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page 1. 2006 World Congress on Chinese Medicine Synergy Research – a new approach to evaluate the efficacy of multi herbal drug combinations in TCM 23 – 25 November 2006, Hong Kong. H. Wagner h.wagner@cup.uni-muenchen.de.

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  1. page 1 2006 World Congresson Chinese Medicine Synergy Research – a new approach to evaluate the efficacy of multi herbal drug combinations in TCM 23 – 25 November 2006, Hong Kong H. Wagner h.wagner@cup.uni-muenchen.de Department of Pharmacy, Center of Pharma Research – University of Munich

  2. Traditional Medicine of many countries has used primarily herbal drug combinations from its very beginning • In most cases higher efficacy than a single herbal drug • Less or lacking adverse effects in comparison to single herbs or isolated single constituents • Dose reduction of the single components of the combination possible

  3. Complex Pathophysiology • Hypothesis, meanwhile in many cases approved: A complex pathophysiology can be influenced more positively by a combination of several low dosaged constituents or the corresponding extracts than by a single highly dosaged isolated constituent, a synthetic compound or a single plant extract.“

  4. In Chemotherapy we observe a pradigm shift Monodrug Therapy • Multidrug- and Multitarget- Therapy(e.g. AIDS-, cancer-, hypertension-therapy)

  5. -0.5 120 100 -1 80 -1.5 60 -2 40 -2.5 20 -3 0 0 10 10 20 20 30 30 40 40 50 50 60 60 weeks weeks Comparison of the efficacy of differentAnti-AIDS drug combinations Increase of helper-T-cells(cells / mm3) Decrease of HIV-1 RNAin plasma (log10 -copies / ml) Zidovudin / Lamivudin / Delaviridin Zidovudin / Delaviridin Zidovudin / Lamivudin

  6. Novel multitarget therapy of cancer immunostimulants healthy tissue inhibitors of angiogenesis cytostatics stimulants ofoncogen-suppressorgenes cancer cells inducers of apoptosis

  7. Drug-synergism of phytopharmaceuticals plant extract different targets(multitargeting) one target additive, agonistic pharmacological effects overadditive, potentiated pharmacological effects

  8. E = observed effect da and db = doses of agents a and b Definition of synergy according to 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)

  9. Pharmacological proof of synergy effects by the isobol method (Berenbaum 1985) Dose B antagonism zero-interaction synergism Dose A antagonism = negative interaction synergism = positive interaction or potentiation zero-interaction = effects-addition of individual components

  10. 14 12 10 8 6 4 2 0 zero-interaction synergism 0.5 1 1.5 2 2.5 3 3.5 Isobol-curve for 50% inhibition of a Ginkgolide AB-combination* Ginkgolide A [µM] Ginkgolide B [µM] 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 [µg/ml] 2.40 2.20 1.80 1.55 1.40 1.30 Ginkgolide A [µM] 4.41 3.60 2.21 1.27 0.88 0.29 Ginkgolide B [µM] 1.42 1.72 2.12 2.43 2.57 2.79

  11. OH 9-THC C H O 5 1 1 Tetrahydrocannabinol (THC) exerts polyvalent pharmacological activities antiphlogistic antiemetic anxiolytic muscle relaxing analgesic appetite stimulating sedative

  12. 10 0 -10 -50 D9Tetrahydrocannabinol (1mg/kg) Cannabis extract (5mg/kg) Containing 20% D9THC P<0.002 by ANOVA -20 -30 -40 0 10 20 30 40 50 60 70 80 90 Pharmacological evidence for synergistic effects • Percentage change in resistance to Flexion ± SEM Time (min) 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)

  13. Polyvalent effects of herbal drugs • Pharmacological effects of Garlic preparations Inhibition of thrombocyte aggregation Allicin Ajoene 2-Vinyl dithin Oligosulfids CyclooxigenaseI + II / 5lipoxygenaseinhibition Apoptosisinducing effectin humanleucemic cells Antioxidative Cholesterinbiosynthesisinhibition Inhibition ofiNOS expression

  14. Clinical evidences of synergy effects(according to Williamson, 2001) • Salix alba (Schmidt et al. 2001) • Hypericum perf. (Schultz et al. 2000) • Valeriana off. + Humulus lupulus (Hindmarch 1975) • Valeriana + Kava-kava (Wheatley 2001) • Urtica dioica + Pygeum africanum (Hartmann et al. 1990) • Ginseng + Ginkgo (Scholey and Kennedy 2001)

  15. Which mechanisms underlie the pharmacological and therapeutic synergy effects ? • enhancement of bioavailability by increased solubility and/or resorption rate of individual constituents of an extract • polyvalent and multitarget actions of individual constituents of an extract • elimination of undesired antagonistic effects by constituents of an extract

  16. Application of the Omic (microarray/biochip) technologies in Phytomedicine • G. Ulrich-Merzenich, H. Zeitler,D. Jobst, D. Panek, H. Wagner,Phytomedicine in press for issue January 2007 Change of paradigms towards the application of complex mixtures in medicine  a new field of phytogenomics, proteogenomics and metabolomics Increase of the number of proteins/genes that can be detected simultaneously(200.000 spots of oligonucleotides/cm2) Possibility to relate complex mixtures to complex effects in form of gene/protein expression profiles

  17. Omic Technology I Bio-chip (photo by Miltenyi Biotec) Red:induction Green:repression Black: no differential regulation

  18. Omic Technology II Cluster analysis

  19. Futural aspects of the omic technology for Phytomedicine • Complex mixtures cause multitarget effects on molecular base an 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.

  20. First results of the DNA-Microarray application to Phytomedicines I • The gene expression profiles induced by two sojabean extracts were compared with those of the single phytoestrogens (daidzein, genistein). • The profiles of the extracts correlated with those of the phytoestrogens, but the estimated concentrations of phytoestrogens in the extracts were roughly 1/100 of 10 µM pure daidzein used.

  21. How can the multitarget therapy concept be rationalized for the TCM-therapy ? • Enhanced research efforts to search for the major bioactive compounds of TCM-drugs • Improvement of the fingerprint analytical technique and standardization methods • Systematic pharmacological investigations of single TCM-drugs and fixed TCM-formulars • Integration of the OMIC (Microarray) technique • Controlled clinical trials

  22. First attempts to transfer the multitarget concept into a TCM-multidrug combination and to rationalize it Stroke therapy in TCM: • Prospects for drug discovery and development By X. Gong and N.J.Sucher Phytomedicine 9: 478-484 (2002)

  23. Existing standard therapy for ... Acute therapy Anti-coagulants Thrombolytics rt-PA + Aspirin + (Heparin) plasminogen activator given within 3hrs stroke onset Stroke recovery -blockers ACE inhibitors Adrenoceptor agonists Nootropics N-methyl- D-aspartate (NMDA)-antagonists Stroke prevention Anti-coagulants Inhibitors of platelet adhesion and aggregation HMG-CoA-reductase inhibitors

  24. TCM equivalent of stroke is a syndrome called 'wind stroke' Characterized by facial paralysis dysphasia,or aphasia and/or hemiplegia, caused by'internal or external wind' 'Yin and Qi weakness, liver fire, wind phlegm,phlegm-dampness or blood stasis'

  25. Pathogenic factors causing 'wind stroke' according to TCM The ethiology of wind stroke may involve relationships and interactions Imbalance between Yin and Yang Disturbance of the blood and Qi circulation Deficiency of 'liver Yin' and kidney Yin Stagnation of phlegm and dampness Externalwind Stag-nation Phlegm Internalliverwind Fire

  26. TCM-stroke therapeuticals • > 100 Chinese medicines used for stroke prevention and therapy 'Drugs for treatment of exterior syndrome ('diaphoretics'), clearing away internal heat' = Antipyretics? = Antiinflammatory drugs Drugs for relieving rheumatism Drugs for promoting the circulation of blood and removing stasis = Antithrombotic drugs 'Drugs for calming the liver and subduing wind' = Neuroprotective drugs Source: Huong, 1994

  27. Major active constituents of TCM-drugs used for „wind stroke“ therapy Salvia mil- tiorrhiza (radix) Paeonia rubra/ lactiflora (radix) Stephania tetrandra (radix) Uncaria rynchophylla (bark) CorynoxeineTetrandrine Tanshinone I Paeoniflorin Cnidiumlactone Tetramethyl-pyrazine Gastrodin Ligusticum chuanxiong (rhizoma) Gastrodia elata (rhizoma)

  28. X. Gong and N.J. Sucher, Stroke therapy in traditional Chinese medicine (TCM):prospects for drug discovery and develpment Phytomedicine 9, 478-484 (2002) Radix Salviae miltiorrhizae Radix Stephaniae tetrandae Radix Paeoniae rubrae 4 3 1 2 Rhizoma Ligustici Rhizoma Gastrodiae Ramulus Uncariae Overall pharmacological profile of a TCM fixed combination for stroke therapy celebral blood flow increasing microcirculation improving antithrombotic neuroprotective antiischemic inhibition of lipid peroxides

  29. Pharmacological profile of TCM-anti-stroke drugs

  30. Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice • Panel of coronal slices of the brain 24h after middle cerebral artery occlusion Control Tanshinone IIA treatment The slices were stained with TTC to show the area of infarct (white) Tanshinone IIA treatment showed a significant decrease in infarct when compared with control Source: N. J. Sucher et al., Phytomedicine 10:286-291, 2003

  31. Summary TCM drugs Groups of TCM drugs have been identified as potential sources for compounds with pre-dominant effects on: The chemical and pharmacological evaluation of TCM drugs for stroke therapy and prevention has revealed that it is possible to rationalize most of the TCM concepts in terms of Western Medicine Circulation Thrombogenesis Inflammatory processes Neuroprotection

  32. East meets West Synergy research and omic technology might be the key to evaluate and rationalize the TCM-concept of therapy Research is the Best Medicine

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