Volume 7-6

Petasites /Asthma Original Research
Petasites hybridus (Butterbur root)
Extract in the Treatment of
Asthma – An Open Trial
Ulrich Danesch, PhD
Abstract
eosinophils and neutrophils, to the airways where The efficacy and tolerability of a butterbur root
they cause alterations in epithelial integrity, extract (Petadolex®) for the treatment of
abnormalities in autonomic neural control of asthma was analyzed in a prospective, non-
airway smooth vascular tone, increased vascular randomized, open trial. Subjects included 64
permeability, mucus hypersecretion, change in adults and 16 children/adolescents treated for
mucociliary function, increase in airway smooth two months with the extract, followed by two
muscle responsiveness, and structural changes in months during which the intake of the extract
was optional. Concomitant asthma medication
Increased appreciation of the role of in- was permitted. The number, duration, and
flammation in the pathophysiology of asthma has severity of asthma attacks decreased, while
led to new treatment strategies. Studies have peak flow, forced expiratory volume (FEV1), and
shown improvements in asthma symptoms caused all measured symptoms improved during
by high doses of inhaled corticosteroids are asso- therapy. In addition, more than 40 percent of
ciated with improvement in markers of airway patients using asthma medications at baseline
inflammation.4,5 These observations confirm the reduced intake of these medications by the end
strong link between airway inflammation, bron- of the study. This study suggests the Petasites
chial hyperresponsiveness, and asthma symptoms hybridus extract Petadolex is an effective and
safe therapy for the treatment of asthma.
(Altern Med Rev 2004;9(1)54-62)
consists of long-term therapy (control medication)and quick-relief therapy (relief medication).
Introduction
Current management guidelines stress theimportance of first-line therapy with inhaled corticosteroids (e.g., beclomethasone, budesonide, disorder of the airways.1,2 In the past, the fluticasone, triamcinolone) to suppress the predominant pathophysiology of acute asthma was inflammatory process.2 The main concern with considered to be bronchospasm occurring in inhaled corticosteroid treatment is the potential for response to a variety of specific and nonspecific dose-related systemic effects, including adrenal stimuli such as allergens and irritants. However, suppression, osteoporosis, growth inhibition, skin the main pathophysiology of the attack is now bruising, cataracts, and ocular hypertension.6 understood to be an inflammatory response, withinflammation leading to bronchospasm.3 Theinitial trigger in asthma may be the release of Ulrich Danesch, PhD – Biology from the University of inflammatory mediators from bronchial mast cells, Heidelberg, Germany; past research position, Stanford, macrophages, T-lymphocytes, and epithelial cells.
School of Medicine; currently in research and developmentfor Weber & Weber, the manufacturer of Petadolex.
Correspondence address: Muenchner Strasse 13, D- activation of other inflammatory cells, such as Page 54 Alternative Medicine Review ◆ Volume 9, Number 1 ◆ 2004
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Cromolyn and nedocromil sodium have similar since 1972 and licensed as a pharmaceutical un- anti-inflammatory properties, but are less effective der German regulations. This same extract has in treating asthma than inhaled corticosteroids.
been available in the United States since 1997 as The cysteinyl leukotrienes C4, D4, and E4 cause smooth muscle constriction and prolifera- Historically, Petasites has been used thera- tion and are important mediators in the pathophysi- peutically for its analgesic effects and to reduce ology of the inflammatory process. Based on this spasms in the gastrointestinal tract and in asthma.
knowledge, a new class of anti-inflammatory Recently, a multicenter, randomized, double-blind, agents – the leukotriene antagonists – were de- placebo-controlled clinical trial for migraine pro- veloped.7 Leukotriene antagonists possess both phylaxis was conducted on 229 evaluable patients anti-inflammatory and bronchodilation activity.
with and without aura. The study found Petasites Two types can be distinguished based on mecha- extract safe and effective in reducing the frequency nism of action: leukotriene-receptor-antagonists of migraine attacks, the number of migraine days (zafirlukast and montelukast) and leukotriene-syn- per month, and headache intensity.12 The first clini- thesis-inhibitors (zileuton). These medications cal experiences with Petadolex in patients with appear to improve lung function and reduce the asthma were published by Gruia.13 In vitro exami- use of inhaled and oral corticosteroids; however, nations with smooth muscle cells of various ori- they have the potential for side effects. Zileuton gins14 and in guinea pig tracheal rings15 confirmed requires liver function monitoring and systemic the spasmolytic activity of Petasites. In addition vasculitis has been associated with zafirlukast and to spasmolytic action, Petasites exhibits anti-in- flammatory activity. In mouse macrophages16 and porcine leukocytes17 Petasites extract was shown for acute and long-term asthma management, of- to inhibit inflammatory leukotriene synthesis.
ten in conjunction with oral corticosteroids and/ A clinical trial of Petasites root powder in or leukotriene antagonists. Long-acting beta-ago- patients with chronic asthma and chronic bron- nists like salmeterol and formoterol act as chitis demonstrated improved lung function in all bronchodilators by relaxing the smooth muscle groups treated with Petasites powder.18 The ben- cells of the airways. In contrast, short-acting beta- efit was probably at least in part due to the inhibi- agonists like salbutamol, fenoterol, terbutaline, tion of leukotrienes. Trials using synthetic albuterol, pirbuterol, and reproterol are used for leukotriene antagonists have shown superiority quick relief on demand rather than as control medi- compared to placebo in respect to various lung function parameters, such as FEV1, peak expira- The Petasites extract used in this study – tory flow, use of relief medication, and number of Petadolex®, softgel capsules (manufactured by Weber & Weber International GmbH & Co. KG, Germany) contain 50 mg of a standardized lipo- and rhinitis is recognized as a risk factor for sub- philic extract of the rhizome of Petasites hybridus, sequent asthma. A Petasites leaf extract (CO2-ex- the butterbur plant. The extract is obtained by high tract Ze339 – not identical to Petadolex) was pressure, liquid carbon dioxide extraction in a stan- shown to be equally effective as cetirizine in the dardized and patented procedure, and contains a treatment of seasonal allergic rhinitis in a random- minimum of 15 percent petasins. Petasins are a ized controlled trial.20 In another trial, levels of group of sesquiterpene compounds mainly thought inflammatory mediators (including histamine and to be responsible for the pharmacological actions leukotrienes) in the nasal fluid of individuals with of the butterbur extract.8,9,10 The manufacturing allergic rhinitis were significantly reduced after process removes pyrrolizidine alkaloids that are taking a Petasites extract for five days.21 In an- potentially hepatotoxic and carcinogenic.11 The other randomized, controlled trial with 20 patients finished product has been available in Germany with seasonal allergic rhinitis, CO2-extract Ze339 Alternative Medicine Review ◆ Volume 9, Number 1 ◆ 2004 Page 55
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Table 1. Demographic and Baseline Characteristics
Subjects
ber 2000 to March2002; 77.5 percenthad mild asthma, of the disease. In ad-dition to Petadolex,all other available Study Design
Additonal asthma medication, percent of patients phase and a treat-ment phase lasting2-4 months. Duringthe run-in phase, pa- protected against AMP-induced nasal responsive- tients recorded asthma symptoms, dosage of ness. This observation is in keeping with an inhi- asthma medication, and number, duration, and bition of leukotriene synthesis by Petasites, since severity of asthma attacks. Patients then received leukotriene receptor antagonists also attenuate the trial medication and a diary. Adults took 50 mg Petadolex three times daily, while children were given 50-150 mg daily, depending on age.
examine the efficacy and safety of an extract of Patients were examined by their physician four Petasites hybridus in the treatment of asthma.
and eight weeks after issue of trial medication.
FEV1 was measured each time. After two monthsof treatment, patients were free to continue withthe trial medication for another two months; hencethe maximum duration of treatment was fourmonths, the minimum two months.
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Efficacy Measurements
by the following parameters: number, duration, andseverity of asthma attacks; asthma symptoms (cough-ing, difficulty breathing, chest tightness, difficultyexhaling, wheezing, expectoration) using a four-point weeks 13-16
scale; FEV1; peak flow; asthma medication usage; and evaluation by patient and physician.
Statistical Analysis
weeks 9-12
statistics (mean, standard deviation, median, mini-mum, maximum, and quartiles). Changes in asthmamedication, FEV1, and peak flow were calculatedintra-individually and expressed as percentage weeks 5-8
Asthma Attacks
Seventeen of the study’s 80 subjects reported an asthma attack during the study (21.3%), eight of whom had attacks during the retrospective (baseline) weeks 1-4
period. The number of asthma attacks was calculatedper week and per patient. Asthma attacks decreasedby 48.1 percent from baseline to week 8 of the treat-ment period. In the first four weeks of the follow-upphase, during which intake of Petadolex was optional, baseline
asthma attacks decreased further (by a total of 70.4%) but increased during the last four weeks, mainly due to one child who had an exceptionally high number of asthma attacks (n=34) while attending school campduring hay fever season (Table 2).
Duration of asthma attacks was calculated per week, per attack, and per patient. The duration of asthma attacks was documented for 74 of 103 at- tacks. The mean duration of asthma attacks during le 2.
weeks 1-4 was strongly affected by one patient who b
reported an attack that lasted nine hours, leading to Ta
Petadolex (number of valid cases in brackets) Asthma attac
an increase in the mean duration. Apart from thatperiod (i.e., weeks 1-4) the duration of asthma at-tacks was reduced by 90.5 percent (Table 2).
and per patient. Severity decreased continuously point scale (0=no attack, 1=mild, 2=moderate, 3=se- during treatment up to week 8 (by 68.5%) and dur- vere). Severity was calculated per week, per attack, ing the follow-up phase during which intake ofPetasites extract was optional (total decrease versusbaseline by 83.3%) (Table 2).
Alternative Medicine Review ◆ Volume 9, Number 1 ◆ 2004 Page 57
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Figure 1. Lung Function: Change in FEV1
Asthma Symptoms
during Treatment with Petadolex (n=65) (coughing, difficulty breathing, chesttightness, difficulty exhaling, wheezing,expectoration) were recorded in each patient’s diary using a four-point verbalscale over the duration of the study. After ing on the type of symptom. Followingthe initial treatment phase slightly more than half of the patients (n=39) continuedon the extract, while the remainder (n=31) ing time, patients discontinued the volun-tary phase, with 64 percent of subjects symptoms increased in severity at the end of the observation period (week 16) com-pared to week 8 in the group that had dis- Figured as percentage change from baseline (week 0); data points represent mean values with standard continued Petadolex. In contrast, mostsymptoms improved further (weeks 8-16)in the group on Petadolex. Figures 2a and2b illustrate the course of asthma symp-toms during the study, using the symptom Pulmonary Function
For the efficacy evaluation, patients were only included if they had lung function (FEV1, Asthma Medication
peak flow) measured at each of the three visits (baseline, after four weeks, and after eight weeks).
treated with inhaled corticosteroids at the begin- Not every patient had lung function measured and ning of the study. At the end of the study (weeks documented in this trial, thus resulting in variable 9-16) 42.9 percent of the evaluable patients (n=14) valid cases. Since lung function is dependent on had reduced the amount of inhaled steroids dur- age, sex, weight, and the type of test instrument ing therapy with Petadolex; and one patient in- used, the percentage change from baseline was creased dosage. The reduction in the amount of calculated intra-individually. The mean improve- inhaled steroids was calculated intra-individually ment for FEV1 (Figure 1) was 11.3 percent (n=65), as percentage change from baseline, which cor- for peak flow 28.5 percent (n=50). Comparing rects for the different brands and potencies of in- baseline with the treatment effect after eight haled medications. Values for all four treatment weeks, 70.6 percent of the evaluable patients phases must have been available for inclusion in (n=68) had an improved FEV1 and 83.9 percent the analysis. After 9-16 weeks (n=14) there was a of patients (n=56) had an improved peak flow.
16.1-percent reduction in the amount of inhaledsteroids used (Figure 3).
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Figure 2a. Wheezing: Change of the
acting beta-agonists; 48.3 percent of these patients reduced the amount of short-acting beta-agonistsduring weeks 9-16. The daily dosage was reduced by a mean of 13.4 percent, calculated as percent-age change from baseline (n=29).
Except for four patients, all subjects with evaluable corticosteroid or short-acting beta-ago- nists data had taken the Petasites extract duringthe follow-up phase.
Evaluation of Efficacy by Patient and
Physician
investigator at the week 8 visit to offer an assess- ment of the efficacy of their treatment. Improve-ments were rated as very good, good, moderate,or poor. Ninety-five percent (n=72) reported Data points represent mean values with standard Figure 2b. Wheezing: Change of
the Mean Score Starting at Week 8
Petadolex was effective in treating their in Patients Treated with (n=39) or asthma, with 83 percent (n=63) rating theirimprovement as very good or good (Figure 4). The physician evaluation was comparable,with an efficacy rating of very good or good Safety and Tolerability
good by 67 of 76 patients (88.2%). None ofthe 76 patients or physicians rated the tolerability as “poor.” During the study, 11 subjects. Adverse events reported by children were abdominal pain/flatulence, sneezing, allergic conjunctivitis, allergic rhinitis, andhalitosis. Adults reported hair loss, coughing, depression. Two patients required treatment of adverse events. One patient was treated for allergic rhinitis and the other patient was Data points represent mean values with standard Alternative Medicine Review ◆ Volume 9, Number 1 ◆ 2004 Page 59
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daily asthma attacks was reduced by nearly half.
Figure 3. Asthma Medication: Change in
Attacks decreased further in the follow-up phase, Inhaled Corticosteroid Usage during only to increase at the very end due to the afore-mentioned patient with an extraordinary number of attacks. Asthma duration and severity decreasedeven more effectively – by 80-90 percent – at the end of the follow-up phase. In this subgroup ofpatients with asthma attacks, 66.7 percent had an improved FEV1 and 91.7 percent had improved sess and monitor airflow obstruction. IncreasedFEV1 and peak flow are indicative of an improved airflow. More than a 10-percent increase in FEV1 in this study should be considered clinically rele- vant. With 70.6 percent of the patients having anincreased FEV1 and 83.9 percent having increased peak flow, it can not be concluded the mean im- provement in lung function was due to dramaticchanges in only a few patients.
In the one-third of the study’s patients who treated asthma only with Petadolex capsules, no Figured as percentage change from baseline (week impairment of lung function was observed at the 0); data points represent mean values with standard end of the study, and 80 percent of those patientshad an improved FEV1 or peak flow. This sug-gests Petadolex may be effective in the treatment depression. The adverse events were not rated by of asthma not only in combination with additional the treating physician to be causally related to the asthma medication but also as a stand-alone medi- intake of Petadolex and did not lead to withdrawal Subjects who took Petadolex capsules also noted a mean 50-percent, self-reported improve- Discussion
ment in documented asthma symptoms after two months of treatment. Although in the final two study was to analyze the efficacy and tolerability months the use of Petasites extract capsules was of Petadolex capsules in patients with mild-to- optional, one-half of the patients continued tak- moderate asthma. Eighty patients completed the ing the extract. Compared to week 8, the severity study – none was excluded from the analysis.
of symptoms decreased further in the group re- However, due to missing data, not all variables maining on Petadolex, whereas symptoms in- could be analyzed for the complete patient popu- creased in severity in the group that discontinued Petadolex. Coughing was an exception, probably influenced by two acute cases of bronchitis. The from Petasites hybridus taken for 8-16 weeks may results of the follow-up phase support the obser- be effective in reducing the severity of various vation suggesting improvement was due to treat- In the course of the study, 21.3 percent of In vitro, the same extract used in this study the study population reported asthma attacks. Af- has demonstrated spasmolytic as well as anti-in- ter two months of treatment the mean number of flammatory activities. Beta-agonists and cortico-steroids are standard therapies for asthma, which, Page 60 Alternative Medicine Review ◆ Volume 9, Number 1 ◆ 2004
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Figure 4. Assessment of Efficacy by the Patient (n=76)
age 6-9 age 10-12 age 13-17 age >=18 all patients Very good=very good improvement, good=good improvement, moderate=moderate improvement, poor=unchanged or worse condition as noted, is characterized by bronchoconstriction and inflammation of airway cells. In this study, treatment with Petadolex led to a reduction in the dropouts due to adverse events. The low number use of beta-agonists and corticosteroids by a mean of adverse events and the conclusion that the ad- of 15 percent. In the follow-up phase, the usage verse events were not rated to be causally related of corticosteroids was further reduced, with 43- to intake of the extract demonstrates Petadolex was and 48-percent of evaluable patients able to re- safe and well tolerated in this trial.
duce corticosteroids and beta-agonists, respec- The study results suggest the Petasites tively. The circumstance of patients reducing the hybridus extract Petadolex is an efficacious and amount of asthma medication of their own accord well-tolerated therapy for the treatment of asthma and without being instructed to do so by the in- Disclosure
medications at the end of the study suggests the improvements in lung function were due to therapy was funded by Weber&Weber, Inning, Germany, with Petadolex and not to increased asthma co- medication. Of evaluable patients with an im-proved FEV1, 87.5 percent had also reduced theamount of corticosteroids. Only one patient in-creased steroid usage. A similar result was ob- Alternative Medicine Review ◆ Volume 9, Number 1 ◆ 2004 Page 61
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