMON NAMES (Linda S-Roth.
2010)
American cone flower, black
sampson, black susans, cock-up-hat, comb flower, cone flower, hedgehog, Indian
head, Kansas snakeroot, Missouri snakeroot, purple cone flower, red sunflower,
rudbeckia, sampsonroot, scurvyroot, snakeroot.
ORIGIN (Linda S-Roth. 2010)
Echinacea is a perennial found in
only three states: Missouri, Nebraska, and Kansas. It is cultivated in much of
the world. Echinacea is a Native American remedy.
PHARMACOPOEIAL AND OTHER MONOGRAPHS (Barnes, J., et al. 2007)
Ø
AHP (E. purpurea root)(G1)
Ø
BHC 1992(G6)
Ø
BHMA 2003(G66)
Ø
BHP 1996(G9)
Ø
BP 2007(G84)
Ø
Complete German Commission E 1998(G3)
Ø
ESCOP 2003(G76)
Ø
Expanded German Commission E 2000(G4)
Ø
Martindale 35th edition(G85)
Ø
Ph Eur 2007(G81)
Ø
USP29/NF24(G86)
Ø
WHO volume 1 1999(G63)
LEGAL CATEGORY (LICENSED PRODUCTS) (Barnes, J., et al. 2007)
GSL(G37)
PRODUCT
AVAILABILITY (Linda S-Roth. 2010)
Capsules, fluid extract, juice,
solid (dry powdered) extract, sublingual tablets, tablets, tea, tincture
NOTE: Some extracts may be
standardized to 4% to 5% echinacoside; others are standardized to phenolics.
Plant
Parts Used:
Rhizome, roots; depending on
developmental stage of growth: flowers, juice from the stem, leaves, whole
plant
CONSTITUENTS
(Barnes, J., et
al. 2007)
ALKAMIDES
At least 20,
mainly isobutylamides of straight-chain fatty acids with olefinic and/or
acetylenic bonds,(1–5) e.g. isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic
isobutylamide,(6) present in the roots and aerial parts of Echinacea
angustifolia and Echinacea purpurea, but mainly absent from Echinacea pallida.
Isobutylamides from the roots of E. purpurea contain mainly 2,4-dienoic units
whilst those of E. angustifolia contain mainly 2-monoene units.(4) The
synthesis of the acetylenic amide N-(2-methylpropyl)-2E-undecene-8,10-diynamide,
a constituent of E. angustifolia root, has been reported.(7) E. purpurea root
reportedly contains 0.01–0.04% alkamides.(G52)
PHENYLPROPANOIDS Caffeic acid glycosides (e.g.
echinacoside,(8) verbascoside, caffeoylechinacoside), caffeic acid esters of
quinic acid (e.g. chlorogenic acid = 5-caffeoylquinic acid, isochlorogenic acid
= 3,4- and 3,5-dicaffeoylquinic acid, cynarin = 1,3- dicaffeoylquinic acid) and
of tartaric acid (e.g. caftaric acid = 2-caffeoyltartaric acid, cichoric acid =
2,3-dicaffeoyltartaric acid).(9) Varying mixtures of caffeic acid derivatives
are present in the three species, with echinacoside being the major component of
the roots of E. angustifolia and E. pallida(9) (0.5–1.0%),(G52) and cichoric
acid being a major component of E. purpurea roots (0.14–2.05%),(10) and aerial
parts (1.2–3.1%).(11, G52) Cynarin is reportedly present in E. angustifolia
root,(6, 9) but not in the roots of the other two species.
POLYSACCHARIDES Polysaccharides PS1 (a
methylglucuronoarabinoxylan, mol. wt 35 kDa),(12) PS2 (an acidic
rhamnoarabinogalactan, mol. wt 450 kDa) and a xyloglucan (mol. wt 79 kDa) have
been isolated from E. purpurea herb.(13, 14, G52) Polysaccharides and
glycoproteins are present in E. purpurea herb and E. pallida root.(G52) The
pressed juice from the aerial parts of E. purpurea (and the herbal medicinal
product Echinacin prepared from the juice) contain heterogeneous
polysaccharides (mol. Wt <10 kDa), inulin-type fractions (mol. wt 6 kDa) and
an acidic highly branched arabinogalactan polysaccharide (mol. Wt 70 kDa).(15)
The pressed juice of E. purpurea aerial parts has yielded an arabinogalactan-protein
(AGP) comprising 83% polysaccharide (galactose–arabinose 1.8 : 1), uronic acids
(4–5%) and protein (7%) with high concentrations of serine, alanine and hydroxyproline.(16)
The AGP (mol. wt 1.2 _ 106 Da) has a highly branched polysaccharide core of 3-,
6-, and 3,6-linked galactose residues with terminal arabinose and glucuronic
acid units.(16)
VOLATILE
OILS E. pallida
root (0.2–2.0%)(G52) mainly contains polyenes and polyacetylenes including
pentadeca-1,8Z-diene and a range of ketoalkenes and ketoalkenynes
(ketopolyacetylenes), principally pentadeca-8Z-ene-2-one, pentadeca-8Z,11Z-diene-2-one,
pentadeca-8Z,13Z-diene-11-yne-2-one, tetradeca-8Z-ene-11,13-diyne-2-one and
others.(17, G52) These alkenes are unstable and readily oxidise to 8-hydroxy
derivatives.(G52) The alkenes of E. pallida and E. purpurea root are distinctly
different from those of E. angustifolia which are mainly alkylketones.(5) The
volatile oil from the aerial parts of the three species contains borneol,
bornyl acetate, germacrene D, caryophyllene and other components.(G2, G52).
OTHER
CONSTITUENTS A series of other constituents
has been reported including the saturated pyrrolizidine-type alkaloids tussilagine
and isotussilagine (0.006%) from E. angustifolia and E. purpurea.(18)
Flavonoids, including quercetin, kaempferol, isorhamnetin and their
glycosides(G52) and also anthocyanins, are present in the aerial parts of E.
purpurea (0.48%).(G2) The major flavonoid of the aerial parts of E.
angustifolia has been identified as patuletin-3-rutinoside,(19) and not rutin
as previously reported.(20) Free phenolic acids, including p-coumaric, p-hydroxybenzoic
and protocatechuic acids, have been isolated from the aerial parts of E.
angustifolia and E. purpurea.(21) Other miscellaneous compounds reported
include betaine, fatty acids, simple sugars, sterols and vanillin. The presence
of 'melanin' in material from cultured E. angustifolia plants has been reported.(22)
Phytomelanin deposits are stated to be present in the roots of E. pallida and
E. angustifolia, but absent from E. purpurea roots.(G75)
QUALITY
OF PLANT MATERIAL AND COMMERCIAL PRODUCTS
Alkamide concentrations vary
between species and between different parts of the plant.(23) Commercial root
samples of E. purpurea have been shown to vary in their alkamide content (0.12–1.2%).(11)
In Germany, 25 commercial echinacea preparations were assayed for their
alkamide (dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide) and cichoric
acid contents.(24) Some products were highly concentrated, whereas others had
no detectable concentrations of alkamide or cichoric acid. Large differences
were observed between comparable products from different manufacturers.
Several commercial echinacea
products have performed poorly in examinations of their quality. Of 25
commercial echinacea products purchased in the USA only 14 (56%) passed
assessments for their quality.(25) Six were inadequately labelled, three of
them not stating the species used, one not stating the plant part and two liquid
preparations had no concentrations given for their echinacea content. The
remaining 19 products were assessed for their stated content of particular
species and for claimed concentrations of phenols. Twelve of these products
were labelled as containing only E. purpurea and two of them failed, as one contained
only 54% of the expected concentration of phenols and the other had three times
the accepted concentration of microbes as set out in World Health Organization
(WHO) guidelines. Two products were allegedly prepared from E. angustifolia and
both failed, one having only one-third of the stated phenolic content and the
other having no detectable echinacoside. Five further products allegedly
containing a mixture of species were also assessed and one failed because
echinacoside could not be detected. Analysis of 59 commercial products
available in the US revealed that 10% had no measurable echinacea content, 48% were
not consistent with their labels in respect of the species present, and of 21
standardised preparations, 57% did not meet the standards stated on their
labels; often products did not contain the species stated.(26)
A fresh plant product of echinacea
herb has been shown to possess three times the amount of alkamide than a
product prepared from dried plants and this has been attributed to loss on drying.(27)
The alkamide and cichoric acid contents of six commercial preparations of E.
purpurea expressed juice have been shown to be variable (0.1–1.8 mg/mL and 0.0–0.4%,
respectively).(28) Ten commercial preparations of echinacea were analysed for
their betaine content and concentrations ranged from 0.04–0.64%.(29)
The concentrations of some constituents
may be affected during growing, drying or storage of the plant material. The
yields of some constituents are affected when plants are grown under conditions
of drought stress.(30)Analysis of roots of E. angustifolia dried at a range of
temperatures between 23oC and 60oC indicated that there
were no significant changes in the alkamide content, whereas 25% and 45% of the
echinacoside content was lost at 30oC and 60oC,
respectively.(31) By contrast, roots of E. purpurea at _18oC in
deep-freeze for 64 weeks were found to have lost 40% of their alkamide
content.(32) An aqueous–alcoholic extract of E. purpurea and its dried extract
were stored at different temperatures for seven months and then assayed for
their alkamide and phenylpropanoid content.(33) The amount of the major
alkamide (dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide) in the liquid
preparation was not significantly affected by storage at 25oC and 40oC,
whereas the cichoric acid content declined. However, the reverse occurred for
the dried extract when there was a significant loss of alkamide at storage
temperatures of 25oC and 40oC but no significant loss of
cichoric acid content.
The effects of drying temperatures
on the constituents of all three echinacea species have been investigated.(34) The
results showed that there was an increase in cichoric acid for E. purpurea and
E. pallida. Furthermore, increased moisture content resulted in higher
concentrations of echinacoside for E. angustifolia and E. pallida and of
chlorogenic acid in E. angustifolia. The polysaccharide contents were significantly
decreased by raised moisture levels in the roots of E. angustifolia and E.
pallida.
The presence of colchicine in commercial
echinacea products in the USA has been reported,(35) although subsequent
analysis of 17 commercial echinacea products purchased in pharmacies in Chicago,
USA, did not detect colchicine in any of the samples.(36)
Detailed descriptions of E.
purpurea root for use in botanical, microscopic and macroscopic identification
have been published, along with qualitative and quantitative methods for the
assessment of E. purpurea root raw material.(37)
HERBAL USE
(Barnes, J., et
al. 2007)
Echinacea
has a long history of medicinal use for a wide variety of conditions, mainly
infections, such as syphilis and septic wounds, but also as an 'anti-toxin' for
snakebites and blood poisoning.(38, G50)
Traditionally, echinacea was
known as an 'anti-infective' agent, and was indicated in bacterial and viral
infections, mild septicaemia, furunculosis (persistent recurring episodes of
painful nodules in the skin) and other skin conditions, including boils, carbuncles
and abscesses.(G6, G7, G60, G69) Other traditional uses listed include
naso-pharangeal catarrh, pyorrhoea (periodontitis) and tonsillitis, and as
supportive treatment for influenza-like infections and recurrent infections of
the respiratory tract and lower urinary tract and, externally, for poorly
healing superficial wounds.(G66)
Current interest in the medicinal
use of echinacea is focused on its immunostimulant (increasingly described as
immunomodulatory) effects, particularly in the treatment and prevention of the common
cold, influenza and other upper respiratory tract infections (see
Pharmacological Actions; Clinical studies).
ACTIVITIES (Duke, J.A., et al. 2002)
Activities—Alterative (f; PED; PNC); Analgesic (1; DEM; FNF; PED); Antibacterial (1; PED; PNC); Antiedemic (1; PHR; WHO); Antiexudative (1; PED); Antihyaluronidase (1; BGB; MAB; PNC;
WHO); Antiinflammatory (1; FNF; PH2;
WAM; WHO); Antiintegrase (1; FNF;
JAD); Antiseptic (1; PED); Antispasmodic (1; CAN); Antitumor (1; PNC; WHO); Antiviral (1; APA; WAM; WHO); Bactericide (1; FAD; PH2; WAM; WHO); Bifidogenic (1; AKT; FNF); Bitter (f; PED); Candidicide (1; BGB); Collagen
Sparing (1; MAB); Cyclooxygenase
Inhibitor (1; MAB; PH2); Fungicide
(1; FAD; PED); Immunostimulant (1;
CAN; PH2; WAM; WHO); Interferonigenic
(1; APA); 5-Lipoxygenase Inhibitor
(1; PH2; WHO); Phagocytotic (1; KOM;
PIP; WHO); Prebiotic (1; AKT; FNF); Protisticide (1; MAB); Sialagogue (1; DEM; PED); TNFgenic (1; APA); Trichomonicide (1; MAB; PNC); Vasodilator
(1; CAN); Vulnerary (1; APA; MAB;
PH2; PNC).
PHARMACOLOGICAL ACTIONS (Barnes, J., et al. )
There is a vast
scientific literature on the pharmacological activities of Echinacea species
based on in vitro and in vivo (animal) studies. Research has focused on
investigating the immunomodulatory activity of echinacea preparations, although
other activities, such as antiviral, antifungal, anti-inflammatory and
antioxidant properties have also been explored. Effects on the immune system
may play a role in some of these other activities.
The pharmacological
activities of echinacea preparations cannot be attributed to a single
constituent or group of constituents. Rather, several groups of constituents – the
alkamides, caffeic acid derivatives, polysaccharides and alkenes– appear to
contribute to activity.
However, it has
been reported that following oral administration in man, alkamides are bioavailable,
whereas caffeic acid derivatives are not and, therefore, cannot contribute to
activity (see Clinical studies, Pharmacokinetics).(39)
IN
VITRO AND ANIMAL STUDIES
IMMUNOMODULATORY ACTIVITY Currently, there is a view that immunomodulatory,
rather than immunostimulatory, is the most appropriate term to describe the
immunological effects of echinacea,(40) although 'immunostimulatory' is still used and is ubiquitous
in the earlier scientific literature on echinacea. It has been suggested that
broad stimulation of the various highly complex components of the immune system
is unlikely to be beneficial, since some immune responses are harmful.(40)
The immunological effects of a
wide range of echinacea preparations comprising different species, plant parts
and types of extract, have been investigated extensively in vitro and in vivo.
Collectively, the data indicate that echinacea preparations do have effects on
certain indices of immune function,(40, 41) although at present there is no
clear picture as to which specific preparations have the greatest activity. A
summary of some of the scientific literature on the immunological effects of
echinacea is given below. Enhancement of macrophage function has been
documented for various preparations of echinacea in vitro and in vivo in
studies using a range of methods, such as the carbon clearance test and
measurement of cytokine production, as indicators of macrophage
activity.(42–44) In vitro experiments with human macrophages found that fresh
pressed juice and dried juice from the aerial parts of E. purpurea stimulated
production of cytokines, including interleukin 1 (IL-1), IL-10, and tumour
necrosis factor a (TNFa).(45)
Other studies have reported that
purified polysaccharides from E. purpurea induced macrophage production of
IL-1,(46) and that a polysaccharide arabinogalactan isolated from plant cell
cultures of E. purpurea induced TNFa and interferon b2 production by murine
macrophages.(47) Polysaccharides obtained from plant cell cultures of E.
purpurea have also been shown previously to have immunological activity in
vitro.(48) In another series of in vitro experiments, E. purpurea induced
macrophage activation (as assessed by TNFa production) following simulated
digestion (incubation of echinacea with gastric fluid) in an attempt to mimic effects
following oral administration.(49) Other work has demonstrated that E. 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.(50)
In an in vitro study, peripheral
blood mononuclear cells (PBMCs) from healthy individuals and from patients with
chronic fatigue syndrome and acquired immune deficiency syndrome (AIDS)
incubated with increasing concentrations of extracts of E. purpurea led to
enhanced natural killer function of PBMCs.(51) In vivo, oral administration of
E. purpurea root extract has been reported to increase numbers of natural
killer cells in normal,(52) leukaemic,(53) and ageing mice.(54)
A subsequent in vivo study,
conducted using a rigorous randomised, double-blind design, assessed the
effects of an echinacea product (Nature's Resource, CVS Pharmacy, USA; capsules
containing echinacea aerial parts 1.05 g and cichoric acid 10.5 mg) in 16
ageing male rats.(55) Animals received echinacea (species and method of
preparation were not stated although, as aerial parts were used, the species
may have been E. purpurea) 50 mg/kg body weight (equivalent to cichoric acid
0.5 mg/kg), or placebo, orally as a bolus dose in peanut butter each morning
for eight weeks. Mean circulating total white cell counts were significantly
higher in echinacea-treated rats than in the control group for the first two
weeks (p < 0.05), although baseline counts for the two groups and a precise
p value or confidence intervals were not given in a report of the study, and
concentrations of IL-2 were significantly higher in echinacea-treated rats,
compared with the control group, for the last five weeks of the study (p < 0.05).
Differential white cell counts were significantly altered throughout the 8-week
study period in the echinacea group, compared with the control group: proportions
of lymphocytes and monocytes increased while those of neutrophils and
eosinophils decreased with echinacea, compared with placebo.(55) There were no
changes in the phagocytic activity of circulating leukocytes, as assessed by ability
to ingest latex particles, in either group during the study.
Other in vivo studies (rats) have
shown that administration of water–ethanol extracts (100 mL twice daily by oral
gavage for four days) of E. purpurea roots and aerial parts containing defined concentrations
of cichoric acid, polysaccharides and alkamides stimulated phagocytic activity
of macrophages; activity was increased with increasing concentrations of the
three components.(56) Subsequently, an increase in
lipopolysaccharide-stimulated nitric oxide release was observed by macrophages
obtained from the spleens of rats previously treated with the echinacea extracts.
A similar set of experiments demonstrated stimulation of alveolar macrophage
function by alkamides administered to healthy rats.(57)
A proprietary preparation
containing E. purpurea root extract and liquorice (Glycyrrhiza glabra) root extract
stimulated phagocytosis in vitro and in vivo, as demonstrated by the carbon clearance
test, following oral administration to mice.(58) The combination product produced
a greater immunostimulatory effect in this test than did either extract tested
alone. Another combination preparation, comprising aqueous–ethanol extracts of E.
purpurea and E. pallida root, Baptisia tinctoria root and Thuja occidentalis
herb, administered orally via the diet or drinking water to mice for seven days
enhanced the antibody response to sheep red blood cells.(59)
In contrast with the extensive body
of research supporting the immunostimulatory effects of echinacea preparations,
some recent work has reported a lack of effect. No evidence of natural killer 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, E. purpurea and E.
pallida, in their diet.(60)
A concentration-dependent and
cell-type specific de novo synthesis of TNF-a mRNA in primary human CD14þ
monocytes/ macrophages in vitro has been described for an E. purpurea extract
(Echinaforce, Bioforce).(61) The alkamide constituents appeared to be
responsible for this effect, at least in part, mediated via the cyclic AMP and
other pathways and involving activation of NF-kB. Further experiments using
these cells and an anti-cannabinnoid-2 (CB2) polyclonal antibody and the CB2 antagonist
SR-144528 resulted in inhibition of the induction of TNF-a mRNA.
ANTIVIRAL ACTIVITY Antiviral activity has been
described for various different preparations of
echinacea following in vitro studies. An
'indirect' antiviral effect was documented in experiments involving addition of glycoprotein-containing fractions
obtained from E. purpurea root to mouse spleen cell
cultures.(62) Interferon-a and -b produced
by the cells were then tested for activity against vesicular stomatitis virus.
These glycoproteincontaining fractions were also tested directly against herpes
simplex virus (HSV) and were reported to reduce the number of plaques by up to
80%, although raw data were lacking and statistical tests do not appear to have
been carried out.
In other in vitro
studies, the antiviral activity of an aqueous solution of E. purpurea herb was
tested against aciclovirsusceptible and aciclovir-resistant strains of HSV-1 and HSV-2.(63)
In aciclovir-susceptible strains of HSV-1 and HSV-2, median ED50 (effective
dose) values for the echinacea preparation were 1 : 100 (range 1 : 25 to 1 :
400) and 1 : 200 (range 1 : 50 to 1 : 1600), respectively. Similarly, for
aciclovir-resistant HSV-1 and HSV-2, median ED50 values (range) were 1 : 100 (1
: 50 to 1 : 400) and 1 : 200 (1 : 50 to 1 : 3200), respectively.
An n-hexane extract of E. purpurea root,
an ethanolic extract of E. pallida var. sanguinea herb and the isolated
constituent cichoric acid were the most potent inhibitors of HSV-1 in in vitro studies
designed to assess light-activated antiviral activity.(64) The minimum
inhibitory concentrations (MIC) for these preparations were 0.12, 0.026 and
0.045 mg/mL, respectively.
Other in vitro studies using
mouse fibroblasts found that preincubation with E. purpurea herb juice and
methanolic and aqueous extracts of E. purpurea root resulted in resistance to influenza
A2, herpes, and vesicular stomatitis virus
infection for 24 hours.(65)
ANTIFUNGAL AND
ANTIBACTERIAL ACTIVITIES
Activity against several yeast strains, including Saccharomyces cerevisiae and Candida
albicans, has been described for n-hexane extracts of E. purpurea roots.(66)
Antifungal activity was observed under near ultraviolet light irradiation and,
in some cases, was also light independent. The pure polyacetylenic compound trideca-1-ene-3,5,7,9,10-pentayne,
isolated from E. purpurea root extracts, demonstrated marked light-mediated
inhibition of growth of S. cerevisiae.(66) Anti-Candida activity for E.
purpurea extracts has also been described previously.(40)
In contrast, n-hexane extracts of
the fresh roots of E. pallida var. pallida and E. pallida var. angustifolia
(identified according to a revised taxonomy(67) showed no measurable inhibition
of C. albicans, but an amphotericin-B-resistant strain (D10) of C. albicans and
Tricophyton mentagrophytes were susceptible to E. pallida var. pallida root
extract in the presence of UV light.(68) Studies in mice have described a
dose-dependent protective effect for polysaccharide fractions from E. purpurea plant
cell cultures against lethal-dose infection with C. albicans and Listeria monocytogenes
when administered intravenously within less than 18 hours of the infection
dose.(69) A similar finding was reported when such polysaccharide fractions
were administered to immunosuppressed mice both before and after lethal dose infection
with C. albicans and L. monocytogenes.(70)
Antibacterial activity against
Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus
aureus has been demonstrated for a multi-herbal preparation containing E. purpurea
root extract, although it was stated that the observed antibacterial effects
were most likely attributable to one of the other ingredients, extract of
onion.(71)
ANTI-INFLAMMATORY
ACTIVITY In vivo
anti-inflammatory activity has been reported for a polysaccharide fraction
(PSF) obtained from E. angustifolia roots in the carrageenan-induced rat paw oedema
test and in the croton oil mouse ear test, with the PSF administered
intravenously and topically, respectively.(72) The isolated PSF was twice as
active as the total aqueous extract in the carrageenan-induced oedema test, and
about half as active as indometacin in the croton oil test. An aqueous extract
of E. angustifolia roots was also reported to be more effective than benzydamine
(a topical non-steroid anti-inflammatory drug (NSAID)) in the croton oil
test.(73) Further work using fractions of an aqueous extract of E. angustifolia
roots administered topically to mice in the croton oil test attributed the
observed anti-inflammatory activity mainly to intermediate and high molecular
weight fractions.(74)
Oral administration of higher
(100 mg/kg) but not lower (30 mg/kg) doses of E. purpurea dry root powder
(containing 1.5% total polyphenols, calculated as chlorogenic acid) inhibited carrageenan-induced
paw oedema in mice; the effect was stated to be similar to that of indometacin
0.25 mg/kg, although this was not tested statistically.(75) Further exploration
suggested that the observed effect may be due to downregulation of
cyclooxygenase 2 (COX-2) expression by the echinacea preparation. In vitro inhibition
of cyclooxygenase 1 (COX-1) and, to a lesser extent, COX-2 has been described
for alkamides isolated from E. purpurea roots,(76) and in vitro inhibition of
5-lipoxygenase (5- LO) and cyclooxygenase (from sheep seminal microsomes) has been
reported for polyunsaturated alkamides from E. angustifolia roots.(77)
Inhibition of 5-LO has also been described
for extracts of roots of E. purpurea, E. pallida var. pallida and E. pallida var.
angustifolia (identified according to a revised taxonomy).(67) IC50 values (mg
root/mL assay volume) were 0.642, 1.08 and 0.444, respectively, and
corresponding alkamide concentrations in the root of each species were 0.05%,
trace, and 0.2%, respectively.(68)
Anti-inflammatory and cicatrising
activities have been reported for gel preparations containing echinacoside 0.4
mg and E. pallida root extract 100 mg following studies in rats with
experimental skin abrasions and excision wounds.(78) These effects were observed
48 and 72 hours after topical administration, and were stated to be greater
than those observed for E. purpurea root extract and control. However, no statistical
analysis was reported. The wound-healing properties documented for echinacea
have been attributed in part to a polysaccharide fraction, which is thought to
inhibit the action of hyaluronidase.(79) Ethanol extracts of E. purpurea roots
and aerial parts have been reported to inhibit fibroblast-induced collagen
contraction, although the significance of this activity for wound healing needs
to be investigated.(80)
Other studies have documented a
protective effect for echinacoside, isolated from E. angustifolia root, and
other caffeoyl esters against free radical-induced degradation of collagen, an
experimental model for skin damage caused by exposure to ultraviolet light.(81)
Other activities A long-chain alkene from E. angustifolia is stated to possess
antitumour activity in vivo, inhibiting the growth of Walker tumours in rats
and lymphocytic leukaemia (P388) in mice.(82) In an assay of the mosquitocidal
activity of alkamides isolated from dried E. purpurea roots, a mixture of
dodeca-2E,4E,8Z,10Etetraenoic acid isobutylamide and dodeca-2E,4Z,8Z,10Z-tetraenoic
acid isobutylamide at a concentration of 100 mg/mL achieved 87.5% mortality of
Aedes aegyptii L. mosquito larvae within 15 minutes. Several other alkamides
assayed also demonstrated mosquitocidal activity, but required longer
incubation periods and were less effective.(76)
Free radical-scavenging activity
has been documented for alcoholic extracts of the roots and leaves of E.
purpurea, E. angustifolia and E. pallida in vitro.(7) Dodeca-2E,4E,8Z,10E/Z-tetraenoic
isobutylamides found in Echinacea species (but isolated in this experiment from
Echinacea atrorubens root) were transported across Caco-2 monolayers, an in
vitro model for intestinal absorption, over a 6-hour period.(83) Transport
kinetics did not differ significantly following modification of the model (by
preincubation of Caco-2 cells with lipopolysaccharide and phorbol
12-myristate-13-acetate) to mimic inflammation. A similar study explored the transport
of 12 alkamides and 5 caffeic acid conjugates from a proprietary preparation of
echinacea (Echinacea Premium Liquid; MediHerb, Australia), which contains a 60%
ethanol/water extract of E. angustifolia root (200 mg/mL) and E. purpurea root
(300 mg/mL).(84) Almost all of the caffeic acid conjugates permeated poorly
through the Caco-2 monolayers: their uptake was no better than that of control
(mannitol, which is poorly absorbed); only cinnamic acid diffused readily
(apparent permeability coefficient, Papp, = 1 _ 10_4 cm/second). By contrast,
both 2,4-diene and 2-ene alkamides readily diffused through the monolayers,
although Papp values varied (range: 3 _ 10_6 to 3 _ 10_4 cm/second), depending
on structure. Saturated compounds and those with N-terminal methylation had
lower permeability coefficients. These findings suggest that alkamides, but not
caffeic acid conjugates, are likely to cross the intestinal barrier and thus be
bioavailable following oral administration.(84)
CLINICAL STUDIES
Pharmacokinetics There are only limited
data on the clinical pharmacokinetics of echinacea preparations (see also
Pharmacological Actions, In vitro and animal studies, Other activities). One
study reported that dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide
(alkamide) was detectable in blood one hour after oral administration of 65mL
of a concentrated ethanolic extract of E. purpurea herb (containing 4.3 mg
isobutylamides) on an empty stomach to a single healthy volunteer.(85)
In a study
involving nine healthy volunteers who ingested four Echinacea Premium tablets
(MediHerb, Australia; each tablet contains E. angustifolia root extract 150 mg,
containing 2.0 mg alkamides, and E. purpurea root extract 112.5 mg, containing
2.1 mg alkamides) after a high-fat breakfast, alkamides were detected in plasma
obtained from blood samples taken 20 minutes after ingestion and some alkamides
were detectable for 12 hours post echinacea ingestion.(86) The mean (standard
error of mean) maximum plasma concentration (Cmax) for total alkamides was 336
(131), time to Cmax was 2.3 (0.5) hours and the area under the plasma
concentration time curve (AUCt) was 714 (181) mg equivalent/h/L. Most alkamides
found in echinacea were detected in plasma. In contrast, caffeic acid
conjugates could not be detected and therefore were reported not to be
bioavailable.(86)
In a randomised,
open, crossover study, in which 11 healthy volunteers received a single oral
dose of 2.5 mL of a 60% ethanolic extract of E. angustifolia roots (containing
2.0 mg tetraene per 2.5 mL) in the morning following an overnight fast, Cmax
for tetraene (a polyene) was reported to be around 11 ng/mL.(87)
Therapeutic
effects
Clinical trials of preparations containing echinacea have focused on testing
effects in preventing and treating the common cold and other upper respiratory
tract infections (URTIs); some preliminary studies have explored the effects of
echinacea in other infections, such as genital herpes, and as an adjunctive
treatment in cancer chemotherapy. The rationale for the use of echinacea in
these conditions is for its immunomodulatory activity. Collectively, the
findings of studies of echinacea are difficult to interpret as studies have
assessed preparations containing different species of echinacea and/or different
plant parts of echinacea, administered as monopreparations or in combination
with other herbal ingredients, and products manufactured by different processes
and with different dosage forms. Hence, the different preparations tested will
vary quantitatively and qualitatively in their chemical composition (i.e. will
contain different profiles and concentrations of chemical constituents).
IMMUNOMODULATORY ACTIVITY One
of the first systematic reviews of studies of echinacea-containing preparations
assessed evidence of their immunomodulatory effects.(88) The review included 26
controlled clinical trials, of which six investigated the treatment of URTIs
and influenza-like syndromes, seven explored the treatment of other infections,
such as sinusitis, bronchitis and candida, six studied the prophylaxis of URTIs
and influenza-like syndromes, four tested the reduction by echinacea of adverse
effects of antineoplastic treatment and three explored the effects on
immunological parameters in patients with infections or malignancies.(88)
Most studies reported that echinacea-containing
preparations were superior to placebo in the indications tested. However,
trials included in the review tested different species, parts and preparations
(e.g. pressed juice, extract) of echinacea administered via different routes (including
oral and parenteral) and with different dosage regimens. In addition, many studies
were of poor methodological quality (only eight achieved more than 50% of the
maximum score in an assessment of quality), several preparations tested
included other herbs in addition to echinacea, and the review included trials
involving patients with a range of conditions, so evidence for the
immunomodulatory activity of echinacea from this review can only be considered
tentative at best. The same research group carried out another systematic review
of five of their randomised, placebo-controlled studies (four were also
conducted double-blind) which investigated the immunomodulatory activity of
preparations of echinacea in healthy volunteers. Again, there were marked
differences between the preparations tested in the studies included in the review:
combination homeopathic preparations containing E. angustifolia at potencies of
D1 and D4 (which can be considered to contain reasonable quantities of starting
material) for intravenous administration; ethanolic extracts of E. purpurea
root and E. pallida root for oral administration; ethanolic extract of 95% E.
purpurea herb and 5% E. purpurea root. In two of the five studies, phagocytic
activity of polymorphonuclear neutrophil granulocytes (the primary outcome measure)
was significantly increased in the echinacea groups, compared with the placebo
groups, although no such effects were noted in the other studies.(89)
Recent studies investigating the
immunomodulatory activity of echinacea species administered to healthy
volunteers have reported different findings. In a randomised, double-blind, placebo-controlled
trial, compared with a placebo group, volunteers who received extracts of E.
purpurea and E. angustifolia with or without the addition of an arabinogalactan
extracted from Larix occidentalis (larch) for four weeks were found to have
increased concentrations of complement properdin (thought to be an indication
of immune system stimulation).(90) Other small placebo-controlled studies have reported
stimulatory effects following 28 days' oral pretreatment with pressed juice of
E. purpurea on the exercise-induced immune response in athletes,(91) and of
administration of purified polysaccharides from cell cultures of E. purpurea to
healthy volunteers.(92) By contrast, a double-blind, placebocontrolled, crossover
study involving 40 healthy volunteers found that oral administration of freshly
expressed juice of E. purpurea herb, or placebo, for two weeks did not enhance phagocytic
activity of polymorphonuclear leukocytes or monocytes, or affect TNFa and IL-1
production.(93)
Preliminary studies have assessed
the effects of a combination preparation containing extracts of E. angustifolia,
Eupatorium perfoliatum (boneset) and Thuja occidentalis (thuja) on cytokine
production in patients who have undergone curative surgery for various solid
malignant tumours,(94) and the immunostimulatory effects of a regimen
comprising intramuscular E. purpurea extract, low-dose intramuscular cyclophosphamide
and intravenous thymostimulin in patients with advanced colorectal cancer.(95) In
another study, the effects of a polysaccharide fraction of E. purpurea herb obtained
from cell cultures in reducing the adverse effects of cancer chemotherapy were
explored in patients with advanced gastric cancer receiving palliative therapy
with etoposide, leucovorin and 5-fluorouracil.(96) Although these studies
reported some positive findings with echinacea, no firm conclusions can be drawn
because of the nature of the study designs, therefore further research in this
area is required.
UPPER RESPIRATORY
TRACT INFECTIONS (URTIS)
Numerous studies have explored
the effects of echinacea preparations in preventing or treating the common cold
and other URTIs. Overall, several, but not all, studies have reported
beneficial effects for certain echinacea preparations, compared with placebo,
for the prevention and treatment of URTIs. However, for the reasons given (see
Pharmacological Actions, Therapeutic effects), current consensus is that there
is insufficient evidence to recommend any specific echinacea preparations, or to
advise on optimal dose and treatment duration.
Prophylaxis A Cochrane systematic review
included 16 randomised and quasi-randomised controlled trials – involving a
total of almost 3400 participants – of extracts of echinacea for preventing (n
= 8) or treating (n = 8) URTIs.(97) The eight 'prevention' trials comprised
five which were placebo-controlled (n = 1272 participants), and which largely
were considered to be of adequate methodological quality, and three (n = 1139
participants) in which the control group received no treatment. The five
placebocontrolled trials tested combination echinacea preparations (n = 2) or
monopreparations of E. purpurea herb or root, or E. angustifolia root (n = 3),
administered orally typically for 8–12 weeks. Two of these studies reported a
statistically significant reduction in the incidence of URTIs in echinacea recipients,
compared with placebo recipients (odds ratios, 95% confidence interval (CI):
0.45, 0.22–0.92 and 0.27, 0.11–0.66). One of these studies also found that in participants
who did acquire infections, the duration was significantly shorter in those who
had received echinacea compared with placebo recipients, although two other studies
reported no difference in this outcome. The three other 'prevention' trials all
involved children and compared a combination preparation containing extracts of
E. angustifolia and E. pallida root, Baptisia tinctoria root and Thuja
occidentalis herb, as well as several homeopathic dilutions, with no treatment.
All three studies reported that the frequency of infection was significantly lower
in the treatment compared with no treatment group (pooled odds ratio 0.36; 95%
CI 0.28–0.46), although the methodological quality of all three studies was
considered inadequate.(97)
An updated Cochrane
review used more restrictive inclusion criteria for trials (e.g. randomised
controlled trials only, trials assessing
multi-herb products excluded), such that the revised review included only five
trials that had been included in the earlier review, and 11 new trials.(98) Two
of the 16 included trials involving children, and the others, adults; 15 trials
used a placebo control design, one compared an echinacea preparation with
another herbal product and no treatment, three trials involved two echinacea
arms, and one involved comparisons with both placebo and no treatment, thus the
total number of comparisons in the review was 22. In contrast with the earlier
review, only three comparisons (from two trials(99, 100)) investigated
echinacea preparations for the prevention of colds, and none of these found
statistically significant differences between the echinacea and placebo groups
with respect to proportion of participants experiencing one or more colds.(98) Details
of the two prevention trials included in the review,(99, 100) as well as those
of several excluded trials, are given below. These trials did not show beneficial
effects for echinacea preparations, compared with placebo, on main outcome measures.(101–104)
A
randomised, double-blind, placebo-controlled trial involved 302 healthy
volunteers recruited from military institutions and an industrial plant who
received an ethanolic extract of E. purpurea root or E. angustifolia root (drug
: extract ratio, 1 : 11 in 30% alcohol), or placebo, 50 drops twice daily on
five days per week (Monday to Friday) for 12 weeks.(99) In an
intention-to-treat analysis (n = 289), the proportion of participants who
experienced at least one URTI was 32% (95% CI: 23–41%) for E. angustifolia
recipients, 29% (95% CI: 20–38%) for E. purpurea recipients, and 37% (95% CI:
27–47%) for placebo recipients; these differences were not statistically significant
(p = 0.55). Similarly, there were no statistically significant differences
between groups in time to occurrence of the first URTI (p = 0.49), or in the
duration of infections (p = 0.29), although it is possible that the study was
not large enough to detect differences. However, a greater proportion of
echinacea recipients believed they had benefited from the study medication than
did placebo recipients (78%, 70% and 56% for E. angustifolia, E. purpurea and
placebo, respectively; p = 0.04).(99) In another randomised, double-blind,
placebo-controlled trial, involving 109 individuals who had experienced more than
three colds or respiratory infections in the previous year, a fluid extract of
E. purpurea prepared from the aerial parts of fresh flowering plants,
administered at a dose of 4mL twice daily for eight weeks, had no statistically
significant effect compared with placebo on the incidence of colds and URTIs
(rate ratio for number of participants in each group with at least one cold or
URTI = 0.88, 95% CI: 0.60–1.22).(100) Likewise, there was no statistically
significant difference between groups in the duration and severity of occurring
colds or URTIs.
Three
further studies(101–103) tested the effects of echinacea for the prevention of
colds due to experimental rhinovirus infection. In one study, adult volunteers
(n = 117 enrolled) with a serum titre of neutralising antibody to rhinovirus of
41 : 4 received echinacea (300 mg) or placebo three times daily for 14 days prior
to and for five days after challenge with rhinovirus (n = 92 challenged due to
study withdrawals). It is not stated in a report of the study(101) whether
random allocation to study group was undertaken, or whether participants were
masked (blind) to treatment allocation, although a blinding check before virus
challenge found that 30 (60%) of the 50 echinacea recipients and 19 (45%) of
the 42 placebo recipients thought they were receiving the 'active' treatment (p
= 0.21). The study did not provide evidence to suggest that echinacea had
effects over those of placebo: rhinovirus infection occurred in 22 (44%) of
echinacea recipients and in 24 (57%) of placebo recipients (rate ratio = 0.77;
p = 0.3), 'clinical' colds developed in 50% and 59% of echinacea and placebo
recipients, respectively (p = 0.77), and there was no difference in mean total
symptom scores (11.4, 95% CI 3.9–18.9 and 13.6, 95% CI 7.5–19.7 for echinacea
and placebo, respectively). However, the study involved small numbers of
participants and a sample size calculation was not reported, hence it is possible
that the study was not large enough to be able to detect a difference if one
existed. Additionally, information on the species of echinacea, plant part
used, type of preparation (e.g. extract) and route of administration used was not
provided in a report of this study.(101)
It was stated that the preparation contained cichoric
acid 0.16% and almost no echinacosides or alkamides, but with this limited
information, it is not possible to say with certainty which species is likely
to have been used, although it may have been E. purpurea. In a subsequent study(102) a randomised,
double-blind trial, 48 healthy adults received a preparation containing the pressed
juice of the aerial parts of E. purpurea in a 22% alcohol base (Echina Guard)
2.5 mL three times daily, or placebo, for seven days before and after
inoculation with rhinovirus (RV-39) by intranasal administration in two inocula
about 30 minutes apart (total dose: 0.25 mL per nostril). The proportions (95%
confidence intervals (CI)) of participants with laboratory evidence of
infection (at least a fourfold increase in RV-39 neutralising antibody titre
and/or recovery of rhinovirus on viral culture), the primary outcome measure,
were 92% (95% CI: 73–99) and 96% (95% CI: 77–100) for echinacea recipients and
placebo recipients, respectively, and with clinical illness (presence of a cold
defined as a five-day total symptom score of five or more and three successive
days of rhinorrhea or participant's positive self-report of a cold) 58% (95%
CI: 37-78) and 82% (95% CI: 60-94) for the echinacea and placebo groups,
respectively (p = 0.114). Thus, the results indicate that, in this study, echinacea
was no more effective than placebo in preventing rhinovirus infection. However,
it is possible that the study did not have sufficient statistical power to
detect a difference between the two groups.(102)
The
lack of effect observed in these two studies raises the question whether or not
the durations of administration (14 and seven days in the respective
studies(101, 102)) of echinacea prior to experimental rhinovirus infection were
sufficient. On the other hand, the observed lack of effect may simply be
because the studies were not large enough to be able to detect a difference between
the treatment and placebo groups. The effects of three different extracts of E.
angustifolia root on the prevention and treatment of experimental rhinovirus
infections were assessed in a randomised, double-blind, placebo controlled
trial involving 437 young healthy volunteers.(103) In the 'prevention' phase of
the study, volunteers received one of the three echinacea extracts 1.5mL three
times daily, or placebo, for 7 days before challenge with 100 50% tissue culture
infectious doses of rhinovirus type 39 (asymptomatic participants only). The chemical
profile of the extracts was reported to be: supercritical carbon dioxide
extract, alkamides 74%, polysaccharides not present; 60% ethanol extract,
polysaccharides 49%, alkamides 2.3%, cynarin 0.16 mg/mL; 20% ethanol extract,
polysaccharides 42%, alkamides 0.1%; echinacoside was not detected in any of
the extracts. At the end of the seven-day period, there were no statistically
significant differences between the echinacea and placebo groups with respect
to the proportion of participants in each group who developed an infection following
rhinovirus challenge (p > 0.05 for all comparisons). Participants who were
challenged with rhinovirus remained in the study for a 'treatment' phase (see Clinical
studies, Treatment).
A
further 'prevention' trial assessed the effects of a combination preparation
containing extracts of aerial parts of E. purpurea and roots of E. angustifolia
(Chizukit, Hadas Corporation Limited, Israel) 50 mg/mL, propolis 50 mg/mL and
vitamin C 10 mg/mL in children.(104) In this randomised, double-blind study,
430 children aged one to five years received 5mL of the preparation (7.5 mL for
children aged four to five years), or placebo, twice daily for 12 weeks over a
winter period. If a respiratory tract infection (RTI) occurred, the dosage was
increased to four times daily for the duration of the episode. In total, 328 children
completed the study. According to an efficacy analysis, the total number of
episodes of illness, the mean number of episodes per child and the proportion
of children with one or more episodes of illness were all significantly lower
in the echinacea group, compared with the placebo group (reductions of 55%, 50%
and 43%, respectively; p < 0.001 for each).(104)
The
authors' justification for not carrying out an intention-to-treat analysis was
that all dropouts occurred in the first week of the trial; however, this
decision should have been made a priori and not because of high dropout rates.(105)
Other methodological limitations of the study are that baseline data, other than
mean age, for the two groups are lacking, so it is not possible to assess the
success of randomisation, and several, rather than one, primary outcomes were
assessed.(105) Additionally, there is a lack of detail regarding the preparation
studied (e.g. types of extracts, content of active constituents).
DOSAGE
(Baernes,
J et al., 2007., Linda, S-Roth.
2010., Duke, J. A et al., 2002)
DOSAGE
IN STANDARD HERBAL
REFERENCE TEXTS
Dosages for oral
administration (adults) recommended in older standard herbal reference texts(G6,
G7) are the same for several indications; examples are given below.
·
E. angustifolia root and/or E. pallida root For various indications, including chronic
viral and bacterial infections, skin complaints, prophylaxis of colds and
influenza, mild septicaemia, furunculosis, naso-pharyngeal catarrh, pyorrhoea
and tonsillitis.
·
Dried root/rhizome 1 g by infusion or
decoction three times daily.(G6, G7)
·
Liquid extract 0.5–1.0 mL (1 : 5 in 45%
alcohol) three times daily,(G6) or 0.25–1.0mL (1 : 1 in 45% alcohol) three
times daily.(G7)
·
Tincture 2–5mL (1 : 5 in 45% alcohol) three times
daily,(G6) or 1–2mL (1 : 5 in 45% alcohol) three times daily.(G7)
IN MORE RECENT
TEXTS
Dosages for oral
administration (adults) described in more recent texts are provided for more
specific indications.
As adjuvant therapy
and for prophylaxis of recurrent infections of the upper respiratory tract
(common colds); treatment should not exceed eight weeks' duration.(G3,
G52)
·
E. pallida root Hydroethanolic extract corresponding to 900 mg
crude drug daily,(G52) e.g. tincture (1 : 5 in 50% ethanol by volume) from dry
extract (7–11 : 1 in 50% ethanol).(G3)
·
E. purpurea herb 6–9mL expressed juice daily.(G3, G52)
·
E. purpurea root 3 x 60 drops of tincture (1 : 5 in 55%
ethanol), equivalent to 3 x 300 mg crude drug daily.(G52)
·
E. angustifolia root 1–3 g
daily
Echinacea
preparations (i.e. containing different echinacea species and plant parts) and,
therefore, dosage regimens tested in clinical trials have varied widely (see
Pharmacological Actions, Clinical studies). Trials of echinacea preparations
for the prevention of upper respiratory tract infections have typically
involved an 8- or 12-week duration of treatment; trials of echinacea
preparations for the treatment of upper respiratory tract infections typically
involve administration of the study medication for 6–10 days.
DOSAGES
• Adult
parenteral:
Dose individualized to age of client and condition (NOTE: parenteral route not
used in the United States; herb used parenterally in Germany)
• Adult PO capsules: 500 mg-1 g tid
(McCaleb et al, 2000)
• Adult PO dried root: 0.5-1 g tid;
can use as tea (Murray, Pizzorno, 1998)
• Adult PO fl uid extract: 1-2 ml
tid (1:1 dilution) mixed in a little water (Bradley, 1992); 2-4 ml tid (Murray,
Pizzorno, 1998)
• Adult PO freeze dried plant:
325-650 mg tid (Murray, Pizzorno, 1998)
• Adult PO pressed juice: 6-9 ml
daily in divided doses (25:1 dilution in 22% alcohol) (McCaleb et al, 2000)
• Adult PO solid (dry powdered)
extract: 150-300 mg tid (6.5:1 dilution or 3.5% echinacoside) (Murray,
Pizzorno, 1998)
• Adult PO tea: 2 tsp (4 g)
powdered herb simmered 15 min in hot water.
• Adult PO tincture: 15-30 drops
bid-qid or 30-60 drops bid (McCaleb et al, 2000); 2-4 ml tid (1:5 dilution)
(Murray, Pizzorno, 1998); other references suggest q1-2hr when person is ill.
Acute
Infections
• Child
PO root tincture: 1⁄2-1 tsp up to q2hr (Romm, 2000)
Skin
Infections
• Child
topical tincture: 1 tbsp root/1⁄4 cup water, use as topical rinse (Romm, 2000)
To
Prevent Colds and Infections
• Child
PO root tincture: 1⁄2 tsp bid (Romm, 2000)
DOSAGES
(ECHINACEA)
1–2 tbsp fresh root (PED); 3 g
dry root (PED); 3 g dry root:15 ml alcohol/15 mg water (PED); 2 tsp root/cup
water to 3 x/day (APA); 1–2 g root as tea 3 x/day (CAN); 0.25–1 ml liquid root
extract (1:1 in 45% ethanol) 3 x/day (CAN); 10–30 drops root tincture 3 x/day;
1–2 droppers tincture (APA); 1–2 ml herb tincture (1:5 in 45% alcohol) 3 x/day
(CAN);
300–400 mg solid extract (APA);
2 (500 mg) capsules (StX to contain 125 mg certified potency Echinacea
angustifolia root extract with at least 3.2–4.8% echinacoside, in a base of
Parthenium integrifolium root, E. angustifolia root, and E. purpurea root) 2–3 x/day
(NH); 2–3 (420 mg) capsules 2–3 x/day.
CONTRA-INDICATIONS, SIDE
EFFECTS/ADVERSE REACTIONS,
INTERACTIONS, WARNINGS
(Linda, S-Roth. 2010;
Duke, J.A., et al. 2002; Barnes, J., et al. 2007)
CONTRAINDICATIONS
Pregnancy
category is 1; breastfeeding category is 2A.
Echinacea should not be given
to children younger than 2 years of age. It should not be used by persons who
have autoimmune diseases such as lupus erythematosus, multiple sclerosis,
HIV/AIDS, or collagen disease or by those with tuberculosis or hypersensitivity
to Bellis sp.
or composite family herbs. Immunosuppression may occur after extended therapy
with this herb; do not use for longer than 8 weeks without a 3-week rest
period.
SIDE EFFECTS/ADVERSE REACTIONS
GI: Hepatotoxicity (Chernecky,
Berger, 2008)
INTEG: Hypersensitivity
reactions
RESP: Acute asthma attack
SYST: Anaphylaxis, angioedema
INTERACTIONS
DRUG
Cytochrome P4503A4 substrates: Echinacea
may inhibit cytochrome P4503A4 enzymes (Jellin et al, 2008).
Interactions—cont’d
Econazole vaginal cream: The
action of this cream may be decreased by echinacea; avoid concurrent use.
Immunomodulators (azathioprine, basiliximab,
cyclosporine,daclizumab, muromonab, mycophenolate, tacrolimus, protease
inhibitors, corticosteroids): Echinacea may decrease the
effects of immunosuppressants,
protease inhibitors, corticosteroids and should not be
used immediately before, during, or after transplant surgery.
LAB TEST
ALT, AST, lymphocyte counts (Echinacea purpurea), serum
immunoglobulin E (IgE), blood erythrocyte sedimentation rate
(ESR): Echinacea
may increase these tests.
Sperm enzyme activity: High
doses of echinacea interfere with sperm enzyme activity.
INDICATIONS (ECHINACEA) — Abscess (1; APA; MAB; PH2); Acne (1; MAB); Adenopathy (1; PHR; PH2); Allergy
(1; MAB); Arthrosis (f; APA; DEM;
WHO); Bacteria (1; PED; PH2; PNC); Bite (f; PH2); Boil (1; APA; PNC); Bronchosis
(2; APA; PHR; PH2; PNC); Bug Bite (f;
APA); Burn (2; FAD; PHR; PH2; WHO); Cancer (1; FAD; PNC; WHO); Cancer, colon (1; APA); Cancer, liver (1; APA); Candida (1; BGB; FNF; MAM; SKY; WHO); Canker Sore (1; FAD; SKY); CFS (1; BGB);
Chemotherapy (1; MAB); Cholecystosis (1; CAN); Cold (2; FAD;
PHR; PH2; WAM; WHO); Cold Sore (1;
APA); Colic (f; DEM); Conjunctivosis (1; APA); Cough (2; PHR; PH2); Cramp (1; CAN; DEM;
PHR); Crohn’s Disease (1; SKY); Cystosis (1; APA; CAN); Dermatosis (1; PNC; WHO); Diabetes (f; MAB); Diphtheria (f; MAB); Dysentery
(1; MAB); Dyspepsia (f; APA); Eczema (1; APA; PNC; WHO); Fever (2; PHR; PH2); Fit (f; DEM); Flu (2; APA; KOM; PH2; WAM); Fungus
(1; FAD; PED); Furunculosis (1; BGB;
CAN; MAB); Gastrosis (f; DEM; PHR); Gingivosis (1; APA; SKY); Goiter (1; MAB); Gonorrhea (1; PHR; PH2); Headache
(1; BGB; PHR; PH2); Hemorrhoid (f;
APA); Herpes (1; FAD; PHR; PH2; WHO);
HIV (1; BGB; JAD); Immunodepression (2; CAN; PHR; PH2; SKY; WAM; WHO); Infection (2; FAD; PED; PH2; SKY; WHO);
Inflammation (1; BGB; DEM; FNF; PH2; WAM; WHO); Leishmaniasis (1; MAB; PH2); Leukopenia (1; PHR); Listeria (1; MAM); Lyme Disease (1; JAD); Mastosis (1; MAB); Measles (f; PHR; PH2); Meningosis
(1; APA); Migraine (f; APA); Mumps (1; APA; DEM); Myalgia (f; DEM); Mycosis (1; FAD; PED); Neck
(f; DEM); Nephrorrhagia (f; MAB); Ophthalmia (f; DEM); Otosis (1; JAD; SKY); Pain (1; DEM; FNF; PED; PH2); Pertussis (1; APA); Pharyngosis (2; BGB; PHR; PH2; PNC); Psoriasis (1; APA; MAB); Pyorrhea
(1; CAN); Radiotherapy (f; WHO); Respirosis (2; APA; PH2; PIP; WHO); Rheumatism (1; APA; DEM; WHO); Rhinosis (1; CAN); Scarlet Fever (1; MAB); Septicemia (1; MAB; PNC); Sinusosis (1; BGB; MAB); Smallpox (f; DEM); Snakebite (f; APA; FAD); Sore
(2; APA; KOM; PH2; WHO); Sore Throat
(1; APA; DEM; FAD; WAM); Spider Bite
(f; FAD); Staphylococcus (1; PH2); Stomachache (f; DEM); Stomatosis (2; PHR; PH2; WHO); Swelling (1; PHR; PH2; WHO); Syphilis (f; MAB); T hirst (1; DEM); Tonsilosis (1; APA; PNC); Toothache (1; APA; FAD); Trichomoniasis (1; MAB); Tuberculosis (1; APA; MAB); Tumor (1; PNC; WHO); Typhus (1; MAB); UTI (2; CAN; KOM; PH2; PHR; PIP; WOI); Vaginosis (1; BGB); Varicosis
(1; WHO); VD (1; PH2); Virus (1; APA;
PH2; WAM; WHO); Worm (f; DEM); Wound (2; FAD; KOM; PHR; PH2; PIP; WHO);
Yeast (1; APA; BGB).
Note: Commission E recommended only E.
pallida root and E. purpurea leaf (KOM, p. 61).
CONTRA-INDICATIONS, WARNINGS
It has been stated that echinacea
is contra-indicated in patients with progressive systemic diseases, such as
tuberculosis, leukaemia and leukaemia-like diseases, collagen disorders,
multiple sclerosis and other autoimmune diseases.(G56) In the UK, some products
also advise against use in AIDS and HIV infections. The
basis
for these statements appears to be a theoretical one, based on evidence that
echinacea preparations have immunomodulatory activity; there is an opposing
view that echinacea is not harmful in autoimmune diseases.(G50) At present,
there is a lack of reliable clinical evidence to support these views, although
in view of the seriousness of the conditions listed, it is appropriate to avoid
use in these disorders until further information is available.
Interactions There are no reported drug
interactions for echinacea, although on the basis of its documented
immunomodulatory activity, as a general precaution, echinacea should only be
used with caution in patients taking immunosuppressant drugs.
A study involving 12 healthy non-smoking
volunteers assessed the effects of E. purpurea root (Nature's Bounty, Bohemia,
New York, USA) on the activity of the cytochrome P450 enzymes CYP1A2, CYP2C9
and CYP2D6 and CYP3A using caffeine, tolbutamide, dextromethorphan and
midazolam, respectively, as probe drugs (i.e. substrates for the respective CYP
enzymes).(135) After a control phase in which volunteers received all of the
probe drugs orally (with the exception of midazolam which was given intravenously
and, later, orally), participants took E. purpurea root 400 mg four times daily
for eight days; the product was stated to contain more than 1% phenols (caftaric
acid, chlorogenic acid, echinacoside and cichoric acid). On the sixth day, the
probe drugs were administered and blood and urine samples were collected as during
the control phase.
The clearance of caffeine after
oral administration was reduced significantly during echinacea administration
compared with values obtained during the control phase (mean (SD): 6.6 (3.8) L/hour
and 4.9 (2.3) L/hour for echinacea and control periods, respectively; p = 0.049), although the half-life (t½) of caffeine, area
under the curve (AUC) and maximum concentration (Cmax) were not significantly
altered. Time to maximum concentration (tmax) was significantly increased for
both caffeine and tolbutamide during echinacea administration, compared with baseline
values (p = 0.015 and 0.004, respectively). Dextromethorphan pharmacokinetics
were unaltered during echinacea administration in the 11 participants who were
extensive metabolisers. The clearance of midazolam following intravenous, but
not oral, administration was significantly increased during echinacea administration,
compared with baseline values (mean (SD): 43 (16)
L/hour and 32 (7) L/hour, respectively; p = 0.003).
These findings
suggest that E. purpurea root inhibits CYP1A2, but not CYP2C9 and CYP2D6, and
that CYP3A activity is selectively modulated: intestinal CYP3A activity is
inhibited and hepatic CYP3A activity is induced. There are several possible explanations
for the selective effects of E. purpurea root on CYP3A activity: the
constituent(s) of echinacea responsible for CYP3A inhibition may not be systemically
available, thus avoiding hepatic CYP3A inhibition; the constituent(s) of
echinacea responsible for CYP3A induction may be rapidly absorbed, thus intestinal
CYP3A induction is avoided; hepatic CYP3A may be induced by a systemically
formed metabolite of a constituent of echinacea; CYP3A induction may involve
tissue-specific activators which are differentially influenced by constituents
of echinacea.(135)
In a subsequent, similar study,
12 healthy volunteers received capsules containing a whole plant extract of E.
purpurea (containing cichoric acid 13.7 mg; chlorogenic acid and echinacoside
were not detected by HPLC analysis) 800 mg twice daily for 28 days. Participants also received three other herbal
products (Citrus aurantium, Serenoa serrulata and Silybum marianum), each
administered separately for 28 days; the four herbal products were administered in random sequence, with a 30-day wash-out
period between each, until each participant had received all four herbal
products. It was stated that there were no statistically significant
differences between serum ratios of probe drugs and their respective metabolites
obtained before and after administration of E. purpurea extract and, therefore,
that the extract had no significant effect on CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activities.
The authors' conclusions, however, included the caveat that the effects of E. purpurea
extract on CYP enzyme activity, particularly that of CYP1A2 and CYP3A4, merit
further study.(136)
The effects of
echinacea products available in Canada on inhibition of the human cytochrome
P450 drug metabolising enzyme
CYP3A4 have been tested in vitro using a fluorometric mitrotitre plate
assay.(137) In the study, 10mL samples of preparations of E. angustifolia
roots, E. purpurea roots and herb, and a 1 : 1
blend of E. angustifolia and E. purpurea (plant parts not specified) were
standardised to contain ethanol 55% and used as stock solutions. Samples of
serial dilutions of these preparations, as well as different concentrations of
the pure compounds echinacoside and cichoric acid, were assayed. The blend of
E. angustifolia and E. purpurea, and E. purpurea herb showed 'moderate'
inhibition of CYP3A4: median (95% CI) inhibitory concentration (IC50) values (%
of full strength preparation) were 6.73 (4.75, 10.09) and 8.56 (5.95, 13.05),
respectively. Echinacoside also showed moderate inhibitory activity (median
IC50 values (95% CI) 6.29 (2.07, 71.56)), whereas cichoric acid showed low
inhibitory activity.(137)
A study in mice fed both
melatonin and an extract of E. purpurea root in their diet reported reduced
numbers of proliferating myeloid cells in the spleen and bone marrow.(138) Further
research is needed to determine whether these findings are
clinically important.
Pregnancy and
lactation There
is a lack of data on the safety of echinacea preparations taken during
pregnancy and lactation and, given that the benefits of specific echinacea
preparations have not been established definitively, excessive use during these
periods should be avoided as a general precaution.
A cohort study compared numbers
of live births, and spontaneous and therapeutic abortions occurring among women
who had taken echinacea preparations during
pregnancy (n = 206, 112 of whom took echinacea during the first trimester) with
those occurring among a control group of 206 women matched for disease (URTI),
maternal age and alcohol and cigarette use.(139) The exposed group of women had
telephoned a hospital teratogen information service regarding the use of
echinacea during pregnancy; the unexposed group had also telephoned the service
for this reason, but subsequently did not use echinacea or used a non-teratogenic
antibiotic instead.
There were no statistically significant
differences between the two groups in assessed outcomes including number of
live births, spontaneous and therapeutic abortions, gestational age, birth weight
and rates of malformations. In the exposed group there were
six major and six minor malformations, compared with seven major and seven minor
malformations in the control group.(139) The study has several limitations,
particularly the small sample size, meaning
that the study would have the statistical power only to detect common malformations,
and self-report of exposure, since it is possible that misclassification could
have occurred (e.g. exposed women reported as unexposed). In addition,
participants used a range of different preparations of echinacea at different
dosage regimens, so the study does not provide adequate evidence for any
specific preparation. Further study is required to establish the safety profile
of echinacea during pregnancy.
PHARMACOLOGY (Linda, S-Roth. 2010)
Pharmacokinetics
Immunosuppression
is thought to occur after extended therapy with echinacea.
Client
Considerations
Assess
•
Assess for hypersensitivity
reactions to this herb, members of the daisy family (genus Bellis) or composite family herbs. If hypersensitivity is
present, discontinue the use of this herb and administer an antihistamine or
other appropriate therapy.
•
Assess for use of econazole
vaginal cream, immunomodulators, cytochrome P4503A4 substrates, protease inhibitors,
and corticosteroids (see Interactions).
Administer
•
Instruct the client to store
echinacea products in sealed container away from heat and moisture.
•
Instruct the client not to use
this herb for longer than 8 weeks without a 3-week rest period.
Teach Client/Family
•
Inform the client that
pregnancy category is 1 and breastfeeding category is 2A.
•
Caution the client not to give
echinacea to children younger than 2 years of age.
•
Caution the client to be
careful not to confuse this herb with other Echinacea spp. that have
different uses.
REFERENCE
Barnes, J., Anderson, L. A., and Phillipson, J.
D. 2007.
Herbal Medicines Third Edition.
Pharmaceutical
Press. Auckland and London. (page
217-236)
Duke,
J. A. with Mary Jo Bogenschutz-Godwin, Judi duCellier, Peggy-Ann K. Duke. 2002. Handbook of Medicinal Herbs 2nd Ed.
CRC Press LLC. USA (page 264-266).
Lim,
T.K. 2014. Edible Medicinal And Non-Medicinal Plants Volume 7, Flowers.
Springer Dordrecht Heidelberg New York London.
Linda
S-Roth. 2010. Mosby’s Handbook Of Herbs &
Natural Supplements, Fourth Edition.
Mosby Elsevier. USA (page 238-241).
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