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Copyright and Use of This Thesis This Thesis Must Be Used in Accordance with the Provisions of the Copyright Act 1968 COPYRIGHT AND USE OF THIS THESIS This thesis must be used in accordance with the provisions of the Copyright Act 1968. Reproduction of material protected by copyright may be an infringement of copyright and copyright owners may be entitled to take legal action against persons who infringe their copyright. Section 51 (2) of the Copyright Act permits an authorized officer of a university library or archives to provide a copy (by communication or otherwise) of an unpublished thesis kept in the library or archives, to a person who satisfies the authorized officer that he or she requires the reproduction for the purposes of research or study. The Copyright Act grants the creator of a work a number of moral rights, specifically the right of attribution, the right against false attribution and the right of integrity. You may infringe the author’s moral rights if you: - fail to acknowledge the author of this thesis if you quote sections from the work - attribute this thesis to another author - subject this thesis to derogatory treatment which may prejudice the author’s reputation For further information contact the University’s Director of Copyright Services sydney.edu.au/copyright Probing herb induced liver injury (HILI) using population data and computational phyto-analysis Woroud Alzaher 430560040 A thesis submitted in fulfilment of the requirements for the degree of Master of Philosophy University of Sydney August 2014 1 I declare that the research presented here is my own original work and has not been submitted to any other institution for the award of a degree Signed: Date: 2 ACKNOWLEDGMENTS I would like to express the deepest appreciation to my supervisor Dr. Romano Fois for his tremendous support throughout the research project and for his endless guidance, enthusiasm, stimulating discussions and patience. I would also like to sincerely thank my supervisors - Professor David Hibbs for his incredible support throughout the research project, ample encouragement and superb search strategies,Professor Iqbal Ramzan for his valuable support throughout the research project, valuable comments and hard questions and Professor Joanne Barnes for her valuable support throughout the research project, her insightful and thought provoking comments and encouragement. I would also like to thank Associate Professor Timothy Chen and Professor Andrew McLachlan for their help, comments and encouragement. I deeply thank my fellow team members, Carmen Wong and Samuel Ho for their valuable help, awesome team work and for the fun we had. It could not have been a better experience and I could not have asked for a better team of students or supervisors. I would like to thank my family, who have been of tremendous support, for their energizing motivation, encouragement and for reminding me of the bigger picture. 3 TABLE OF CONTENTS 1 ABSTRACT ...................................................................................................................................... 14 1 CHAPTER 1: LITERATURE REVIEW ................................................................................................. 16 1.1 Introduction ............................................................................................................................. 16 1.2 Definition of herbal medicines................................................................................................. 17 1.3 Herbal medicine safety ............................................................................................................ 18 1.4 Herb-induced liver injury (HILI) and drug-induced liver injury (DILI) ....................................... 20 1.5 HILI epidemiology .................................................................................................................... 20 1.6 Risk factors ............................................................................................................................... 23 1.7 HILI toxicity profiles ................................................................................................................. 23 1.8 Causality assessment in HILI .................................................................................................... 31 1.9 Mechanism of drug-induced liver injury .................................................................................. 32 1.10 Patterns of drug induced liver injury ................................................................................... 34 1.11 Herbal medicine quality ....................................................................................................... 35 1.12 Heavy metal contamination ................................................................................................ 35 1.13 Pathogenic microorganisms ................................................................................................ 36 1.14 Adulteration ......................................................................................................................... 36 1.15 Botanical misidentification .................................................................................................. 37 1.16 Variable composition ........................................................................................................... 38 1.17 Standardisation .................................................................................................................... 39 1.18 Herbal medicine regulation ................................................................................................. 39 1.19 Australia ............................................................................................................................... 39 1.19.1 Quality, safety and efficacy requirements .................................................................. 40 1.19.2 Registering a complementary medicine on the ARTG ................................................ 41 1.19.3 Pharmacovigilance ...................................................................................................... 41 1.20 United States ....................................................................................................................... 41 1.21 Europe ................................................................................................................................. 43 1.22 CHAPTER 1 SUMMARY ......................................................................................................... 44 2 CHAPTER 2: PHARMACOPHORE MODELLING ............................................................................... 46 2.1 Pharmacophore modelling methods ....................................................................................... 46 2.2 Hepatotoxicity models ............................................................................................................. 49 2.2.1 In vitro models ................................................................................................................ 49 4 2.2.2 In vivo models and clinical studies .................................................................................. 50 2.2.3 Toxicogenomics, proteomics, metabonomics................................................................. 51 2.3 Pharmacophore modelling for herbal hepatotoxicity ............................................................. 52 2.4 Aims of this study ..................................................................................................................... 53 3 CHAPTER 3: METHODS – SIGNAL DETECTION ............................................................................... 54 3.1 Choice of database ................................................................................................................... 54 3.2 Database set-up and cleaning process .................................................................................... 55 3.3 Identifying herb and hepatotoxicity associations .................................................................... 56 3.4 Definition of a herbal medicine ............................................................................................... 56 3.5 Herbal medicine inclusion and exclusion criteria .................................................................... 56 3.6 Selecting search terms for selected herbal medicines ............................................................ 57 3.7 Selecting search terms for liver injury ..................................................................................... 59 3.8 Confounders............................................................................................................................. 60 3.9 Case definitions ........................................................................................................................ 61 3.10 Statistical measures ............................................................................................................. 62 3.11 Definition of signal ............................................................................................................... 62 4 CHAPTER 4: METHODS – PHARMACOPHORE DETERMINATION .................................................. 63 4.1 Herbal medicine selection ....................................................................................................... 63 4.2 Identifying herb constituents ................................................................................................... 65 4.3 Pharmacophore search strategy .............................................................................................
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