Petasites / Groot hoefblad onderzoek

Groot hoefblad

De wortelstok van groot hoefblad (Petasites hybridus), een inheemse Europese plant, wordt al meer dan 2000 jaar gebruikt als geneeskrachtig middel bij ontstekingsziekten. De werkzame bestanddelen zijn petasines (sesquiterpenen). Uit in-vitro studies blijkt dat het vetoplosbare extract van de wortelstok van groot hoefblad de vorming en afgifte van PGE2 en leukotriënen door ontstekingscellen dosisafhankelijk remt.15-17 Het extract is een natuurlijke COX-2- en lipoxygenaseremmer. Ook zijn er aanwijzingen dat groot hoefblad degranulatie van ontstekingscellen remt waardoor minder histamine vrijkomt.

In een klinische studie werd een commercieel preparaat van groot hoefblad (Ze339, gestandaardiseerd op 8 mg petasine per tablet, dosis 4 tabletten per dag) vergeleken met cetirizine bij 125 patiënten met hooikoorts. Het extract van groot hoefblad werkte even goed als het antihistaminicum, maar had in tegenstelling tot het antihistaminicum geen bijwerkingen zoals vermoeidheid en sufheid. Petasites hybridus was ook effectief in een provocatietest met adenosinemonofosfaat (AMP), dat model staat voor een aanval van hooikoorts en wordt gebruikt om de effectiviteit van antihistaminica te testen.19 AMP zorgt voor degranulatie van mestcellen waarbij histamine, leukotriënen en prostaglandines vrijkomen.
In een prospectieve, gerandomiseerde, dubbelblinde studie met 330 mensen met hooikoorts werd het effect van groot hoefbladextract (Ze339, 3x1 tablet per dag) vergeleken met fexofenadine en placebo. Het kruid en medicijn waren even effectief (geen significant verschil) en waren significant beter dan placebo in het verminderen van klachten van hooikoorts.
Een andere klinische studie uit 2004 liet zien dat het effect op hooikoortsklachten dosisafhankelijk is (2 of 3 tabletten per dag). Groot hoefbladextract is effectief bij hooikoorts en is daarmee een uitstekend alternatief voor reguliere medicatie. Het middel wordt goed verdragen en heeft geen bijwerkingen. 

Fiebich BL, Grozdeva M, Hess S et al. Petasites hybridus extracts in vitro inhibit COX-2 and PGE2 release by direct interaction with the enzyme and by preventing p42/44 MAP kinase activation in rat primary microglial cells. Planta Med. 2005;71(1):12-9.
Brune K, Bickel D, Peskar BA. Gastro-protective effects by extracts of Petasites hybridus: the role of inhibition of peptido-leukotriene synthesis. Planta Med. 1993;59(6):494-6.
Thomet OA, Wiesmann UN, Schapowal A et al. Role of petasin in the potential anti-inflammatory activity of a plant extract of petasites hybridus. Biochem Pharmacol. 2001;61(8):1041-7.Schapowal A; Petasites Study Group. Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis. BMJ. 2002;324(7330):144-6.
Lee DK, Carstairs IJ, Haggart K et al. Butterbur, a herbal remedy, attenuates adenosine monophosphate induced nasal responsiveness in seasonal allergic rhinitis. Clin Exp Allergy. 2003;33(7):882-6.
Schapowal A; Study Group. Treating intermittent allergic rhinitis: a prospective, randomized, placebo and antihistamine-controlled study of Butterbur extract Ze 339. Phytother Res. 2005;19(6):530-7.
Kaufeler R, Polasek W, Brattstrom A et al. Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: postmarketing surveillance study. Adv Ther. 2006;23(2):373-84.


 Petasites Research Update. 

 Quantitative analysis of petasin and pyrrolizidine alkaloids in leaves and rhizomes of in situ grown Petasites hybridus plants.:Planta Med. 1998 Apr;64(3):264-7.Wildi E, Langer T, Schaffner W, B¨¹ter KB.Universit?t Basel, Institut f¨¹r Pharmazie--Pharmazeutische Biologie, Witterswil, Switzerland. ewildi@bgumail.bgu.ac.il 

Various locations in Switzerland were screened for Petasites hybridus plants with high petasin and low pyrrolizidine alkaloid content. The mean petasin content of the various populations ranged from 7.4 to 15.3 mg/g dry weight in rhizomes and from 3.3 to 11.4 mg/g dry weight in leaves. Mean pyrrolizidine alkaloid content in rhizomes ranged from 5 to 90 ppm whereas leaves contained between 0.02 to 1.50 ppm. These results suggest that leaves might be a preferable source for harvesting compared to the underground organ due to the finding of high petasin contents and consistently lower amounts of toxic pyrrolizidine alkaloids. 

 Effectiveness of Petasites hybridus preparations in the prophylaxis of migraine: a systematic review.:Phytomedicine. 2006 Nov;13(9-10):743-6. Epub 2006 Sep 20. Review.Agosti R, Duke RK, Chrubasik JE, Chrubasik S.Headache Center Hirslanden, M¨¹nchhaldenstr. 33, 8008 Z¨¹rich, Switzerland. reto.agosti@kopfwww.ch 

The objective of this review was to evaluate the strength of evidence of effectiveness for Petasites hybridus in the prophylaxis of migraine. Several databases and other sources were searched to identify randomised-controlled trials investigating P. hybridus preparations. Two trials totalling 293 patients (60 and 233 patients) were included in this review. Both trials investigated the proprietary Petasites root extract Petadolex. The trials were described in narrative way, taking into consideration methodological quality scores. Pooling of data was not carried out due to the heterogeneity of the results. The extract at higher dose (150 mg) showed a greater decreased frequency of migraine attacks and a greater number of responders (improvement>50%) after treatment over 3-4 months than the extract at lower dose (100 mg) and placebo. Moderate evidence of effectiveness is, thus, available for a higher than the recommended dose of the proprietary Petasites root extract Petadolex in the prophylaxis of migraine. Further rigorous studies are required to confirm effectiveness and safety in long-term use before treatment with Petasites root extract can be recommended as an alternative option in the treatment schedule for the prophylaxis of migraine. 

 An approach to the inheritance of the sesquiterpene chemotypes within Petasites hybridus.:Planta Med. 2006 Oct;72(13):1254-6. Epub 2006 Sep 18.Chizzola R, Langer T, Franz C.Institute for Applied Botany and Pharmacognosy, Department of Veterinary Public Health, University of Veterinary Medicine, Veterinaerplatz 12, 1210 Vienna, Austria. Remigius.Chizzola@vu-wien.ac.at 

Sesquiterpene esters are the active principle in the medicinal plant Petasites hybridus. Two chemotypes, the petasin chemotype and the furanopetasin chemotype, are known, but only the first one is suitable for pharmaceutical purposes. Experimental crossings were performed within and between plants of both chemotypes to study the genetic basis of the occurrence of these sesquiterpenes. The chemotype was determined by TLC in extracts of a small piece of rhizome in the parent plants and the progenies. A model including the combined action of two genes is proposed to explain the inheritance of the chemotypes where the furanopetasin chemotype is under recessive genetic control. 

 Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: postmarketing surveillance study.:Adv Ther. 2006 Mar-Apr;23(2):373-84.K?ufeler R, Polasek W, Brattstr?m A, Koetter U.Max Zeller Sohne AG, Romanshorn, Switzerland. 

The efficacy and safety of the butterbur leaf extract Ze 339 (carbon dioxide extract from the leaves of Petasites hybridus L., 8 mg petasines per tablet) were tested in patients with seasonal allergic rhinitis. In an open postmarketing surveillance study, 580 patients were treated with an average of 2 tablets of Ze 339 daily for 2 weeks. Symptoms of rhinorrhea, sneezing, nasal congestion, itchy eyes and nose, red eyes, and skin irritation were evaluated on a visual analogue scale. Symptoms of seasonal allergic rhinitis improved in 90% of patients. Differences observed before and after therapy were significant and clinically relevant for all symptoms. Improvement reported by the end of the study was found to be inversely related to symptom severity as described at baseline. Efficacy, tolerability, and improvement in quality of life were positively rated by 80%, 92%, and 80% of patients, respectively. A total of 44% of patients were given an antiallergic comedication. This combination did not result in a better effect than was attained with Ze 339 monotherapy. Adverse events occurred at a rate of 3.8%, and gastrointestinal complaints were predominantly nonspecific. Results of this postmarketing surveillance trial are consistent with observations documented in previous randomized, double-blind, prospective, controlled trials of the same extract that were conducted according to Good Clinical Practice (GCP). Butterbur leaf special extract Ze 339 was confirmed by 3 GCP trials and 2 postmarketing surveillance trials to be safe and efficacious in the treatment of patients with seasonal allergic rhinitis. 

 Petasites hybridus extracts in vitro inhibit COX-2 and PGE2 release by direct interaction with the enzyme and by preventing p42/44 MAP kinase activation in rat primary microglial cells.:Planta Med. 2005 Jan;71(1):12-9.Fiebich BL, Grozdeva M, Hess S, H¨¹ll M, Danesch U, Bodensieck A, Bauer R.University of Freiburg Medical School, Dept. of Psychiatry and Psychotherapy, Freiburg, Germany. 

Rhizomes of butterbur, Petasites hybridus L. (Asteraceae), have been used since ancient times for the treatment of inflammatory diseases. In the present study, the effects of lipophilic extracts from rhizomes of Petasites hybridus on the formation and release of prostaglandin E2 were investigated. The extracts had different contents of petasin and isopetasin: A: 2.1 % and 0.4 %, B: 0.2 % and 0.1 %, C: 12.1 % and 6.1 % and D: 21.9 % and 9.4 %, respectively. Direct inhibition of cyclooxygenase (COX) -1 and -2 isoenzymes and inhibition of the expression of COX-2 and p42/44 MAP kinase in rat primary microglial cells were tested. All extracts were found to be only weak direct inhibitors of COX-1 (IC50> 400 microg/mL). However, most extracts revealed a strong inhibitory activity against the inducible isoform COX-2 ( A: IC50=30.4 microg/mL; B: IC50=60.6 microg/mL; C: IC50=22.6 microg/mL; D: IC50=20.0 microg/mL). This activity was not correlated to the content of petasin and isopetasin. Pure petasin and isopetasin neither inhibited COX-1 nor COX-2 (IC50 > 400 microM for both compounds and enzymes). Petasites extracts dose-dependently inhibited LPS-induced and thus COX-2-mediated PGE2 release in primary rat microglial cells (A: IC50= 2.4 microg/mL; C: IC50=5.8 microg/mL and D: IC50=4.6 microg/mL). Also this effect was independent from the petasin and isopetasin content. COX-2 synthesis in microglia was totally blocked with 5 microg/mL of C whereas COX-1 synthesis was not influenced. C and D did not affect the LPS-induced activation of p38 MAPK and IkappaBalpha, but they prevented the LPS-induced activation of p42/44 MAPK. Therefore, these Petasites hybridus extracts can be regarded as natural selective inhibitors of COX-2 and its expression, an effect which is independent from the petasin content. 


 Petasites hybridus root (butterbur) is an effective preventive treatment for migraine.:Neurology. 2004 Dec 28;63(12):2240-4.Lipton RB, G?bel H, Einh?upl KM, Wilks K, Mauskop A.Department of Neurology, Albert Einstein College of Medicine, 1165 Morris Park Ave., Rousso Bldg., Rm. 332, Bronx, NY 10461, USA. rlipton@aecom.yu.edu 

OBJECTIVE: To evaluate the clinical efficacy of a standardized special root extract from the plant Petasites hybridus as a preventive therapy for migraine. METHODS: This is a three-arm, parallel-group, randomized trial comparing Petasites extract 75 mg bid, Petasites extract 50 mg bid, or placebo bid in 245 patients with migraine. Eligible patients met International Headache Society criteria for migraine, were ages 18 to 65, and had at least two to six attacks per month over the preceding 3 months. The main outcome measure was the decrease in migraine attack frequency per month calculated as percentage change from baseline over a 4-month treatment period. RESULTS: Over 4 months of treatment, in the per-protocol analysis, migraine attack frequency was reduced by 48% for Petasites extract 75 mg bid (p = 0.0012 vs placebo), 36% for Petasites extract 50 mg bid (p = 0.127 vs placebo), and 26% for the placebo group. The proportion of patients with a > or =50% reduction in attack frequency after 4 months was 68% for patients in the Petasites extract 75-mg arm and 49% for the placebo arm (p < 0.05). Results were also significant in favor of Petasites 75 mg at 1, 2, and 3 months based on this endpoint. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events, predominantly burping. CONCLUSIONS: Petasites extract 75 mg bid is more effective than placebo and is well tolerated as a preventive therapy for migraine. Petasites 50 mg PO bid was not significantly more effective than placebo on the primary study endpoints. 

 Effects of butterbur treatment in intermittent allergic rhinitis: a placebo-controlled evaluation.:Ann Allergy Asthma Immunol. 2004 Jul;93(1):56-60.Gray RD, Haggart K, Lee DK, Cull S, Lipworth BJ.Asthma & Allergy Research Group, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland. 

BACKGROUND: Butterbur (Petasites hybridus) contains the active ingredient petasin, which exhibits antileukotriene and antihistamine activity. Previous studies of intermittent allergic rhinitis (IAR) have demonstrated a comparable response to butterbur compared with a histamine H1-receptor antagonist on the 36-Item Short-Form Health Survey quality-of-life score. However, there has been no placebo-controlled study of the effects of butterbur use on objective and subjective outcomes in IAR. OBJECTIVE: To evaluate the effects of treatment with butterbur vs placebo on objective and subjective outcomes in IAR. METHODS: A double-blind, placebo-controlled, crossover study was carried out during the grass pollen season in Tayside, Scotland. Thirty-five patients (14 men and 21 women) with IAR received butterbur, 50 mg twice daily, or placebo for 2 weeks. Domiciliary measurements were taken in the morning and evening for peak nasal inspiratory flow (PNIF) (the primary outcome variable), nasal and eye symptoms, and rhinoconjunctivitis-specific quality-of-life score. RESULTS: Butterbur treatment had no significant effect on PNIF, total nasal symptom score, eye symptom score, or quality of life compared with placebo use. Mean (SEM) morning and evening PNIF values were 107 (6) and 114 (6) L/min, respectively, for butterbur vs 105 (6) and 117 (6) L/min for placebo. Mean (SEM) morning and evening total nasal symptom scores (maximum total score, 12) were 3.4 (0.4) and 3.5 (0.4), respectively, for butterbur vs 3.7 (0.3) and 3.8 (0.4) for placebo. CONCLUSIONS: There was no significant clinical efficacy of butterbur use vs placebo use on objective and subjective outcomes in IAR. Further studies are now indicated to investigate the use of butterbur in persistent allergic rhinitis. 

 Effects of S-petasin on cyclic AMP production and enzyme activity of P450scc in rat zona fasciculata-reticularis cells.:Eur J Pharmacol. 2004 Apr 5;489(1-2):29-37.Chang LL, Wun WS, Lin YL, Wang PS.Department of Chemical Engineering, Chinese Culture University, Shih-Lin, Taipei 111, Taiwan, ROC. llchiang@staff.pccu.edu.tw 

Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of P. hybridus, which has been used to relieve gastrointestinal pain, lung disease, and spasms of urogenital tract. We have demonstrated that S-petasin inhibited corticosterone release from rat zona fasiculata-reticularis cells. However, the mechanism and molecular effects of S-petasin on zona fasiculata-reticularis cells are still unclear. This study explored the effects of S-petasin on cellular adenosine 3':5'-cyclic monophosphate (cAMP) production, the functions of steroidogenic enzymes including cytochrome P450 side-chain cleavage enzyme (P450scc), 11beta-hydroxylase, and the expression levels of steroidogenic acute regulatory protein or P450scc. In this experiment, zona fasciculata-reticularis cells were incubated with S-petasin in the presence or absence of adrenocorticotropin (ACTH), 8-bromo-adenosine 3':5'-cyclic monophosphate (8-Br-cAMP), forskolin, 25-OH-cholesterol, deoxycorticosterone at 37 degrees C for 0.5, 1 or 3 h. The media were used to measure the concentration of corticosterone or pregnenolone by radioimmunoassay. The cells were used to measure the content of cAMP by radioimmunoassay and extracted protein for Western blot or messenger RNA (mRNA) for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Our data demonstrated that (1) S-petasin inhibits ACTH- or forskolin-stimulated cellular cAMP production, (2) S-petasin increased the Michaelis constants of P450scc and 11beta-hydroxylase and (3) S-petasin decreased the expression levels and mRNA of steroidogenic acute regulatory protein. In summary, the actions of S-petasin mediate the inhibition of cAMP formation, decrease the activities of key enzymes P450scc and 11beta-hydroxylase, and reduce mRNA of steroidogenic acute regulatory protein and expression of steroidogenic acute regulatory protein. 

 Petasites hybridus (Butterbur root) extract in the treatment of asthma--an open trial.:Altern Med Rev. 2004 Mar;9(1):54-62.Danesch UC.University of Heidelberg, Germany. 

The efficacy and tolerability of a butterbur root extract (Petadolex) for the treatment of asthma was analyzed in a prospective, non-randomized, open trial. Subjects included 64 adults and 16 children/adolescents treated for two months with the extract, followed by two months during which the intake of the extract was optional. Concomitant asthma medication was permitted. The number, duration, and severity of asthma attacks decreased, while peak flow, forced expiratory volume (FEV1), and all measured symptoms improved during therapy. In addition, more than 40 percent of patients using asthma medications at baseline reduced intake of these medications by the end of the study. This study suggests the Petasites hybridus extract Petadolex is an effective and safe therapy for the treatment of asthma. 

 The effects of butterbur on the histamine and allergen cutaneous response.:Ann Allergy Asthma Immunol. 2004 Feb;92(2):250-4.Jackson CM, Lee DK, Lipworth BJ.Tayside Centre for General Practice, University of Dundee, Dundee, Scotland. 

BACKGROUND: Butterbur or Petasites hybridus is an herbal remedy that exhibits antihistamine and antileukotriene activity and has been shown to attenuate the response to adenosine monophosphate challenge in patients with allergic rhinitis and asthma. However, no data are available regarding its effects on the histamine and allergen cutaneous response. OBJECTIVE: To evaluate the effects of butterbur compared with fexofenadine and montelukast on the histamine and allergen wheal and flare cutaneous responses. METHODS: Atopic patients were randomized into a double-blind, double-dummy, crossover study to receive for 1 week butterbur, 50 mg twice daily (8 AM and 10 PM); fexofenadine, 180 mg once daily (10 PM), and placebo once daily (8 AM); montelukast, 10 mg once daily (10 PM), and placebo once daily (8 AM); or placebo twice daily (8 AM and 10 PM). Patients attended the department at 10 AM and had measurements of the cutaneous wheal and flare responses to histamine, allergen, and saline control at 10-minute intervals for 60 minutes. RESULTS: Twenty patients completed the study. The mean +/- SE histamine wheal and flare responses, respectively, were significantly attenuated (P < .05) by fexofenadine (9.4 +/- 1.8 mm2 and 13.5 +/- 3.2 mm2) compared with placebo (15.5 +/- 3.3 mm2 and 179.8 +/- 74.3 mm2) but not by butterbur (16.4 +/- 2.1 mm2 and 297.7 +/- 121.2 mm2) or montelukast (19 +/- 1.9 mm2 and 240.2 +/- 66.6 mm2). The allergen wheal and flare responses, respectively, were also significantly attenuated (P < .05) by fexofenadine (31.1 +/- 6.3 mm2 and 256.9 +/- 86.5 mm2) compared with placebo (65.4 +/- 15.2 mm2 and 1,014.5 +/- 250.0 mm2) but not by butterbur (50.4 +/- 9.2 mm2 and 1,110.3 +/- 256.1 mm2) or montelukast (58.8 +/- 9.1 mm2 and 1,463.6 +/- 295.6 mm2). CONCLUSIONS: Butterbur did not produce any significant effects on the histamine and allergen cutaneous response compared with placebo, whereas mediator antagonism with fexofenadine but not montelukast produced significant attenuation. This finding would suggest that butterbur may not be effective in allergic skin disease. 


 Petasites--Zeller: ZE 339.:Drugs R D. 2003;4(6):378-9. Review. 

The Swiss company Zeller is developing an extract of the plant Petasites hybridus (butterbur) as an antiallergic agent. Petasites hybridus extracts have been known for some time to have therapeutic properties. Zeller's extract is codenamed ZE 339. In in vitro studies, ZE 339 inhibited cysteinyl-leukotriene synthesis in eosinophils and leukotriene B4 synthesis in neutrophils. In mid-2003, ZE 339 was approved, and launched, in Switzerland as Tesalin for the treatment of seasonal allergic rhinitis as a prescription-only product. Tesalin is available as film-coated tablets. Zeller has stated that hepatotoxicity cannot be totally excluded as a possible adverse reaction to Tesalin. 

 Review of complementary and alternative medicine in treatment of ocular allergies.:Curr Opin Allergy Clin Immunol. 2003 Oct;3(5):395-9.Bielory L, Heimall J.Department of Medicine, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA. bielory@umdnj.edu 

PURPOSE OF REVIEW: Ocular allergy is a common complaint of allergy sufferers, many of whom may choose to use complementary and alternative medicine in the treatment of these symptoms. In this review major complementary and alternative medicine modalities including herbal therapies, acupuncture, homeopathy, alternative immunotherapy and behavior modification are assessed for evidence of their effectiveness in the treatment of ocular allergy symptoms. RECENT FINDINGS: Certain herbs including Euphrasia officinalis, Petasites hybridus and Argemone mexicana have been evaluated in control studies in the treatment of ocular allergy. Honey is no more effective than placebo in the treatment of ocular allergy. Acupuncture used regularly has demonstrated some positive trends in ocular allergy sufferers. Homeopathy has shown conflicting results in the treatment of ocular allergy, while alternative forms of immunotherapy have been shown to develop immunologic tolerogenic effects in the control of the condition. SUMMARY: Several forms of complementary and alternative medicine have been studied for their effectiveness in treatment of ocular allergy symptoms. Further research is needed to assess mechanisms of action and to establish practice guidelines for the use of these modalities 

 Butterbur, a herbal remedy, attenuates adenosine monophosphate induced nasal responsiveness in seasonal allergic rhinitis.:Clin Exp Allergy. 2003 Jul;33(7):882-6.Lee DK, Carstairs IJ, Haggart K, Jackson CM, Currie GP, Lipworth BJ.Asthma & Allergy Research Group, Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland, UK

BACKGROUND: Butterbur (BB) or Petasites hybridus, a herbal remedy, exhibits in vitro inhibition of cysteinyl leukotriene biosynthesis. However, no placebo-controlled studies have been performed to evaluate the effectiveness of BB on objective outcomes such as nasal provocation testing in seasonal allergic rhinitis (SAR). METHODS: Twenty patients with grass-pollen-sensitized SAR were randomized in a double-blind, cross-over manner to receive for 2 weeks either BB 50 mg twice daily or placebo (PL) twice daily during the grass pollen season. Nasal adenosine monophosphate (AMP) challenge (the primary outcome) was administered as a single 400 mg/mL dose after each randomized treatment. RESULTS: Spontaneous recovery following AMP challenge (area under the response time profile curve as % x min+/-SEM) was significantly attenuated (P=0.028) with BB (584+/-289) compared to PL (1438+/-240); mean difference: 854 (95% CI 95-1614), and the maximum % peak nasal inspiratory flow reduction from baseline following AMP challenge was significantly blunted (P=0.036) with BB (30+/-4) compared to PL (43+/-5); mean difference: 13 (95% CI 1-25). CONCLUSIONS: BB exhibited protection against AMP-induced nasal responsiveness during the grass pollen season in sensitized patients. This is turn may explain its potential clinical efficacy in patients with SAR. 

 Effects of S-petasin on corticosterone release in rats.:Chin J Physiol. 2002 Dec 31;45(4):137-42.Chang LL, Tseng YC, Lin YL, Wun WS, Wang PS.Department of Chemical Engineering, Chinese Culture University, Shih-Lin, Taipei, Taiwan, Republic of China. llchiang@staff.pccu.edu.tw 

Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of Petasites hybridus. S-petasin has been used to relieve gastrointestinal pain, lung disease, and spasms of the urogenital tract. However, the side effect of S-petasin on endocrine systems are still not clear. This study explored the effects of S-petasin on the release of corticosterone in vivo and in vitro. An intravenous injection of S-petasin (10 microg/kg) decreased both basal and adrenocorticotropin (ACTH)-induced plasma corticosterone concentration in male rats. In vitro, S-petasin (3 x 10(-6) - 10(-4) M) caused a significant reduction of basal and ACTH-stimulated release of corticosterone from the enzymatically dispersed rat zona fasciculata-reticularis (ZFR) cells in a dose-dependent manner. In order to study possible mechanisms, ZFR cells were incubated with S-petasin (10(-5) M) in the presence or absence of forskolin (adenylate cyclase activator, 10(-6) - 10(-4) M), 8-Br-cAMP (a cAMP analogue, 10(-6) 10(-4) M), 25-OH-cholesterol (pregnenolone biosynthesis precursor, 10(-5) M) combined with trilostane (a blocker of 3beta-hydroxysteriod dehydrogenase, 3beta-HSD, 10(-6) M) and deoxycorticosterone (corticosterone biosynthesis precursor, 10(-9) - 10(-6) M) at 37 degrees C for 1h. The concentration of pregnenolone and corticosterone in media were measured by radioimmunoassay. The stimulatory effects of corticosterone secretion induced by forskolin (10(-5) - 10(-4) M), 8-Br-cAMP (10(-5) - 10(-4) M) and deoxycorticosterone (10(-7) - 10(-6) M) were reduced by S-petasin at 10(-5) M. The stimulatory effects of pregnenolone secretion induced by 25-OH-cholesterol combined with or without trilostane was reduced by S-petasin at 10(-5) M. These results suggest that S-petasin inhibits the production of corticosterone from rat ZFR cells in part through decreasing the activities of adenylyl cyclase, P450scc and 11beta-hydroxylase. 

 The common butterbur (Petasites hybridus)--portrait of a medicinal herb.:Forsch Komplementarmed Klass Naturheilkd. 2003 Apr;10 Suppl 1:41-4. Review. German.K?lin P.Bioforce AG, Roggwil. 

For hundreds of years butterbur (Petasites hybridus) has been used against many diseases. Modern indications are the prophylaxis of migraine, tension headache, spasms of the urogenital tract, gastro-intestinal tract and bile duct and hopefully hay fever and asthma in the near future. The petasines, the main components of butterbur, inhibit the synthesis of leucotrienes and decrease the intracellular concentration of calcium which explains the anti-inflammatory and spasmolytic properties of extracts of butterbur. Thanks to extraction with supercritical CO(2) the concentrations of the potentially hepatotoxic and carcinogenic pyrrolizidine alkaloids lie below the detection limits. Until now four cases of a reversible cholestatic hepatitis have been probably associated with long-term administration of butterbur (incidence of 1:175.000). It is unknown which components of butterbur are responsible for the long-term hepatotoxicity. Further side effects involve the gastrointestinal tract and are usually mild. 


 Petasins in the treatment of allergic diseases: results of preclinical and clinical studies.:Int Arch Allergy Immunol. 2002 Oct;129(2):108-12. Review.Thomet OA, Simon HU.Department of Pharmacology, University of Bern, Switzerland. 

Plant extracts are causing an increased interest in the treatment of many chronic diseases, including asthma and other allergic diseases. Several laboratories characterized petasins (petasin, isopetasin, and neopetasin) isolated from extracts of butterbur (Petasites hybridus) as pharmacologically active components, which inhibit leukotriene synthesis in leukocytes. The molecular mechanisms by which petasins abrogate inflammatory effector cell functions have, at least partially, been identified. In vitro studies revealed that petasins may have several intracellular targets and this may depend on the stereoisomer used. In an open clinical trial in patients suffering from allergic rhinitis, a reduction of leukotriene and histamine levels in nasal fluids was associated with the butterbur extract administration. To better evaluate the clinical value in this particular allergic disease, the clinical efficacy of the drug was compared with an established antihistamine treatment scheme in a double-blind study; no significant difference was observed between the two treatment groups. In this article, we critically review recently published work and summarize the current stage in the pharmacological characterization of butterbur extracts. 

 Anti-inflammatory activity of an extract of Petasites hybridus in allergic rhinitis.:Int Immunopharmacol. 2002 Jun;2(7):997-1006.Thomet OA, Schapowal A, Heinisch IV, Wiesmann UN, Simon HU.Department of Pharmacology University of Bern, Switzerland. 

Previous studies have suggested that histamine and leukotrienes (LTs) play an important pathobiological role in IgE-mediated allergic diseases. In vitro studies suggested that an extract of Petasites hybridus (Ze339) blocks LT synthesis in monocytes and granulocytes. Petasins are considered to be the pharmacologically active fraction within Ze339. Patients suffering from allergic rhinitis received three times a day two tablets of Ze339 standardized to 8 mg petasins within a time period of 1 week. After 5 days of treatment, Ze339 significantly improved primary end points, which were day- and nighttime nasal symptoms. Nasal resistance, which was measured by rhinomanometry, gradually decreased as a consequence of Ze339 treatment reaching normal levels after 5 days (rhinomanometry: from 403.5+/-62.0 to 844.8+/-38.8 ml). Levels of inflammatory mediators in nasal fluids and serum were measured 90 min after drug administration every day in the morning. After 5 days of treatment, a significant reduction of histamine (from 153.7+/-32.1 to 53.0+/-8.4 pg/ml) and LT levels (LTB4: from 313.1+/-46.5 to 180.6+/-32.2 pg/ml; cysteinyl-LT: from 137.0+/-42.2 to 70.1+/-16.5 pg/ml) could be observed. Moreover, quality-of-life scores significantly improved. The drug had no effect on the distribution of lymphocyte subpopulations in the blood as well as on the capacity of blood leukocytes to generate cytokines and lipid mediators. These results suggest that Ze339 is effective in treating allergic rhinitis patients by decreasing levels of nasal inflammatory mediators. 


 Sesquiterpene constituents in Petasites hybridus.:Phytochemistry. 2002 Apr;59(8):795-803.Saritas Y, von Reuss SH, K?nig WA.Institut f¨¹r Organische Chemie, Universit?t Hamburg, Martin-Luther-King-Platz 6, D-20146, Hamburg, Germany. 

The essential oil of the rhizomes of Petasites hybridus (Asteraceae) was investigated by gas chromatography, mass spectrometry, 1- and 2-dimensional NMR techniques and chemical correlations. Two new sesquiterpene hydrocarbons, petasitene and pethybrene, could be identified. Petasitene is the parent sesquiterpene hydrocarbon to the known norsesquiterpene albene. The absolute configuration of petasitene could be assigned by conversion of natural albene to petasitene by partial synthesis. Pethybrene is a tricyclic sesquiterpene hydrocarbon, which rearranges to the structurally related alpha-isocomene under acidic conditions. Several sesquiterpenes were isolated from the hydrodistillation products of Petasites hybridus and investigated by spectroscopic methods and chemical correlations 

 Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis.:BMJ. 2002 Jan 19;324(7330):144-6.Schapowal A; Petasites Study Group.Allergy Clinic, Hochwangstrasse 3, CH-7302 Landquart, Switzerland. andreas.schapowal@freesurf.ch 

OBJECTIVES: To compare the efficacy and tolerability of butterbur (Petasites hybridus) with cetirizine in patients with seasonal allergic rhinitis (hay fever). DESIGN: Randomised, double blind, parallel group comparison. SETTING: Four outpatient general medicine and allergy clinics in Switzerland and Germany. PARTICIPANTS: 131 patients were screened for seasonal allergic rhinitis and 125 patients were randomised (butterbur 61; cetirizine 64). INTERVENTIONS: Butterbur (carbon dioxide extract tablets, ZE 339) one tablet, four times daily, or cetirizine, one tablet in the evening, both given for two consecutive weeks. MAIN OUTCOME MEASURES: Scores on SF-36 questionnaire and clinical global impression scale. RESULTS: Improvement in SF-36 score was similar in the two treatment groups for all items tested hierarchically. Butterbur and cetirizine were also similarly effective with regard to global improvement scores on the clinical global impression scale (median score 3 in both groups). Both treatments were well tolerated. In the cetirizine group, two thirds (8/12) of reported adverse events were associated with sedative effects (drowsiness and fatigue) despite the drug being considered a non-sedating antihistamine. CONCLUSIONS: The effects of butterbur are similar to those of cetirizine in patients with seasonal allergic rhinitis when evaluated blindly by patients and doctors. Butterbur should be considered for treating seasonal allergic rhinitis when the sedative effects of antihistamines need to be avoided. 


 An extract of Petasites hybridus is effective in the prophylaxis of migraine.:Altern Med Rev. 2001 Jun;6(3):303-10.Grossman W, Schmidramsl H.Department of Neurology, Municipal Hospital, Munchen-Harlaching, Germany. 

OBJECTIVE: Migraine is still an unsolved problem. This clinical trial investigates the efficacy and tolerance of Petasites hybridus in the prophylaxis of migraine. METHODS: A randomized, group-parallel, placebo-controlled, double-blind clinical study was carried out with a special CO2 extract from the rhizome of Petasites hybridus. Following a four-week run-in phase, 60 patients received either the special Petasites hybridus extract Petadolex or placebo at a dosage of two capsules (each capsule contains 25 mg) twice daily over 12 weeks. Outcome variables included the frequency, intensity and duration of migraine attacks as well as any accompanying symptoms. RESULTS: The frequency of migraine attacks decreased by a maximum of 60 percent compared to the baseline. This reduction in migraine attacks with Petadolex was significant (p < 0.05) compared to placebo. No adverse events were reported. Petasites was exceptionally well tolerated. CONCLUSIONS: The results suggest that migraine patients can benefit from prophylactic treatment with this special extract. The combination of high efficacy and excellent tolerance emphasizes the particular value that Petasites hybridus has for the prophylactic treatment of migraine. 

 Monograph. Petasites hybridus.:Altern Med Rev. 2001 Apr;6(2):207-9. 

Petasides hybridus (butterbur) is a perennial shrub, found throughout Europe as well as parts of Asia and North America, that has been used medicinally for centuries. During the Middle Ages butterbur was used to treat plague and fever; in the 17th century its use was noted in treating cough, asthma, and skin wounds. The plant can grow to a height of three feet and is usually found in wet, marshy ground, in damp forests, and adjacent to rivers or streams. Its downy leaves can attain a diameter of three feet, making it the largest of all indigenous floras, and their unique characteristics are responsible for the plant's botanical and common names. The genus name, Petasites, is derived from the Greek word petasos, which is the felt hat worn by shepherds. The common name of butterbur is attributed to the large leaves being used to wrap butter during warm weather. Other common names include pestwurz (German), blatterdock, bog rhubarb, and butter-dock. Currently, the primary therapeutic uses for butterbur are for prophylactic treatment of migraines, and as an anti-spasmodic agent for chronic cough or asthma. It has also been used successfully in preventing gastric ulcers, and in treating patients with irritable bladder and urinary tract spasms. 

 Role of petasin in the potential anti-inflammatory activity of a plant extract of petasites hybridus.:Biochem Pharmacol. 2001 Apr 15;61(8):1041-7.Thomet OA, Wiesmann UN, Schapowal A, Bizer C, Simon HU.Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland. 

A large production of leukotrienes (LTs) can be induced in human eosinophils or neutrophils by priming with granulocyte-macrophage colony-stimulating factor and subsequent stimulation with platelet-activating factor (PAF) or the anaphylatoxin C5a. Here, we investigated the effects of a plant extract of petasites hybridus (Ze339) and its isolated active sesquiterpene ester petasin in these two in vitro cell models. Zileuton, a 5-lipoxygenase inhibitor, was used as a positive control. All compounds inhibited both cysteinyl-LT synthesis in eosinophils and LTB(4) synthesis in neutrophils. In contrast, only Ze339 and petasin, but not zileuton, abrogated PAF- and C5a-induced increases in intracellular calcium concentrations. These data suggest that Ze339 and petasin may block, compared to zileuton, earlier signalling events initiated by G protein-coupled receptors in granulocytes, perhaps at the level of or proximal to phospholipase C(beta). Taken together, petasin appears to be one major active compound of petasites hybridus extract, since it demonstrates the same inhibitory activities on calcium fluxes and subsequent LT generation in both eosinophils and neutrophils as Ze339 does. 

 The etiologies, pathophysiology, and alternative/complementary treatment of asthma.:Altern Med Rev. 2001 Feb;6(1):20-47. Review.Miller AL.Thorne Research, Inc, Dover, ID 83825, USA. alan@thorne.com 

A chronic inflammatory disorder of the respiratory airways, asthma is characterized by bronchial airway inflammation resulting in increased mucus production and airway hyper-responsiveness. The resultant symptomatology includes episodes of wheezing, coughing, and shortness of breath. Asthma is a multifactorial disease process with genetic, allergic, environmental, infectious, emotional, and nutritional components. The underlying pathophysiology of asthma is airway inflammation. The underlying process driving and maintaining the asthmatic inflammatory process appears to be an abnormal or inadequately regulated CD4+ T-cell immune response. The T-helper 2 (Th2) subset produces cytokines including interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, and IL-13, which stimulate the growth, differentiation, and recruitment of mast cells, basophils, eosinophils, and B-cells, all of which are involved in humoral immunity, inflammation, and the allergic response. In asthma, this arm of the immune response is overactive, while Th1 activity, generally corresponding more to cell-mediated immunity, is dampened. It is not yet known why asthmatics have this out-of-balance immune activity, but genetics, viruses, fungi, heavy metals, nutrition, and pollution all can be contributors. A plant lipid preparation containing sterols and sterolins has been shown to dampen Th2 activity. Antioxidant nutrients, especially vitamins C and E, selenium, and zinc appear to be necessary in asthma treatment. Vitamins B6 and B12 also may be helpful. Omega-3 fatty acids from fish, the flavonoid quercetin, and botanicals Tylophora asthmatica, Boswellia serrata and Petasites hybridus address the inflammatory component. Physical modalities, including yoga, massage, biofeedback, acupuncture, and chiropractic can also be of help. 

 Inhibition of testosterone secretion by S-petasin in rat testicular interstitial cells.:Chin J Physiol. 2000 Sep 30;43(3):99-103.Lin H, Chien CH, Lin YL, Chen CF, Wang PS.Department of Physiology, School of Life Science, National Yang-Ming University, Taipei, Taiwan, ROC. 

S-petasin, a kind of sesquiterpene ester, is the anti-inflammatory ann analgesic component of the butterbur (Petasites hybridus). The clinical benefit of S-petasin is the spasmolytic activity, but its side effects on the reproductive endocrinology are not clear yet. The present study was to explore the effects of S-petasin on the secretion of testosterone in vivo and in vitro. We found that single intravenous injection of S-petasin (1 microg/kg) decreased basal plasma testosterone concentration in adult male rats. The enzymatically dispersed rat testicular interstitial cells were incubated with S-petasin (0-4.3 x 10(-5)M) in the presence or absence of human chorionic gonadotropin (hCG, 0.05 IU/ml), forskolin (adenylyl cyclase activator, 10(-5) M), and androstenedione (testosterone biosynthesis precursor, 10(-9) M) at 34 degrees C for 1 h. The concentrations of testosterone in the incubation medium were measured by radioimmunoassay. S-petasin at 4.3 x 10(-7) M was effective to reduce the basal and hCG-stimulated release of testosterone in rat testicular interstitial cells. The stimulatory effects of testosterone secretion induced by forskolin and androstenedione were significantly reduced by S-petasin at 4.3 x 10(-5) M and 4.3 x 10(-6) M, respectively. These results suggest that S-petasin inhibits the production of testosterone in rat testicular interstitial cells in part through diminishing the activities of adenylyl cyclase and 17-ketosteroid reductase. 


 An extract of Petasites hybridus is effective in the prophylaxis of migraine.:Int J Clin Pharmacol Ther. 2000 Sep;38(9):430-5.Grossmann M, Schmidramsl H.Department of Neurology, Municipal Hospital, M¨¹nchen-Harlaching, Germany. 

OBJECTIVE: Migraine is still an unsolved problem. This clinical trial investigates the efficacy and tolerance of Petasites hydridus in the prophylaxis of migraine. METHODS: A randomized, group-parallel, placebo-controlled, double-blind clinical study was carried out with a special CO2 extract from the rhizome of Petasites hybridus. Following a 4-week run-in phase, 60 patients received either the special Petasites hybridus extract petadolex or placebo at a dosage of 2 capsules (each capsule contains 25 mg) twice daily over 12 weeks. Outcome variables included the frequency, intensity and duration of migraine attacks as well as any accompanying symptoms. RESULTS: The frequency of migraine attacks decreased by a maximum of 60% compared to the baseline. This reduction in migraine attacks with petadolex was significant (p < 0.05) compared to placebo. No adverse events were reported. Petasites was exceptionally well tolerated. CONCLUSIONS: The results suggest that migraine patients can benefit from prophylactic treatment with this special extract. The combination of high efficacy and excellent tolerance emphasizes the particular value that Petasites hydridus has for the prophylactic treatment of migraine. 

 Variability in chemical constituents in Petasites hybridus from Austria.:Biochem Syst Ecol. 2000 Jun 1;28(5):421-432.Chizzola R, Ozelsberger B, Langer T.Institute for Applied Botany, University of Veterinary Medicine Vienna, Veterin?rplatz 1, A-1210, Vienna, Austria 

Petasites hybridus (Asteraceae), butter bur, is an ancient medicinal plant with spasmolytic sesquiterpene esters. Two chemotypes, the petasine and the furanopetasine chemotype, occur in Austria. The first one is considered as pharmaceutically useful due to its spasmolytic constituents, but it is restricted to the northern parts of the Alps. This use, however, is impaired by the presence of low amounts of toxic pyrrolizidine alkaloids (PA), mainly senecionine and intergerrimine. PA are usually concentrated in the metabolically active parts of the complex rhizome which are the thickenings just below the leaves. They are also present in flower stalks but are almost absent in leaf buds, the petioles and the leaf blades. The alkaloids showed a great variability within and between populations; the values recorded ranged from less than 2 to 500mgkg(-1) PA, median PA of 77 populations varied from 2 to 191mgkg(-1) in the rhizomes. In nearly 25% of the samples analysed the PA content was below 10mgkg(-1), another 25% had between 10 and 20mgkg(-1) PA. Histograms of PA concentrations in a population often showed a distinct skewness toward lower alkaloid contents. Alkaloid content was independent of sesquiterpene chemotype. The seasonal influence on PA content of rhizomes was little in comparison to the variability within the population or within the rhizome itself. Nevertheless, when comparable rhizome parts within a population were considered, the PA content may remain stable over several years. Although plants totally free of PA could not yet be found, it is possible to select populations low in alkaloids. Several populations of the petasine chemotype containing less than 10mgkg(-1) in the rhizomes could be found in the area investigated. 

 Petasites hybridus: a tool for interdisciplinary research in phytotherapy.:Pharm Acta Helv. 1998 Feb;72(6):359-62.Debrunner B, Meier B.Zeller AG, Romanshorn, Switzerland. 

The 3rd Petasites gathering took place in Romanshorn, Switzerland on March 29, 1996 and gave 16 European scientists the opportunity to transmit their latest considerable discoveries to interested researchers working in different scientific disciplines such as pharmacognosy, botany, chemistry, pharmacology, medicine or clinical pharmacy. The newest findings on Petasites hybridus as a significant plant drug showed very promising aspects of therapeutic utility. Great progress has been made in chemical analytical methods and the determination of pharmacological activities. Substantial advances have also occurred in the production of bioassay procedures and plant materials, particularly utilizing cell- and tissue-culture techniques. 

 A competitive enzyme immunoassay for the pyrrolizidine alkaloids of the senecionine type.:Planta Med. 1996 Jun;62(3):267-71.Langer T, M?stl E, Chizzola R, Gutleb R.Institut f¨¹r Botanik und Lebensmittelkunde, Veterin?rmedizinische Universit?t Wien, Austria. 

We developed an immunoassay with antibodies against retrorsine to detect the closely related senecionine, the main alkaloid in various Asteraceae. Sensitivity is about 23 pg (68 fmol) for senecionine. Cross reactivity of monocrotalin, retrorsine N-oxide, senkirkine (< 0.1%), and seneciphylline (3.6-34.5%) was resolved. The alkaloid content in leaves of Petasites hybridus (Asteraceae) was determined to be 3.86 ppm, calculated as senecionine, which was far less than in rhizomes (104.8 ppm). Additionally, we proved specificity by taking immunograms from different parts of Petasites hybridus. The test is a suitable tool for assessing the toxic potential of medicinal plants containing senecionine. 


 Identification and characterization of inhibitors of peptido-leukotriene-synthesis from Petasites hybridus.:Planta Med. 1994 Aug;60(4):318-22.Bickel D, R?der T, Bestmann HJ, Brune K.Institut f¨¹r Anatomie, Universit?t Regensburg, Federal Republic of Germany. 

Extracts from Petasites hybridus were found to inhibit peptido-leukotriene biosynthesis in isolated peritoneal macrophages. Chemical analysis by gas chromatography coupled with mass and infrared spectroscopy facilitated the identification of three isomeric oxopetasan esters, petasin, and isopetasin as the main compounds of these extracts. Fractionations obtained by column chromatography of the most effective extract indicated a correlation between peptido-leukotriene biosynthesis inhibition and the content of isopetasin, a sesquiterpene ester of isopetasol and angelic acid, as well as the isomeric oxopetasan esters. Petasin, a structural isomer of isopetasin, however, was found to be inactive. It may even reduce the peptido-leukotrine inhibitory effect of isopetasin. It is concluded that isopetasin and the oxopetasan esters in Petasites hybridus inhibit the biosynthesis of the vasoconstrictive peptido-leukotrienes. This effect may contribute to some of the medicinal properties of Petasites hybridus extracts such as, e.g., gastroprotection and spasmolytic activity. 

 Gastro-protective effects by extracts of Petasites hybridus: the role of inhibition of peptido-leukotriene synthesis.:Planta Med. 1993 Dec;59(6):494-6.Brune K, Bickel D, Peskar BA.Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen, Federal Republic of Germany. 

Extracts from Petasites hybridus are in therapeutic use for more than 2000 years. They have been claimed to improve gastrointestinal pain, lung-diseases such as asthma and cough, as well as spasms of the urogenital-tract. We have investigated these claims in animal models of gastro-intestinal ulcers and confirmed that alcoholic extracts of Petasites hybridus block the ethanol-induced gastric damage and reduce small intestinal ulcerations induced in rats by indomethacin. Searching for a possible mode of action, we found that ethanolic extracts of Petasites hybridus inhibit the peptido-leukotriene biosynthesis in mouse peritoneal macrophages but leave prostaglandin biosynthesis unimpaired. We conclude that the active principle could be useful in the treatment of gastro-intestinal human diseases and that Petasites hybridus may contribute to the inhibition of calcium-dependent processes such as leukotriene biosynthesis.



Over de mannelijke en vrouwelijke planten 
De soort is tweehuizig, met mannelijke en vrouwelijke planten. Deze vormen hier en in noordelijk Europa grote populaties, die uitsluitend uit een sexe bestaan. Wanneer ze bloeien, zien ze er zo verschillend uit, dat het niet verbazend is, dat Linnaeus en velen na hem twee soorten onderscheidden: Tussilago petasites L. voor de mannelijke en T. hybrida L. voor de vrouwelijke vorm. In 1779 beschouwde Lamarck de soorten als varieteiten van een soort, en ze werden als hermafrodite en vrouwelijke rassen van een soort beschouwd door de eminente botanici Willdenow (1803) en De Candolle (1805), maar dat bleef lang onopgemerkt. Wadt (1813) speculeerde aan de hand van veldonderzoek, dat het de verschijningsvormen van een soort waren, hetgeen door de grote composieten-deskundige Cassini (1826) bevestigd werd. In Nederland duurt alles wat langer. Kops in 1814 zegt 'buiten twijfel ... twee onderscheidene soorten' en Suringar (1870) heeft de twee nog steeds gescheiden, zij het onder een naam, P. officinalis Moench. Oudemans (1873) heeft beide dan als synonymen van een soort. Merkwaardig genoeg beeldt hij een vruchtje af!

Fig. 1: mannelijke bloem


Fig. 2: lokbloem

Fig. 3: vrouwelijke bloem 
U moet maar eens een aantal hoofdjes open peuteren en de bloemen met een loupe bekijken. Het mannelijke hoofdje heeft zo'n 20--50 functioneel mannelijke bloemen. Er is echter een duidelijke en grote stempel, en vroeger meende men, dat de bloem tweeslachtig was, en verbaasde zich erover, dat er nooit vruchten aan kwamen. Een blik in het ovarium laat meteen de reden zien: er zit geen ovulum in. In de literatuur (bijv. door Weeda en anderen, 1991) wordt verder nog de aanwezigheid van een klein aantal functioneel vrouwelijke lintbloemen vermeld, die langs de buitenrand van het hoofdje staan. Zulke bloemen zijn er inderdaad, maar functioneel zijn ze niet, want het ovarium is loos. Dat ze niet zouden ontwikkelen, omdat de bloeistengel zo snel verwelkt, zoals Weeda en anderen zeggen, lijkt mij een niet aantoonbare bewering. Het is zelfs onwaarschijnlijk, omdat in de regel stengels verwelken, als er geen bevruchting heeft plaats gevonden, en uitgroeien en stevig blijven, als dat wel het geval is. Bij de verwante Winterheliotroop, P. pyrenaicus (L.) G. Lopez (1987) [overigens in de meest recente boeken nog steeds P. fragrans (Vill.) Presl genoemd] zijn die bloemen wel fertiel en zetten zaad, en mogelijk heeft men daaruit afgeleid, dat dat bij P. hybridus 'dus' ook zo zou moeten zijn.
De mannelijke bloeiwijzen verwelken dus vrij snel na de bloei, in tegenstelling tot de vrouwelijke, die wel een meter hoog, en daardoor heel opvallend worden. Dit is mogelijk een van de redenen, dat men in de herbaria meer vrouwelijke dan mannelijke planten aantreft, en de flora's daarom de vrouwtjes voor algemener houden. Het is spijtig, dat bij het maken van de verspreidingskaart voor de Atlas (Van der Meijden et al., 1989) er geen twee kaartjes voor de mannelijke en vrouwelijke planten gemaakt zijn.

De vrouwelijke hoofdjes bevatten tot meer dan 100 buisvormige bloemen. Weliswaar zijn er helmhokken aanwezig, maar deze produceren geen stuifmeel, terwijl de stempels dun en draadvormig als een vorkje erboven staan. Het ovarium bevat een ovulum, zoals dat hoort. In het midden van het hoofdje treft men enkele bloemen aan, die sprekend lijken op de functioneel mannelijke van de mannelijke plant. Men heeft ze dan ook wel als mannelijk beschreven en zich wederom afgevraagd, waar de vruchten toch bleven (bijv. Contant, 1970). De antheren produceren echter geen stuifmeel, maar wel nectar, dat bij de levende plant als een druppeltje op de kroonslippen gepresenteerd wordt. Ook hier is het ovarium loos.
We hebben dus 4 typen bloemen, elke sexe met twee ervan. Kers (1991) vertelt echter, dat er nog twee bloemtypen zijn, en dat er in feite twee soorten mannelijke en twee soorten vrouwelijke vormen zijn met soms zelfs tweeslachtige bloemen, die zelf-incompatibel zijn, maar bij kruisbestuiving zaad kunnen produceren. Ik heb ze in Nederland niet gezien, maar het zou de moeite waard zijn er eens in 't veld naar te kijken of ze bij ons ook voorkomen.

Er wordt gezegd, dat de mannelijke planten eerder bloeien dan de vrouwelijke, het schijnt ongeveer een week te schelen, maar het echte begin van de bloei is slecht te schatten, omdat de bloei begint, zodra het eerste hoofdje van de bloeiwijze boven de grond komt en open gaat. De plant is dan nog zeer onopvallend.
Het materiaal in het Rijksherbarium vertoont voor het mannetje een bloeitijd van 22 februari tot 23 April, voor het vrouwtje 19 maart tot 12 mei met een uitschieter tot 28 Mei in 1929. Waarschijnlijk was dat jaar de bloei opgeschoven ten gevolge van de zeer zware winter, die wij in Leiden ons herinneren als de winter, waarin ons Stadhuis afbrandde en het bluswater de ruine tot een ijspaleis omtoverde.
Vegetatief zijn de sexen niet onderscheidbaar, terwijl voor beiden het chromosoomgetal 2n = 60 is (zie ook Sørensen & Christiansen, 1964). Novotny' en anderen (1966) ontdekten dat een wortel extract twee chemische rassen opleverde: de ene helft bevatte de terpenoide furaan, de andere helft petasine, maar of deze stoffen met de geslachten overeen komen werd door hen niet vermeld.

VERSPREIDING
Als je verhalen leest  het voorkomen van de soort, dan valt op, dat in Centraal Europa men het over gemengde populaties heeft van mannelijke en vrouwelijke planten, en vruchtzetting vermeld wordt. Het oorspronkelijke verspreidingsgebied wordt aangegeven als Zuid en Midden West- en Centraal Europa met Midden Duitsland als noordelijkste rand (E. Jager in Heinrich en anderen, 1972). Noordelijker worden de vrouwelijke planten steeds zeldzamer en in Scandinavie komen die zo goed als niet voor, in Engeland voornamelijk in de Midlands. Over Nederland valt helaas geen schatting te maken: de vrouwelijke planten bloeien langer dan de mannelijke, en bij het maken van de verspreidingskaart voor Nederland zijn mannetjes en vrouwtjes niet apart gescoord. In het Rijksherbarium liggen 36 mannetjes en 54 vrouwtjes, en dat zegt dus niets over de frequenties. Wel zijn in Nederland de populaties kennelijk altijd eenslachtig, afkomstig van een enkel stukje wortelstok.
De bloemen worden bezocht door vroege bijen en hommels, Citroenvlinders en zweefvliegen. De vrouwelijke planten leveren nectar in de centrale vergrote bloemen, de mannelijke nectar en stuifmeel. De bloemen zouden ook een sterke kruidnagellucht verspreiden om de insecten aan te lokken, ik heb daar in Nederland maar weinig van gemerkt. Kennelijk moeten de planten toch wel heel dicht bij elkaar staan om natuurlijke bestuiving voor elkaar te krijgen. Naar verluidt groeien mannelijke en vrouwelijke populaties wel in elkaars buurt, maar in Nederland is slechts eenmaal een stengel gevonden met kiemende vruchten erin.

De specialist Muller, die een boek over Europese kiemplanten (1978) geschreven heeft, heeft heel lang moeten zoeken, voordat hij er van Groot Hoefblad een te pakken kreeg. Zijn speurtocht is eigenlijk de oorzaak van mijn interesse in deze soort. Hij kwam namelijk op het Rijksherbarium, waar ik toen assistent van Professor Van Steenis was. Van Steenis vond echter maar een raar verhaal, dat er nooit kiemplanten zouden zijn en besloot er iets aan te doen. In de Hortus in Leiden stonden indertijd vrouwelijke planten in een perk ongeveer 30 meter van de wallekant van de Witte Singel, waar nog steeds een grote mannelijke populatie is. Hoewel er mannetjes van andere soorten vlak in de buurt stonden en bekend is, dat Groot Hoefblad kan hybridiseren met ten minste P. albus (L.) Gaertn. en P. paradoxus (Retz.) Baumg. (Novotny' en anderen, 1966), waren de vruchten altijd loos, zoals Muller al gezegd had. Ook het Nederlandse herbarium materiaal had geen ontwikkelde vruchten. 

Begin maart in het jaar daarna (1968) plukten Professor Van Steenis en ik een toef mannelijke bloeiwijzes en ranselden daar op sadistische wijze een aantal vrouwelijke bloeiwijzes van alle kanten mee, en zetten tenslotte de mannetjes in een torentje om de slachtoffers heen. Dat hielp! De planten groeiden en groeiden tot wel anderhalve meter hoogte en eind Mei bleken er een grote massa zeer rijpe vruchten gevormd te zijn, die zeer snel en gemakkelijk kiemden, tot op vochtige watten in de prullenbak toe. Dat toont dus aan, dat de planten niet steriel zijn, en zich dus goed zouden kunnen voortplanten, als ze de kans zouden krijgen. Waarom is dat dan in Nederland niet het geval, althans nog niet? Ik denk, dat komt, omdat we hier, en in Scandinavie, Engeland en Noordelijk Duitsland te maken hebben met eenslachtige populaties. Deze populaties zijn ontstaan door verwildering uit oude tuinen Ze zijn" ontstaan uit een enkel stuk wortelstok, waardoor de hele populatie eigenlijk één plant, één kloon is. Omdat gemengde populaties kennelijk erg zeldzaam zijn, en zoals in 1998 bleek(zie naschrift JVF),dat bestuivers afwezig zijn) treedt er in de regel geen bestuiving op."
In Noordoost Duitsland, vertelt de Oecologische Flora van Weeda en de vader en zoons Westra (1991) valt het voorkomen vrijwel overal samen met menselijke nederzettingen, die soms al lang geleden verlaten zijn. Gezien de historie van artsenijplant, denk ik, dat dat hier net zo is, en dat de soort van origine niet inheems is, maar een archeofyt. Ook Van Ewijk (1981) denkt, dat de soort in de Middeleeuwen uit Zuid Duitsland is ingevoerd. In de Oostelijke staten van de V.S. is de soort ook ingevoerd, en Gray's Manual vermeldt (Fernald, 1950), dat het als een bijzonder stinkend substituut voor tabak gebruikt wordt. 

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