CHUV, 9. 2. 2006
Efficacy and safetyof Butterbur leaves extract Ze 339
in allergic rhinitis
Andreas Schapowal MD, PhD, DSc (hon)Specialist of oto-rhino-laryngology, allergology
and clinical immunologyLandquart
CHUV, 9. 2. 2006
Bousquet J, van Cauwenberge P, Khaltaev N.From Allergic Rhinitis and its Impact on Asthma (ARIA) in collaboration with the World Health Organization. J Allergy Clin Immunol 2001; 108 (5) Part 2; S147-S334.
CHUV, 9. 2. 2006
Therapy of allergic rhinitis
Sneezing Rhinorrhea Nasal obstruction
Itching Eyesymptoms
Oral H1-Blockers ++ ++ + +++ ++
nasalocular
++0
++0
+0
++0
0++
Nasal steroids +++ +++ +++ ++ ++Cromoglycates
nasalocular
+0
+0
+0
+0
0++
Vasoconstrictorsnasaloral
00
00
+++++
00
00
Anticholinergics 0 ++ 0 0 0
Antileukotrienes 0 + +++ 0 ++
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Petasites hybridusButterbur extract Ze 339 in allergic rhinitis
1. Cultivation (Petzell®, leaves)
2. Extraction (non-critical CO2)
3. Pharmacology, Pharmacokinetic
4. Clinical trials 4.1. proof of principle4.2. Ze 339 vs. cetirizine4.3. Ze 339 vs. placebo, dose-finding4.4. Ze 339 vs. placebo and fexofenadine
5. Clinical evaluation
CHUV, 9. 2. 2006
Cultivation (Petzell, leaves)
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Stucture of Petasin
O RH
2
1
11
O
R3
7
1
11
petasin chemovariety furanopetasin chemovariety
O
OO
O
OO
O
OO 1
37
8
O
OO
O
OO
O
OO
S S S
petasin isopetasin neopetasin
S-petasin S-isopetasin S-neopetasin
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Extraction (non-critical CO2)
1.Total Σ of 6 petasins 20.3 %(petasin, neo- and isopetain;neo-S-petasin, S-petasin and iso-S-petasin
2. Total fatty acids 40.2 %unsaturated cis-fatty acids 1.1poly unsaturated cis-fatty acids 33.8unsaturated trans-fatty acids 0.0saturated fatty-acids 5.3
3. Aroma components 7.0 %4. Steroids/ Phytosterols 1.2 %5. Pyrrolizidine alkaloids n.d. (35 ppb)
6. Remainders 30 %(apolar const. without chromophors; water[ca. 6.0%])
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Pharmacology, Pharmacokinetic
membrane phospolipids
arachidonic acid
cyclooxygenase-1 and -2 5 - lipoxygenase-prostaglandins and -cyclins - leukotrienes - thromboxane (hay-fever, asthma, (rheumatism, M. Alzheimer) atopical dermatitis)
Ze 339
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Role of petasin in the potential antiinflammatory activity of a plant extract of petasites hybridus.
OAR Thomet, UN Wiesmann, A Schapowal, C Bizer, HU Simon
Biochemical Pharmacology (2001), 61: 1041-47
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Inhibiton of cysteinyl-leukotrienes
in eosinophils and neutrophils
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Inhibition of intracellular calcium by Ze 339 and petasin,
but not by neopetasin and isopetasin
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Pharmacology, Pharmacokinetic
Mode of action
* Leukotriene - synthesis is inhibited
* Intracellular calcium ist blocked: release of inflammation mediators is blockedwithin 30 min (↓ ECP)
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4. Clinical trials4.1. Proof of principle (n=6)
baseline 1st day 5th day
NASAL LAVAGE FLUIDLTB4 (pg/ml) 313.1 ± 46.5 180.6 ± 32.2
cysteinyl-LT (pg/ml) 137.0 ± 42.2 70.1 ± 16.5histamine (pg/ml) 153.7 ± 32.1 53.0 ± 8.4
SERUMpetasin (ng/ml) < 2.0 7.7 ± 1.7 15.1 ± 2.3ECP (µg/l) 18.7 ± 4.1 13.7 ± 3.5 11.5 ± 1.8
URINEpetasin < 2.0 > 300.0
(ng/mmol creatinine)
Anti-inflammatory activity of an extract of Petasites hybridus in allergic Rhinitis. OAR Thomet, A Schapowal, IVWM Heinisch, UN Wiesmann, HU Simon; Intern. Immunopharmacol. 2: 997-1006 (2002)
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Very good effect on nasal obstruction: Normal rhinomanometry by day 6
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4. Clinical trials4.2. Ze 339 vs. cetirizine (Zyrtec®)
Inclusion criteria: allergic rhinitis (history), Prick-Testsneezing, rhinorrhea, itchy nose/eyes, nasal congestion18 years and older
Exclusion criteria: alcohol- and drug abuse, pregnancy, child nursingconsumptive diseases, transplantation
Assessment of quality of life: Allergy, 19: 5-34 (1994)
Primary variable: validated SF 36 questionnaire Bousquet et al., J Allergy Clin Immunol 98 (2): 309-16, (1996)
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4. Clinical trials4. 2. Ze 339 vs. cetirizine (Zyrtec®)
Randomisedn = 131
Butterbur Ze 339n = 65
Cetirizine n = 66
Safety AnalysisITT: n = 61dropouts: n=4
1 asthma; 3 AE-GI
Efficacy AnalysisITT: n = 61PP: n = 51
protocol violation: n=10
Safety AnalysisITT: n = 64drop outs: n=2
withdr. info. consent, AE
Efficacy AnalysisITT: n = 64PP: n = 51
protocol violation: n=13
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4. Clinical trials4. 2. Ze 339 vs. cetirizine (Zyrtec®)
Thesis: Ze 339 is not inferior to cetirizine PRIMARY VARIABLES
Item p-Valuephysical function 0.001emotional function 0.001vitality 0.001mental health 0.001general health 0.001physical activity 0.001social functioning 0.001pain 0.001
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Comparison of groups regarding the primaryvariables in SF-36 questionnaire
(procentual differences begin vs. end of therapy)
0%20%40%60%80%
100%120%140%160%180%
1 2 3 4 5 6 7 8
Ze 339
Cetirizin
1 physical function, 2 emotional function, 3 vitality, 4 mental health, 5 general health, 6 physical activity, 7 social functioning, 8 pain
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4. Clinical trials4.3. Ze 339 vs. placebo
Inclusion criteria: allergic rhinitis (history), Prick testsneezing, rhinorrhoea, itchy nose/eyes, nasal congestion18 years and older
Exclusion criteria: alcohol and drug abuse, pregnancy, child nursingconsumptive diseases, transplantation
Severity of symptoms: FDA, Guidance for Industry, April 2000
Primary variable: sum of symptoms score
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4. Clinical trials4.3. Ze 339 vs. placebo
Randomisedn = 186
3 tabs. Ze 339n = 60
Placebo n = 61
Safety AnalysisITT: n = 53
Efficacy AnalysisITT: n = 53PP: n = 50
protocol violation: n=6
Safety AnalysisITT: n = 61
Efficacy AnalysisITT: n = 55PP: n = 50
protocol violation: n=8
2 tabs. Ze 339n = 65
Efficacy AnalysisITT: n = 57PP: n = 54
protocol violation: n=7
Safety AnalysisITT: n = 57
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4. Clinical trials4.3. Ze 339 vs. placebo
Patienten-Tagebuch SelbstbeurteilungSymptome Summenscore "Allergische Rhinitis"
Median 25%-75% Bereich ohne Ausreißer
PlaceboPestwurz ND
Pestwurz HD
Therapie
-1200
-1000
-800
-600
-400
-200
0
200
400
Diff
eren
z Th
erap
iebe
ginn
/End
e V
isue
lle A
nalo
gska
la
Self assessment - patient diary
Efficacy
P LD HD
Visu
al a
nalo
gous
sca
le –
diffe
renc
e be
gin
/ end
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4. Clinical trials4.3. Ze 339 vs. placebo
begin
begin
begin
begin
begin
begin
begin
begin
begin
begin
begin
begin
end
end
end
end
end
end
end
end
end
end
end
end
0
40
80
120
160
sneezing itchy nose/eye rhinorrhea nose congestion
P LD HD P P PHD HDHDLD LD LD
B B B B B B B B B B B BE E E E E E E E E E E E
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4. Clinical trials4.3. Ze 339 vs. placebo
Responders Patients Percent CHI-Square p
Ze 339 3 tab. 51 56 91.0 %
Ze 339 2 tab. 44 62 70.9 % < 0.007
Placebo 27 59 45.7 %
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4. Clinical trials4.3. Ze 339 vs. placebo
PRIMARY VARIABLESp-Value
3 tablets are superior to placebo < 0.001
2 tablets are superior to placebo < 0.001
3 tablets are superior to 2 tablets = 0.024
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4. Clinical trials4.4. Ze 339 vs. placebo and fexofenadine
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Efficacy of Ze 339 vs. fexofenadine and placeboTotal score day 14, four symptoms
(improvement indicated by reduced values)
Placebo (n = 107)Ze 339 (n = 110)Fexofenadine (n = 113)
Hypothesis: 1. Ze 339 and fexo-
fenadine are superior to placebo;
2. Ze 339 is not inferior to fexofenadine
Tot
al sc
ore
P<0.001
Ze 339 vs. fexofenadine:one-sided equivalence (non-inferiority) p < 0.001
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Efficacy of Ze 339 vs. fexofenadine and placebo
Improvement vs. baseline (%)
0
10
20
30
40
50
running nose sneezing itchy nose itchy eyes
Ze 339
Plac.
Fexo
P< 0.0001P< 0.0001 P< 0.0001 P< 0.0001
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Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis.
A. Schapowal, BMJ 2002; 324: 1-4
Butterbur Ze 339 for the treatment of intermittent allergic rhinitis.
Dose-dependent efficay in a prospective, randomized, double-blind, placebo-controlled study
A. Schapowal, Arch Otolaryngol Head Neck Surg. 2004; 130: 1381-1386
Treating intermittent allergic rhinitis: A prospective, randomized, placebo and antihistamine-controlled
study of Butterbur extract Ze 339
A. Schapowal, Phytother Res 2005; 19: 530-537
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Ze 339 / Tesalin® in clinical evaluation (n=103)
Symptoms at begin of therapy (mean on scale of 0-10 points)
Comparison of the means of symptoms: prior, during and after treatment
Mittelwert der Symptome vor der Behandlung
9876543210Missing
Perc
ent
30
20
10
0
7272727272727272N =
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10
8
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32177260
735137
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60
60
9
CHUV, 9. 2. 2006
Ze 339 / Tesalin® in clinical evaluation (n=103)
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Me
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6
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4
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2
1
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11
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2
33
5
6
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Me
an
6
5
4
3
2
1
0
11
2
3
3
4
4
5 Rhinorrhea
nachherTag 14Tag 7Tag 4Tag 3Tag 2Tag 1v orher
Me
an
7
6
5
4
3
2
1
0
22
2
3
4
4
5
6 Nasal obstruction
nachherTag 14Tag 7Tag 4Tag 3Tag 2Tag 1vorher
Me
an
6
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4
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1
0
111
2
3
3
4
6
SneezingItching
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6
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2
3
3
4
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Itchy eyes
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an
4,5
4,0
3,5
3,0
2,5
2,0
1,5
1,0
,5
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1,4
1,9
2,3
2,6
3,2
3,9
Red eyes
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an
2,0
1,8
1,6
1,4
1,2
1,0
,8
,6
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,8
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1,31,2
1,3
1,8
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an
8
7
6
5
4
3
2
1
0
111
5
4
7
6
Cough,itchy throat
(n=5)eczema(n=38)
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Conclusions* Ze 339 inhibits leukotriene synthesis and intracellular calcium
dose-dependently* Onset of action 30 min after oral administration* Ze 339 down-regulates all symptoms of allergic rhinitis* Ze 339 is highly significant superior to placebo* Ze 339 is not inferior to cetirizine and fexofenadine * Ze 339 is safe (routine laboratory tests, urine analysis, ECG;
toxicological data, mutation tests)* Tesalin® is approved by Swissmedic since June 2003,
has to be prescribed and has to be paid by health insurancesince December 2003
* Investigations regarding atopic dermatitis and asthma are underway