Butterbur

Scientific Name(s):Three accepted species: Petasites frigidus (L.) Fr., Petasites hybridus (L.) Gaertner, Meyer and Scherb., and Petasites japonicus . Family: Asteraceae (Aster)

Common Name(s): Blatterdock , bog rhubarb , bogshorns , butter-dock , butterbur , butterfly dock , coltsfoot , exwort , fuki (Japanese), pestilence-wort , pestwurz (German), Petadolex , Petaforce , Tesalin , ZE339

Uses

Commercial preparations derived from butterbur include Petadolex (available in the United States since 1997), Tesalin , and Petaforce . A few small clinical trials (some open label) have shown some benefit in the treatment of migraines and allergic rhinitis.

Dosing

Trials in migraine, allergic rhinitis, and asthma have used butterbur extracts in dosages ranging from 50 to 75 mg twice daily. Tesalin 16 to 32 mg in divided doses has been used in allergic rhinitis. Trials have included subjects 6 years of age and older.

Contraindications

Consider the use of butterbur-containing preparations in congestive heart failure a relative contraindication because of negative chronotropic effects demonstrated in animal experiments.

Pregnancy/Lactation

Contraindicated. Preparations may contain liver toxins with carcinogenic and mutagenic potential.

Interactions

None well documented.

Adverse Reactions

GI symptoms comprise the majority of reported adverse reactions. Inhibition of testosterone production has been reported.

Toxicology

Pyrrolizidine alkaloids found in butterbur are known liver toxins with carcinogenic and mutagenic potential. Commercial dosage forms must be free of hepatotoxic pyrrolizidine alkaloids.

Botany

Butterbur is a perennial shrub native to Europe that has very large, downy leaves. It commonly grows in wet, marshy ground or on sandbars near streams. The distinctive pink-lilac flowers grow on large spikes and appear before the leaves in spring. P. japonicus is commonly grown and consumed in Japan. 1 , 2

History

The generic name petasites is derived from the Greek word petasus , a type of broad-brimmed hat worn by shepherds, referring to the broad, downy leaves. The name butterbur relates to the use of the leaves to wrap butter. During the Middle Ages, butterbur leaves and roots were used to treat cough, plague, and fever.

P. japonicus is a common vegetable in Japan; the baked flower bud is used in traditional medicine as an expectorant or in the treatment of asthma. Other traditional uses include the treatment of gastric ulcer and bee stings. 2 , 3

Chemistry

Butterbur contains senecionine and other toxic pyrrolizidine alkaloids in the leaf and root; a competitive immunoassay has been developed for determination of alkaloid content. High-performance liquid chromatography (HPLC) analyses of both plant parts indicate that, on average, leaves have lower alkaloid levels than roots. 4 , 5

A large number of sesquiterpenes have been isolated from butterbur, with petasin and related eromophilanes being the most pharmacologically important. 6 , 7 , 8 , 9 , 10 The sesquiterpene distribution varies according to plant part, growth season, and plant location. 5 , 11 , 12 HPLC methods for quantitative determination of petasin have been reported, 13 , 14 and the existence of a distinct chemovar with furanoeremophilanes has been noted. The petasin series of compounds is unstable in storage, with rearrangements occurring in dry plant materials and in stored extracts. The biosynthesis of petasin has been elucidated. 15 Differences in sesquiterpene profiles of various European petasites species have been studied. 16 Other constituents of butterbur include the flavonoid glycosides isoquercitrin and astralagin. 17

Uses and Pharmacology

Allergic rhinitis

Several clinical trials have been conducted on commercial preparations of butterbur to evaluate their efficacy in the management of allergic rhinitis. Both subjective and objective data serve as end points and measures of efficacy. 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25

Efficacy over placebo has been demonstrated, and equivalence to fexofenadine 180 mg and cetirizine 10 mg has been shown. Dosages used in these trials range from Tesalin 16 to 32 mg (in divided doses) and Petadolex 100 mg in adults, with durations of 7 to 14 days.

Mechanisms of action for butterbur in allergic rhinitis relate to a role in leukotriene activity rather than an antihistaminic effect. 3 , 18 , 25

Asthma

There are limited trials evaluating the efficacy of butterbur extracts in asthma. One small trial (N = 16) found improvement in the primary outcome of bronchial hyper-responsiveness with Petaforce 50 mg for 1 week. 26 A reduction in asthma attacks was reported in another open-design trial after subjects were administered Petadolex 150 mg. 27

Migraine

Three clinical trials have evaluated the efficacy of a butterbur extract ( Petadolex ) for the prevention of migraines, all recording a decrease in the number of migraine attacks per month. A number of responders in these trials achieved at least a 50% reduction in attacks. 28 , 29 , 30 , 31 , 32 Dosages of Petadolex ranging from 50 mg twice daily 28 , 29 , 33 to 75 mg twice daily 30 were used in these trials for periods of 3 to 5 months. One of the trials, an open-label design, included children 6 to 9 years of age and adolescents up to 17 years of age. 30

Other effects
Antibacterial

Triterpenoids extracted from butterbur rhizome demonstrated in vitro activity against Bacillus subtilis equivalent to chloramphenicol, but showed no activity against Escherichia coli or Staphylococcus aureus . 34

Anti-inflammatory

In rat gastric ulceration models, butterbur extract blocked the effects of ethanol and indomethacin. 28 , 35 , 36

Antioxidant

In vitro experiments conducted to explain the active chemical components of butterbur have demonstrated its antioxidant effect. 37 , 38 , 39 , 40 , 41

Cardiac

The active chemical component, petasin, has been investigated for reported hypotensive effects. Petasin (both the s- and iso-s- forms) has, in both in vitro experiments and in rat studies, exerted a negative chronotropic effect on cardiac tissue. A reduced rate in atrial firing and a dose-dependent bradycardiac effect were demonstrated. At the cellular level, blockade of the calcium channels was suggested, but the mechanism of action was not established. 42 , 43 , 44 , 45 Clinical trials are lacking.

Dosage

Commercial extracts of butterbur, free of pyrrolizidine, have been used in clinical trials. Trials in migraine and asthma have used Petadolex 50 to 75 mg twice daily. 23 , 27 , 28 , 29 , 30 Tesalin 16 to 32 mg in divided doses has been used in allergic rhinitis. 18 , 19 , 20 , 21 , 22 , 23 , 24 Trials included subjects 6 years of age and older. Studies in special populations, such as renal or hepatic function impairment, are not available.

Pregnancy/Lactation

Use is contraindicated. Preparations may contain liver toxins with carcinogenic and mutagenic potential. 2 , 46

Interactions

None well documented. A theoretical interaction with calcium channel antagonists and inotropic drugs exists. 43 , 44

Adverse Reactions

Few adverse reactions have been reported in clinical trials; however, these trials have been of short duration (maximum, 4 to 5 months). The majority of documented symptoms are GI in nature. 3 , 20 , 21 , 24 Inhibition of testosterone production has been demonstrated by butterbur extracts in animal experiments. 29 Liver function was unaffected in a 2-week trial of a commercial (pyrrolizidine-free) preparation, but the trial was not large enough to establish harm. 24

Toxicology

Pyrrolizidine alkaloids are liver toxins with carcinogenic and mutagenic potential. 2 , 3 , 4 , 36 Commercial butterbur preparations utilize an extraction process to remove the pyrrolizidine content.

Bibliography

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18. Gex-Collet C, Imhof L, Brattström A, Pichler WJ, Helbling A. The butterbur extract petasin has no effect on skin test reactivity induced by different stimuli: a randomized, double-blind crossover study using histamine, codeine, methacholine, and aeroallergen solutions. J Investig Allergol Clin Immunol . 2006;16:156-161.
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40. Matsuura H, Amano M, Kawabata J, Mizutani J. Isolation and measurement of quercetin glucosides in flower buds of Japanese butterbur ( Petasites japonicus subsp. gigantea Kitam.). Biosci Biotechnol Biochem . 2002;66:1571-1575.
41. Lin CH, Li CY, Wu TS. A novel phenylpropenoyl sulfonic acid and a new chlorophyll from the leaves of Petasites formosanus KITAMURA. Chem Pharm Bull (Tokyo) . 2004;52:1151-1152.
42. Wang GJ, Shum AY, Lin YL, et al. Calcium channel blockade in vascular smooth muscle cells: major hypotensive mechanism of S-petasin, a hypotensive sesquiterpene from Petasites formosanus . J Pharmacol Exp Ther . 2001;297:240-246.
43. Wang GJ, Liao JF, Hintz KK, et al. Calcium-antagonizing activity of S-petasin, a hypotensive sesquiterpene from Petasites formosanus , on inotropic and chronotropic responses in isolated rat atria and cardiac myocytes. Naunyn Schmiedebergs Arch Pharmacol . 2004;369:322-329.
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