Wagner 26 Key Note Address

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
Folie 1
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
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

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
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")
Folie 5
or
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))
Folie 6
Books for Fingerprint Analysis
by Prof. Xiao Peigen
Folie 7
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
Folie 8
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
Folie 9
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

Folie 10
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)
Folie 11
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)
Folie 12
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)

Folie 13
Omic Technology
Bio-chip
(photo by Miltenyi Biotec) Red: induction Green: repression Black: no differential regulation
Folie 14
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.
Folie 15
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
Folie 16
Inflammatory diseases
High through put screening methods
Thousands of plant extracts or pure compounds can be screened per month

Folie 17
Folie 18
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

Folie 19
Synergy research as answer to the paradigm change in Drug Therapy
Monosubstance Therapy
Multidrug- and Multitarget- Therapy

(e.g. AIDS-, cancer-, hypertension-therapy)
Folie 20
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
Folie 21
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
Folie 22
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
Folie 23
Drug-synergism of phytopharmaceuticals
plant extract
one target
different targets (multitargeting) overadditive, potentiated pharmacological effects

Folie 24
additive, agonistic pharmacological effects
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
Folie 25
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

Folie 26
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)
Folie 27
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)

Folie 28
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)

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)
Folie 30
Tetrahydrocannabinol (THC) exerts polyvalent pharmacological activities

antiphlogistic
anxiolytic
OH
antiemetic
analgesic
C 5H11
9-THC
muscle relaxing
appetite stimulating
sedative
Folie 31
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)
Folie 32
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)
Folie 33
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)
Folie 34
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
Folie 35
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

Folie 36
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

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
Folie 38
Synergism between natural products and antibiotics against bacterial infection II

Isopimaric acid Carnosic acid Carnosol
OH HO O H OO C O C O2 H HO
OH
Folie 39
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
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)
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
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
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
Folie 45
Folie 46
Combination of natural products and synthetic drugs to combat fungal infections

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
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)
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
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
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
Folie 51
Folie 52

Wagner 26 Key Note Address

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International Herbal Conference 2009

Approaching a new generation of novel Phytopharmaceuticals Synergy-Research

antibiotics is increasing dramatically

Characteristic of novel Phytopharmaceuticals

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

Which efforts are mandatory to achieve this goal?

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

German Commission E-Monographs as model

245 positive monographs of single plants and fixed combinations

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

Books for Fingerprint Analysis

by Prof. Xiao Peigen

TLC Fingerprint Analysis of Angelicae sinensis radix (Danggui)

Anisaldehyde sulphuric acid reagent (VIS)

Angelica pubescens Angelica dahurica

mAU 200 400

mAU 200 400 0

Angelica apaensis Heracleum moellendorffii Heracleum candicans Aralia cordata

mAU 200 400

mAU 200 400 0

mAU 0 200 400

Aristolochic acids detectable up to 8 pg/g Herbal drug

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

Retention Time (min)

Aristolochic acids detectable up to 400 pg

Differentiation of Codonopsis species by DNA fingerprinting

M = 100 bp mol. weight marker

with a 800 bp intensive band

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

Treatment of bronchitic asthma and allergic rhinitis

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

Futural aspects of the omic technology for Phytomedicine

mixtures consequences for legislation and patenting

Development of novel Phytopharmaceuticals New drugs of high priority worldwide wanted

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

High through put screening methods

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

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

therapeutic superiority may be due to synergy- and multitarget effects

Synergy research as answer to the paradigm change in Drug Therapy

Multidrug- and Multitarget- Therapy

Comparison of the efficacy of different Anti-AIDS drug combinations

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

Zidovudin / Lamivudin / Delaviridin

Definition of synergy effects

expected from the sum of the individual agents

The effect of a combination is greater than that of

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

different targets (multitargeting) overadditive, potentiated pharmacological effects

additive, agonistic pharmacological effects

Isobol measurements of Ginkgolide AB-combination*

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

Concomitant constituents increase the solubility and

resorption rate and thereby the bioavailability of bioactive compounds

(antibiotic drug) with resistance mechanism of pathogenic microorganisms

by components of the drug combination