HERBAL
MEDICINAL
PLANT
----------------------------------------------------------
BUTTERBUR
Petasites hybridus (L.) P. Gaertn., B. Meyer et Scherb.
(Asteraceae/Compositae)
BY
RETTODWIKART THENU
BUTTERBUR
(buh’tuhr-buhr)
Petasites
hybridus (L.) P. Gaertn., B. Meyer et
Scherb. (Asteraceae/Compositae) +
SUMMARY AND PHARMACEUTICAL COMMENT
The chemistry of butterbur is well documented. There is evidence
from preclinical studies to indicate that the eremophilane sesquiterpene
constituents (e.g. petasin and isopetasin), found in the petasin chemovar, are
important for activity. However, there are some conflicting reports and it is not
clear precisely which constituents are most active. Furthermore, certain
activities have been documented for the furanoeremophilane sesquiterpenes found
in the furanopetasin chemovar of Petasites hybridus.
There is evidence from preclinical studies of the
antiinflammatory, anti-allergic and antispasmodic properties of butterbur
extracts and/or their constituents, hence supporting some of the traditional
uses. Precise mechanisms of action have not yet been elucidated, although
inhibition of leukotriene synthesis, phospholipase A2 activity and 5- lipoxygenase
translocation, and effects on intracellular calcium ion concentrations have
been documented in in vitro studies. The implications of binding of certain
butterbur constituents at dopamine D2, histamine H1 and muscarinic receptors,
described following in vitro studies, require further investigation.
There is a paucity of well-designed, randomised clinical trials
of butterbur extracts. Existing trials generally have involved individuals with
seasonal allergic rhinitis and migraine and have tested the effects of only a
small number of herbal medicinal products containing butterbur extracts. While
most of these studies have reported beneficial effects for butterbur extracts,
methodologically rigorous investigation of efficacy in allergic rhinitis and
migraine prophylaxis is limited and large, well-designed clinical trials are
required. Similarly, at present, there is insufficient evidence from randomised
clinical trials to support the use of butterbur extracts in patients with
asthma and bronchitis.
There is also only limited information on the safety of butterbur
extracts and further investigation in this area is required. On the basis of
small, randomised clinical trials, certain butterbur extracts appear to be
well-tolerated when taken at recommended doses for relatively short periods (clinical
studies have involved ingestion for up to four months); adverse events reported
most frequently are gastrointestinal symptoms. Chronic toxicity studies are lacking,
and there is a lack of clinical information on the safety of long-term use.
Against this background, butterbur should not be used for long periods, nor at
higher than recommended doses (see below). Spontaneous reports of liver damage
associated with the use of a butterbur root extract have been received in
Germany. On the basis of this information, the Swiss regulatory authority for
medicines revoked the licences for certain butterbur products marketed in
Switzerland.
No drug interactions have been reported for butterbur extracts.
Based on data from preclinical studies, there is a theoretical possibility that
butterbur extracts potentially could interact with hypertensive and
antihypertensive medicines, leukotriene receptor antagonists and
agonists/antagonists at dopamine D2, histamine H1 and muscarinic M3 receptors.
Both chemotypes (petasin and furanopetasin) of P. hybridus contain unsaturated pyrrolizidine
alkaloids, and these compounds occur in low concentrations throughout all parts
of the plant.(G19) These constituents are known to be hepatotoxic in humans,
and have been shown to be carcinogenic and mutagenic in preclinical studies (see
Comfrey). Several manufacturers of products containing butterbur include in
their manufacturing processes steps to remove the unsaturated pyrrolizidine
alkaloids to concentrations below the detectable limit (e.g. <35 parts per billion).
However, there remains the possibility that toxic quantities of unsaturated
pyrrolizidine alkaloids may be present in poorly processed products, and any
products which contain Petasites species as a result of botanical misidentification
or adulteration.
There is a view that butterbur is unsuitable for use as a tea or
infusion.(G69) This is because the N-oxides of unsaturated pyrrolizidine
alkaloids, which can be formed from unsaturated pyrrolizidine alkaloids during
storage of plant material but which can also be present in raw plant material,
are more water soluble than the parent compounds and are, therefore, extracted
more easily during preparations of herbal teas and infusions.(G19)
The dose of butterbur should be such that the daily intake of
unsaturated pyrrolizidine alkaloids, including their Noxides, is not greater
than 1 mg.(G3) The duration of use of butterbur should not exceed a total of
4–6 weeks in a year.(G3)
OTHER COMMON NAMES
Blatterdock, bog rhubarb, bogshorns,
European pestroot, flapperdock, langwort, sweet coltsfoot,
umbrella leaves, western coltsfoot
SPECIES (FAMILY)
Petasites
hybridus (L.) P. Gaertn., B. Meyer et Scherb. (Asteraceae/Compositae).
Tussilago
petasites
SYNONYM(S)
Butterdock, Butterfly Dock, Capdockin, , P. officinalis Moench, P.
ovatus Hill, P. sabaudus Beauv.,
P. vulgaris
Desf., Umbrella Plant(G34)
ORIGIN
Butterbur is a perennial found
in Europe and Asia.
PHARMACOPODIAL AND OTHER MONOGRAPHS
German Commission E (root and leaf).(G3)
Martindale 35th edition(G85)
LEGAL CATEGORY (LICENSED PRODUCTS)
Butterbur is not on the GSL. There are no licensed products containing
butterbur available in the UK.
CONSTITUENTS
Two chemovars of P.
hybridus have been described, which differ markedly in the profile of
sesquiterpenes present in the root/ rhizome and
leaf. The furanopetasin chemovar contains furanoeremophilane sesquiterpenes,
whereas the petasin chemovar contains esters of the eremophilane sesquiterpenes
petasol, isopetasol and neopetasol.(1–3) The furanopetasin chemovar contains
exclusively furanoeremophilane sesquiterpenes: petasin sesquiterpenes are not
found in this chemovar.(2, 4) Eremophilanlactones have been reported as
constituents of the furanopetasin chemovar,(1) but it has been shown that they
are produced by rearrangement of 9-hydroxy-furanoeremophilanes during storage
of raw plant material.(5)
Both chemotypes contain unsaturated pyrrolizidine alkaloids,(6) and
these compounds occur throughout all parts of the plant.(G19)
Leaf
Alkaloids
Pyrrolizidine type, mainly senecionine and integerrimine.(7) Content may vary
from 0.02–1.50 parts per million (ppm),(8) or <0.1–3.9 or 27.7 ppm (for
leaves and leafstalks, respectively).(7)
Flavonoids
Astragalin, isoquercitrin, quercetin.(G2)
Sesquiterpenes
Furanopetasin chemovar: furanoeremophilane type, including
9-hydroxy-furanoeremophilanes and 9-oxo-furanoeremophilanes.(2) Petasin chemovar:
eremophilane type, mainly petasin and neopetasin (2.8 and 1.9 mg/g of dried
plant material, respectively), also isopetasin, and the sulfur-containing
compounds neo-S-petasin, S-petasin and iso-S-petasin (= S-isopetasin; trace).(3)
Other constituents Tannins, mucilage,
volatile oil (about 0.1%), triterpenoid saponins (traces).(G2)
Rhizome, Root
Alkaloids
Pyrrolizidine type, mainly senecionine, its isomer integerrimine and
senkirkine.(9) Concentration can vary from 2–500 ppm.(10) Values reported following
specific investigations include 5–90 ppm(8) and 6–105 (mean 49.2) ppm
(calculated as senecionine);(7) concentrations of senecionine and senkirkine
have been reported as 11.3 and 25.8 ppm, respectively.(11)
Sesquiterpenes
Furanopetasin chemovar: furanoeremophilane type,(1) mainly furanopetasin and
9-hydroxy-furanoeremophilane (approximately 16–21% and 30–37%,
respectively),(2) as well as furanoeremophilane, 2-senecioyl-furanopetasol,
2-tigloyl-furanopetasol and 2-methylthioacryloyl-furanopetasol (6–10%).(2) Petasin
chemovar: eremophilane type, mainly petasin (9.4, 7.0 and 7.0 mg/g of dried
plant material for rhizomes, roots and runners, respectively), also isopetasin,
neopetasin, iso-S-petasin, neo-Spetasin and S-petasin.(3) Minor compounds
include 3-methylcrotonyl-and methacryloyl-esters of petasol, neopetasol,
isopetasol, 3-desoxyneopetasol and 3-desoxyisopetasol.(12)
Volatile oil A mixture of at least 26 compounds
of which 1- nonene, 1-undecene, albene, furanoeremophilane and fukinanolide are
major components; minor compounds include the novel sesquiterpene hydrocarbons
petasitene and pethybrene.(13)
Quality Of Crude Material And Marketed
Products
As
with other medicinal plants, the profile of constituents in different parts of P. hybridus can vary both qualitatively
and quantitatively depending on various factors, and this has implications for
safety and efficacy. The petasin content of the underground parts of plants (petasin
chemovar) grown in four different locations in Switzerland ranged from 6.6–13.8
mg/g across regions.(14) Furthermore, although plants showed an approximately
similar relative distribution of the six main petasin sesquiterpenes (petasin,
isopetasin, neopetasin, iso-S-petasin, neo- S-petasin and S-petasin), there were
exceptions: for example, in plants grown in the Krauchthal region, the content
of S-petasin was approximately half that of neo-S-petasin, whereas in plants grown
in the Chessiloch region, S-petasin content was greater than that of
neo-S-petasin. Raised temperatures and storage conditions also affect the
profile of constituents in P. hybridus
(petasin chemovar) roots. Under moderate drying conditions (408C in the dark),
isomerisation occurs: sesquiterpene esters with petasol and neopetasol skeletons
form the corresponding esters with isopetasin skeletons.(15) The isomerisation
of neopetasin to petasin occurs more readily than that of petasin to isopetasin
(half-life for neopetasin and petasin: 49 and 205 days, respectively). In the
furanopetasin chemovar, 9-hydroxy-furanoeremophilanes rearrange to the corresponding
eremophilanlactones during drying and storage of raw plant material.(5)
Some manufacturers of herbal medicinal products containing butterbur
state that the unsaturated pyrrolizidine alkaloids are removed from the product
before it is released for sale.(16) One method used to achieve acceptably low
concentrations (the German Commission E advised that the maximum daily intake is
1 mg)(G3) of these alkaloids is by multiple applications of a method involving
a cation-exchange resin;(17) other methods of separating pyrrolizidine
alkaloids from several plants, including P.
hybridus, containing these compounds have been described.(11) A different
approach to achieving extremely low concentrations of pyrrolizidine alkaloids
is to cultivate clones of wild-type plants previously selected for almost
absence of these constituents. Achievement of an initial step – in vitro propagation
of wild-type plants – in this approach has been documented.(18)
USES
USES
Butterbur is used to treat respiratory conditions such as
asthma, whooping cough, and coughs resulting from other respiratory illnesses.
It is used as a diuretic, sedative, and treatment for irritable bowel syndrome
and arthritis. Butterbur is also used topically for wound healing. Use in the
United States is uncommon.
INVESTIGATIONAL USES
Researchers are experimenting with the use of butterbur
to treat migraine headaches, urinary tract spasms resulting from calculosis,
prevention of gastric ulcers, and seasonal allergic rhinitis (Schapowal, 2002;
Thome et al, 2002).
FOOD USE
Butterbur is not used in foods.
HERBAL USE
Butterbur root has been used traditionally for the treatment of fevers,
wheezing and colds and as a diuretic and vermifuge.(19, G34) It is also reputed
to be a heart stimulant, cardiac tonic and antispasmodic, and to promote
menstruation. It has been used externally for treating persistent sores and
other skin problems.
Butterbur root was approved by the German Commission E for use
as supportive therapy for acute spastic pain in the urinary tract, particularly
if urinary stones were present.(G3) Modern-day use of butterbur and clinical
trials of products containing butterbur have focused on its use in seasonal
allergic rhinitis and migraine prophylaxis.
Figure 1. Butterbur
(Petasites hybridus).
Figure 2. Butterbur
– dried drug substance (root)
Figure 3. Butterbur
– dried drug substance (leaf) (Barnes, J et al., 2007)
ACTIONS
Antimigraine
Action
One
study showed that a group of migraine sufferers who received butterbur
experienced a 56% reduction in the number of migraine headaches. In addition,
the headaches experienced by this group were of shorter duration than those
experienced by participants who received a placebo (Eaton, 1998). Butterbur
extract was more effective than a placebo and is well tolerated to prevent
migraines (Lipton et al, 2004).
Antispasmodic
Action
The
active chemical components petasin and isopetasin may be responsible for the antispasmodic
action of butterbur, which includes reduction of spontaneous activity and spasm
in the smooth muscle system. Butterbur thus may have the potential for treating
urinary tract spasms resulting from calculosis (Eaton, 1998).
Carcinogenesis
Action
The
butterbur root contains pyrrolizidine alkaloids, which in animal studies have
been linked to the development of cancer and hepatotoxicity. The recommendation
is that human daily intake of pyrrolizidine alkaloids not exceed 1 mcg (Reglin
et al, 1998). New formulas of butterbur are available in which the pyrrolizidine
alkaloid content is well below this recommended level (pyrrolizidine
alkaloid–free Petasites
sp.).
Other Actions
Studies
have shown that butterbur may be used for seasonal allergic rhinitis, without sedative
effects of traditional antihistamines (Schapowal, 2002; Thome, 2002). Butterbur
possesses COX-2 inhibitors and may be used for infl ammatory conditions (Fiebich
et al, 2005).
PHARMACOLOGICAL ACTIONS
Several pharmacological activities, including anti-inflammatory,
anti-allergic and antispasmodic effects, have been described for butterbur root/rhizome
and leaf following preclinical studies. Extracts of butterbur have been tested
clinically in patients with seasonal and perennial allergic rhinitis
(hayfever), bronchial asthma and chronic obstructive bronchitis, and in
prophylaxis of migraine headaches. The precise chemical constituents responsible
for the documented effects of butterbur are not clearly understood, although several
preclinical studies have shown that the petasin constituents, such as petasin
and isopetasin, are important for certain pharmacological activities.
These compounds may have several intracellular targets, and
there is some evidence that the stereoisomers may have different affinities at
these, even bringing about different effects.(24) However, other in vitro
studies have reported that petasin is inactive,(25) and activities for the
furanoeremophilane and eremophilanlactone constituents have been
documented.(26)
Published papers and texts often use the words root and rhizome
interchangeably, although this is not strictly correct. This monograph uses
terms exactly as published in the reference material, since it is not possible to
say otherwise with certainty precisely which plant part was meant. Published
reports also often fail to state which chemovar of P. hybridus was used.
In Vitro And Animal Studies
Pharmacokinetics Petasins have been shown to be bioavailable following
studies in rabbits fed butterbur leaf extract (containing 50 mg petasin) twice
daily for seven days; petasins were detected by gas chromatography-mass spectrometry
(GC-MS) within the low nanogram range.(27)
Anti-Allergic and Anti-Inflammatory Properties
Inhibition of peptido-leukotriene
(LT) biosynthesis in murine peritoneal macrophages has been documented
following in vitro experiments using several different extracts of butterbur
root and leaf.(25, 28) A petroleum ether extract of P. hybridus ground root showed the greatest inhibitory activity of
LT synthesis from mouse peritoneal macrophages stimulated with calcium
ionophore A23187 (10_6 mol/L): 12.6, 95.1 and 100% inhibition at concentrations
of P. hybridus extract of 6.3, 31.0
and 94.0 mg/mL, respectively (p < 0.01 versus control).(25) By contrast, a
pyrrolizidine alkaloidfree extract showed no activity in this assay, and the
addition of the pyrrolizidine alkaloids senkirkine and senecionine to this extract
and to the macrophage-containing tissue culture system also failed to result in
inhibition of LT synthesis.(25) A report of this work does not describe the constituents
of the pyrrolizidine alkaloid-free extract, so the latter results for lack of
activity are difficult to interpret.
Further
work involving fractions of the active P.
hybridus root extract indicated that isopetasin and the oxopetasan esters
(= eremophilanlactones, the presence of these is due to rearrangement of
9-hydroxy-furanoeremophilanes during drying and storage as stated above) were
important for activity: the content of isopetasin and oxopetasan esters in the
fractions correlated with inhibition of LT synthesis in a
concentration-dependent manner.(25) By contrast, petasin was not important for
activity, but appeared to reduce the activity of isopetasin in this assay.
Other in vitro studies, however, have reported that petasin is one
of the major active compounds of P.
hybridus extract. Isolated petasin and a standardised high-pressure carbon
dioxide extract of P. hybridus
(containing 14.1% petasin; ZE-339, Zeller) inhibited the synthesis of
cysteinyl-LTs in eosinophils and LTB4 in neutrophils which had been primed with
granulocyte-macrophage colony-stimulating factor and subsequently stimulated
with platelet-activating factor (PAF) or the anaphylatoxin C5a.(29) Petasin,
ZE-339 and the positive control zileuton (a 5-lipoxygenase inhibitor) achieved
similar inhibition of cysteinyl-LTs and LTB4 in eosinophils and neutrophils,
respectively, in these models (IC50 (concentration for 50% inhibition) 4 24
mg/mL in each case).
In other in vitro studies using a similar model of eosinophil stimulation,
ZE-339 showed greater inhibition of cysteinyl-LT synthesis than did a fraction
containing petasin, isopetasin and neopetasin.(30) When each of these latter
compounds was tested separately in this model, all inhibited C5a- and
PAF-induced cysteinyl-LT synthesis in a concentration-dependent manner and to
the same extent as zileuton (positive control). However, the release of
eosinophil cationic protein (ECP) from eosinophils (a measure of eosinophil
degranulation) was inhibited by petasin, but not by isopetasin, neopetasin or
zileuton. Similarly, petasin, but not isopetasin, neopetasin or zileuton,
suppressed cytosolic phospholipase A2 activity, 5-lipoxygenase translocation
and PAFand C5a-induced increases in intracellular calcium ion concentrations. These
findings suggest that the different petasin constituents of butterbur may act
upon different intracellular signalling molecules.(30) Extracts of P. hybridus rhizomes with different petasin
and isopetasin contents (2.1 and 0.4, 0.2 and 0.1, 12.1 and 6.1, and 21.9 and
9.4% petasin and isopetasin respectively) are weak inhibitors of
cyclo-oxygenase 1 (COX-1) in vitro (IC50 > 400 mg/mL) and strong inhibitors
of the inducible isoform COX-2 (IC50 20 to 30.4 mg/mL), apart from the extract
with the lowest petasin and isopetasin content (IC50 60.6 mg/mL).(31) The
former three extracts also inhibited lipopolysaccharide-induced and, therefore,
COX-2-mediated prostaglandin E2 release in primary rat microglial cells in a
concentration-dependent manner (IC50 < 6 mg/mL); this effect was also
independent of the petasin and isopetasin contents. The extract containing
petasin 12.1% and isopetasin 6.1% completely inhibited COX-2 synthesis in
microglia at a concentration of 5 mg/mL whereas COX-1 synthesis was unaffected.
Overall, these findings suggest selective inhibition of COX-2 and its
expression.(31)
Gastroprotective effects A petroleum ether extract of P. hybridus ground root protects against
gastrointestinal damage induced by ethanol and indometacin (indomethacin) in
vivo.(28) P. hybridus root extract
0.83, 2.5 and 7.5 mg/kg administered intragastrally to fasted rats 30 minutes
before intragastral administration of 1.5mL ethanol significantly reduced
gastric mucosal damage in a dosedependent manner, compared with control (p <
0.05). In an experiment involving normally fed rats, indometacin (8 mg/kg orally)
was administered with P. hybridus
root extract (6.3, 12.5 or 25 mg/kg orally), cimetidine (50 mg/kg orally) or
control, followed by a second dose six hours later, and sacrifice after a
further 16 hours. Compared with control, all doses of P. hybridus root extract significantly inhibited
indometacin-induced intestinal damage (p < 0.05), and P. hybridus root extract 2 _ 25 mg/kg inhibited intestinal damage
to a greater extent than did cimetidine (p < 0.05).(28)
Other activities Extracts of butterbur rhizome from both
petasin and furanopetasin chemovars of P.
hybridus have been reported to inhibit the binding of radioactive ligands
at dopamine D2 and histamine H1 receptors to a similar extent. The greatest
inhibition was observed for extracts with the highest content (>60%) of eremophilane
constituents. For example, for a rhizome extract from the petasin chemovar, mean
(standard error of mean; SEM) IC50 values for inhibition of dopamine D2 and
histamine H1 radioligand binding were 38 (3) and 155 (52), respectively.(26) Fractions
of the petasin chemovar extract inhibited radioligand binding in a
concentration-dependent manner, with the highest affinities displayed by the
petasin and desoxyneopetasol fractions. This was confirmed in assays with
individual constituents in which the lowest IC50 values were determined for
petasin and isopetasin. The furanopetasin chemovar constituents hydroxyfuranoeremophilane
and furanopetasin also inhibited radioligand binding, as did the eremophilanlactones
eremophilanolide and hydroxy-eremophilanolide, albeit with markedly lower
affinities than the eremophilanes.(26)
Petasin, isopetasin, S-petasin and iso-S-petasin, isolated from Petasites
formosanus, a species related to P.
hybridus, relaxed histamine-, carbachol-, potassium chloride- and LTD4-induced
precontractions of isolated guinea-pig trachea in a concentrationdependent manner.(32)
S-Petasin was more potent than petasin and isopetasin for precontractions
induced by all four reagents. S. Petasin relaxed the precontractions induced by
all four reagents in a non-selective manner, with IC50 values of <10 mmol/L,
whereas iso-S-petasin selectively relaxed precontractions induced by carbachol
and potassium chloride, with IC50 values of around 10 mmol/L for each. The reason
for these differences in the respective profiles of activity, and the influence
of isomerisation (S-petasin to iso-S-petasin) is not clear. The documented
relaxant effects of S-petasin and iso-S-petasin from P. formosanus on precontracted
guinea-pig trachea may be due to antispasmodic and antimuscarinic properties,
respectively.(33) Following a study using isolated guinea-pig atria, it has
been reported that iso-Spetasin may act preferentially on tracheal muscarinic
M3 receptors, rather than cardiac M2 receptors.(34)
Hypotensive activity has been documented for S-petasin and iso-S-petasin
isolated from P. formosanus. In rats, a dosedependent hypotensive effect
occurred following intravenous administration of S-petasin or iso-S-petasin
(0.1–1.5 mg/kg body weight for each); in vitro experiments indicated that these
compounds have a relaxant effect on precontracted rat aortic ring segments and
that this may be due in part to blockade of calcium ion (Ca2þ) channels in
vascular smooth muscle cells by Spetasin and iso-S-petasin.(35, 36)
S-Petasin from P. formosanus has been shown to have negative chronotropic
activity in vivo. In anaesthetised rats, S-petasin (1.0–1.5 mg/kg body weight,
intravenously) induced bradycardia in a dose-dependent manner within a few
seconds of administration and the effect persisted for up to 11 minutes after
administration.(37) The highest administered dose of S-petasin (1.5 mg/kg body
weight intravenously) evoked a maximal reduction in heart rate of approximately
25%. S-Petasin had a negative inotropic effect in isolated rat atria and
depressed the amplitude of contraction of rat cardiac myocytes. Iso-S-petasin
also depresses cardiac contraction as demonstrated by in vitro studies
involving ventricular myocytes.(38) The mechanism for the observed negative cardiac
chronotropic and inotropic effects of S-petasin and iso-Spetasin may be through
inhibition of cardiac L-type voltagedependent Ca2þ channels.(37, 38) Further
work has shown that Spetasin decreases the amplitude of L-type Ca2þ currents in
NG108-15 cells (a mouse neuroblastoma and rat glioma hybrid cell line) in a
concentration-dependent manner (IC50 = 11mmol/L).(39)
CLINICAL STUDIES
Several
clinical trials of butterbur extracts have been conducted and have involved
individuals with, for example, seasonal and perennial allergic rhinitis and
migraine. While many of these studies have reported beneficial effects with
butterbur, rigorous investigation of the efficacy of butterbur extracts is
limited and further large, well-designed clinical trials are required.
Pharmacokinetics There are limited pharmacokinetic data for the
constituents of butterbur extracts. The bioavailability of petasin has been
reported following a study involving healthy volunteers who received a single
dose of two (n = 24) or four tablets (n = 24) of butterbur leaf extract
(ZE-339) orally; each tablet contained 8mg petasins.(27) The time to maximal
petasin concentrations (tmax) was around 1.6 hours in each group (mean (standard
deviation, SD): 1.62 (0.50) and 1.61 (0.93) hours for the lower and higher dose
groups, respectively), whereas the mean (SD) half-life was 7.16 (4.61) and 7.62
(3.34) hours for the lower and higher dose group, respectively. Maximal mean
(SD) petasin concentrations were 25.5 (14.8) and 58.1 (26.7) ng/mL for the lower
and higher dose groups, respectively.(27) In a proof-ofprinciple study in which
six patients with seasonal (n = 4) and perennial (n = 2) allergic rhinitis each
received butterbur extract (ZE-339) three tablets twice daily, serum petasin
concentrations reached steady state after five days' treatment (mean (SD) 15.1 (2.3)
ng/mL (A Brattström, Zeller AG, personal communication, 19 July 2004).
Another study described monitoring compliance by measuring serum
petasin concentrations using an enzyme-linked immunosorbent assay,(40) but
these results were not reported.
Therapeutic effects
Seasonal and Perennial Allergic Rhinitis In a randomised, double-blind,
double-dummy, parallel-group study involving 125 individuals with seasonal allergic
rhinitis, the effects of a carbon dioxide extract of butterbur leaf (ZE-339)
one tablet four times daily (equivalent to 32 mg petasins daily) were compared
with those of the non-sedating antihistamine cetirizine 10 mg each evening. At
the end of the two-week study, butterbur recipients (n = 61) achieved similar
scores to cetirizine recipients on the SF-36 (Short Form 36; a selfassessment scale
for medical and health outcomes), the primary outcome measure.(21) There were
also no differences between groups with respect to secondary outcome measures, including
the clinical global impression score. The overall frequency of adverse events
was similar in both groups (see Toxicity).
The
statistical power of the study only allowed the conclusion to be drawn that
butterbur was not inferior to cetirizine (i.e. the study does not demonstrate
equivalence of the two preparations),(41) and the study has been criticised for
its choice of subjective outcome measures and interpretation.( 42, 43)
A
subsequent study used an objective outcome measure – the adenosine
monophosphate (AMP) nasal provocation test (AMP is important in the pathway
leading to the release of allergic inflammatory mediators, such as histamine,
cysteinyl leukotrienes and prostaglandins) – to assess the effects of butterbur.
In a randomised, double-blind, crossover trial, 20 individuals with seasonal
allergic rhinitis ceased any existing treatment for the condition
(antihistamines and/or intranasal corticosteroids) one week before starting
treatment with butterbur 50 mg (Petaforce; Bioforce), or placebo, twice daily for
two weeks.(20) No further details of the preparation were provided in the
report of the study, although Petaforce marketed in the UK contains butterbur
root extract 25 mg per capsule (containing not less than 15% petasins
calculated as isopetasin).
At
the end of each treatment period, participants underwent AMP challenge
(described as two applications to each nostril of a 400 mg/mL solution
delivered via a pump actuator spray device) and spontaneous recovery was
monitored by measuring peak nasal inspiratory flow (PNIF) at regular intervals
over on hour. Time to recovery was significantly attenuated and the maximum
fall in PNIF was significantly less in butterbur recipients compared with
placebo recipients (p = 0.028 and 0.036, respectively).(20) The study design
did not incorporate a wash-out period between the two phases of the study, and
it is not clear whether there could have been any carry-over effect in patients
who received butterbur during the first phase of the study and what influence,
if any, this may have had on the results.
In
a randomised, double-blind, parallel group, controlled trial, 330 individuals
with seasonal allergic rhinitis and a history of seasonal allergic rhinitis for
at least two seasons in consecutive years, received a carbon dioxide extract of
butterbur leaves (ZE-339, tablets standardised for 8.0 mg total petasins per
tablet) one tablet three times daily (n = 110), fexofenadine (Telfast) 180 mg
each morning (n = 113), or placebo (n = 107), for two weeks; double dummy
preparations were used to achieve blinding.(44) At the end of the study, both butterbur
extract and fexofenadine were superior to placebo with respect to the primary
outcome variable (the change in evening total symptom scores, determined for
the previous 12-hour period, from baseline values to the 2-week endpoint) (p <
0.001), and there was no statistically significant difference between the two
active treatment groups (p = 0.37). With respect to secondary outcome
variables, responder rates were significantly higher in the butterbur extract
and fexofenadine groups (p < 0.001 for both versus placebo), and there was
no statistically significant difference between the two active treatment groups
(p = 0.88).(44) Outcomes of statistical analyses for the other secondary outcome
variables were not reported. In a similar randomised, double-blind, parallel
group trial, 186 individuals with seasonal allergic rhinitis and a history of
seasonal allergic rhinitis for at least two seasons in consecutive years,
received a carbon dioxide extract of butterbur leaves (ZE-339, tablets
standardised for 8.0 mg total petasins per tablet) one tablet three times daily
(n = 60), one tablet twice daily (n = 65), or placebo (n = 61), for two weeks to
assess the relationship between dose and response.(45) At the end of the study,
changes in symptom scores from baseline were significantly greater for both
butterbur groups when compared with placebo (p < 0.001) and the change in
symptom scores for the higher-dose butterbur group was significantly greater
than that for the lower-dose butterbur group (p = 0.02).
The
effects of butterbur extract (Petaforce) 50 mg twice daily in perennial allergic
rhinitis were compared with those of fexofenadine 180 mg daily in a randomised,
double-blind, placebo-controlled, crossover study involving 16 individuals.
Participants stopped their existing treatment for allergic rhinitis one week before
starting their randomised treatment; treatments were taken for one week, with a
one-week wash-out period between each randomised treatment. At the end of the
study, the maximum percentage fall from baseline values in PNIF after nasal AMP
challenge was significantly attenuated in the butterbur and fexofenadine
groups, compared with the placebo group (mean (SEM) for butterbur, fexofenadine
and placebo: 34 (3), 39 (3) and 46 (3), respectively; p < 0.05).(46) The
total nasal symptom score, a secondary outcome measure, was also significantly
improved for the butterbur and fexofenadine groups, compared with the placebo
group (p < 0.05). This study is limited in that the duration of treatment
was short, and the sample size calculation was not based on detecting differences
in nasal symptom scores, so a larger study is needed to confirm the latter
result.
Asthma and Bronchitis At
present, there is insufficient evidence from well-designed randomised
controlled trials to support the efficacy of butterbur extracts in asthma and
bronchitis. In a randomised, double-blind, crossover study, 16 patients with
atopic asthma who had been stabilised on inhaled corticosteroid therapy for at
least three months before the study received butterbur (Petaforce) 25 mg twice
daily (no further details stated in the report although Petaforce marketed in
the UK contains not less than 15% petasins calculated as isopetasin), or
placebo, for one week.(47) Participants stopped any treatment with long-acting b2-agonists
one week before and for the duration of the study. At the end of the study, bronchial
hyper-responsiveness in response to AMP bronchial challenge was significantly
improved in butterbur recipients compared with placebo recipients (p < 0.05),
and concentrations of inflammatory markers (exhaled nitric oxide, serum eosinophil
cationic protein and peripheral blood eosinophil count) were significantly
suppressed in the butterbur group, compared with the placebo group (p < 0.05
for each).(47)
In a preliminary trial, 80 individuals (aged 6–85 years) with mild
or moderate asthma received a lipophilic carbon dioxide extract of butterbur
rhizome (Petadolex; standardised to contain at least 15% petasins) 50 mg three
times daily (equivalent to 22.5 mg petasins daily; dose reduced for children depending
on age) for a minimum of two months following a two-week run-in phase. A report
of this study attributes several improvements to administration of butterbur,
including reductions in the number, duration and severity of asthma attacks, increases
in peak flow and forced expiratory volume in one second (FEV1), and reduced use
of existing asthma medications.( 48) However, such conclusions may be flawed
because of the design and methodological limitations of the study and because
no statistical analysis was undertaken.
Allergic Skin Reactions A randomised,
double-blind, doubledummy, controlled, crossover trial assessed the effects of butterbur
on the histamine and allergen cutaneous response in 20 atopic patients with
asthma or allergic rhinitis and sensitisation to at least one common household
allergen, such as house dust mite, on skin prick testing.(49) Participants received
butterbur (Petaforce) 50 mg twice daily (no further details given),
fexofenadine 180 mg daily, montelukast 10 mg daily, or placebo, for one week;
existing treatment with antihistamines and leukotriene receptor antagonists was
stopped one week before and for the duration of the study, although existing
treatment for asthma or allergic rhinitis was continued.
Each day, approximately
two hours after taking the first daily dose of study medication, each
participant underwent skin prick testing with the allergen that had previously been
shown to provoke the greatest response in that individual, as well as with
histamine (1.7 mg/mL; no further details reported) and 0.9% sodium chloride as
control. Mean histamine and allergen wheal and flare responses were significantly
attenuated by fexofenadine, compared with placebo, but not by butterbur or
montelukast.(49)
Migraine prophylaxis The
rationale for the use of butterbur in migraine prophylaxis is centred around
the understanding that vasoconstrictive and neurogenic inflammatory processes
are involved in the generation of migraine headaches, and that butterbur and
certain of its isolated constituents have been shown in preclinical studies to
have anti-inflammatory properties.( 22) However, at present, rigorous clinical
investigation of the effects of butterbur extracts in preventing migraine is limited.
In
a randomised, double-blind, parallel-group trial, 60 hospital outpatients with
migraine (minimum of three attacks per month for the three months prior to the study
and a minimum of two attacks in the four-week run-in phase) received a carbon
dioxide extract of P. hybridsus rhizome
(Petadolex) two capsules twice daily (equivalent to 100 mg extract or 15 mg
petasins daily), or placebo, for 12 weeks.
None
of the participants were previous users of the butterbur extract.(22) Inclusion
and exclusion criteria for the study were in accordance with the International
Headache Society guidelines.( 50) The frequency of migraine attacks in the last
four weeks of the study was significantly lower in the butterbur group,
compared with the placebo group: the mean (SD) numbers of attacks during the
month were 1.7 (0.9) and 2.6 (1.1), for the butterbur and placebo groups,
respectively; p < 0.05). The number of days with migraine during the last
four weeks of the study also decreased significantly in the butterbur group,
compared with the placebo group (mean (SD) number of days at baseline and weeks
8–12: 3.4 (1.6) and 1.7 (0.9) versus 3.0 (1.3) and 2.6 (1.2), for butterbur and
placebo, respectively; p < 0.05). There were no statistically significant differences
between the two groups in the duration and intensity of migraine headaches at
the end of the study.(22)
The
study has several limitations which should be considered when interpreting the
results. A sample size calculation was not carried out, baseline
characteristics (apart from age and variables relating to migraine attacks) of
participants were not provided in a report of the study, so it is not clear if
the randomisation was successful (i.e. whether or not the two groups were
similar at baseline) and differences at baseline in the frequency of migraine
attacks are not considered in the analysis. There are further flaws in the
statistical analysis, for example, the analysis was carried out only with those
participants who adhered to the protocol (i.e. an intentionto- treat analysis
was not carried out), efficacy parameters were not defined a priori,(51) the
results are reported without 95% confidence intervals and precise p-values are
not provided.
Against
this background, an independent re-analysis of the data from this study was
undertaken. Data entry from original case report forms was completely repeated
under the principles of good clinical practice (which includes double data
entry and consistency checks), and all four primary efficacy criteria and data
from all three time points (four, eight and 12 weeks) were evaluated equally
weighted in an attempt to avoid bias by posthoc selections of efficacy
criteria.(51) All analyses were undertaken with data from the
intention-to-treat population (i.e. all patients who were randomised and took
the study medication at least once).
The
new analysis confirmed the findings of the original analysis and stated that
all 12 primary efficacy criteria (number of attacks, number of days with
attacks, mean duration and mean intensity of attacks at all three time points)
were significantly reduced in the butterbur group, compared with the placebo
group, and the most conservative analysis showed that seven of these 12
variables were still statistically significant.(51) However, the possibility of
bias in this retrospective re-analysis cannot be excluded entirely, and other methodological
issues remain, such as the lack of a sample size calculation.
A
larger randomised, double-blind, placebo-controlled trial of a butterbur
extract for migraine prophylaxis has since been conducted. In the trial, 245
patients with migraine (two of six attacks per month for the three months prior
to the study and a minimum of two attacks in the four-week run-in phase; with or
without aura and meeting International Headache Society criteria) received an
extract of butterbur rhizome (Petadolex) 50 mg twice daily, 75mg twice daily,
or placebo, for 16 weeks.(23) Overall, 202 participants completed the study
(perprotocol analysis) and 229 were included in the intention-totreat analysis.
At the end of the study, the mean number of migraine attacks was reduced by
45%, 32% and 28%, compared with baseline values, for the butterbur extract 150
mg daily, 100 mg daily and placebo groups, respectively.
This finding was statistically significant for butterbur extract
150 mg daily versus placebo (p = 0.005; intention-to-treat analysis).(23) The
proportion of 'responders' (proportion of participants with > 50% reduction
in mean attack frequency per month relative to baseline) was significantly
higher for the butterbur 150 mg group when compared with the placebo group (p <
0.05), but there was no statistically significant difference in this outcome
for butterbur 100 mg, compared with placebo.
The effectiveness of a carbon-dioxide extract of P. hybridus rhizome
(Petadolex) at doses ranging from 50–150 mg, depending on participant's age,
were explored in 108 young people (aged 6–17 years) with a history of migraine
for at least one year diagnosed according to International Headache Society
criteria, in a prospective, open-label, multi-centre, four-month trial.(52) At
the end of the study, the frequency of migraine attacks was reduced by 63%,
compared with baseline values, and 77% of participants experienced a reduction
in the frequency of migraine attacks of at least 50%. As this study did not
involve a control group, the effects cannot be attributed to treatment with
butterbur, and the hypothesis that butterbur rhizome extract reduces the
frequency of migraine attacks in this patient population requires testing in
rigorous randomised controlled trials involving sufficient numbers of
participants.
ACTIVITIES
Analgesic
(1; BIS; HH2; PH2; SHT); Antiinflammatory (1; IJI1; SHT); Antileukotriene (1;
IJI1; PH2; SHT); Antilithic (2; KOM; SHT); Antimigraine (1; IJI1);
Antispasmodic (2; KOM; PHR; PH2; SHT); Antiulcer (1; HH2); Aperitif (f; PH2);
Aquaretic (f; SHT); Carcinogenic (1; PHR; PH2); Cardiotonic (f; GMH);
Cytoprotective (f; PH2); Diaphoretic (f; MAD); Diuretic (f; GMH; MAD; PHR;
PNC); Dysuria (2; KOM); Emmenagogue (f; MAD); Hepatotoxic (1; PHR; PH2);
Mutagenic (1; PHR; PH2); Sedative (f; BIS); Stimulant (f; PNC); Teratogenic (1;
PHR; PH2); Tonic (f; PNC); Vermifuge (f; MAD).
INDICATIONS
Adenopathy
(f; JLH); Agitation (f; PH2); Anorexia (f; PHR; PH2); Asthma (f; MAD; PHR;
PH2); Backache (f; GMH); Bladder Stone (2; PHR; PH2); Bronchosis (f; PHR; PH2);
Cancer (f; JLH); Cholecystosis (f; PHR; PH2); Cold (f; GMH); Colic (f; PHR;
PH2; SHT); Cough (f; MAD; PHR; PH2); Cramp (1; KOM; PHR; PH2; SHT);
Dysmenorrhea (f; BIS); Dyspnea (f; GMH); Dysuria (f; GMH; MAD; SHT); Enterosis
(f; BIS; PHR; PH2); Fever (f; GMH; MAD); Gastrosis (f; PHR; PH2); Headache (f; PHR;
PH2); Hepatosis (f; PHR; PH2); Hoarseness (f; MAD); Inflammation (1; IJI1;
SHT); Insomnia (f; BIS; PH2); Kidney Stone (2; PHR; PH2); Migraine (1; IJI1;
PH2); Nervousness (f; BIS); Neuralgia (f; GMH); Pain (2; BIS; HH2; KOM; PHR;
PH2; SHT); Pancreatosis (f; PHR; PH2); Pertussis (f; PHR; PH2); Plague (f;
GMH); Psychasthenia (2; HH2); Respirosis (f; PH2); Sore (f; GMH; PHR; PH2);
Sore Throat (f; MAD); Stone (2; PHR; PH2; SHT); Stress (f; PH2); Ulcer (1;
HH2); Uterosis (f; MAD); UTI (f; PHR; PH2; SHT); Water Retention (f; GMH; MAD;
PHR; PNC); Worm (f; GMH; MAD); Wound (f; PHR; PH2).
PRODUCT AVAILABILITY
Capsules:
25 mg; cigarette; extract; fl uid extract; fresh leaves
Plant
Parts Used: Flowers, leaves, roots, stems
Aerial parts, leaf, rhizome, root
DOSAGES
DOSAGES
·
Adult PO infusion: pour boiling
water over 1.2-2 g of herb, steep 10 min, strain, drink 2-4 oz as often as qid
(Moore, 1996)
·
Adult PO fl uid extract: 1-3 ml
tid (1:2 dilution) (Moore, 1996)
·
Asdult topical: apply fresh
leaves as a poultice prn
DOSAGES
The
German Commission E advised that the dose of butterbur should be such that the
daily intake of unsaturated pyrrolizidine alkaloids, including their N-oxides,
is not greater than 1 mg.(G3) The duration of use of butterbur should not exceed
a total of 4–6 weeks in a year.(G3)
As An Antispasmodic and For Other
Traditional Uses
Dosages
described in the herbal literature are typically preparations equivalent to 4.5–7
g dried butterbur root daily in the form of an ethanolic or lipophilic extract.(G3,
G69) trials involving adults with
seasonal allergic rhinitis, one study
used
a butterbur root extract (containing not less than 15% petasins calculated as
isopetasin; Petaforce) (D Martin, Bioforce (UK) Ltd, personal communication, 10
June 2004) 50 mg twice daily for two weeks,(20) whereas another study tested a
butterbur leaf extract (ZE-339) one tablet four times daily (equivalent to 32
mg petasins daily) for two weeks.(21) Trials of butterbur in migraine
prophylaxis have tested a carbon dioxide extract of butterbur rhizome
(Petadolex) at doses of 50 or 75 mg twice daily (equivalent to at least 15 or 22.5
mg petasins daily, respectively) for 12 or 16 weeks.(22, 23)
DOSAGES
4.5–7 g/day dry herb (KOM; PH2; SHT); 1.2–2 g
powdered herb/cup water, 2–3 x/day
(HH2; PH2). “Teas should not be used” (PH2).
CONTRAINDICATIONS, INTERACTIONS, AND SIDE EFFECTS
Contains
pyrrolizidine alkaloids (PAs). Not recommended due to PAs and sesquiterpene
lactones (PNC). Daily dose should not exceed 1 g PAs; do not dose more than
4–6 weeks a year (SHT). Botanically similar to Tussilago farfara. Adequate
data about PA content not available. PAs are toxic to humans, with liver damage
with cirrhosis and ascites, or seneciosis, or veno-occlusive disease (VOD)
reported in almost all cases of severe or fatal intoxications, from intakes of
0.5–3.3 mg/kg (AEH). Commission E reports all plant parts contain hepatotoxic,
genotoxic, and carcinogenic PAs. Contraindicated in pregnancy and lactation
(AEH). Gruenwald (PHR) makes the following contradictory statements,
back-to-back, first his template, “No health hazards or side effects are known
in conjunction with the proper administration of designated therapeutic
dosages.” Then, the conflicting statement, “One should entirely forgo any administration
of the drug, due to the presence of pyrrolizidine alkaloids with hepatotoxic
and carcinogenic effects in the parts of the plant above ground, as even mere
traces of the alkaloids present a danger” (PHR).
CONTRA-INDICATIONS, WARNINGS
In
view of the known toxicity, the German Commission E recommended that the
maximum daily intake of unsaturated pyrrolizidine alkaloids is 1 mg, and that
the duration of use should not exceed 4–6 weeks in a year.(G3) In Switzerland,
there are concerns regarding reports in Germany of hepatotoxicity associated
with the use of certain products containing butterbur root extract (see Side-effects,
Toxicity).
Drug Interactions No
reports of drug interactions with butterbur extracts were identified. Certain
constituents of butterbur have been documented in preclinical studies to have hypotensive
activity and negative chronotropic and negative inotropic effects. Against this
background, and on a theoretical basis, the possibility of interactions with
hypertensive and antihypertensive medicines should be considered. Likewise, several
constituents of butterbur have been documented to displace the binding of
ligands at dopamine D2 and histamine H1 receptors, so there is a theoretical
possibility of interactions with medicinal agents acting at these receptors.
Pregnancy and Lactation In
view of the lack of safety data and the possible hepatotoxic effects of poorly
processed butterbur extracts, the use of products containing butterbur is
contraindicated in pregnancy and by breastfeeding women.
CONTRAINDICATIONS
Butterbur should not be used during pregnancy and
breastfeeding. It should not be given to children. Persons with decreased
gastrointestinal or genitourinary motility should avoid the use of this herb;
symptoms may worsen. The pyrrolizidine alkaloids in this herb can cause
irreversible hepatic damage.
SIDE EFFECTS/ADVERSE REACTIONS
EENT: Color change of sclera
GI: Nausea, vomiting, anorexia, abdominal pain, color
change of stools, constipation, hepatotoxicity
GU: Diffi culty in urination
INTEG: Color change of skin
RESP: Dyspnea, shortness of breath
SYST: Carcinogenesis
(resulting from high levels of pyrrolizidine alkaloids)
INTERACTIONS
Drug
Anticholinergics,
antimigraine agents, beta-blockers: The
effects of anticholinergics, antimigraine agents, and beta-blockers may be
enhanced by the use of butterbur; avoid concurrent use.
Herb
Pyrrolizidine
alkaloid (UPA)-containing herbs: Butterbur
may add to toxicity (Jellin et al, 2008).
Lab Test
Hepatic function
tests: Butterbur may increase hepatic
function tests (Jellin et al, 2008).
SIDE-EFFECTS, TOXICITY
As with many herbal medicines, the safety of butterbur preparations
has not yet been adequately assessed: only limited preclinical and clinical
safety and toxicity data are available (see below). One of the main issues
regarding the clinical use of butterbur extracts concerns the unsaturated
pyrrolizidine alkaloid constituents which are known to be hepatotoxic in
humans, and have been shown to be carcinogenic and mutagenic in preclinical studies
(see Comfrey).
These alkaloids may be present in low concentrations in all
parts of the plant (see Constituents). Several manufacturers of products
containing butterbur include in their manufacturing processes steps to remove
the unsaturated pyrrolizidine alkaloids to concentrations below the detectable limit
(e.g. <35 parts per billion).(53) However, there remains the possibility
that toxic quantities of unsaturated pyrrolizidine alkaloids may be present in
poorly processed products, and any products which contain Petasites species as
a result of botanical misidentification or adulteration.
Butterbur is a member of the Asteraceae family, and members of
this family may cause allergic reactions in sensitive individuals, especially
those with an existing hypersensitivity to other members of the
Asteraceae/Compositae. No reports of allergic reactions to butterbur were
identified.
CLINICAL DATA
Swissmedic, the competent authority for licensing medicines in Switzerland,
has revoked the licences for certain products containing butterbur root extract
following spontaneous reports received in Germany of liver damage associated
with their use.(54) At the time of writing, the German authority had not taken
any regulatory action, but was monitoring the situation. There is only limited
information available for butterbur from long-term postmarketing surveillance
studies. Clinical trials reported to date generally have involved only small
numbers of participants, mostly with allergic rhinitis or migraine who are generally
otherwise healthy, and have involved ingestion of butterbur preparations for
relatively short periods of time (up to four months). Some clinical trials have
not adequately reported data on safety, and two randomised, double-blind,
placebocontrolled trials involving individuals with seasonal allergic rhinitis
or asthma who received butterbur extracts and in which participants continued
to take their existing medication (inhaled or intranasal corticosteroids,
long-or short-acting b2-agonists)( 47, 49) have either not assessed or not
reported data on safety parameters at all.
In a randomised, double-blind, trial involving 125 individuals with
seasonal allergic rhinitis who received butterbur extract (ZE-339) equivalent
to 32 mg petasins daily, or cetirizine 10 mg daily, for two weeks, the
frequency of adverse events was similar in both groups (proportions of
butterbur and cetirizine recipients who reported adverse events were 10% and
11%, respectively).(21) Eight of the 12 adverse events reported by cetirizine
recipients and two of the 10 adverse events reported by butterbur recipients
were classified as fatigue or drowsiness. Raised liver enzyme activity (no further
details provided) and pruritus were reported for one butterbur recipient each,
but not for cetirizine recipients.
In a randomised, double-blind, placebo-controlled, crossover study,
20 patients with seasonal allergic rhinitis stopped taking any existing
treatment one week before receiving butterbur (Petaforce) 50 mg twice daily for
two weeks (no further details of the preparation were provided in a report of
the study, although Petaforce marketed in the UK contains not less than 15%
petasins calculated as isopetasin). At the end of the study, liver function test
values (blood concentrations of alanine aminotransferase (ALT), bilirubin,
alkaline phosphatase (ALP) and albumin) were reported to be similar for
butterbur and placebo groups,(20) although no statistical analysis was carried
out. Furthermore, this study involved only small numbers of participants and
was conducted over a short time period and, therefore, cannot provide adequate
data on safety.
In a randomised, double-blind, parallel group, controlled trial in
which 330 individuals with seasonal allergic rhinitis received a carbon dioxide
extract of butterbur leaves (ZE-339, tablets standardised for 8.0 mg total
petasins per tablet) one tablet three times daily (n = 110), fexofenadine
(Telfast) 180 mg each morning (n = 113), or placebo (n = 107), for two weeks, the
frequency of adverse events was similar in all three groups (9.1, 7.1 and 6.5% for
the butterbur, fexofenadine and placebo groups, respectively).(44) There were
no differences between the three groups with respect to changes in mean liver
function test values at the end of treatment from baseline values,(44) although
no statistical analyses were reported. This finding is of limited value because
of the short treatment period. Furthermore, it would be more useful to know
whether or not liver function test values were raised in any individual
butterbur recipients, rather than reporting mean values for the group.
Open, uncontrolled studies of butterbur extracts (ZE-339 and Petadolex)
in patients with seasonal and/or perennial allergic rhinitis or asthma have
reported that butterbur was well tolerated,(40, 48) although the design of
these studies renders them unsuitable for an adequate assessment of safety. In
one of these studies, in which participants (aged 6–85 years) with mild or moderate
asthma received a lipophilic carbon dioxide extract of butterbur rhizome
(Petadolex; standardised to contain at least 15% petasins) 50 mg three times
daily (reduced for children depending on age) for a minimum of two months,
seven participants reported 11 adverse events.(48) These included abdominal
pain, flatulence, sneezing, allergic conjunctivitis, allergic rhinitis and
halitosis (reported by children) and hair loss, coughing, dyspnoea, difficulty
exhaling and depression (reported by adults). None of these was judged by the
study physician to be causally related to butterbur ingestion and none led to
withdrawal of participants from the study. In a randomised, double-blind,
placebo-controlled trial involving 60 individuals with migraine who received a
carbon dioxide extract of P. hybridus
rhizome (Petadolex) two capsules twice daily (equivalent to 100 mg extract
daily), or placebo, for 12 weeks, no adverse events were reported for the
butterbur group and no statistically significant changes from baseline values
were reported for vital signs and physical examination results.(22)
However, two butterbur recipients withdrew from the study, one because
of a suspected pregnancy; the other participant did not provide a reason. An
independent re-analysis of the data from this trial added that, at the end of
the study, three butterbur recipients had liver function test (ALT, aspartate
transaminase (AST)) values which were higher than normal ranges and
significantly higher than baseline values, and that bilirubin concentration and
erythrocyte count were significantly higher than baseline values for the
butterbur group, compared with the placebo group.(51)
These changes were not regarded as being clinically relevant,(51)
although no numerical data were provided to support this judgement. In a larger
randomised, double-blind, placebo-controlled trial, 245 patients with migraine
received an extract of butterbur rhizome (Petadolex) 50 mg twice daily, 75mg
twice daily, or placebo, for 16 weeks.(23) Data from 230 participants were included
in a safety analysis. The most frequently reported adverse events that were
considered possibly related to treatment were gastrointestinal symptoms (not
specified), which occurred in 22, 26 and 7% of participants in the butterbur
extract 75 mg, butterbur extract 50 mg and placebo groups, respectively. There were
no statistically significant differences in the frequencies of adverse events
for the butterbur groups, compared with placebo, except for belching. No
differences in liver function test values were observed between the three
groups. (23)
A review of safety data for a specific preparation of butterbur rhizome
– an extract (Petadolex) standardised to contain a minimum of 15% petasins and
processed to achieve a concentration of unsaturated pyrrolizidine alkaloids of
less than 0.08 ppm –includes data from four postmarketing surveillance studies involving
a total of 188 patients (145 with migraine, including 50 children and
adolescents aged 6–17 years). Adverse events deemed to be possibly or probably
causally related to ingestion of the butterbur product included eructations
(belching; n = 7), bad taste/smell of the product (2) and skin rash (1).(55) However,
it is unclear why these four studies included such a small number of participants:
a single postmarketing surveillance study would normally be expected to include
many more participants.
The review also refers to 93 spontaneous suspected adverse drug reaction
(ADR) reports (75 of which originated from Germany, where the manufacturer is
located) received by the product manufacturer from 1976 to the end of June
2002. In total, 27 of these reports were determined to be possibly (n = 19) or
probably (8) causally related to butterbur administration; the latter included
one case of reversible cholestatic hepatitis.(55) The review states an overall
frequency of suspected ADRs, calculated on the basis of sales figures and the
total number of spontaneous ADR reports received by the manufacturer. However,
for several reasons, these types of data should not be used to calculate frequencies
of suspected ADRs.
The World Health Organization's Uppsala Monitoring Centre (WHO-UMC;
Collaborating Centre for International Drug Monitoring) receives summary
reports of spontaneous reports of suspected adverse drug reactions from
national pharmacovigilance centres of over 70 countries worldwide. At the end
of 2005, the WHO-UMC's Vigisearch database contained a total of 10 reports,
describing a total of 22 adverse reactions, for products reported to contain P. hybridus only as the active
ingredient.(56)
Reactions reported included hepatic enzymes increased (n = 2), hepatic
necrosis (2), hepatitis (1), cholestatic hepatitis (1) and hepatocellular
damage (1) from three case reports. Nine of the reports originated from Germany
and one from Switzerland. In six of the 10 reports, P. hybridus was the sole suspected drug. (These data were obtained
from the Vigisearch database held by the WHO Collaborating Centre for
International Drug Monitoring, Uppsala, Sweden. The information is not
homogeneous at least with respect to origin or likelihood that the
pharmaceutical product caused the adverse reaction. Any information included in
this report does not represent the opinion of the World Health Organization.)
PRECLINICAL DATA
There are limited data from animal toxicity studies for
butterbur preparations, although a review(55) summarises data from unpublished
toxicity studies. Acute toxicity studies in rats yielded LD50 values for a
single-dose oral administration and single-dose intraperitoneal administration
of 5 2.5 and approximately 1 g/kg body weight, respectively. A chronic toxicity
study in rats (n = 200) carried out over 26 weeks established a no adverse
effect level for the lower dose range tested (oral administration; no further details
provided).(55)
Information on mutagenicity and genotoxicity of butterbur extracts
is limited to summaries of unpublished data. An extract of butterbur rhizome
(Petadolex) produced a negative result in the Ames test for mutagenicity using
several strains of Salmonella typhimurium.(57)
In an in vitro test for clastogenic activity in which the butterbur extract was
incubated with cultured human peripheral lymphocytes, the mean number of
chromosomal aberrations was within the reference range of the negative control.(58)
This result was obtained irrespective of whether or not the test included
metabolic activation using a rat liver postmitochondrial fraction. In contrast,
mitomycin C and cyclophosphamide, as positive controls, induced chromosomal damage.
There is some evidence from preclinical studies that S-petasin, a
constituent of butterbur root, rhizome and leaf, has effects on certain
endocrine systems. In rats, S-petasin (10 mg/kg body weight, intravenously)
reduced basal plasma corticosterone concentrations to a significantly greater
extent than did control at 30 minutes after administration (p < 0.05),
although there were no statistically significant differences between groups
when corticosterone concentrations were measured at one, two and three hours
after administration.(59) The same dose of S-petasin also significantly reduced
adrenocorticotrophin (ACTH)-induced increases in plasma corticosterone
concentrations at 30 minutes, but not longer intervals, after administration,
compared with control. Similar effects were observed following in vitro experiments:
S-petasin significantly reduced basal, ACTH- and forskolin (an adenylyl cyclase
activator)-stimulated corticosterone release from rat adrenal gland cells (zona
fasciculata reticularis) in a concentration-dependent manner. Results of further
in vitro experiments suggested that the mechanism for the observed effects is
in part through inhibition by S-petasin of the enzymes adenylyl cyclase (which
catalyses the formation of cyclic AMP), and cytochrome P450 side-chain cleavage
and 11bhydroxylase, which are important in the biosynthesis ofcorticosterone.(59,
60)
S-Petasin (1 mg/kg body weight, intravenously) administered as a
single dose to small numbers of adult male rats reduced basal plasma
testosterone concentrations, compared with control (mean (SEM): 0.81 (0.06) and
1.31 (0.21) ng/mL for S-petasin and control, respectively; p < 0.05).(61) Incubation
of S-petasin at concentrations of 0.14–14.4 mg/mL with rat testicular
interstitial cells led to a concentration-dependent inhibition of testosterone
release. S-Petasin also inhibited forskolin-, human chorionic gonadotrophin-
and androstenidione-induced stimulation of testosterone secretion from rat
testicular interstitial cells in vitro.
CLIENT CONSIDERATIONS
ASSESS
·
Assess the reason the client is
taking butterbur medicinally.
·
Assess for hepatotoxicity:
increased hepatic function test results (AST, ALT, bilirubin), clay-colored
stools, and upper-quadrant pain. If symptoms are present, discontinue use of
butterbur immediately.
·
Assess for medications used
(see Interactions).
ADMINISTER
·
Instruct the client to take PO,
use topically, or smoke.
·
Instruct the client to store
butterbur in a cool, dry place, away from heat and moisture.
TEACH CLIENT/FAMILY
·
Caution the client not to use
butterbur in children or those who are pregnant or breastfeeding until more
research is available.
·
Caution the client not to use
excessive doses of this herb; carcinogens are present in the pyrrolizidine
alkaloids.
·
Caution the client not to
confuse the leaves of butterbur with those of other Petasites spp.
PREPARATIONS
PROPRIETARY SINGLE-INGREDIENT
PREPARATIONS
Germany:
Petadolex; Petaforce V. Switzerland: Pollivita; Tesalin.
PROPRIETARY MULTI-INGREDIENT PREPARATIONS
Switzerland:
Dragees aux figues avec du sene; Dragees pour la detente nerveuse; Relaxane;
Valverde Constipation dragees; Valverde Detente dragees; Wala Pulmonium suc
contre la toux.
EXTRACTS
Ethanolic
extract antispasmodic IC50 = 1.7 mg/ml (very weak cf atropine 1/1,000,000th of
papaverine 1/1000th). LD50 dry drug 870 mg/kg ivn guinea pig, tincture 1250 mg/kg
(HH2), LD50 root extract 2500 orl guinea pig (HH2), LD50 root extract 60 mg/kg
ivn guinea pig (HH2).
REFERENCE
Barnes, J., Anderson, L. A., and Phillipson, J. D. 2007. Herbal
Medicines Third Edition. Pharmaceutical Press. Auckland and
London.
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.
Linda S-Roth. 2010. Mosby’s Handbook Of Herbs & Natural
Supplements, Fourth Edition. Mosby Elsevier. USA
Figure
4. Primary Chemical Components and Possible Actions
(Linda, S-R. 2010)
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