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International Herbal Conference 2009

Herbal Medicine Evaluating of Quality, Efficacy and Safety in the changing global Scenario Bangalore, February 26 28, 2009

Approaching a new generation of novel Phytopharmaceuticals Synergy-Research


Prof. H. Wagner
Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

e-mail: h.wagner@cup.uni-muenchen.de

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Facts
Of about 2000 registered acute and chronic diseases only

~40% are presently curable, a further ~40% diseases are only symptomatically or imperfectly treatable and ~20% not at all
The resistance of pathogenic microorganisms against

antibiotics is increasing dramatically


Of about 350000 plant species, including algae, protozoa,

fungi and bacteria only 20-30% have been investigated thoroughly and only 5-10% are used in Traditional Medicine

The paradigm "Monosubstance(drug) Therapy" failed, now gradually replaced by Multidrug and Multitarget-Therapy Synergy Research mandatory
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 2

Characteristic of novel Phytopharmaceuticals


Standardized, more effective and causatively acting mono-

or multiherbal extracts

Less or lacking side effects

Applicable alone for therapy or in combination with

synthetic drugs or antibiotics

Use also for the treatment of diseases which up to now were

reserved for the synthetic drugs or antibiotics only


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Folie 3

Which efforts are mandatory to achieve this goal?


Appointment of national commissions

inventory of traditionally used medicinal plants to evaluate the medicinal plant resources of a country

Development of Herbal Monographs with valuation of

quality, safety and efficacy of herbs and their extracts

Integration of all modern high-tech analytical and molecular

biological methods inclusive omic technology

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Folie 4

German Commission E-Monographs as model


378 plants used in traditional medicine have been investigated to determine their quality, safety and efficacy

245 positive monographs of single plants and fixed combinations

133 negative or zero-monographs (not recommended for therapy, negative-benefit-risk rate)

Supplemented by ESCOP-, WHO and European Pharmacopoea-Monographs inclusive special Analytical Monographs

Novel Phytopharmaceuticals
Herbal medicinal products from traditional use Herbal medicinal products of well established use ("evidence-based medicine")
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or

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

High-tech analytical and isolation methods for plant screening and isolation work
Thin-layer chromatography (TLC),

thin-layer electrophoresis (TLE) Isotachophoresis (TIP) Capillary electrophoresis (CE) Capillary electrochromatography (CEC) HPLC, gas chromatography (GC) HPLC coupled with MS (chemical and ionization or electrospray ionization technique) Liquid chromatography (LC coupled with UV/MS/NMR/Fourier transform ion cyclotron resonance (FT-ICR))
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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Books for Fingerprint Analysis

by Prof. Xiao Peigen

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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TLC Fingerprint Analysis of Angelicae sinensis radix (Danggui)


# 1 2 3 4 5 R Origin + Species A. sinensis A. sinensis A. sinensis A. sinensis A. sinensis Z-Ligustilide, linoleic acid, falcarindiol A. acutiloba A. dahurica A. pubescens
-Front

Koetzting 08.07.93 Singapore East Earth Herb Inc. Kanton 12.03.96 Kun Ming 12.03.96 Reference compounds + China, authentic China, authentic China, authentic

UV 254 nm
1 2 3 4 5 R 6 7 8

-Start -Front

7 8 9

UV 360 nm
1 2 3 4 5 R 6 7 8

-Start -Front

Anisaldehyde sulphuric acid reagent (VIS)


Zschocke S., Wagner H., Bauer R., Xiao P.G., Chen J.M.: Chinese Drug Monographs and Analysis, in press, 2000
1 2 3 4 5 R 6 7 8

-Start

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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HPLC Fingerprint Analysis of Angelicae pubescens radix (Duhuo), other species and adulterations
100 200
11 10 1 2 3 4 6 5 7 8 9 12

mAU

Angelica pubescens Angelica dahurica

mAU 200 400

10 a b c

Time (min) 20 g ef h i j

k 30

mAU 200 400 0

a b

10

Time (min) 20 g e f

h
i

30 k

Angelica apaensis Heracleum moellendorffii Heracleum candicans Aralia cordata

mAU 200 400

10 c

Time (min) 20 l n

30 k

mAU 200 400 0

10
o c

Time (min)
d

20
h i

30
k

mAU 0 200 400

10

Time (min)

20

30
k

10

Time (min)

20

30

Source: Liu Jianghua, Wagner H, Bauer R, Xiao PG, Chen JM: Chinese Drug Monographs and Analysis, Vol. 2(9), 1999
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Adulteration or mixups of the root of Stephania tetrandra (Hanfangji) with the root of Aristolochia fangchi (Guangfangji)
HPTLC- and HPLC-detection of Aristolochic acids in root samples of Stephania tetrandra
Front

R = 0,5

1 - 4: T1/2: 5: T3: 6 + 7:

Stephania root extract Tetrandrine + Fangchinolin Aristolochic acids I + II Aristolochiae radix Mixtures of Stephania- and Aristolochia root extracts

Start
1 2 3 4 T1/2 5 T3 6 7

Aristolochic acids detectable up to 8 pg/g Herbal drug

Absorbance (AU)

0,06

1
0,04 0,02 0,00 0 5 10 15 20 25 30 25 30

3 2 3

50:50 and 80:20 mixtures of Stephania- and Aristolochia root extracts

Retention Time (min)

Aristolochic acids detectable up to 400 pg


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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Differentiation of Codonopsis species by DNA fingerprinting


1 2 3 4 5 6 = Codonopsis pilosula = Codonopsis tangshen = Codonopsis modesta = Codonopsis nervosa = Campanumoea javania = Platycodon grandiflorus

M = 100 bp mol. weight marker

with a 800 bp intensive band


PCR-RFLP patterns of rDNA ITS using restriction enzyme Hha I after separation by 3.5 % TBE agarose gel
Fu et al., Planta Medica 65: 648-650 (1999)

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Composition of the Japanese herbal medicine Sho-seiryu-to extract (TJ-19)


Pinelliae pernatae tuber Glyzyrrhizae glabrae radix Cinnamomi cassiae cortex Schisandrae chin. fructus Asasari sieb. radix Paeoniae lactifl. radix Ephedrae sin. herba Zingiberis offic. rhizoma

Treatment of bronchitic asthma and allergic rhinitis


Amagaya et al. Phytomedicine 8: 338-347 (2001)
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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3 D HPLC fingerprint analysis of Sho-seiryu-to (TJ-19)extract produced from eight herbal drugs

S. Amagaya et al., Phytomedicine 8: 338-347 (2001)


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Omic Technology

Bio-chip
(photo by Miltenyi Biotec) Red: induction Green: repression Black: no differential regulation

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Futural aspects of the omic technology for Phytomedicine


Complex mixtures cause multitarget effects on molecular

base and lead to characteristic gene- and proteine expression profiles which are different of that of single compounds synergistic effects
Simplification of the standardization process of herbal drug

mixtures consequences for legislation and patenting


The National Center for Toxicogenomics (NCT) in USA, in the

National Institute of Environmental Health Science (NIEHS) provides a reference system of genome wide gene expression data the identification of the toxic potential of chemicals and plant extracts.
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Development of novel Phytopharmaceuticals New drugs of high priority worldwide wanted


Cancer
Therapeutics and preventives

Cardiovascular Antihypertonics Antiatherosclerotics diseases Antiischemics (drugs for stroke prevention) CNS diseases
Therapeutics and preventives for Alzheimer disease Parkinson
Antibacterial drugs (e.g. Antituberculostatics) Antiviral drugs (e.g. Anti-HIV, Anti-Hepatitis B + C) Antiparasidal drugs

Infectious diseases

(e.g. against Malaria, Chagas, Leishmaniasis) Antifungal drugs


Antiasthmatics Drugs against bowle syndrom Antineurodermitic / Antipsoriatic drugs
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Inflammatory diseases

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

High through put screening methods

Thousands of plant extracts or pure compounds can be screened per month


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Traditional Medicine of many countries used herbal drug combinations from its very beginning
Experiences
higher efficacy than a single herbal drug or constituent less or lacking side effects dose reduction possible

Hypotheses

complex (multicausal) pathophysiology can be better positively influenced by a drug combination

than by a single highly dosaged drug more causative therapy possible concomitant symptoms and damages also curable

Conclusion:

therapeutic superiority may be due to synergy- and multitarget effects


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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Synergy research as answer to the paradigm change in Drug Therapy

Monosubstance Therapy

Multidrug- and Multitarget- Therapy


(e.g. AIDS-, cancer-, hypertension-therapy)

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Comparison of the efficacy of different Anti-AIDS drug combinations


Increase of helper-T-cells (cells / mm3)
120 100 80 60 40 20

Decrease of HIV-1 RNA in plasma (log10 -copies / ml)


-0.5 -1 -1.5 -2 -2.5 -3

10

20

30

40

50

60

10

20

30

40

50

60

weeks

weeks

Zidovudin / Lamivudin / Delaviridin

Zidovudin / Delaviridin

Zidovudin / Lamivudin
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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Definition of synergy effects


(Berenbaum Pharmacol. Rev. 41:93-141,1989)
A total effect of a combination is greater than

expected from the sum of the individual agents


E (da,db) > E (da) + E (db)

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)
E = observed effect da and db = doses of agents a and b

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Pharmacological proof of synergy effects by the isobol method (Berenbaum 1985)


Dose B

Dose A
antagonism = negative interaction synergism = positive interaction or potentiation zero-interaction = effects-addition of individual components
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 23

Drug-synergism of phytopharmaceuticals

plant extract

one target

different targets (multitargeting) overadditive, potentiated pharmacological effects


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additive, agonistic pharmacological effects

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Isobol measurements of Ginkgolide AB-combination*


Ginkgolide A [M]
O H O O H O O H O H H O O O
14 12 10 8 6

O H O O H O O H O O H H O O O

O H

O H

4 2

Ginkgolide B [M]
0.5 1 1.5 2 2.5 3 3.5

IC50 values for various dose-combinations of PAF-induced thrombocyte aggregation*


GA : GB 3: 1 2: 1 1: 1 1: 2 1: 3 1 : 10 IC50 [g/ml] 2.40 2.20 1.80 1.55 1.40 1.30 Ginkgolide A [M] 4.41 3.60 2.21 1.27 0.88 0.29 Ginkgolide B [M] 1.42 1.72 2.12 2.43 2.57 2.79
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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

What could be the causes of therapeutic superiority of many herbal drug combinations?
Synergistic multitarget action of extract constituents

Concomitant constituents increase the solubility and

resorption rate and thereby the bioavailability of bioactive compounds


Interaction of one component of the drug combination

(antibiotic drug) with resistance mechanism of pathogenic microorganisms


Elimination or "neutralisation" of adverse acting compounds

by components of the drug combination


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Major constituents of Hypericum perforatum extract

HO

OH

Flavonoids (Rutin, Hyperoside, Quercetin, 13,18-Biapigenin) 5 12%

Hyperforin (Adhyperforin) 1 7%

Hypericin, Pseudohypericin 0.1 0.4%

Procyanidins, Tannins 2 15%

Xanthones (traces)

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Multitarget effects of Hypericum perforatum according to in vitro studies


Presynaptic neuron COMT MAO
_ _

H+ + Na+ ? ? +

Flavonoids Xanthones

Hypericum

Hyperforin Hypericum
Amentoflavon Estrogen
_

Hyperforin Hypericum 13,118-Biapigenin Hypericum


_

b-adr. 5-HT1A/2A DA2,3,4 NMDA GABAA Benzo Sigma Opioid 5-HT6,7 NK-I H1,3

Postsynaptic neuron
Hypothalamus

IL-6 Cortisol Adrenal cortex

CRF TRH CRF _

Hypericin Pituitary

ACTH Prolactin

U. Simmen et al. Pharmacopsychiatry 34 Suppl.. 1: 137-142 (2001)


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Multivalent pharmacological effects of Hypericum-extracts


Chemistry: Hypericins, hyperforin, flavonoids, procyanidins
blockade of 2-receptors modulation of breceptorpacking

down regulation of 5-HT2-receptors

Antidepressive Anxiolytic Nootropic Antiepileptic

monoamine oxidase inhibition

modulation of neurotransmitter concentrations

(Nor-adrenalin, serotonin, GABA, L-glutamate)


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 29

Arguments for existing synergy effects of Hypericum perforatum extracts I


The accompanying procyanidin B2 and hyperoside of the hypericum extract increase the water solubility and oral bioavailability of hypericin by 58% / 34% as evidenced by the forced swim test (Porsolt test)
10

Hypericin [ng/ml]

Hypericin + procyanidinB2

Hypericin

*
0 0 100 200 300 400 500 600 700 800 900 1000 1100

[min]

Plasma levels of hypericin in the presence ( ) and absence ( ) of procyanidin B2


Butterweck et al. Planta Med. 69:189-192 (2003)
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Tetrahydrocannabinol (THC) exerts polyvalent pharmacological activities


antiphlogistic

anxiolytic
OH

antiemetic

analgesic

C 5H11

9-THC

muscle relaxing

appetite stimulating

sedative
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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Pharmacological evidence for synergistic effects


Percentage change in resistance to Flexion SEM
10 0 -10 -20 -30 -40 -50 0 10 20 30 40 50 60 Time (min) 70 80 90
P<0.002 by ANOVA

9Tetrahydrocannabinol (1mg/kg) Cannabis extract (5mg/kg)


Containing 20% 9THC

* *** ***
##

**

***
##

***

Cannabis extract is a better antispastic agent in mice than tetrahydro-cannabinol (THC) at an equivalent dose.
Baker et al. Nature 404:84-87; (2000); in E.M. Williamson Phytomedicine 8(5):401-404 (2001)
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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In vitro and in vivo pharmacological evidences for synergy effects


(according to Williamson, Phytomedicine 8(5):401-409 (2001)
Ginkgo biloba: Ginkgolide mixtures/ Ginkgo extract Piper methysticum: Kava lactones/mixtures of Kava lactones and extract fractions Glycyrrhiza glabra: Licorice extract potentiates other substances and acts as detoxifier Cannabis sativa: Cannabis extract / THC
Valeriana offic.:

Chung et al. (1987)


Singh and Blumental (1997)

Valeriana extract/ individual constituents Zingiber offic.: Zingiber extract/ Beckstrom-Sternberg and mixture of volatile terpenoids Duke (1994) and mixtures Kava-kava + Passiflora incarn. Capasso and Sorrentino (2005)
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Cantelli-Forti et al. (1994) Kimura et al. (1992) Miaorong and Jing (1996) Zuardi et al. (1982) Baker et al. (2000) Hlzl (1997)

Strategies of bacteria to antagonize the effect of antibiotics


A
Receptor or active site modification

C penetration
C*

Decreased

Increased efflux

A* D*

B*

B Enzymatic degradation or
modification of antibiotic
antibiotic drug receptor modified receptor efflux pump enzyme degradation of the drug (Mukesh Doble, Review Phytomedicine in press)

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Synergistic effect of Pelargonium graveolens essential oil with Norfloxacin in inhibiting Staphylococcus aureus ATCC 6538 I
A. Rosato at al. Phytomedicine 14:727 (2007)
The isabole method describing synergy Staphylococcus aureus ATCC 6538
0,6 Norfloxacin g/ml 0,5 0,4 0,3 0,2 0,1

0,1

0,2

0,3 0,4 0,5 0,6 Pelargonium graveolens oil mg/ml

0,7

0,8

Pelargonium graveolens + Norfloxacin Pelargonium graveolens oil mg/ml FIC* = 0.25 FICI = 0.37 Norfloxacin g/ml FICI** = 0.12
* FIC = Fractional inhibitory concentration ** FICI = FIC index = FIC of oil + FIC of Norfloxacin
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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Synergism between herbal and other drugs II


Synergistic effects of 7-Methyl-Juglone (7-MJ) in combination with antituberculous drugs against Mycobacterium tuberculosis
Intercellular MICs and FICs of combination of drugs acting against M. tuberculosis by the radiometric BACTEC method
MIC1) (g/ml) and FIC2) of drugs and drug-combinations against M. tuberculosis H37Rv strain H37Rv 7-Methyl-Juglone (7-MJ) Rifampicin (RMP) Isoniazide (IN) 7-Methyl-Juglone + Rifampicin 7-Methyl-Juglone + Isoniazide
1) Minimum inhibitory concentration 2) Fractional inhibitory concentration

MIC g/ml 5 0.5 0,06 1.25/0.125 0.62/0.007

FIC g/ml 0.5 0.24


FIC 0.5 synergistic effect FIC = 1 additive effect FIC > 2 antagonistic effect

Results

7-MJ has superior extracellular and intracellular activity against M.t. relative to streptomycin The combination of 7-MJ with IN reduces the MICs of both compounds by eight-fold

NB Bapela et al. Phytomedicine 2006, 13:630-635


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Synergism between herbal and other drugs III


Synergistic effects of Vitis vinifera seeds (grape seed extract = GSE) with amphotericin B (Amp) against disseminated Candidiasis in mice
5 4

Survivors

MST (Days) DPBS Amp alone GSE alone Amp plus GSE
10 20 30 40

3 2 1

11.4 14.4' 17.6' 38.4

3.2 2.6 7.3 8.0

Days

Results

Combination of grape seed extract with Amp. B results in a more than 75% reduction of Amp. B 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 0,5mg/kg bw.

Ref. Han Yongmoon Phytomedicine 2007, in press


Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 37

Synergism between natural products and antibiotics against bacterial infection I


(Hemaiswarya et al., Phytomedicine 15: 639 - 652 (2008))
OH HO HO O HO O HO OH OH HO OH HO CO O OH HO CO O O CO O OC OH OH OH HO HO O CH2 O OH O O O
6

OH

HO

HO HO

OH
OH O OH

O O
3

O OH OH

OH

Epigallocatechin gallate (EGCg)

HO
OH

OH OH

Corilagin

Tellimagrandin I

Natural products: e.g. Rugosin B, Tea catechin, Baicalin, Plumbagin, isoflavones, essential oil (e.g. 1,8-cineol, -terpineol)

+
Antibiotics: e.g. Penicillin, Ampicillin, Vanomycin, Gentamicin, Ciprofloxacin, Tetracycline, Erythromycin

=
Modifiers of Multidrug resistance mechanisms
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 38

Synergism between natural products and antibiotics against bacterial infection II


(Hemaiswarya et al., Phytomedicine 15: 639 - 652 (2008))
Isopimaric acid Carnosic acid Carnosol

OH HO O H OO C O C O2 H HO

OH

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Folie 40

Comparative double blind study with Hypericum extract and Imipramine


Indication: moderate neurotic depression
Score
Imipramine 25 20 15 10 5 0 1 2 4 6 Li 160

Weeks

Dosage:

3 x 300 mg extract /day 80-100 mg Hypericines, Hyperforine, Amentoflavone, Procyanidines Imipramine: 3 x 25/35 mg Hypericum:

Parameter: Hamilton-Depression Scale (HAMD)


Vorbach et al. 1997 / Woelk 2000
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 41

Multitarget therapy of dyspepsia and motilityrelated disorders of the gastrointestinal tract with a combination of 9 plant extracts
Iberis amara (totalis)
Angelica archangelica (radix) Matricaria chamomilla (flos) Carum carvi (fruits) Silybum marianum (fruits) Melissa officinalis (folium) Mentha piperita (folium) Chelidonium majus (herba) Glyzyrrhiza glabra (radix)
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 42

Clinical evidence of Iberogast, a multidrug phytopharmaceutical for the treatment of dyspepsia

12 clinical trials and 3 metaanalyses performed

Clinical studies in comparison with the

prokinetics Metoclopramide and Cisapride

Result: Full therapeutic equivalence or superiority over the synthetic drugs No or lesser side effects
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 43

Treatment of dyspepsia and motility-related disorders of the gastrointestinal tract


with a herbal drug combination (Iberogast , consisting of 9 plant extracts)
Multiple mechanisms of the disease
Iberis Angelica Carum Silybum Chelidonium Glycyrrhiza Chamomilla Melissa Mentha

atonia
hypo- hypermotility motility

spasms

acid secretion

ulcus/ inflammation

radical production

Phytomedicine Suppl. V 13 (2006)

none

moderate

strong effects
Folie 44

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Option for Monotherapy


Hypermotility
Spasmolytic agent (Buscopan )

Hypomotility

Prokinetics (e.g. Cisaprid , Metoclopramid , 5-HT-Antagonists)

Hypersensibility

no standard therapy available

Hyper acid secretion

proton pump inhibitor (e.g. Omeprazol )

Inflammation/Ulcus

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Folie 46

Combination of natural products and synthetic drugs to combat fungal infections


(Hemaiswarya et al., Phytomedicine 15: 639 - 652 (2008))
Natural products
Allium sativum Essential oils of Peucedanum grav. Agastache rugosa (estragole) Euphorbia characias Santolina oil Anethol

Synthetic drugs
Ketaconazole Ketaconazole Ketaconazole Ketaconazole Clorimazole Miconazole

Fungal species
Trichophyton spec. Trichophyton spec. Trichophyton spec. Trichophyton spec. Candida albicans Candida albicans

Essential oil of Thymus vulgaris

Amphotericin b

Candida albicans
Folie 47

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Future Outlook of Antimalaria Drugs


Malarone, artemisinin derivatives combined with

lumefantrine or doxycycline and mefloquine combined with tetracycline or doxycycline have been evaluated with improvement of the cure rate in uncomplicated malaria
Artemisinin derivatives intravenously or

intrarectally combined with mefloquine may be alternatives to intravenous quinine for treatment of severe malaria
Arch. Med. Res. 33: 416 - 421 (2002)
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
Folie 48

Futural multitarget therapy I


Example 1: Cancer therapy

immunostimulants

healthy tissue

inhibitors of angiogenesis

cytostatics
stimulants of oncogen-suppressor genes

cancer cells
inducers of apoptosis

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Folie 49

Futural multitarget therapy II


Example 2: Therapy of Hepatitis B+C
immunostimulants antioxidants antifibrotics antiinflammatory drugs HBV/HCV

Liver

Virostatic drugs

inhibitors of apoptosis liver protecting agents

Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

Folie 50

Conclusion Progress in the field of high tech analysis, molecular biology, synergy 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
Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany
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Prof. H. Wagner Center of Pharmacy Research Pharmaceutical Biology University of Munich Germany

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