common butterbur - helhetsdoktorn · butterbur rhizome extract is effective in the prophylaxis of...

Common butterbur

Petasites hybridus (L.) Gaertner et al.

A.Vogel

B i o f o r c e M o n o g r a p h

which have been characterised onlyto a small extent. The effects must beattributed to the whole extract and notto individual constituents, even if theprincipal substances with their effectsare known in many cases.

Butterbur extracts include sesquiter-pene esters, pyrrolizidine alkaloidsand essential oil 5. This consists ofcompounds derived from fatty acidand terpene metabolism. Only thequantitatively predominating peta-sines (sesquiterpene esters), theeffects of which have been studied invitro and in clinical studies, and thepotentially toxic and carcinogenicpyrrolizidine alkaloids will bediscussed below. The structure ofmany other constituents has not yetbeen elucidated and their effects arethus unknown.

Sesquiterpene estersUp to now, the structure of more than20 derivatives of the isomericsesquiterpene esters p e t a s i n e ,i s o p e t a s i n e and neopetasine h a sbeen elucidated (Fig. 4).

Medicinal plantand drugsemployed Common butterbur (Petasiteshybridus, syn. Petasites officinalis;Asteraceae family, Compositae) isnative to all of Europe, northern andwestern Asia. It was introduced inNorth America.

Shortly after the snow thaws, often asearly as the end of February in thelowlands, its reddish inflorescenceappears on the still bare earth in wetground that is rich in nutrients suchas the banks of rivers and streams.

The leaves, up to 60 cm in diameter,(Fig. 2) only unfold during flowering,which lasts until April; children still liketo use them as hats today. The plantalso owes its name to these largeleaves. The Greek physicianDioscurides (c. 50 AD) compared theleaves to a broad-brimmed rain hat

(petasos in Greek) and gave it thename Petasites 1.Metre-long runners arise from therootstock (rhizome), along whichcentimetre-thick nodules are formedrepeatedly (Fig. 3). Thin roots run outfrom these. The rhizomes (Petasitidisrhizoma) and the leaves (Petasitidisfolium) are used as a drug.

HistoricalDioscurides used the finely poundedleaves as a poultice for skin ulcers 2.In his herbal of 1664, the Germanphysician and botanist Ta b e r-naemontanus recommended the rootpowder of the «Pestilentzwurz» orbutterbur for internal use also inabdominal colic and asthma and asa mucolytic 3.

Because of the diuretic and sweat-producing effect, the root powder wasalso used in plague, hence the name«Pestwurz» or «plague-root». TheEnglish name is believed to havebeen given it because the largeleaves were formerly used to wrapbutter in hot weather.

In traditional European phytotherapy,coltsfoot (Tussilago farfara) for a longtime displaced butterbur as amucolytic cough medicine, until themarked spasmolytic characteristics ofthe root extract were confirmedexperimentally recently 4. Theseresults, obtained with modernresearch methods, opened up wholenew areas of indications for butterbur.

Pharmacologyof theconstituents Plant extracts are mixtures of manysubstances, the components of

Fig. 1: Flower head of Petasites hybridus

Fig. 2: Common butterbur in its naturallocation: the large leaves have openedafter flowering. The white pappus hairsof the fruits typical of compositae(Asteraceae) are easily identified.

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B i o f o r c e M o n o g r a p h C o m m o n B u t t e r b u r

Their a n t i - i n f l a m m a t o r y and s p a s-m o l y t i c actions have been wellinvestigated: The marked a n t i -inflammatory effect of the petasines isdue to the well- documentedinhibition of leukotriene synthesis 6,7:On the one hand, petasine inhibitsthe intracellular release of calciumfrom the endoplasmic reticulum, thusinhibiting the calcium-dependent 5-lipoxygenase (Fig. 5) of the leuko-cytes. On the other hand, 5-lipo-xygenase is inhibited by petasine,neopetasine and isopetasine in asecond, as yet unclarified way. The 5-lipoxygenase is thus inhibited at twostages.

In addition, the release of E C P(eosinophilic cationic protein) fromeosinophilic granulocytes is reduced.The importance of leukotrienesynthesis antagonism can beexplained briefly by comparison withsynthetic substances: The anti-inflammatory action of the leukotrienereceptor antagonists (e.g. zafirlukastand montelukast) is due toantagonism of the Cys-LT1 receptorsfor the leukotrienes LT C4, LT D4 andLT E4 ( =SRSA: slow reactingsubstances of anaphylaxis) 8.Inhibitors of leukotriene s y n t h e s i ssuch as butterbur rhizome extract

reduce the synthesis of a l lleukotrienes, including LT B4, theleukotactic effects of which are notblocked by the leukotriene receptorantagonists 6. The superiority of thesynthetic leukotriene s y n t h e s i sinhibitor zileuton (licenced in the USAfor the indication of asthma) overleukotriene receptor antagonists wasdocumented in two studies in chronicurticaria 9,10.

The mechanism of the spasmolyticeffect of the Petasites extracts has notyet been conclusively elucidated:

Bucher in 1951 described thespasmolytic effect of an extract ofPetasites root on the isolated guineapig intestine, which was comparableto papaverine 4.

It was shown that S-petasine (Fig. 4),a sulphur-containing derivative ofpetasine, has an equally goodrelaxant effect on the smooth muscleof the isolated guinea pig trachea asthe phosphodiesterase inhibitoraminophylline. This effect is probablyproduced by a reduction in theintracellular calcium concentration 11.More recent investigations show thatS-petasine has a vasodilator effect invitro, which is probably due to directinhibition of the calcium channels inthe cell membranes of vascularsmooth muscle 12.

It is apparent from these studies thatbutterbur extracts not only have a

spasmolytic effect on the intestine buthave a relaxant effect on smoothmuscle generally.

For the sake of completeness, afurther chemical feature of butterburmust be mentioned: there are twochemotypes of Petasites hybriduswhich cannot be distinguishede x t e r n a l l y, the petasine and thefuranopetasine type 13.

The furanopetasine type containspotentially cytotoxic furanoeremo-philans instead of petasines (Fig. 6);

however, these are converted duringconventional drying processes intoeremophilanlactones, which have atoxic effect only at higherconcentrations.

Distinguishing the two chemotypes isof subordinate importance practicallysince finished preparations arestandardised to a minimum petasinecontent.

Pyrrolizidine alkaloids (PA)Pyrrolizidine alkaloids (PA) (Fig. 7)have so far been discovered in over350 plant species from 13 families 13.They taste bitter and protect theplants from being eaten by animals.PAs are widespread in the Astera-

A.Vogel

Fig. 3: Butterbur rhizome

Fig. 4: Four of the over 20 known sesquiterpene esters of Petasites hybridus(petasine chemovariety)

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Petasine Neopetasine

Isopetasine S-Petasine

ceae (Compositae) and almostubiquitous in the Boraginaceae (e.g.Symphytum officinale, comfrey). ThePAs are present as hydrophilicnontoxic N-oxides in the rhizome ofthe butterbur. It is only after “reductivetoxification” by bacteria of the bowelflora that the now lipophilic PAs areabsorbed and oxidised in the liver bycytochrome P-450, and thenmetabolised to toxic or carcinogenic(alkylating) pyrrole derivatives. In theworst case, PA intoxication canmanifest itself as Budd-C h i a r isyndrome (hepatic vein occlusion).The carcinogenicity leads to benignand malignant epithelial hepatictumours (hepatomas, hepatocellularcarcinomas, cholangiomas, haeman-gioendotheliomas etc.) 14.Due to special extraction methods(see below), the concentrations ofPAs in finished medicines are belowthe detection limit of 0.1 ppm 13 andare therefore safe toxicologically.

Extractionmethods Rhizomes, which currently are stillobtained from collection in the wild,are used for the preparation of

finished medicines. La r g e - s c a l eculture of the petasine chemovarietywill be available soon in order toensure sustained use of the plant. Alicence application for an extract ofthe leaves is in process while goingto press. The constituents are todayextracted with liquid CO2 (lipophilic)under increased pressure. This

process results in extracts that arepractically pyrrolizidine-free (de-tection limit of 0.1 ppm), as thehydrophilic PA N-oxides are notextracted alongside. The PA had tobe removed from ethanolic extracts

subsequently by means of cationexchangers.

Tea (equivalent to an aqueousextract) made from leaves orrhizomes should no longer be used,as the PA content exceeds thepermitted 0.1 µg daily 13.


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5-lipoxygenase (5-LO)(Ca-dependent)

Petasines and synthetic 5-LO inhibitors

5-hydroperoxieicosatetraenic acid(5-HPETE)

Prostaglandins

= Cysteinyl leukotriene = SRSA

Cyclo-oxygenases (COX1, COX2)

Phospholipids

Phospholipase A2

Arachidonic acid (AA)

Actions of the SRSA (slow reacting substances of anaphylaxis):● Contraction of smooth muscle in bronchi and blood vessels.● Increase in vascular permeability with consequent perivascular oedema.Leukotriene receptor antagonists block the effect of cysteinyl leukotrienes LT C4 ,LT D4 and LT E4. Petasines and synthetic 5-lipoxygenase inhibitors blockthe synthesis of all leukotrienes. The leukotactic effect of the LT B4 is thus alsoprevented.

Inhibitory effect of the petasines (petasine, isopetasine, neopetasine)LT = Leukotriene

Fig. 5: Arachidonic acid cascade and site of action of the petasines

Fig. 6: Sesquiterpenes of the furanopetasine chemovariety

LT C4

LT D4

LT E4

LT A4

LT B4

(leukotactic)

Furanoeremophilane Eremophilanlactone

Senkirkin

Alkaloid N-oxide, polar,salt-like, nontoxic

tertiary alkaloid(senecionin), lipophilic, toxic

Integerrimin

2 examples of pyrrolizidine alkaloids

Fig. 7: Pyrrolizidine alkaloids are synthesisedin the root as N-oxide derivatives. Reductive toxification to the tertiary alkaloids takesplace only in the human digestive tract.

reductivetoxification

IndicationsOnly the indications confirmed bystudies are discussed in this chapter.However, for the sake of complete-ness, Table 1 lists the traditional usesof butterbur alongside the modernuses.

Migraine prophylaxisButterbur rhizome extract is effectivein the prophylaxis of migraine; in arandomised, double-blind, placebo-controlled study of parallel groups of60 patients (50 mg Petasites rhizomeextract twice daily) for 12 weeks, thenumber of attacks per month (Fig. 8)fell from 3.3±1.5 at the start to 1.3±0 . 9after 8 weeks (Tab. 2), which isequivalent to a maximum reduction of60% (placebo 17.2%) compared to thebaseline 1 5. The number of migrainedays per month also fell significantly (p< 0.05) from 3.4±1.6 days at the startto 1.7±0.9 days after 12 weeks. Theintensity and duration of the attacksdid not decrease significantly.

The tolerability was assessed by thepatients as excellent. No adverseeffects occurred. The extractemployed is therefore comparable tothe commonly used syntheticmigraine prophylactic drugspropranolol (- 38.2%), timolol (-43.9%)16 and flunarizine (- 39%)17

with regard to the percentagereduction in the number of attacksper month. The intensity and durationof the attacks were not influenced bythese drugs either.

The leukotriene antagonism of thebutterbur rhizome extract might beinvolved in this prophylactic effect onmigraine: in an open study in 17patients, the leukotriene receptorantagonist montelukast, which isemployed in the treatment of asthma,was significantly effective in reducingthe frequency of migraine attacks 18.In addition, petasine inhibits a rise inthe intracellular calcium concen-tration, just like the calciumantagonists (e.g. flunarizine) that havelong been used in migraineprophylaxis.

As with all drugs used for migraineprophylaxis, the mechanism of actionhas still not been elucidated in detail.

Tension headachesThe efficacy in tension headaches(vasomotor headaches) wasdemonstrated in a multicentreprospective clinical study of 33patients in general practices inSwitzerland 19. A general practicestudy by Gruia in 1986 of 22 patientsfor 4 weeks obtained similar results.H o w e v e r, the efficacy in migraineprophylaxis exceeded that invasomotor headache 20.The available studies indicate efficacyin tension headaches.

Spasm of the urogenitaltract The spasmolytic activity of butterburextracts, similar to papaverine, wasdemonstrated in 1951 by Bucher inthe isolated guinea pig intestine 4. In1955, Aebi et al. were the first toisolate and characterise twosubstances with a spasmolytic actionfrom rhizomes of Petasites hybridusand named them petasine andisopetasine respectively 21.

In a controlled study with 20 patientsin each of the 2 treatment groups, abutterbur extract in the subacutestage of ureteric colic (i.e. aftertreating the acute symptoms withpapaverine i.v.) demonstrated asimilar effect to N-butylscopolamine(Buscopan®): the 2 groups receivedeither 1 Buscopan® tablet 5 timesdaily or 2 capsules of butterburrhizome extract up to 2-hourly (max.14 caps daily).

Despite this high dosage, no adverseside effects occurred 22.

A general practice clinical study in 40patients showed a good effect incystitis, renal/ureteric stones and painin prostatitis 23.

A.VogelB i o f o r c e M o n o g r a p h C o m m o n B u t t e r b u r

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Indication traditional modern

Migraine - +

Tension headache ✔ (+)

Cramp-like pains in the

urinary tract ✔ +

Cramp-like pains in the

gastrointestinal and biliary area ✔ (+)

Dysmenorrhoea ✔ (+)

Emmenagogue ✔ -

Back pain ✔ -

Cough ✔ -

Asthma ✔ (+)

Allergic rhinitis - + [L]

Wound healing, external ✔ [L] -

Unless specially stated, rhizomes (extract or powder) were used. ✔ traditional use+ indication confirmed by studies. – not used(+) indication inadequately confirmed by studies [L] leaf extract or pounded leaves used externally

Table 1: Butterbur indications

The use of butterbur extracts in mildto moderate colic-like pains of theexcretory urinary tract thus appearsjustified.

In folk medicine, butterbur is alsoused in dysmenorrhoea.

Meier (1994) describes a placebo-controlled double-blind pilot study in14 subjects with primary dys-menorrhoea using a preparation thatincluded 90 mg of an alcoholicbutterbur dried extract; 3 pills weretaken daily for 3 months. There was amarked decrease in pain comparedto placebo, especially on the 2nd dayof menstruation, which indicates thatbutterbur extract is effective 24.

Spasm of the digestivetract Although butterbur is used in folkmedicine in pain of the digestive tractand biliary tract, there are no studiesin this regard that meet currentstandards.

H o w e v e r, a good effect can beexpected from the mechanism ofaction discussed above and theresults of investigations in animalmodels 4.

AsthmaThe traditionl use of butterbur inasthma was investigated in recentstudies:

In a clinical study of 22 patients withasthma or tracheobronchitis, Gruia(1986) assessed the result oftreatment as good to very good in94% of cases 20.

In an open clinical study (1998)Petasites hybridus (pulverisedrhizome) was investigated for itsefficacy and tolerability in 70 patients(3 groups) with chronic asthma orchronic obstructive bronchitis:

The authors found a significantimprovement (p<0.05) in the FEV1(forced expiratory volume in1 sec.) 180 minutes afteradministration of 600 mg root powderin the first group (30 patients). In thesecond group (20 patients), thebronchial hyperreactivity in the

metacholine test improved 120minutes after the same single dose ofroot powder (p<0.05). The third group(20 patients) received 600 mg ofdrug 3 times a day for 14 days. This resulted in an improvement inthe metacholine test, but this was notsignificant 25.

Unfortunately, more precise figurescannot be found in the study. Thus,


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Weeks after start of treatment

2

3

4

0 4 8 12

1

0

5

Butterbur extract50 mg twice daily (n=33)

Placebo (n=27)

p<0.05

**

*

*

Table 2: Number of migraine attacks permonth (total ± SD)

Fig. 8: Frequency of migraine attacks per month during treatment with butterbur extractor placebo:

After a preliminary period of 4 weeks to determine the baseline levels, 33 patients weretreated with butterbur extract (50 mg twice daily) and 27 patients with placebo. From the4th week until the end of the study, the number of migraine attacks had fallensignificantly with treatment with butterbur extract compared to placebo (* results with p <0.05). A maximum reduction in the number of attacks of 60 % compared to the baselinelevels (Tab.2) was recorded after 8 weeks.

Weeks after start of treatment 0 4 8 12

Butterbur extract 3.3±1.5 1.8±0.8 1.3 ±0.9 1.7 ±0.9

Placebo 2.9 ±1.2 2.2±0.7 2.4±0.8 2.6±1.1

neither of these studies meetspresent-day requirements. Theefficacy in asthma must be confirmedby controlled clinical studies. Apossible effect could be attributed tothe inhibition of leukotriene synthesisdescribed above, the inhibition ofeosinophilic cationic protein (ECP)and the relaxant effect on the smoothmuscle of the airways 11,26.

Allergic rhinitisIn a placebo-controlled, randomiseddouble-blind study, 61 patientsreceived 1 tablet of a CO2 extract ofbutterbur leaves 4 times daily(standardised to 8 mg total petasinesper tablet) and 64 patients received 1tablet of cetirizine in the evening fortwo weeks. The results showed thatthe extract studied is equally effectiveas cetirizine in allergic rhinitis, butwithout its sedative side effect 27.The good effect is explained by theinhibition of leukotriene synthesis bythe petasines.

Prospects forfurther possibleindications Leukotrienes are important in thepathogenesis of many inflammatorydiseases.

On the basis of analogy, new areas ofindications could open up forbutterbur extracts wherever leuko-trienes play a part in pathogenesis:Leukotriene synthesis inhibitors suchas zileuton are currently beinginvestigated in inflammatory boweldisease such as Crohn’s diseaseand ulcerative colitis ; the results ofinvestigations in animal models and clinical studies are promising 28,29.Interestingly, sulphasalazine and 5-aminosalicylic acid, which are usedas standard drugs in chronicinflammatory bowel diseases, also

have an inhibitory effect onleukotriene synthesis in the mucosaof the small and large intestinebesides their other effects 8.

A case study of 2 patients and anopen clinical study of 12 patients withchronic urticaria suggest that theleukotriene receptor antagonistszafirlukast and montelukast areeffective. In both studies, the bettereffect of the leukotriene synthesisinhibitor zileuton was found to beincreased by inhibition of LT B4

9,10.

Various lipoxygenase inhibitors weresuccessfully tested clinically topicallyor systemically in psoriasis also 30,31.

The future will show whetherbutterbur extract is also effective inthese indications.

Dosage andduration of use Only one CO2 root extract has beenavailable on the market up till now; itis available as a spissated extract incapsule form and contains 4–11 mgtotal petasines per capsule of 25 mgextract. For migraine prophylaxis, 50mg root extract are taken twice dailyfor at least 3-6 months (registereddosage).

In the first month, the dose can beincreased to 75 mg twice daily inorder to increase the effect 32.A dosage of 25-50 mg 2-3 times aday is recommended for spasticpains.

When going to press, a licenceapplication for CO2 leaf extract intablet form (standardised to 8 mgtotal petasines per tablet) for theindication allergic rhinitis was inprogress.

Restrictions onuseThere have been no investigations ofuse during pregnancy and lactationand in children. Butterbur extractsshould therefore not be taken bychildren under 12 years, pregnantwomen and breastfeeding mothers.

Adverse effectsThere have been only rare reports ofside effects. The numbers of sideeffects were recorded inadequately inthe cited studies.In most cases these were mildgastrointestinal complaints such asburping, nausea or a sensation ofpressure in the stomach region. Moresevere gastrointestinal side effectsare hardly to be expected, asbutterbur extract was even found tohave gastroprotective effects 33.There have also been isolated reportsof reversible allergic skin reactions. Up to now there have been 3 casesof cholestatic hepatitis probablyassociated with the prolonged use ofbutterbur rhizome extract for migraineprophylaxis. In all 3 cases, themarkedly raised liver parametersreturned to normal in a short timeafter stopping the preparation. Thissuggests nonpredictable drug-induced hepatitis due to an allergicimmunological reaction, which isfamiliar as a very rare side effect ofinnumerable widely usedmedications (e.g. including diazepamor paracetamol) 34. Since the hepatitisin all cases only became apparentafter more than 4 weeks of daily useof butterbur extract, it appears rationalto measure liver function tests(transaminases, γ-GT, alkalinephosphatase and total bilirubin) andto stop the medication immediately ifthese parameters are increased.Risk factors for the development ofcholestatic hepatitis during prolonged


7

treatment with butterbur extract arealcohol abuse and additional long-term medication with potentiallyhepatotoxic medicines.

Butterbur extract overall isdistinguished by a very goood sideeffect profile. The very rare cholestatichepatitis can easily be prevented byappropriate precautions.

Interactions No interactions have been identifiedso far.

OverdoseNo adverse side effects wereobserved even with the highestdosage employed so far of 14capsules of 25 mg daily in uretericcolic 22.

Acknowledge-mentWe thank Prof. Dr. med. ReinhardSaller, Director of natural medicinesection, Dept. of Internal Medicine,University Hospital Zürich, for hiscritical reading of the manuscript andhis helpful additions.

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Band VI Teil 4. Verlag Paul Parey, 1987:680 –86.

2. Dioskurides Pedanius. De materia medica. 4.Buch.http://members.fortunecity.com/dioskurides/

3. Tabernaemontanus Iacobus Theodorus.Kräuterbuch. Faksimile einer Aufl. von1664:1127-28. http://www.kraeuter.ch/

4. Bucher K. Über ein antispastisches Prinzip inPetasites officinalis Moench. Arch. exper.Path. u. Pharmakol. 1951;213:69-71 .

5. Hänsel R. et al. Petasites. In: HagersHandbuch der pharmazeutischen Praxis. 5.Aufl.1995:81-105.

6. Thomet OA. Antiiflammatory effects ofPetasites hybridus and its compounds invitro and evidence for in vivo efficacy inallergic rhinitis patients. Dissertation aus dermedizinischen Kinderklinik der UniversitätBern, Mai 2001.

7. Thomet OA et al. Role of petasin in thepotential anti-inflammatory activity of a plantextract of petasites hybridus. BiochemicalPharmacology.2001;61:1041-47.

8. Forth W et al. Allgemeine und speziellePharmakologie und Toxikologie. 8. Aufl.Urban & Fischer, München . Jena 2001.

9. Ellis MH Successful treatment of chronicurticaria with leukotriene antagonists. JAllergy Clin Immunol.1998;102:876-77.

10. Asero R et al. Leukotriene receptorantagonists in chronic urticaria. Allergy.2001;56:456-57.

11. Ko W et al. Mechanisms of relaxant action ofS-Petasin and S-Isopetasin, Sesquiterpenesof Petasites formosanus, in isolated Guineapig trachea. Planta Med. 2001;67:224-29.

12. Wang GJ et al. Calcium channel blockade invascular smooth muscle cells: majorhypotensive mechanism of S-Petasin, ahypotensive sesquiterpene from Petasitesformosanus. J Pharmacol exp Ther.2001;297:240-246.

13. Hänsel R et al. Pharmakognosie-Phytopharmazie, Springer Verlag,6.Aufl.1999.

14. Habs M et al. Risikobewertungpyrrolizidinhaltiger Arzneistoffe. DeutscheApothekerzeitung. 1992 Sept; 132(38):1939-43.

15. Grossmann M, Schmidramsel H. An extractof Petasites hybridus is effective in theprophylaxis of migraine. Int J Clin PharmacolTher. 2000(9);38:430-35.

16. Tfelt-Hansen P et al. Timolol vs propranololvs placebo in common migraineprophylaxis: a double-blind multicenter trial.Acta Neurol Scand. 1984;69:1-8.

17. Sorensen PS et al. A placebo-controlled,double-blind, cross-over trial of flunarizine incommon migraine. Cephalgia. 1986;6:7-14.

18. Sheftell F et al. Montelukast in theprophylaxis of migraine: A potential role forleukotriene modifiers. Headache.2000;40:158-163.

19. Bommer S et al. Wirksamkeit undVerträglichkeit von Petadolor N. Einemultizentrische, prospektive Praxisstudie beiPatienten mit Kopfschmerzen, Zervikal- undLumbalsyndrom. Schweiz. Zschr.Ganzheitsmedizin.1995;5:254-56.

20. Gruia FS. Zur biologischenSchmerzbekämpfung. Ergebnisse einerPraxisstudie am Beispiel einesPhytotherapeutikums. Erfahrungsheilkunde.1986(6); 35:396-401.

21. Aebi A et al. Inhaltsstoffe von Petasiteshybridus (L) Fl.Wett. Pharmaceutica ActaHelvetiae.1955;29:277-279.

22. Bauer HW, Kühne P. Therapie vonHarnleiterkoliken mit einem neuenSpasmoanalgetikum. Therapiewoche. 1986(9);36:3765-59.

23. Barsom S. Behandlung von Koliken undSpasmen in der Urologie mit einempflanzlichen Spasmolytikum.Erfahrungsheilkunde.1986 (11);35:1-11.

24. Meier B. Die Pestwurz – Stand derForschung. Zeitschrift für Phytotherapie.1994;15:268-284.

25. Ziolo G, Samochowiec L. Study on clinicalproperties and mechanisms of action of

Petasites in bronchial asthma and chronicobstructive bronchitis. Pharmaceutica ActaHelvetiae. 1998;72:359-380.

26. Ko WC et al. Relaxant effects of Petasin inisolated guinea pig trachea an theirstructure-activity relationships. Planta Medica.2000;66:650-52.

27. Schapowal A. Randomised controlled trial ofbutterbur and cetirizine for treating seasonalallergic rhinitis. BMJ 2002;324:1-4.

28. Zingarelli B et al. Effects of zileuton, a new 5-lipoxygenase inhibitor, in experimentallyinduced colitis in rats. AgentsActions.1993;93:150-156.

29. Kim JH et al. Levels of Peptidoleukotriene E4are elevated in active Crohn’s disease. JPediatr Gastroenterol Nutr. 1995;20:403-407.

30. Harris RR et al. Clinical activity of leukotrieneinhibitors. Int J Immunopharmac.1995;17(2):147-156.

31. Zhu Y, Stiller MJ. Preview of potentialtherapeutic applications of leukotriene B4inhibitors in dermatology. Skin PharmacolAppl Skin Physiol. 2000;13:235-245.

32. Göbel H et al. Spezialextrakt ausPetasitesrhizom ist wirksam in derMigräneprophylaxe : Eine randomisierte,multizentrische, doppelblinde,placebokontrollierte Parallelgruppenstudie.Abstract. Der Schmerz 2001 Okt;15(Supplement 1).

33. Brune K et al. Gastro-protective effects byextracts of Petasites hybridus: the role ofinhibition of petptido-leukotriene synthesis.Planta Med. 1993;59:494-496.

34. Teschke R. Toxische Lebererkrankungen:Alkohol, Arzneimittel, Gewerbe- undNaturtoxine. Georg Thieme Verlag, 2001.


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I m p r e s s u mCopyright Bioforce AG,Grünaustrasse/Postfach 76, 9325 RoggwilMay 2002

Author: Dr. med. Peter KälinGeneral medicine FMHDipl. Natw. ETHMedical AdvisorTel. 071 454 61 61. E-mail [email protected]

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