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An Evidence-Based Systematic Review of Echinacea ( E. angustifolia DC, E. pallida, E. purpurea ) by the Natural Standard Research Collaboration

Authors:

Abstract

A small clinical trial assessing the potential benefit of oral echinacea for recurrent herpes genitalis found no effect. Conclusions cannot be considered definitive without further trials. Vonau et al. conducted a randomized, placebo controlled, cross-over trial to evaluate the therapeutic use of echinacea for recurrent genital herpes. Fifty patients were randomly allocated to a treatment sequence of either echinacea extract (800 mg orally twice/day) for six months followed by placebo for six months, or vice versa. Number of recurrences and several indicators of disease status (Visual Analogue Scale of pain, CD4 counts, neutrophil counts) were assessed before and after treatments. No statistically significant differences were found between the groups. Although the sample size was relatively small, a relevant treatment benefit would likely have been detected if present.
NATURAL STANDARD REVIEW
An Evidence-Based Systematic Review
of Echinacea (E. angustifolia DC,
E. pallida, E. purpurea)
by the Natural Standard
Research Collaboration
Ethan Basch, MD
Catherine Ulbricht, PharmD
Samuel Basch, MD
Sean Dalton, MD, MPH, PhD
Edzard Ernst, MD, PhD
Ivo Foppa, MD, ScD
Phillippe Szapary, MD
Natasha Tiffany, MD
Carolyn Williams Orlando, MA
Mamta Vora, PharmD
Ethan Basch is affiliated with Memorial Sloan Kettering Cancer Center; Catherine
Ulbricht is affiliated with Massachusetts General Hospital; Samuel Basch is affiliated
with Mt. Sinai Medical Center, NY; Sean Dalton; Edzard Ernst is affiliated with Uni
-
versity of Exeter; Ivo Foppa is affiliated with Harvard University; Philippe Szapary is
affiliated with University of Pennsylvania; Natasha Tiffany is affiliated with Harvard
Medical School; Carolyn Williams Orlando; Mamta Vora is affiliated with Northeast
-
ern University.
Natural Standard (www.naturalstandard.com) Copyright © 2005. Reprinted with
permission.
Journal of Herbal Pharmacotherapy, Vol. 5(2) 2005
Available online at http://www.haworthpress.com/web/JHP
doi:10.1300/J157v05n02_06 57
CLINICAL BOTTOM LINE/EFFECTIVENESS
Brief Background
Echinacea species are perennials which belong to the Aster family
and which originate in eastern North America. Traditionally used for a
range of infections and malignancies, the roots and herb (above ground
parts) of echinacea species have attracted recent scientific interest due
to purported “immune stimulant” properties. Oral preparations are pop
-
ular in Europe and the U.S. for prevention and treatment of upper respi
-
ratory tract infections (URI), and Echinacea purpurea herb is believed
to be the most potent echinacea species for this indication. In the U.S.,
sales of echinacea are believed to represent approximately 10% of the
dietary supplement market.
1
For URI treatment in adults, numerous human trials have found
echinacea to reduce duration and severity, particularly when initiated at
the earliest onset of symptoms. However, the majority of trials, largely
conducted in Europe, have been small or methodologically flawed. Al-
though highly suggestive, the evidence cannot be considered definitive
in favor of this use. There are recent negative results of a U.S. trial in
adults, although this study used a whole-plant echinacea preparation
containing both E. purpurea and E. angustifolia.
For URI treatment in children, a lack of benefit has been reported in a
well-designed trial, with an excess of rash with echinacea versus placebo.
2
Therefore, at this time, this use of echinacea may not be advisable.
For URI prevention (prophylaxis) in adults and children, daily
echinacea has not been shown effective in human trials, although one
study of a combination of echinacea, propolis, and vitamin C in children
has reported positive results.
3
Preliminary studies of oral echinacea for genital herpes and radia-
tion-associated toxicity remain inconclusive. Topical E. purpurea juice
has been suggested for skin and oral wound healing, and oral/injectable
echinacea for vaginal Candida albicans infections, but evidence is lack
-
ing in these areas.
58 JOURNAL OF HERBAL PHARMACOTHERAPY
The German Commission E discourages use of echinacea in patients
with autoimmune diseases, but this warning is based on theoretical con-
siderations rather than human data.
Historical or Theoretical Uses Which Lack Sufficient Evidence
Abscesses, acne, bacterial infections, bee stings, boils, burn wounds,
4
candidiasis, diphtheria, dizziness, dyspepsia, catarrh, eczema,
4
gingi-
vitis, hemorrhoids, herpes labialis,
5
HIV infection,
6
insect bites,
7-9
ma-
laria, migraine headache, nasopharyngeal catarrh, pain, psoriasis,
pyorrhea, recurrent vaginal candidiasis,
10
respiratory infections in dogs,
11
rheumatism, septicemia, snake bites, skin ulcers,
4
skin wounds ,
4
Staph-
ylococcal infections, Streptococcal infections, syphilis, tonsilitis, ty-
phoid, urinary tract infection, urinary disorders,
12
whooping cough.
13
Expert Opinion and Historic/Folkloric Precedent
Natural medicine experts frequently recommend echinacea species
oral extracts for treatment of the common cold, and for other conditions
requiring “immune stimulation.” It is occasionally recommended for
topical treatment of wounds. Internal use of Echinacea pallida root and
E. purpurea herb (above ground parts) has been approved by the Ger
-
man Commission E expert panel for supportive therapy of influenza-
like infections.
Despite a paucity of scientific evidence, the German Commission E
has approved E. purpurea orally for supportive treatment of chronic re
-
spiratory infections, lower urinary tract infections, and for topical treat
-
Natural Standard Review 59
Scientific Evidence for Common/Studied Uses
Indication
Evidence Grade
Upper respiratory tract infections: treatment (adults)
B
Upper respiratory tract infections: prevention (adults and children)
C
Radiation-associated leukopenia
C
Cancer
C
Upper respiratory tract infections: treatment (children)
D
Genital herpes
D
ment of poorly healing wounds/chronic ulcerations. These indications
are also noted in monographs published by the World Health Organiza
-
tion.
Traditionally, echinacea roots and herbs were used by indigenous
Americans for a wide variety of conditions, ranging from snakebites to
malignancies.
Brief Safety Summary
Likely Safe: Echinacea is considered safe for internal use by most
practitioners. Scientific evidence suggests safety when used orally or
topically in recommended doses for a maximum of eight consecutive
weeks.
Possibly Safe: One small preliminary study suggests safety in preg
-
nant women and children if taken as directed, although further evidence
is warranted in this area.
Possibly Unsafe: Echinacea may cause allergic reactions in atopic
patients. Some experts discourage use in cancer patients, tuberculosis,
leukocytosis, collagenosis, multiple sclerosis, AIDS, HIV infection, or
autoimmune diseases, although this is based on theory rather than on
human data, and there are no case reports of adverse events in such pa-
tients. The risk of rash in children may outweigh potential benefits in in-
dications for which efficacy is not clearly demonstrated, such as common
cold treatment.
Likely Unsafe: Echinacea may cause allergic reactions in patients
with allergies to members of the Asteraceae/Compositae plant family
(ragweed, chrysanthemum, marigold, daisy).
DOSING/TOXICOLOGY
General
Recommended doses are based on those most commonly used in
available trials, or on historical practice (not necessarily proven effica
-
cious). However, with natural products it is often not clear what the op
-
timal doses are to balance efficacy and safety. Preparation of products
may vary from manufacturer to manufacturer, and from batch to batch
within one manufacturer. Because it is often not clear what the active
component(s) of a product is, standardization may not be possible, and
the clinical effects of different brands may not be comparable.
60 JOURNAL OF HERBAL PHARMACOTHERAPY
Combination echinacea products, such as those containing goldenseal,
may not be clinically active due to low echinacea concentrations.
Standardization
Some manufacturers standardize echinacea extracts to 4.0-5.0%
echinacoside, while others standardize to cichoric acid. Because the ac
-
tive constituent(s) has not been identified, standardization may not be
clinically relevant in predicting effectiveness.
A recent well-conducted study examined the constituents of 59 com
-
mercially available echinacea preparations, and found that 10% con
-
tained no measurable echinacea, and of the 21 standardized products,
43% met the quality standards listed on the labels.
1
Adult Dosing (18 Years and Older)
Oral
Capsules (of powdered herb): For treatment of upper respiratory tract
infections, the dose recommended most often by experts is 500-1000 mg
three times/day, for 5-7 days.
14
A total daily dose of 900 mg/day has been
shown superior to 450 mg/day for improvement of cold/flu symptoms.
15
Expressed Juice: The dose recommended most often by experts is
6-9mL daily in divided doses, for 5-7 days.
Tincture (1:5): The dose recommended most often by experts is 0.75
to 1.5 mL, gargled then swallowed, 2-5 times/day, for 5-7 days (daily
dose should have equivalent of 900 mg dried echinacea root). Some herb-
alists prefer tinctures due to purported immune stimulation at the level of
tonsillar lymphoid tissues when tinctures are gargled before swallowing.
Tea: The dose recommended most often by experts is 2 tsp. (4 g of
echinacea) of coarsely powdered herb simmered in 1 cup of boiling water
for 10 minutes, daily for 5-7 days. “Echinacea Plus®” tea, manufactured
by Traditional Medicinals (equivalent of 1.275 mg of dried herb and root
per tea bag) has been shown to reduce upper respiratory tract infection
symptoms when 5-6 cups are taken on the first day and titrated down by 1
cup/day for the next 5 days.
16
Topical
Semisolid Preparation: For wound/ulcer healing, the dose recom
-
mended most often by experts is 15% pressed herb (non-root) juice
semisolid preparation applied daily.
Natural Standard Review 61
Parenteral
Parenteral preparations of echinacea are no longer approved for use
in Germany, and are generally not available commercially. Severe reac
-
tions have been reported following parenteral use.
16
Pediatric Dosing (Younger Than 18 Years)
Note
In a study of echinacea for the treatment of cold symptoms in chil
-
dren ages 2-11, an increased incidence of rash was reported, without
significant measured benefits.
2
Oral
Dose recommendations in children are often weight-based and calcu-
lated from the adult recommended dose (adult dose is based on 70kg
male; doses have been reduced proportionately for child’s weight).
Other approaches have included reduction of adult doses by 50-67 per-
cent.
Intramuscular/Parenteral
Three studies of 257 subjects total (infants to 14 year olds with
whooping cough) found no adverse effects with 1-2 mL of squeezed
aqueous extract (0.1g/2 mL) given intramuscularly twice daily for
3-21 days.
13,18-22
Safety of intramuscular preparations has not been
established, and should be approached cautiously. Parenteral prep
-
arations of echinacea are no longer approved for use in Germany.
Toxicology
Symptoms after parenteral administration (not often recommended)
have included shivering, fever, and muscle weakness, as documented in
one human report of acute toxicity.
23
In vitro toxic effects have been observed on cells at extremely high
echinacea concentrations.
10
The LD
50
of intravenous echinacea juice was found to be 50 mL/kg in
one animal study.
24
62 JOURNAL OF HERBAL PHARMACOTHERAPY
PRECAUTIONS/CONTRAINDICATIONS
Allergy
Oral and Topical Formulations: Individuals with asthma or atopy
may be predisposed to allergic reactions from oral/topical use of
echinacea, consistent with IgE-mediated hypersensitivity.
25
Anaphylaxis
associated with echinacea has been reported in a 37 year-old woman
with a history of atopy.
26
She subsequently was found to have a positive
skin prick test, and radioallergosorbent (RAST) testing confirmed
IgE binding to echinacea. In a poorly described series of 23 case re
-
ports of IgE-mediated hypersensitivity reactions, causality was ascribed
to echinacea as “certain” in two cases, and “probable” in ten cases. Ad-
equate details of methodology were not provided.
27
The same authors
published a 2002 report from their referral center in Australia which
documented four cases of anaphylaxis or bronchospasm following in-
gestion of echinacea, and one case of maculopapular rash.
25
All five
individuals subsequently reacted positively to skin prick and RAST
testing for echinacea hypersensitivity. The authors also noted 26 cases
reported to the Australian Adverse Drug Reactions Advisory Commit-
tee between 1979-2000 of urticaria, angioedema, bronchospasm, or
anaphylaxis associated with echinacea use. More than six brands and
multiple formulations (tea, tablets, liquid) were implicated. No deaths
occurred.
In a study of echinacea use in children ages 2-11, an increased inci-
dence of rash was reported (7.1% with echinacea vs. 2.7% with placebo,
p = 0.008).
2
To determine the prevalence of echinacea sensitivity in the popula-
tion at large, 100 atopic patients who had never taken echinacea were
tested with skin prick tests, and a positive response was elicited in 20%,
with negative controls.
25,27
In a study of 1032 subjects who were patch tested topically with vari
-
ous plant extracts, two reacted to E. angustifolia.
28
Injections: Five cases of severe reactions following injection of
Echinacin® have been reported, characterized by angioedema, hypotension,
anaphylactic shock, and rash; a 63-year-old patient developed bilateral
hand swelling, erythema, and pruritis after oral ingestion of Esberitox®.
17
Other cases of allergic reactions have been reported after parenteral use
of echinacea products,
29,30
and there is no supportive evidence from hu
-
man trials to favor parenteral over oral use.
Natural Standard Review 63
Theoretically, individuals sensitive to members of the Asteraceae/
Compositae plant family may be more likely to experience allergic re
-
sponses (ragweed, chrysanthemums, marigolds, daisies, etc.).
Adverse Effects
General: Echinacea has been well tolerated in clinical practice and in
trials, with few adverse events reported. In children, three studies of 257
subjects total (infants to 14 year olds with whooping cough) found no
adverse effects with 1-2 mL of squeezed aqueous extract (0.1 g/2 ml)
given intramuscularly twice daily for 3-21 days.
13,18-22
Dermatologic: Urticaria and allergic rashes have been reported.
25
There is one published case of recurrent erythema nodosum in associa-
tion with use of echinacea.
31
In a study of children ages 2-11, rash oc-
curred in 7.1% of children treated with echinacea, vs. 2.7% with
placebo (p = 0.008).
2
Neurologic/CNS: Mild drowsiness and headache have been reported
in <1% of study subjects.
32
Dizziness has been rarely noted.
25
Cardiovascular: One case of atrial fibrillation has been reported in
association with echinacea use.
25
Specific details are not available.
Gastrointestinal: The most frequently cited adverse events from clin-
ical trials are gastrointestinal, including transient mild nausea or vomit-
ing (<1%), sore throat (<1%), and abdominal pain (<1%).
23
In one
study, 13% reported adverse effects which were largely gastrointesti-
nal, although the authors felt echinacea was the likely cause in only one
case (additional details were not provided).
32
Seven cases of hepatitis
associated with echinacea use were reported to the Australian Adverse
Drug Reactions Advisory Committee between 1979-2000.
25
However,
specific details of these cases are not available.
Genitourinary/Reproductive: One in vitro study of zona free hamster
oocytes concluded that high concentrations of echinacea reduce the
penetration of hamster sperm. At low concentrations, penetration was
comparable to control. In vitro incubation of hamster sperm with
echinacea for seven days indicated significant denaturation of sperm
DNA and reduced viability.
33
Renal: One case of acute renal failure has been reported in associa
-
tion with echinacea use.
25
Specific details are not available.
Hematologic: Long-term use of echinacea may be associated with
leukopenia,
34
although further data is needed in this area before a firm
conclusion can be reached.
64 JOURNAL OF HERBAL PHARMACOTHERAPY
Precautions/Warnings/Contraindications
Use cautiously in patients prone to atopic reactions, due to predispo
-
sition towards allergic reactions with oral/topical echinacea.
Use caution with parenteral preparations of echinacea (no longer ap
-
proved for use in Germany). Safety is not established, and in diabetics,
parenteral administration may worsen glycemic control.
Use tinctures cautiously with alcoholic patients and in patients taking
disulfiram or metronidazole: many tinctures contain significant concen
-
trations of alcohol (range: 15% to 90%).
The German Commission E warns against use of echinacea in pa
-
tients with AIDS/HIV, collagen vascular diseases, multiple sclerosis,
or tuberculosis, due to theoretical adverse effects on immune func
-
tion, although no specific trial data support this assertion.
Pregnancy and Lactation
In preliminary studies, oral echinacea has not appeared to pose a
teratogenic risk. One controlled, prospective study of 206 pregnant
women found no differences in the incidence of birth defects, gesta-
tional age, maternal weight gain, birth weight, pregnancy outcome, or
fetal distress from echinacea use.
35,36
In this study, different formula-
tions were used by pregnant women: 58% used capsule/tablet (250-
1000 mg/day) and 38% tinctures (5-30 drops/day) varying in alcoholic
content from 25-45%. Duration of use varied but was typically continu-
ous for 5-7 days. The statistical power of this study, however, was lim-
ited, leaving the possibility of undetected adverse gestational effects.
The German Commission E expert panel considers oral echinacea in
recommended doses safe for use in pregnancy and lactation. However,
most experts do not recommended parenteral administration during
pregnancy. Tinctures may be ill-advised due to 15-90% alcohol con
-
tent, although the absolute quantity of alcohol ingested from tinctures at
recommended doses is likely to be relatively small.
Further data are warranted in this area.
INTERACTIONS
Echinacea/Drug Interactions
Amoxicillin: There is one poorly described case report of a 19-year-
old patient ingesting amoxicillin and an unclear echinacea preparation
Natural Standard Review 65
who developed rhabdomyolysis, shock, and death; further details were
not provided.
17
Disulfiram (Antabuse®): Echinacea tinctures often contain high al
-
cohol content (15-90%), and theoretically may elicit a disulfiram reac
-
tion.
Econazole Nitrate (Spectazole®): There is preliminary evidence to
suggest that use of echinacea with topical Econazole decreases the re
-
currence rate of vaginal Candida infections.
37
Hepatotoxic Agents: Natural medicine practitioners often caution
that echinacea may cause hepatotoxicity, and recommend avoiding
concomitant use with other potentially hepatotoxic drugs (anabolic
steroids, amiodarone, methotrexate, ketoconazole, etc.). However,
there is no clear evidence from basic science or human reports that
echinacea causes significant liver toxicity. Some have noted that it lacks
the 1,2 unsaturated necrine ring system that causes hepatotoxicity of
pyrrolizidine alkaloids.
38
Immunosuppressant Drugs, Oral Corticosteroids: In theory, echinacea’s
immunostimulant properties may interfere with immunosuppressant
therapy (including azathioprine, cyclosporin, and prednisone). This
possibility has not been systematically studied in humans.
Metronidazole (Flagyl®): A disulfiram reaction can occur when
metronidazole and alcohol are used concomitantly. Due to the high al-
cohol content in some echinacea tinctures, this combination theoreti-
cally may cause such a reaction.
Echinacea/Herb/Supplement Interactions
Immunostimulant Agents: Positive Interaction: Echinacea is
sometimes used in combination products which are purported to syn
-
ergistically stimulate the immune system. For example, Esberitox®
(PhytoPharmica, Germany) contains Echinacea purpurea, Echinacea
pallida, wild indigo root (Baptisia tinctoria), and thuja (white ce
-
dar). There is no available human evidence supporting these interac
-
tions.
Vitamin B: While echinacea itself has not been found to interact
with vitamin B, many echinacea preparations are coupled with
goldenseal (Hydrastis canadensis), which is purportedly an antibi
-
otic, and may decrease intestinal microflora and absorption of vita
-
min B. These preparations may have low levels of echinacea, and
66 JOURNAL OF HERBAL PHARMACOTHERAPY
may not be efficacious against viral induced upper respiratory tract
infections.
Kava: Multiple reports of hepatotoxicity associated with kava use
have been reported, believed to be most common with heavy or chronic
use. Caution should be exercised with concomitant use of echinacea,
which some natural medicine practitioners have warned may cause liver
toxicity as well. However, there is no clear evidence from basic science
or human reports that echinacea causes significant liver toxicity. Some
have noted that it lacks the 1,2 unsaturated necrine ring system that
causes hepatotoxicity of pyrrolizidine alkaloids.
38
This potential inter
-
action remains theoretical.
Echinacea/Food Interactions
Insufficient available evidence.
Echinacea/Lab Interactions
Insufficient available evidence.
MECHANISM OF ACTION
Pharmacology
Immunostimulatory properties of echinacea appear to target both
non-specific and specific immune function. Non-specific effects in-
clude increases in macrophage proliferation and phagocytosis, as well
as secretion of interferon, tumor necrosis factor, and interleukin-1 (in
vitro and in vivo).
39-44
Specific immune responses include activation of
alternate complement pathway components, and elevated levels/activ
-
ity of T lymphocytes and natural killer (NK) cells.
15,45-47
The echinacea
species E. purpurea is believed to have the strongest potency on the im
-
mune system.
48
Immunostimulation may depend on dosage and fre
-
quency of administration: Cell-mediated immunity can be stimulated
by one therapeutic administration followed by a “free” interval of one
week, but can be depressed by daily administration of higher doses.
10
Other studies have failed to elicit these responses.
In animal studies, E. angustiflora has exhibited anti-inflammatory
49
and
antihyaluronidase activity, a likely function of its polysaccharide fraction,
50
which may stimulate wound healing.
51
Natural Standard Review 67
In rats, an increase of primary and secondary antigen-specific IgG
production has been seen with continuous echinacea treatment.
52
Echinacea may possess microbiocidal activity against Candida
albicans, Listeria monocytogenes,
53
influenza virus,
54
vesicular stom
-
ach virus, and herpes simplex virus (HSV-1 and HSV-2).
55
The rele
-
vance of these in vivo findings remains unclear.
Constituents of the root oil of E. angustiflora and E. pallida have
been shown to possess antitumor activity in vivo.
56
Pharmacodynamics/Kinetics
Insufficient available reliable data.
HISTORY
Used in traditional medicine by Native Americans of the Great Plains
region, there are nine known species of echinacea, all which grow east
of the Rocky Mountains.
Echinacea was adopted by central U.S. settlers in the 1800s. In the
1920s, American Eclectic physicians added echinacea to their pharma-
copoeia. However, after the introduction of antibiotics, echinacea use
fell out of favor.
Echinacea’s historical use against infections has found renewed in-
terest due to recent rises in antibiotic resistance, and the limitations of
available anti-viral drugs.
68 JOURNAL OF HERBAL PHARMACOTHERAPY
EVIDENCE TABLE
Condition Study
Design
Author, Year N Statistically
Significant?
Quality of
Study
0-2=poor
3-4=good
5=excellent
Magnitude
of Benefit
ARR NNT Comments
Upper
respiratory
tract
infection
(URI)
treatment
Randomized
controlled
(RCT),
double-blind
Brinkeborn,1
999
246 Yes 5 Medium 25-
35%
3-4 Examined
severity but not
duration of
symptoms; higher
concentration more
effective.
URI
treatment
RCT,
double-blind
Barrett,
2002
148 No 5 None NA NA No differences in
self-reported
severity or duration
of symptoms.
Unrefined combination
of
E. Purpurea
and
E. angustifolia
com
-
pared to alfalfa
("placebo"); may
not have been
adequately powered.
Natural Standard Review 69
Condition Study
Design
Author, Year N Statistically
Significant?
Quality of
Study
0-2=poor
3-4=good
5=excellent
Magnitude
of Benefit
ARR NNT Comments
URI
treatment
(children)
RCT,
double-blind
Taylor,
2003
407 No 4 None NA NA No differences in
parent-reported
symptom severity
or duration. Increased
risk of rash with
echinacea.
URI
treatment
RCT,
double-blind
Brinkeborn,
1998
119 Yes 5 NA NA NA This is a preliminary
report of Brinkeborn,
1999 (same trial).
URI
treatment
RCT,
double-blind
Henneicke-
von Zepelin,
1999
263 Yes 5 Small NA NA Combination
product Esberitox
reduced severity &
duration.
URI
treatment
RCT,
double-blind
Hoheisel,
1997
120 Yes 4 Medium 20% 5 Decreased duration
& severity;
subjective outcome.
URI
treatment
RCT Dorn,1997 160 Yes 3 Large NA NA Decreased
duration &
severity.
URI
treatment
RCT Lindenmuth
2000
95 Yes 3 Small NA NA Decreased duration
& severity with early
treatment.
URI
treatment
RCT,
double-blind
Thom, 1997 66 Yes 3 Large NA NA Kanjan herbal
mixture
decreased duration
of symptoms.
URI
treatment
RCT:
dosing trial
Braunig,
1992
180 Yes 2 Large NA NA 900mg/day more
effective than
450mg. Methods
poorly
described.
URI
treatment
RCT:
dosing trial
Braunig,
1993
160 Yes 2 Large NA NA Use of
Echinacea
pallida
. Methods
poorly described.
URI
treatment
RCT,
single blind
Scaglione,
1995
32 Yes 1 Medium NA NA Cold-X (combination)
reduced the # of
tissues used &
duration.
URI
prevention
RCT,
double-blind
Grimm,1999 109 No 4 Small 9% 11 Level of statistical
power questionable;
no significant
preventive effect;
median symptom
duration
reduced by 1/3.
URI
prevention
Equivalence
trial, double-
blind
Melchart,
1998
302 Yes 4 Small 6% 17
E. angustiflora
vs.
E. purpurea
. No
effect of echinacea
vs. placebo on URI
incidence, but
positive subjective
efficacy.
70 JOURNAL OF HERBAL PHARMACOTHERAPY
EVIDENCE TABLE (continued)
Condition Study
Design
Author, Year N Statistically
Significant?
Quality of
Study
0-2=poor
3-4=good
5=excellent
Magnitude
of Benefit
ARR NNT Comments
URI preven
-
tion
RCT, dou
-
ble-blind
Schoneberger,
1992
108 NA 3 Large 7% 14 Reduced
incidence,
severity and
duration, but
methods &
statistics
insufficiently
described.
URI preven
-
tion
RCT Berg, 1998 42 Yes 2 Medium NA NA Methodologi
-
cally weak
study in
male ath
-
letes prior to
competition.
URI preven-
tion
Controlled
(not random-
ized or
blinded)
Turner, 2000 117 No 1 None 13% 8 Poor
statistical
power; low
content of
pharmaco-
logically
active
compounds.
URI preven-
tion
RCT Forth, 1981 95 Yes 1 Large 32% 3 Large
preventive
effect; meth-
odologically
weak.
Radiation-
associated
leukopenia
RCT Bendel,1988 50 No 1 None NA NA No power
calculation;
unclear if
sample size
sufficient to
sense differ
-
ences.
Radiation-
associated
leukopenia
RCT Sartor, 1972 48 Yes 1 Large NA NA Combination
product
Esberitox
reduced #
days of
radiation
missed due
to leukopenia.
Genital her
-
pes
RCT Vonau, 2001 50 No 4 NA NA NA No effect of
6 months of
combination
product
Esberitox.
Natural Standard Evidence-Based Validated Grading Rationale™
Grades reflect the level of available scientific evidence in support of
the efficacy of a given therapy for a specific indication.
Expert opinion and folkloric precedent are not included in this as
-
sessment, and are reflected in a separate section of each monograph
(“Strength of Expert Opinion and Historic/Folkloric Precedent”).
Evidence of harm is considered separately; the below grades apply
only to evidence of benefit.
A Jadad score is calculated using the seven items in the table below.
The first five items are indications of good quality, and each counts as
one point towards an overall quality score. The final two items indicate
poor quality, and a point is subtracted for each if its criteria are met. The
range of possible scores is 0 to 5.
Natural Standard Review 71
Level of Evidence Grade Criteria
A (Strong Scientific Evidence)
Statistically significant evidence of benefit from > 2 properly
randomized trials (RCTs), OR evidence from one properly
conducted RCT AND one properly conducted meta-analysis, OR
evidence from multiple RCTs with a clear majority of the
properly conducted trials showing statistically significant
evidence of benefit AND with supporting evidence in basic
science, animal studies, or theory.
B (Good Scientific Evidence)
Statistically significant evidence of benefit from 1-2 properly
randomized trials, OR evidence of benefit from >1 properly
conducted meta-analysis OR evidence of benefit from >1 cohort/
case-control/non-randomized trials AND with supporting
evidence in basic science, animal studies, or theory.
C (Unclear or conflicting scientific evidence)
Evidence of benefit from > 1 small RCT(s) without adequate
size, power, statistical significance, or quality of design by
objective criteria,* OR conflicting evidence from multiple RCTs
without a clear majority of the properly conducted trials showing
evidence of benefit or ineffectiveness, OR evidence of benefit
from >1 cohort/case-control/non-randomized trials AND without
supporting evidence in basic science, animal studies, or theory,
OR evidence of efficacy only from basic science, animal studies,
or theory.
D (Fair Negative Scientific Evidence)
Statistically significant negative evidence (i.e., lack of evidence
of benefit) from cohort/case-control/non-randomized trials, AND
evidence in basic science, animal studies, or theory suggesting
a lack of benefit.
F (Strong Negative Scientific Evidence)
Statistically significant negative evidence (i.e., lack of evidence
of benefit) from > 1 properly randomized adequately powered
trial(s) of high-quality design by objective criteria.*
Lack of Evidence
Unable to evaluate efficacy due to lack of adequate available
human data.
* Objective criteria are derived from validated instruments for evaluating study quality, including the 5-point
scale developed by Jadad et al., in which a score below 4 is considered to indicate lesser quality methodologi
-
cally (Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the
quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17[1]:1-12).
† Listed separately in monographs in the “Historical or Theoretical Uses which Lack Sufficient Evidence”
section.
EVIDENCE DISCUSSION
Upper Respiratory Tract Infection–Treatment (Adults)
Summary: Oral echinacea is frequently recommended to reduce the
duration and severity of upper respiratory tract infections (URI). Nu-
merous trials have been conducted in this area, but have largely been of
limited methodological quality (or used combination products). None-
theless, the sum of existing positive evidence is highly suggestive–
albeit not definitive. A sufficiently-sized, rigorously blinded study us-
ing doses previously found effective (Echinacea purpurea extract 900
mg/day for 6-8 days) and using accepted outcome measures is war-
ranted, in order to further characterize optimal timing, dosage, fre-
quency of administration, and magnitude of benefit. Consideration
should also be given to the possible differential efficacy of various
echinacea species, and their different plant parts (root vs. above ground
herb).
Systematic Reviews: A systematic review of studies (before 1994) of
echinacea for immunomodulatory indications
57
found six randomized,
placebo controlled, double-blind trials examining efficacy in the treat
-
ment and prevention of URI.
15,58-62
The authors concluded that, despite
some evidence of immunomodulatory action of echinacea, no clear rec
-
ommendations could be made for the treatment of URI with echinacea.
Individual trials are discussed below.
72 JOURNAL OF HERBAL PHARMACOTHERAPY
Jadad Score Calculation
Item Score
Was the study described as randomized (this includes words such as randomly, random, and ran
-
domization)?
0/1
Was the method used to generate the sequence of randomization described and appropriate (table
of random numbers, computer-generated, etc.)?
0/1
Was the study described as double blind? 0/1
Was the method of double blinding described and appropriate (identical
placebo, active placebo, dummy, etc.)?
0/1
Was there a description of withdrawals and dropouts? 0/1
Deduct one point if the method used to generate the sequence of randomization was described
and it was inappropriate (patients were allocated alternately, or according to date of birth, hospital
number, etc.).
0/1
Deduct one point if the study was described as double blind but the method of blinding was inap
-
propriate (e.g., comparison of tablet vs. injection with no double dummy).
0/1
Barrett et al. published a similar review, but included trials published
up to 1998.
63
Nine studies evaluating treatment efficacy,
14,15,59-62,64,65
plus one unpublished trial (Galea, 1996) were identified. Most studies
had significant methodological limitations, and often used ad hoc
symptom scores. The authors nevertheless concluded that the use of
echinacea for treatment of early cold symptoms may be “cautiously
supported,” while long-term or preventive use was not recommended.
Giles et al. presented a review of studies on echinacea efficacy in pre
-
vention and treatment of the common cold published since 1994.
66
Five
such trials were included in the analysis.
14,32,65,67,68
The authors con
-
cluded that the “efficacy of echinacea for treating common cold symp
-
toms remains unclear, yet it appears a suitable alternative for suitable
patients.”
A review of the efficacy of echinacea to prevent or treat the common
cold
69
concluded that echinacea may be effective for preventing and
treating the common cold, but more studies are needed to determine
which preparations are most effective. All included randomized con-
trolled trials are discussed in detail below.
Randomized Trials (higher quality): A well-conducted randomized,
placebo controlled double-blind trial of 246 participants found that
Echinaforce® (6.78 mg Echinacea purpurea crude extract based on 95%
herb and 5% root per tablet) and a 7 concentration (48.27 mg) both sig-
nificantly reduced severity of cold symptoms.
32
Participants took two
tablets three times daily after onset of symptoms, and were advised to
continue until they “felt healthy” (7 days maximum). The primary end-
point was reduction in a 12-symptom complaint-index scale: improve-
ment was documented for subjects who experienced reductions in
complaint-index by >60% (physician scale) or >50% (patient scale). This
otherwise methodologically strong study would have benefited from a
more established, validated symptom-scale. Preliminary results of this
trial in 119 patients were reported elsewhere.
64
Braunig et al. conducted a randomized, placebo controlled, dou
-
ble-blind dosing trial on the efficacy of echinacea extract in the treat
-
ment of the common cold. In this study, 180 otherwise healthy patients
with symptoms of the common cold were allocated to either placebo (no
details provided), Echinacea purpura radix 50% ethanolic extract 450
mg/day, or 900 mg/day.
15
Randomization and blinding procedures, and
treatment plans were not clearly described. At days 0, 3-4, and 8-10,
cold symptoms (fatigue, sweats, teary eyes, stinging eyes, sore throat,
ear aches, myalgia, headache) were assessed by a 4-point scale (0 = not
present, 1 = mild, 2 = moderate, 3 = severe) and patients were clinically
Natural Standard Review 73
assessed. The two target variables were duration of illness, and reduc
-
tion of symptoms. Only the higher dose of echinacea was superior to
placebo in reducing symptoms (p < 0.0001). Although this finding is
suggestive, the poor description of methods limits the usefulness of this
study.
A randomized, placebo controlled double-blind trial of 160 patients
with symptoms of acute upper respiratory infection found an alcoholic
extract of Echinacea pallidae radix to significantly reduce both sever
-
ity and duration of upper respiratory tract infection symptoms.
14
Nei
-
ther the method of herb extraction nor a product name was specified.
Ninety drops/day were given over 8-10 days (unclear whether one or
several doses were given). Benefit of echinacea vs. placebo was re
-
ported in terms of illness length (p < 0.0001), overall symptom score (p
< 0.0004), and “whole” clinical score (p < 0.001). However, limited in-
formation was provided regarding statistical analysis or measurement
instruments. Although this study is suggestive, without further method-
ological details, results are difficult to interpret.
A randomized, double-blind, placebo controlled study of 120 par-
ticipants found the duration and severity of common cold symptoms to
be significantly decreased with Echinaguard® (squeezed sap of E.
purpurea).
65
The dose given was 20 drops in water every 2 hours for the
first day, followed by 3 times daily (up to a total of 10 days). Efficacy
was assessed by a short structured interview which included questions
regarding the nature of illness (“real cold?”), fever, severity vs. previ-
ous episodes of common cold, onset of improvement, and duration of
treatment. Fewer subjects in the Echinaguard® group experienced a
“real cold” after initiation of treatment vs. placebo (40% vs. 60%, p =
0.044). Median time to improvement was significantly shorter in the
Echinaguard® group than placebo (0 vs. 5 days, p < 0.0001). Limita
-
tions of this study include unclear standardization of the product used,
and incomplete description of randomization, blinding, statistical anal
-
ysis, dropouts, or validation of the measuring questionnaire.
Lindenmuth and Lindenmuth conducted a randomized controlled
trial of “Echinacea Plus” tea vs. a placebo for upper respiratory tract
symptoms.
16
The tea contained the equivalent of 1.275 mg of dried herb
and root per tea bag. Participants were instructed to drink 5-6 cups of tea
on the first day and titrate down by 1 cup/day for the next 5 days. The
experimental group rated the effectiveness of echinacea tea as 4.1 on a
5-point scale (SD 0.96), while the control group rated their tea 2.8 (SD
0.095), with a p value < 0.001. There was also a statistically significant
74 JOURNAL OF HERBAL PHARMACOTHERAPY
(although small) difference in the number of days symptoms lasted and
in the number of days before symptoms diminished in the treatment
group vs. control. Statistical analysis may not have been appropriate
(t-test for sum scores), but this methodological weakness would not
likely explain the results. Therefore, echinacea tea, when taken at the
first onset of symptoms, may be effective in relieving symptoms of the
common cold and in abbreviating the course of the illness.
In a well-conducted randomized, double-blind, placebo controlled
multicenter trial, Henneicke-von Zepelin et al. examined the efficacy of
the combination product Esberitox® (includes ethanolic-aqueous ex
-
tracts of 2 mg herba thujae occidentalis, 7.5 mg radix echinaceae,10
mg radix baptisiae tinctoriae).
70
The study enrolled 263 patients with
acute common colds who were not suffering from any chronic condition
affecting immune system function. Patients received either Esberitox®
N three tablets/day or placebo for 7-9 days. Primary outcomes were
general well-being (Welzel- Kohnen color scale), physician evaluated
symptom severity (clinical global impression item-1 [CGI-1]), and rhi-
nitis score/bronchitis score (10-point scales). Patient follow-up was on
days 0, 4, and 8. The “total efficacy value,” a combination of all out-
come measures, showed a >20% effect at study completion (p < 0.05).
The improvement in well-being was most prominent (33.9%, p =
0.0048), followed by rhinitis score. Time to response, defined as a 50%
decrease in symptom score, was significantly shorter in the treatment
group vs. placebo (p = 0.022). These findings suggest that an herbal
combination containing echinachea significantly reduces the severity
and duration of the common cold when given at the early onset of symp-
toms. However, the question of whether this effect is attributable to the
echinacea component of Esberiox® cannot be addressed within the
framework of this study.
Thom and Wollan found a significantly faster improvement of cold
symptoms with Kanjang, a mixture containing echinacea, Siberian gin
-
seng, and Vasaka.
71
Sixty-six patients with common cold symptoms
were randomly assigned to either Kanjang (15 mL three times daily,
containing 4.5 g/day of E. purpurea radix) or placebo. Improvement of
cold symptoms was assessed by a 10-point Visual Analogue Scale
(VAS) on days 2, 4, and 10 after onset of treatment. The difference be
-
tween groups was most pronounced on day 4, when the average global
efficacy VAS score was approximately 6 in the Kanjang group vs. 1 in
the placebo group (p = 0.001). As with other studies using combination
products, this study does not permit specific inference regarding the ef
-
ficacy of echinacea.
Natural Standard Review 75
Lesser Quality Studies: Braunig and Knick report a study evaluating
the efficacy of Echinacea pallida for the treatment of URI.
59
In this
study, 180 otherwise healthy patients with symptoms of URI were ran
-
domly allocated to either Echinacea pallida radix (Pascotox®, 900 mg/
day) or placebo for 8-10 days. Outcome was measured by “overall clini
-
cal assessment” and by symptom scores as described for the prior
study.
15
Follow-up was at days 0, 3-4, and 8-10. Duration of illness was
reduced from 13 to 10 days for bacterial infections and from 13 to 9
days for viral infections (neither the endpoint of illness, nor the basis for
diagnosis of viral vs. bacterial infection was clearly defined). Improve
-
ment in total symptom score was faster with Echinacea pallida than
with placebo (p < 0.0001) and faster for viral vs. bacterial infections.
The authors concluded that Echinacea pallida is effective in the treat-
ment of URI and at lest as effective as Echinacea purpurea. However,
the poor description of methods limits the usefulness of this study.
Scaglione and Lund evaluated the efficacy of an herbal mixture con-
taining echinacea for the treatment of the common cold in a random-
ized, placebo controlled, single-blind trial.
72
Thirty-two patients with
cold symptoms, but otherwise healthy, were randomized to receive ei-
ther four effervescent tablets/day of Cold-X® (Vitamin C 100 mg,
Echinacea purpurea root extract 20.1 mg, eucalyptus leaf extract 12.3
mg, fennel seed extract 10.3 mg) or placebo (4 glucose tablets/day).
Main outcome variables were duration of illness based on rhinorrhea
and the number of paper tissues used (measurement method not de-
scribed). Overall number of tissues used was 882 in the echinacea group
vs. 1168 in the control group. Mean duration of cold symptoms was 3.4
vs. 4.4 days, respectively (p < 0.01; the statistical method used was in
-
completely described and may have been inappropriate). These findings
suggest that treatment of the common cold with Cold-X® may be effec
-
tive. However, due to the lack of double-blinding and the use of an
herbal combination, no firm conclusions can be drawn.
In children, a combination of echinacea, propolis, and vitamin C has
been reported to reduce the number and duration of cold episodes.
3
The
independent effects of echinacea are not clear.
Negative Studies: Barrett et al. conducted a randomized, controlled,
double-blind study in 148 college students with recent onset of cold
symptoms.
73
Enrollees were assigned to receive either alfalfa (“pla
-
cebo”), or an encapsulated mixture of unrefined Echinacea purpurea
herb (25%) and root (25%), plus Echinacea angustifolia root (50%).
The dose of echinacea was 1 gram taken six times on the first day of
symptoms, then three times daily on each additional day of illness, up to
76 JOURNAL OF HERBAL PHARMACOTHERAPY
10 days. Measured outcomes included self-reported symptom duration
and severity. The authors found no differences between groups: mean
duration of symptoms was 5.75 days with placebo, and 6.27 days with
echinacea (between-group difference -0.52, 95% CI -1.09 to 0.22 days).
No significant treatment effect was found. This study has been criti
-
cized for the lack of use of a standardized alcohol extract of echinacea,
the choice of a product that contained more than one species, and for the
choice of alfalfa as a “placebo,” as it may have some action itself.
74-79
In
addition, although there were 148 participants, the sample size may not
have been adequate to detect differences in the primary outcome of
self-reported symptoms. Therefore, due to methodological weaknesses,
this study cannot be considered conclusive.
Taylor et al. conducted a randomized, double-blind, placebo con-
trolled study in 407 children (ages 2-11), in whom 337 URIs were
treated with echinacea, and 370 with placebo.
2
The primary outcome
was parent-reported symptom duration and severity. Secondary out-
comes included peak severity of symptoms, number of days of fever,
and global assessment of symptoms. The median duration of URIs
overall was 9 days, and there was no significant difference in duration
between groups. No differences in any secondary outcomes was noted
either. Although there was no significant difference between groups in
adverse events overall, there was a significantly greater incidence of
rash in the echinacea group than in the placebo group (7.1% with
echinacea vs. 2.7% with placebo, p = 0.008). This study suggests that
echinacea may not alleviate upper respiratory tract infection symptoms
in young children.
Upper Respiratory Tract Infection–Prevention
(Adults and Children)
Summary: The evidence for echinacea’s efficacy in the prevention
of upper respiratory tract infections (URI) is equivocal. The available
randomized controlled studies have substantial methodological weak
-
nesses. Lack of statistical power may explain some of the negative re
-
sults, which are largely based on moderate sample sizes and brief
follow-up periods (person-time of observation may be insufficient).
Even if there is a preventive effect of echinacea, it is likely small at best.
A large well-designed longitudinal study is warranted in this area.
Systematic Reviews: A systematic review of studies (before 1994)
of echinacea for immunomodulatory indications
57
found three ran
-
domized, placebo controlled and double-blind trials which examined
Natural Standard Review 77
the efficacy of echinacea in the prevention of URI.
80-82
The authors con
-
cluded that, despite some evidence of immunomodulatory action of
echinacea, no clear recommendations could be made for the prevention
of URI with echinacea.
Barrett et al. published a similar review, but included trials pub
-
lished up to 1998.
63
Four trials evaluating prevention efficacy were in
-
cluded.
67,80-82
Most studies had significant methodological limitations,
and often used ad hoc symptom scores. The authors concluded that the
long-term or preventive use of echinacea should not be recommended.
A review of the efficacy of echinacea to prevent or treat the common
cold concluded that echinacea may be effective for preventing and treat
-
ing the common cold, but more studies are needed to determine which
preparations are most effective.
69
All included randomized controlled
trials are discussed in detail below.
Randomized Trials (higher quality): A double-blind, randomized,
placebo controlled trial of 109 participants found that E. purpurea
(fresh expressed juice of whole flowering plant harvested without
roots), 4 mL twice/day for eight weeks, did not significantly lower the
incidence or severity of common colds.
68
Although no preventive effect
of E. purpurea juice was found, there was a statistically non-significant
reduction in the duration of cold symptoms (4.5 days in the echinacea
group vs. 6.5 days in the placebo group, p = 0.45). The size of this study,
considering its prospective nature, may not have been adequate to detect
small but significant benefits with sufficient statistical power. It was
otherwise well-conducted.
In a placebo controlled, non-randomized, unblinded experiment,
Turner et al. investigated the effect of echinacea vs. placebo in 92 sub
-
jects challenged with rhinovirus type 23.
83
Subjects were treated for two
weeks before and five days after innoculation with 300 mg three times/
day of echinacea (n = 50) or placebo (n = 42). A clinical diagnosis of a
cold was subsequently made in 44% of echinacea subjects and 57% of
placebo subjects. Mean symptom scores were lower in the echinacea
group vs. placebo throughout the study (overall mean 13.6 vs. 11.4),
and similar differences were observed for individual symptom scores
(total rhinorrhea and mean nasal obstruction scales). However, none of
the differences were statistically significant. A potential weakness is
that almost no echinacosides or alkamides were found by high-pressure
liquid chromatography in the echinacea preparation. In addition, the
power of this study to detect a reduction in risk from 50% to 20% was
only 75%.
78 JOURNAL OF HERBAL PHARMACOTHERAPY
In a randomized, controlled, open trial, Forth and Beuscher examined
the efficacy of two echinacea preparations to prevent URI.
82
Ninety-five
healthy subjects were randomly allocated to either Esberitox® liquid 25
drops three times daily, Esberitox® three tablets daily, or placebo.
Esberitox® liquid includes ethanolic-aqueous extracts of herba thujae
occidentalis (2 mg), radix echinaceae (7.5 mg), and radix baptisiae
tinctoriae (10 mg), while Esberitox® tablets add 20 mg Vitamin C/tab
-
let to these ingredients. Treatment duration varied from 3-17 weeks, and
the main outcome measured was rhinitis. In both echinacea groups
combined, two-thirds did not suffer from URI, while in a placebo group
this proportion was only one-third (p < 0.005). The difference between
the two echinacea groups was not statistically significant. Although
these results suggest efficacy of echinacea, a proper statistical analysis
would have compared the number of events per treatment time rather
than the overall risk per group. It is unlikely, however, that this would
have substantially changed the results.
Melchart et al. conducted a randomized, placebo controlled, double-
blind study comparing the efficacy of E. angustiflora vs. E. purpurea.
67
In this equivalence trial, 302 healthy volunteers without signs of URI
were randomly assigned to receive 1 mL of extract from the root of ei-
ther plant in 30% alcohol (twice daily from Monday-Friday, for 12
weeks), or placebo. There was no difference between the three treat-
ment arms in terms of the main effect measure (time to first URI epi-
sode). However, the study may have been too small to detect small to
medium-sized treatment effects due to low statistical power. Notably,
78% in the E. angustiflora, 70% in the E. purpurea, and 56% in the pla-
cebo group believed subjectively that they benefited from the treatment
(p = 0.04). Although suggestive, the use of validated symptom indices
might have been advantageous for identifying effects of either treat
-
ment.
Schoneberger evaluated the potential of echinacea to prevent URI in
a randomized, placebo controlled trial.
81
In this study, 108 otherwise
healthy patients “at risk for URI” were randomly allocated to receive
Echinacea purpura juice (4 mL twice daily) or placebo juice for 8
weeks. Randomization and blinding methods were not described. Pri
-
mary outcome variables were the number and severity of URI episodes.
Secondary outcomes included time to first URI and URI duration. In the
echinacea group, 23 URIs were observed (78% were mild) vs. 35 in pla
-
cebo (63% were mild). The average duration of symptoms was 5.3 vs.
7.5 days, respectively. The proportion of URI-free patients was 35% vs.
27%. Although no statistical analysis was presented, the difference be
-
Natural Standard Review 79
tween the echinacea and placebo groups appeared to be substantial in
terms of overall number, duration, and severity of URI.
Lesser Quality Studies: Several trials of lower methodological qual
-
ity have examined the effects of echinacea for the prevention of URI
symptoms. In a 1974 study of 284 children attending a summer camp,
Freyer treated half of subjects with an herbal combination containing
echinacea (Esberitox®) and left the other half untreated.
84
In the echinacea
group, 30% contracted a cold vs. >50% in the no-treatment group. Al
-
though these findings are suggestive, the observational nature renders
interpretation difficult. In an earlier study (1965), children on a pediat
-
ric ward were given either oral Esberitox® (six weeks on average) or no
treatment.
85
Incidence, prevalence and number of febrile days were sub
-
stantially lower in the Esberitox® group vs. control, but the lack of ran-
domization or blinding limits the value of this study. In a 1961 study,
Helbig enrolled 644 children hospitalized for non-URI causes, and ran-
domly allocated them to Esberitox® or no treatment.
86
Overall, there
was no difference between the two groups. A post-study analysis lim-
ited to children hospitalized for >14 days found that fewer children
treated with Esberitox® suffered from new common cold episodes, but
no statistical analysis was presented. This method of historical data re-
shuffling cannot be considered valid. In a randomized, controlled trial
in 42 male athletes given echinacea for 28 days prior to competition,
subjects receiving echinacea were found to have lower serum and urine
levels of soluble interleukin 2 receptors (sIL-2R), and significantly
fewer respiratory infections vs. placebo.
87
However, details of method-
ology and statistical analysis are limited.
Radiation Associated Leukopenia
Summary: The evidence from a small number of randomized trials
evaluating efficacy of echinacea in the treatment of radiation-induced
leukopenia is equivocal. Studies have used the combination product
Esberitox®, which includes ethanolic-aqueous extracts of herba thujae
occidentalis, radix echinaceae, and radix baptisiae tinctoriae.
Evidence: Bendel et al. randomly allocated 50 women receiving
post-mastectomy radiation therapy to an herbal combination containing
echinacea (Esberitox N®, 50 drops daily throughout the radiation treat
-
ment period) or to placebo.
88
Effects on leukocyte counts and other he
-
matological parameters were assessed before and after radiation. No
statistically significant differences were found. Despite the question
-
80 JOURNAL OF HERBAL PHARMACOTHERAPY
able statistical power of the study, the benefit of echinacea is likely to be
small at best.
In contrast, Sartor found a substantial effect of Esberitox® on radia
-
tion-induced leukopenia.
89
Forty-eight patients undergoing six weeks
of radiation therapy were assigned randomly to Esberitox® or no
adjuvant treatment. In the Esberitox® group, 46% missed zero days of
therapy because of leukocyte counts < 3000/mm
3
vs. 18% in the un
-
treated group. Although these proportions were not statistically com
-
pared, they are highly suggestive. The mean number of missed treatment
days did not differ significantly, although these results are not interpret
-
able due to an inadequate t-test.
In a case series, Pohl found a statistically significant increase in leu-
kocyte counts in 55 patients undergoing radiation therapy after treat-
ment with Esberitox® (various doses and routes of administration).
90
This observational study is suggestive mechanistically but of limited
clinical value.
Additional weak evidence is provided by Bendel et al. in a random-
ized trial of 70 women receiving radiation therapy for breast cancer.
91
No change in incidence of infection was noted, although bone marrow
toxicity was reportedly lessened. The methodologic and histologic cri-
teria were poorly described, weakening the clinical applicability of re-
sults.
Cancer
Summary: There is insufficient evidence to recommend for or against
the use of echinacea for any type of cancer. Only preliminary data from
case series are available, without any evidence of benefit.
Evidence: Cytokine levels were monitored in 35 brain tumor patients
who were given 3 mL/day of a 40% E. angustifolia herbal therapy. Af
-
ter four weeks, no change in white blood cell counts or cytokine produc
-
tion was noted. The clinical significance of these findings is unclear.
92
Preliminary studies have been conducted to assess the safety of
combination chemotherapy including Echinacin® (E. purpurea). In
one study, 15 patients with advanced, metastatic colon cancer who
had already undergone standard treatment with chemotherapy/surgery
were given low-dose cyclophosphamide, thymostimulin, and Echinacin®.
81
The mean survival time was four months. In a case series, five patients with
advanced hepatocellular carcinoma were treated with a combination
regimen including Echinacin®, and mean survival was 10 weeks.
82
Natural Standard Review 81
Upper Respiratory Tract Infection–Treatment (Children)
Summary: Initial research suggests that echinacea may not be helpful
in children for alleviation of cold symptoms,
2
possibly because parents
are not able to recognize the onset of common cold symptoms soon
enough to begin treatment, or because the dose of echinacea for use in
children is not clear.
93,94
It is also possible that echinacea is more effec
-
tive in adults than children due to fundamental differences in causes of
upper respiratory tract infection symptoms in children versus adults (bac
-
terial versus viral causes; different viruses; different sites of infec
-
tion; etc). Until additional research is available, echinacea cannot be
considered effective in children for this use. Furthermore, an excess
of rash has been associated with echinacea use in this research, and
therefore the risks may outweigh the potential benefits in this
population.
Evidence: Taylor et al. conducted a randomized, double-blind,
placebo controlled study in 407 children (ages 2-11), in whom 337
URIs were treated with echinacea, and 370 with placebo.
2
The pri-
mary outcome was parent-reported symptom duration and severity.
Secondary outcomes included peak severity of symptoms, number of
days of fever, and global assessment of symptoms. The median dura-
tion of URIs overall was 9 days, and there was no significant differ-
ence in duration between groups. No differences in any secondary
outcomes was noted either. Although there was no significant differ-
ence between groups in adverse events overall, there was a signifi-
cantly greater incidence of rash in the echinacea group than in the
placebo group (7.1% with echinacea vs. 2.7% with placebo, p =
0.008). This study suggests that echinacea may not alleviate upper
respiratory tract infection symptoms in young children, and risks
may outweigh potential benefits.
Genital Herpes
Summary: A small clinical trial assessing the potential benefit of
oral echinacea for recurrent herpes genitalis found no effect. Con
-
clusions cannot be considered definitive without further trials.
Vonau et al. conducted a randomized, placebo controlled, cross-
over trial to evaluate the therapeutic use of echinacea for recurrent
genital herpes.
95
Fifty patients were randomly allocated to a treatment
sequence of either echinacea extract (800 mg orally twice/day) for six
82 JOURNAL OF HERBAL PHARMACOTHERAPY
months followed by placebo for six months, or vice versa. Number of
recurrences and several indicators of disease status (Visual Analogue
Scale of pain, CD4 counts, neutrophil counts) were assessed before
and after treatments. No statistically significant differences were
found between the groups. Although the sample size was relatively
small, a relevant treatment benefit would likely have been detected if
present.
PRODUCTS STUDIED
Brands Used in Statistically Significant Clinical Trials
Echinacin® (Madaus AG, Germany), Echinaguard® (Nature’s Way,
USA), Echinaforce® (Bioforce), EchinaFresh (Enzymatic Therapy),
Esberitox® (Enzymatic Therapy), Esberitox® N, Pascotox®, Resistan®,
Biracial® (Destiny BioMediX Corp).
“Echinacea Plus® tea (Traditional Medicinals): equivalent of 1.275
mg of dried herb and root per tea bag.
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... x The following drugs interacted with HMPs (Table 2): anaesthetics [16], anti-arrhythmic agents [15,27], antibiotics [19,34,36,39,40,42,46,48,49,52,53], anticoagulants [13, 15, 16, 18, 24, 26, 27, 29, 33, 34, 36, 37, 39, 40, 44-46, 49, 50, 52, 53], anticholinergics [17,22], antidepressants [25,26,33,45], antidiabetics [26,27,38,40,43,47,[50][51][52][53], antihypertensives [16, 29, 33, 41, 43-46, 49, 53], anti-inflammatory agents [13,16,35,46,52,53], antimicrobials [31], antineoplastics [11,14,31,36,[39][40][41][42][43][51][52][53], antiplatelet agents [13,15,24,25,27,29,33,34,36,37,39,40,44,45,49,50,52,53], anti-epileptic drugs [13,41,45], antivirals [31,40,45,51,52], calcium channel blockers [24,26,30], cholesterol lowering agents [10,13,24,26,27,40,41,44,45,50,53], CYP-450 metabolized agents [18,21,25,29,32,34,40,42,45,48,49,53], diuretics [26,30,43], hormonal agents [18,24,26,31,40,41,43,45,49,53,54], hypoglycaemics [9,10,19,20,28], immunnosupressants [31,34,37,40,43,46,48] laxatives [27,37,50], leukotriene inhibitors [14], sedatives [12,13,23,25,45], selective serotonin re-uptake inhibitors [23,33] and vasolidators [30,44]. ...
... x The following drugs interacted with HMPs (Table 2): anaesthetics [16], anti-arrhythmic agents [15,27], antibiotics [19,34,36,39,40,42,46,48,49,52,53], anticoagulants [13, 15, 16, 18, 24, 26, 27, 29, 33, 34, 36, 37, 39, 40, 44-46, 49, 50, 52, 53], anticholinergics [17,22], antidepressants [25,26,33,45], antidiabetics [26,27,38,40,43,47,[50][51][52][53], antihypertensives [16, 29, 33, 41, 43-46, 49, 53], anti-inflammatory agents [13,16,35,46,52,53], antimicrobials [31], antineoplastics [11,14,31,36,[39][40][41][42][43][51][52][53], antiplatelet agents [13,15,24,25,27,29,33,34,36,37,39,40,44,45,49,50,52,53], anti-epileptic drugs [13,41,45], antivirals [31,40,45,51,52], calcium channel blockers [24,26,30], cholesterol lowering agents [10,13,24,26,27,40,41,44,45,50,53], CYP-450 metabolized agents [18,21,25,29,32,34,40,42,45,48,49,53], diuretics [26,30,43], hormonal agents [18,24,26,31,40,41,43,45,49,53,54], hypoglycaemics [9,10,19,20,28], immunnosupressants [31,34,37,40,43,46,48] laxatives [27,37,50], leukotriene inhibitors [14], sedatives [12,13,23,25,45], selective serotonin re-uptake inhibitors [23,33] and vasolidators [30,44]. ...
... x The following drugs interacted with HMPs (Table 2): anaesthetics [16], anti-arrhythmic agents [15,27], antibiotics [19,34,36,39,40,42,46,48,49,52,53], anticoagulants [13, 15, 16, 18, 24, 26, 27, 29, 33, 34, 36, 37, 39, 40, 44-46, 49, 50, 52, 53], anticholinergics [17,22], antidepressants [25,26,33,45], antidiabetics [26,27,38,40,43,47,[50][51][52][53], antihypertensives [16, 29, 33, 41, 43-46, 49, 53], anti-inflammatory agents [13,16,35,46,52,53], antimicrobials [31], antineoplastics [11,14,31,36,[39][40][41][42][43][51][52][53], antiplatelet agents [13,15,24,25,27,29,33,34,36,37,39,40,44,45,49,50,52,53], anti-epileptic drugs [13,41,45], antivirals [31,40,45,51,52], calcium channel blockers [24,26,30], cholesterol lowering agents [10,13,24,26,27,40,41,44,45,50,53], CYP-450 metabolized agents [18,21,25,29,32,34,40,42,45,48,49,53], diuretics [26,30,43], hormonal agents [18,24,26,31,40,41,43,45,49,53,54], hypoglycaemics [9,10,19,20,28], immunnosupressants [31,34,37,40,43,46,48] laxatives [27,37,50], leukotriene inhibitors [14], sedatives [12,13,23,25,45], selective serotonin re-uptake inhibitors [23,33] and vasolidators [30,44]. ...
Article
Objectives: The aim of this overview of systematic reviews (SRs) is to evaluate critically the evidence regarding interactions between herbal medicinal products (HMPs) and synthetic drugs. Methods: Four electronic databases were searched to identify relevant SRs. Results: Forty-six SRs of 46 different HMPs met our inclusion criteria. The vast majority of SRs were of poor methodological quality. The majority of these HMPs were not associated with severe herb-drug interactions. Serious herb-drug interactions were noted for Hypericum perforatum and Viscum album. The most severe interactions resulted in transplant rejection, delayed emergence from anaesthesia, cardiovascular collapse, renal and liver toxicity, cardiotoxicity, bradycardia, hypovolaemic shock, inflammatory reactions with organ fibrosis and death. Moderately severe interactions were noted for Ginkgo biloba, Panax ginseng, Piper methysticum, Serenoa repens and Camellia sinensis. The most commonly interacting drugs were antiplatelet agents and anticoagulants. Conclusion: The majority of the HMPs evaluated in SRs were not associated with drug interactions with serious consequences. However, the poor quality and the scarcity of the primary data prevent firm conclusions.
... Echinacea species (e.g., Echinacea purpurea [L.] Moench, E. angustifolia DC., E. pallida [Nutt.] Nutt.) of the family Asteraceae are North American perennials whose roots and aerial parts have been used traditionally for a variety of medicinal purposes [15,16]. Echinacea formulations containing either root or whole plant extracts are marketed for their "immune stimulatory" properties and for prevention of the common cold [15,16]. ...
... Nutt.) of the family Asteraceae are North American perennials whose roots and aerial parts have been used traditionally for a variety of medicinal purposes [15,16]. Echinacea formulations containing either root or whole plant extracts are marketed for their "immune stimulatory" properties and for prevention of the common cold [15,16]. Echinacea's popularity as an immune stimulator has placed it among the 10 topselling botanicals in the U. S. for many years. ...
... (For reviews of clinical efficacy see references [15][16][17][18][19].) The three species most commonly encountered are chemically dissimilar. ...
Article
Full-text available
In Part 2 of this review, a critical examination of the pertinent scientific literature is undertaken in order to assess the interaction risk that popular dietary supplements may pose when taken concomitantly with conventional medications. Botanicals most likely to produce clinically important herb-drug interactions are those whose phytochemicals act as mechanism-based inhibitors of cytochrome P450 enzyme activity (e.g., HYDRASTIS CANADENSIS, PIPER NIGRUM, SCHISANDRA CHINENSIS) or function as ligands for orphan nuclear receptors (e.g., HYPERICUM PERFORATUM). In addition, several external factors unrelated to phytochemical pharmacology can augment the drug interaction potential of botanical supplements.
... (e.g., E. purpurea [L.] Moench, Echinacea angustifolia DC., E. pallida [Nutt.] Nutt.) of the family Asteraceae are North American perennials, whose roots and aerial parts have been used traditionally for a variety of medicinal purposes [249,250]. Echinacea formulations containing either root or whole plant extracts are marketed for their "immune stimulatory" properties and for the prevention of colds [249,250]. Echinacea's popularity as an immune stimulator has placed it among the 10 top-selling botanicals in the United States for many years. ...
... Nutt.) of the family Asteraceae are North American perennials, whose roots and aerial parts have been used traditionally for a variety of medicinal purposes [249,250]. Echinacea formulations containing either root or whole plant extracts are marketed for their "immune stimulatory" properties and for the prevention of colds [249,250]. Echinacea's popularity as an immune stimulator has placed it among the 10 top-selling botanicals in the United States for many years. While evidence from in vitro and animal studies lend credence to Echinacea preparations as immunomodulators, clinical findings remain equivocal (for reviews of clinical efficacy, see . ...
... The process can be administratively inefficient, incomplete, and may not reflect the patient's actual experience. There is growing evidence that physicians tend to underestimate patient symptoms, and that patients are often reluctant or forget to report important aspects of their health status on routine postoperative assessments [5][6][7][8][9][10][11][12][13][14]. ...
Article
Objective To evaluate the feasibility of an electronic symptom-tracking platform for patients recovering from ambulatory surgery. Method We assessed user response to an electronic system designed to self-report symptoms. Endpoints included compliance, postoperative symptoms, patient satisfaction. An 8-item symptom inventory (pain, nausea, vomiting, shortness of breath, fever, swelling, discharge, redness) was developed and made available on postoperative days (POD) 2–6. Responses exceeding defined thresholds of severity triggered alerts to healthcare providers. Symptoms, alerts, actions taken, urgent care center (UCC) visits, hospital admissions were tracked until POD 30. Patient satisfaction was evaluated on POD 7. A patient was defined as “responder” if at least 5/8 items on at least 3 PODs were completed. The assessment method was deemed successful if 64/100 patients responded. Results 97/102 patients were evaluable; 65 met “responder” criteria (67% responder rate; 95% CI 57–76%). 321 surveys were completed (median 4/patient), 248 (77%) in ≤2 min. Involving caregivers and allowing additional symptom-reporting improved the responder rate to 72% (95% CI 58–84%). Most commonly-reported moderate, severe, very severe symptoms were pain, nausea, swelling; 71% reported moderate to very severe pain on POD 2. Phone calls and adjustment of medications adequately addressed most symptoms. Two patients (2%) presented at UCC before, 6 (6%) after, POD 6; 1 (1%) was admitted. Most agreed or strongly agreed that electronic symptom-tracking was helpful, easy to use, and would recommend it to others. Conclusion Electronic symptom-tracking is feasible for patients undergoing ambulatory gynecologic cancer surgery. Symptom burden is high in the early postoperative period. Addressing patient-reported symptoms in a timely, automated manner may prevent severe downstream adverse events, reduce UCC visits and admission rates, and improve outcomes.
... A relevant traditional use for this species is topically on inflamed wounds (Uzun et al., 2004). practitioners include topical application to promote wound healing (Basch et al., 2005). ...
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This chapter is composed of sections dealing with some of the well known but, with respect to clinical studies, not always well investigated traditional and alternative treatments against common cold. It includes data on phytotherapy, apitherapy, ayurvedic remedies, homeopathic remedies, Schuessler’s biochemistry, acupuncture and acupressure, nasal irrigation and inhalation.
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