DPhG Weihrauch-Symposiumanlässlich des 75. Geburtstages
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 1
Prof. Dr. Dr. h.c.mult. Hildebert Wagner
Center of Pharma Research – Department of Pharmacy – University of Munich
e-mail: [email protected]
von Prof. Dr. H. P. T. Ammon
5. April 2008
Boswellia and the Complement System:A multiherbal drug for multitarget therapy
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 2
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 3
Komplement-System
Bindeglied zwischen humoralen und zellulären Reaktionsketten in angeborenen und adaptiven Immunantworten
Klassischer Weg Alternativer WegInduktion über Binding an Antikörper auf
pathogenen ZellenInduktion durch Antikörper unabhängige
direkte Bindung an pathogene Zellen
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 4
Funktionen und biologische Wirkungen von Komplementfragmenten
n Eliminierung von Pathogenen (Bakterien, Viren, Tumorzellen) durch Opsonierung, Phagozytose und Lyse.
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 5
n Inhibierung einer Anaphylotoxin-Bildung (C5a, C3a, C4a-Komplementfaktoren) durch Hemmung der Komplementaktivierung (z.B. durch Boswelliasäuren)
n Stimulierung der Chemotaxis von Granulozyten und Makrophagen Eliminierung von Antigen-Antikörper-Komplexen ("Immunkomplexen")
Boswelliasäuren
H
H CH3
CH3
R2
CH3
CH3H3C
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 6
ββββ-Boswelliasäure: R1, R2 : H
Acetyl-ββββ-Boswelliasäure: R1 : – C – CH3, R2 : H
11-Keto-ββββ-Boswelliasäure: R1 : H, R2 : = O
Acetyl-11-Keto-ββββ-Boswelliasäure: R1 : – C – CH3, R2 : = O
O
=
O
=
HCOOH
H3C
R1O
Inhibition of the classical pathway (CP) and the alternative pathway (AP) of the complement system by
triterpenes: reduction of hemolysis (%)
Glycyrrhetic acid Oleanolic acid Ursolic acidCucurbitacin I
Concentration of test compounds
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 7
ββββ-Boswellic acid
Crataegolic acidQuillaic acid
50 – 60% Harz5 – 9% Ätherischöl
Inhaltsstoffe von Boswellia carteriGummmiresinol / Olibanum
n 1-Octylacetat
n 1-Octanol
n (Iso)Cembren
n (Iso)-Incensol
n ββββ-Boswelliasäure
n Acetyl- ββββ-Boswelliasäure
n 11-Keto- ββββ-Boswelliasäure
n Acetyl-11-Keto- ββββ-
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 8
Polysaccharide
n (Iso)-Incensol
n αααα, ββββ-Pinen
n Cadinen
n Campher
n αααα-Phellandren
n Borneol
n Verbenon
n (+)Carvon u.a.)
n Acetyl-11-Keto- ββββ-Boswelliasäure
n Tirucallsäure
n Homo-Heteroglucane
Fact
Several standardized phytoextract preparations (multidrug mixtures) show
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 9
at appropriate indications and dosages therapeutic equivalence with chemotherapeutics but with
less or lacking adverse effects in comparison to chemotherapeutics
What could be the causes ofthis therapy equivalence?
n Synergistic and multitarget actions of bioactive constituents of the extracts
n Enhancement of the solubility / resorption rate and thereby the bioavailability of bioactive compounds by concomitant
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 10
n Elimination or "neutralization" of adverse acting substances of extracts
n Interaction with resistance mechanisms of pathogenic microorganisms
the bioavailability of bioactive compounds by concomitant constituents of the extracts
Drug-synergism of phytopharmaceuticals
plant extract
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 11
overadditive, potentiated pharmacological effects
additive, agonistic pharmacological effects
different targets(multitargeting)
one target
n A total effect of a combination is greater than expected from the sum of the individual agents
E (da,db) > E (da) + E (db)
Definition of synergy according to Berenbaum (Pharmacol. Rev. 41:93-141,1989)
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 12
E = observed effect da and db = doses of agents a and b
n The effect of a combination is greater than that of each of the individual agents
E (da,db) > E (da) and E (da,db) > E (db)
Ginkgolide A [µM]
Ginkgolide B [µM]
14
12
10
8
6
4
2
O O
OH
O
O
O
OO
HO
HO
OH
OH
H
O O
OH
O
O
O
OO
HO
HO
OH
H
H
Isobol-curve for 50% inhibition of a Ginkgolide AB-combination*
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 13
IC50 – values for various dose-combinations of PAF-induced thrombocyte aggregation*
GA : GB
3 : 12 : 11 : 11 : 21 : 31 : 10
IC50 [µg/ml]
2.402.201.801.551.401.30
Ginkgolide A [µM]
4.413.602.211.270.880.29
Ginkgolide B [µM]
1.421.722.122.432.572.79
Ginkgolide B [µM]0
0.5 1 1.5 2 2.5 3 3.5
O H
Ginkgo biloba: Ginkgolide mixtures/ Chung et al. (1987)Ginkgo extract
Piper methysticum: Kava lactones/mixtures Singh and Blumental (1997)of Kava lactones and extract fractions
Glycyrrhiza glabra: Licorice extract potentiates Cantelli-Forti et al. (1994)
In vitro and in vivo pharmacological evidences for synergy effects
(according to Williamson, Phytomedicine 8(5):401-409 (2001)
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 14
Glycyrrhiza glabra: Licorice extract potentiates Cantelli-Forti et al. (1994)other substances and acts Kimura et al. (1992)as detoxifier Miaorong and Jing (1996)
Cannabis sativa: Cannabis extract / THC Zuardi et al. (1982)Baker et al. (2000)
Valeriana offic.: Valeriana extract/ Hölzl (1997)individual constituents
Zingiber offic.: Zingiber extract/ Beckstrom-Sternberg andmixture of volatile terpenoids Duke (1994)and mixtures
Kava-kava + Passiflora incarn. Capasso and Sorrentino (2005)
Presynaptic neuron
H+
Na++ ?
COMTMAO
?
β-adr.5-HT1A/2ADA2,3,4 NMDA
Scheme of proposed biological targets of Hypericum perforatum according to in vitro
studies
+_
_
_
HyperforinHypericum
FlavonoidsXanthones
Hypericum
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 15
_
Postsynaptic neuron
Hypothalamus
Cortisol
IL-6
Adrenal cortexPituitaryACTH
Prolactin
CRF
CRF
TRH
DA2,3,4 NMDA
Opioid
GABAA
BenzoSigma
5-HT6,7
H1,3
NK-I
_
_
HyperforinHypericum
Amentoflavon
HyperforinHypericum
Hypericum
Estrogen
13,118-Biapigenin
Hypericin
Therapy with willow bark extract in comparison with Aspirin
n Indication: osteo-arthritis of the hip and knee,feverish rheumatic disease,low back pain
n Recommended dosage: 1400 mg willow bark extract(ESCOP) @ 240 mg salicylalcohol-derivatives calc. as salicin
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 16
derivatives calc. as salicin
n Pharmacokinetic studies: 240 mg salicin ð 10 µMol/l salicylicacid; 1000 mg ASP ð 500 µMol/lsalicylic acid
n Clinical trials: Chrubasik et al. JAMA 109:9-14 (2000)Schmidt et al. Phytother. Res. 15:344-350 (2001) Bieger et al. J. Rheumatol. 31:212-213 (2004)
Synergism between herbal andother drugs I
Synergistic effects of Vitis vinifera seeds (grape seed extract = GSE) with amphotericin B (Amp) against disseminated Candidiasis in mice
Surv
ivors
2
3
4
5
11.4 ± 3.214.4' ± 2.617.6' ± 7.338.4 ± 8.0
MST (Days)
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 17
Ref. Yongmoon Han Phytomedicine 2007, in press
n Combination of grape seed extract with Amp. B results in a more than 75% reduction of Amp. B
n The MST value of the mice group which received the combination was greater than MST value from mice group given four times Amp. B dose of 2mg/kg bw.
Results
Days
Surv
ivors
0
1
4010 3020
DPBSAmp aloneGSE aloneAmp plus GSE
healthy tissueimmunostimulants
inhibitors of
Examples of multitarget therapy
Example 1: Cancer therapy
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 18
cancer cells
cytostatics
inducers of apoptosis
inhibitors of angiogenesis
stimulants ofoncogen-suppressor
genes
Progress in the field of synergy research and omic technology can
Conclusion
Prof. Dr. Dr. h.c.mult. Hildebert Wagner – Center of Pharma Research – Department of Pharmacy – University of Munich Folie 19
research and omic technology can give phytotherapy a new legitimacy and the possibility to treat diseases which up to now were reserved for
chemotherapy only