TCM as Science and Evidencebased Clinical Practice Olavi
TCM as Science and Evidencebased Clinical Practice Olavi Pelkonen Department of Pharmacology and Toxicology University of Oulu, Finland olavi. pelkonen@oulu. fi Possible Synergies between Western and Traditional Chinese Medicines, Prague, Czech Republic, Feb 23, 2017.
Olavi Pelkonen – frame of reference and/or conflict of interest • EMA/HMPC: co-opted member (in toxicology) 2005 – 2016 • EFSA: panel member of the PPR Panel 2015 -2018 • WHO working group on interaction of herbal medicines with other medicines • Collaboration - Pharma companies (Orion etc) from 1979 up to 2007 • SMEs/startups (Novamass, Admescope) from 1998 until 2010 • Retired May 1, 2010
Problems concerning plant-derived herbal medicines • Inadequate evidence base, despite relevant druglike activities • Conceptual frameworks partially incompatible with science-based medicine • Quality of publications often ’uneven’ • Poor quality control and misuse ( ADRs) • Lack of use of proper scientific tools to address complexity and individuality • Limited funding and collaborations
Change of disease landscape • Chronic diseases often complex – multiple pathways and derangements Conventional therapy – polypharmacy • Herbal medicines – multiple components for multiple targets and pathways Personalized prevention and treatment Basic and clinical research
Complex drugs require complex tools § HMs are complex primarily plant extract-based medicines with numerous constituents (50 -500 primary components) § PK/PD characteristics of individual components can be studied with established methods, but complex mixtures require omics techniques § Due to complexity, ‘omics’ approaches and integrated system thinking are required at all levels of study of HMs § Clinical trials, in principle, “integrate” the PK/PD of HM at the level of therapeutic/adverse outcomes and are thus equally important to HMs as for conventional drugs
Tools Genomics, epigenomics (PCR, NGSeqs) Transcriptomics (PCR, NGSeq)s Proteomics (2 DGE, MS, IA)s Metabolomics (NMR, MS)s Biomarkers See, Jiang et al, Exp Opin Drug Metab Toxicol 2015
Potential role of omics in research and development of herbal medicinal products Analytical Quality control Genomewide Expression profiles PD-TD/PK-TK Omics techniques Biomarkers for Preclinical and clinical studies Bioavailability Internal xenometabolome Mechanisms of actions screening Integration and analysis of data by systems biology approaches
The GP-TCM JEP Special Issue 20 open-access papers on state of art & Gx. Ps
中医药规范研究学会 The Good Practice in Traditional Chinese Medicine Research Association Founded in Leiden, April 16 th, 2012
Oulu 65 o North
Multi-component medicines Multi-component therapeutics, including herbal medicines, is defined as ‘a concerted pharmacological intervention of multiple compounds interacting with multiple targets and possessing mutually interdependent activities that are required for an optimal effect’ (Chan 1995). Chan K. Progress in traditional Chinese medicine. Trends Pharmacol Sci 1995; 16(6): 182 -187.
Multi-component medicines With complex medicines, the interactions between components of the medicine and potential molecular targets are more complex than those associated with a single chemical entity Chinese authors stress that the active principle in TCM is actually the whole complex medicinal preparation (via a multitude of direct and indirect interactions) The reductionistic approach is not appropriate for multicomponent medicines (Xue & Roy 2003) Instead, more global, systems biology approaches should be applied (Wang et al 2009) Wang J, van der Heijden R, Spruit S, Hankermeier T, Chan K, van der Greef J, Xu G, Wang M. Quality and safety of Chinese herbal medicines guided by a systems biology perspective. J Ethnopharmacol 2009; 126(1): 31 -41. Xue T, Roy R. Studying traditional Chinese medicine. Science 2003; 300(5620): 740 -741.
TCM and metabolomics The link between TCM and “classical” molecular pharmacology metabolomics due to its ability to analyze, in principle, multiple complex mixtures simultaneously (TCM complex mixtures are suggested to induce multiple changes in endogenous metabolome) (Wang et al 2005; Qiu 2007).
Science supplements (Tai-Ping Fan, Cambridge Uni, UK) • • 1 st part December 2014 2 nd part January 2015 3 rd part October 2015 4 th part March 2016? Williamson EM, Chan K, Xu Q, Nachtergael A, Bunel V, Zhang L, Ouedraogo M, Nortier J, Qu F, Shaw D, Liu X, Stévigny C, Kahumba J, Pelkonen O, Duez P. Evaluating the safety of herbal medicines: Integrated toxicological approaches. Science 2015; 347 (6219 Suppl): S 47 -S 49. DOI: 10. 1126/science. 347. 6219. 337 -c
Characteristics of herbal medicines Complex plant-derived mixtures Variable composition of products Seasonal and geographical variations Plant varieties Unknown active ingredients Identification may also be uncertain Manufacturing and storage variations Variable formulations and dosages However, in principle exposure is defined!
Unanswered questions concerning plant -derived herbal medicines • Is it necessary/desirable/feasible to screen all the identifiable components by in silico/in vitro/HTP/etc for virtual/actual outcomes or is the threshold analysis adequate? • what is the reliability of assessing a single component by the threshold analysis against the background of a complex mixture of partially unknown composition? • What is the value of a composite exposure estimation of a variable chemical mixture in the frame of the threshold analysis?
Acknowledgements • HMPC/EMA since 2005 (Konstantin Keller/Werner Knöss/Gert Laekeman/ Jacqueline Wiesner etc) • The Academy of Finland Diet/herb project 2006 -2011 (Khaled Abass, Danielle Sevior, Jorma Ahokas, Moshe Finel, Pia Vuorela) • FP 7 Project GP-TCM 2009 -2012 (Qihe Xu, Tai-Ping Fan, De-an Guo, Halil Uzuner, Pierre Duez etc)
Problems of endo- vs xenometabolomes Lan & Jia, CDM 2010
Lan & Jia, CDM 2010
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