efficacy and safety of butterbur leaves extract ze 339 in ...chuv, 9. 2. 2006 efficacy and safety of...

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 ++

CHUV, 9. 2. 2006

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)

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

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%])

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

Inhibiton of cysteinyl-leukotrienes

in eosinophils and neutrophils

CHUV, 9. 2. 2006

Inhibition of intracellular calcium by Ze 339 and petasin,

but not by neopetasin and isopetasin

CHUV, 9. 2. 2006

Pharmacology, Pharmacokinetic

Mode of action

* Leukotriene - synthesis is inhibited

* Intracellular calcium ist blocked: release of inflammation mediators is blockedwithin 30 min (↓ ECP)

CHUV, 9. 2. 2006

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)

CHUV, 9. 2. 2006

Very good effect on nasal obstruction: Normal rhinomanometry by day 6

CHUV, 9. 2. 2006

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)

CHUV, 9. 2. 2006

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



CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006


Randomisedn = 186

3 tabs. Ze 339n = 60

Placebo n = 61

Safety AnalysisITT: n = 53






2 tabs. Ze 339n = 65




CHUV, 9. 2. 2006


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

CHUV, 9. 2. 2006


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

CHUV, 9. 2. 2006


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 %

CHUV, 9. 2. 2006


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

CHUV, 9. 2. 2006

4. Clinical trials4.4. Ze 339 vs. placebo and fexofenadine

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

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 =

nachherTag 14Tag 7Tag 4Tag 3Tag 2Tag 1v orher

10

8

6

4

2

0

-2

32177260

735137

1417232

60

60

9

CHUV, 9. 2. 2006

Ze 339 / Tesalin® in clinical evaluation (n=103)


Me

an

6

5

4

3

2

1

0

11

2

2

33

5

6

nachherTag 14Tag 7Tag 4Tag 3Tag 2Tag 1vorher

Me

an

6

5

4

3

2

1

0

11

2

3

3

4

4

5 Rhinorrhea


Me

an

7

6

5

4

3

2

1

0

22

2

3

4

4

5

6 Nasal obstruction


Me

an

6

5

4

3

2

1

0

111

2

3

3

4

6

SneezingItching


Me

an

6

5

4

3

2

1

0

11

2

2

3

3

4

5

Itchy eyes


Me

an

4,5

4,0

3,5

3,0

2,5

2,0

1,5

1,0

,5

1,11,1

1,4

1,9

2,3

2,6

3,2

3,9

Red eyes


Me

an

2,0

1,8

1,6

1,4

1,2

1,0

,8

,6

1,0

,8

1,11,0

1,31,2

1,3

1,8

nachherTag 14Tag 7Tag 4Tag 3Tag 2Tag 1

Me

an

8

7

6

5

4

3

2

1

0

111

5

4

7

6

Cough,itchy throat

(n=5)eczema(n=38)

CHUV, 9. 2. 2006

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

CHUV, 9. 2. 2006

Merci pour votre attention!

[email protected]

efficacy and safety of butterbur leaves extract ze 339 in ...chuv, 9. 2. 2006 efficacy and safety of...

Documents