Plenary Lectures
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ABSTR A CTS PLENARY LECTURES Examples of genetic biomarkers for efficacy are expression of HER2 and trastuzumab, variants of CYP2D6 and tamoxifen, wild-type K-ras and panitumumab and expression and mutations of EGFR and several EGFR- TKIs. Examples of genetic biomarkers for safety are HLA-allelic variants L01. Intoxications with plants and methodologies for the as well as in immune-mediated hypersensitivities and toxicities of abacavir safety assessment of herbal medicines (HLA-B*5701), and carbamazepine (HLA-B*1502). Examples for pharmacogenomic-based dose-prediction to enhance efficacy and improve K. Hostettmann safety are warfarin, tricyclic antidepressants, and efavirenz. These examples Laboratoire de Pharmacognosie et Phytochimie, École de Pharmacie document the continuing development of pharmacogenomics/toxicogenomics Genève-Lausanne, Université de Genève, 1211 Genève 4, Switzerland as an important contributor to improved drug therapy. Since humans exist on Earth, there have been intoxications with plants. Personalized medicine is a strategy to improve clinical outcome by precise Toxic plants were even used to win battles and wars and famous historical diagnosis (e.g. subphenotypes of cancers) by optimizing drug choice and drug figures and artists were victims of plants. It has been rumoured that dose to the problem and need of the individual patient, by taking into account Alexander the Great (356-323 B.C.) was intoxicated by white hellebore the individual’s genome sequence and environmental and host factors. The (Veratrum album, Liliaceae). The painter Vincent Van Gogh (1853-1890) reasonable hope is that this strategy will decrease the number of adverse drug drank frequently alcohol in excess and mainly absinthe prepared from reactions (ADRs) and increase the efficacy of drug therapy. Artemisia absinthium (Asteraceae) which caused some mental disorders. Since a couple of years, intoxications with medicinal plants, edible plants and herbal medicines are becoming more and more frequent. This is due L03. Best practice post mortem forensic toxicology to the fact that numerous persons are interested in all what is natural and O.H. Drummer believe that natural means safe! In Switzerland, for example, there are about TIAFT President and Head (Forensic and Scientific Services), Victorian eight times more intoxications with plants than with mushrooms. This is Institute of Forensic Medicine, and Adjunct Professor, Department of due to the poor botanical knowledge of many people who collect plants Forensic Medicine, Monash University, 57-83 Kavanagh Street, Southbank themselves. Confusions between Allium ursinum (Liliaceae) and Colchicum 3006, Australia autumnale, and even Convallaria majalis, occur every year. Some people In recent years the science of forensic toxicology has evolved substantially even can not distinguish Taxus baccata (Taxaceae) from Pinaceae species due to an increasing understanding of its applications in death investigations such as Abies alba or Picea abies. Herbal drugs which are on the market can and availability of increasingly sensitive analytical equipment. In parallel to also be victims of botanical confusions, as exemplified by the Chinese plant this development there has been an increased understanding of the limitations Aristolochia fangchi (Aristolochiaceae). in interpretations requiring a much more structured approach to analysing Microscopic analysis enables to detect very quickly falsifications of herbal such data. medicines and some examples will be shown. TLC is also an important In most jurisdictions toxicology is requested on selected cases primarily technique but the sensitivity is low. Hyphenated techniques such as LC/MS to assist in the determination of the cause of death particularly when drugs and LC/NMR are appropriate tools for the rapid identification of contaminants (and other poisons) are suspected of being misused. However toxicology is such as pyrrolizidine alkaloids which are hepatotoxic, anacardic acids which also very useful when use of non-prescribed drugs may lead to behavioural are strong allergens and many other classes of toxic plant constituants. changes precipitating aggressive or violent outcomes (e.g. benzodiazepines, Microcapillary NMR, due to its high sensitivity, will play a more important amphetamines, cocaine etc.). Toxicology can also assist in establishing access role in the future. The above mentioned technique can also be applied to the to medications to detect underlying disease (e.g. epilepsy, heart disease or standardisation of herbal drugs. depression) and compliance to medication, effectively becoming therapeutic drug monitoring. In order to achieve the best result an appropriate choice of specimen is required and where possible an ante-mortem specimen taken L02. Genomic medicine: impact on drug efficacy and in hospital to test a sample closer to the cause of the hospitalisation and to toxicity avoid the complications of post mortem redistribution. Interpretation of any U.A. Meyer toxicology data can only occur when the context of the case is fully known Pharmacology/Neurobiology & Program in Computational and Systems and medical records are available including access to medications and other Biology, Biozentrum, University of Basel, Klingelbergstrasse 50-70, substances. This is often lacking and needs to be included in any forensic CH-4056 Basel, Switzerland toxicology case review. Interindividual variability in drug efficacy and toxicity is a major cause Increasingly, speedy turn-around of cases can facilitate an investigation. In of therapeutic failure and contributes to high attrition rates during drug death investigations a quick result hours later or the next day can inform development. How can we learn to better predict the clinical efficacy and the medical investigator and the coroner as to the need, or otherwise, for safety of an old or new drug? The interindividual variation of the human an invasive autopsy, particularly if drugs are considered to have played a genome sequence can explain and predict the individual response in some role (directly or indirectly) in the death. The increasing use of tandem MS drug therapies (pharmacogenomics, toxicogenomics), but environmental techniques, particularly LC-MS/MS has allowed ultra-quick analytical (e.g. smoking, other drugs) and host factors (e.g. age, sex, previous diseases) systems to be developed for a large range of targeted substances. More also contribute to variability for most drug treatments. recently this and related techniques now allow laboratories to include more The search for genomic biomarkers for efficacy or adverse reactions has substances at a lower concentration than that was hitherto possible. focused on variations of genes for drug metabolizing enzymes, in particular The presentation will explore these developments, pros and cons of key cytochromes P450 or MHC Class I genes for immune-mediated toxicities. specimens and provide delegates with information on how toxicologists can A summary of pharmacogenomic biomarkers in the context of approved best assist the civil and criminal justice systems. drug labels is available at http://www.fda.gov/cder/genomics/genomic_ Keywords: post mortem toxicology, ante mortem specimens, redistribution, biomarkers_table.htm. tandem-MS, medical history S1-1 Article available at http://www.ata-journal.org or http://dx.doi.org/10.1051/ata/2009055 Ann Toxicol Anal. 2009; 21(S1) Abstracts L04. Application of high resolution LC/MS for the analysis Results: The number of blood samples sent by the police for toxicological of pharmaceutical compounds, biological fluids and natural analysis has now increased 14-fold after the zero-limit law came onto force. products In 80-85% of cases the blood samples contain one or more banned substance either alone or together with ethanol. The offenders were predominantly men R.S. Plumb, J.K. Nicholson (85-95%) and their age depended on the drug identified in blood. Biological Chemistry, Imperial College South Kensington, London, SW7, UK Introduction: The identification of drug impurities, metabolites and Drugs verified in blood N Mean age Mean conc. Median Highest degradation products forms a critical part of the drug discovery and samples mg/L mg/L mg/L development processes. More recently the analysis of biological fluids for Ethanol 32,814 40 1740 1780 5180 changes in endogenous components concentrations, Metabonomics, has Amphetamine 9,162 37 0.77 0.60 22.3 become an important part of the systems biology approach to mechanistic Methamphetamine 644 36 0.34 0.20 3.7 biology. The analysis of pharmaceutical products biological fluids and Ecstasy (MDMA) 493 26 0.23 0.10 3.5 natural products requires high-resolution separation techniques and mass Tetrahydrocannabnol (THC) 7,750 33 1.9 1.0 36 spectrometry to correctly profile, characterize and identify the components. γ-hydroxybutyrate (GHB) 548 26 89 82 340 Aim: The purpose of our work was to demonstrate the application of high Cocaine 160 29 0.069 0.05 0.31 resolution chromatography employing sub 2 mm particles and elevated Benzoylecognine 160 29 0.80 0.60 3.0 flow rates combined with high speed MS and accurate mass MS/MS for the Morphine 2,029 33 0.046 0.03 1.13 analysis of pharmaceutical products and biological fluids. 6-acetyl morphine 52 33 0.016 0.01 0.10 Methods: Drug metabolites were obtained from development DMPK Codeine 1,391 36 0.047 0.01 2.4 studies, urine and plasma samples were obtained from safety assessment Diazepam 1,950 38 0.36 0.20 6.2 studies