ORCID Profile
0000-0001-8983-2353
Current Organisation
University of Zurich
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Publisher: Oxford University Press (OUP)
Date: 20-03-2018
DOI: 10.1093/JAT/BKY017
Abstract: Forensic postmortem case interpretation can be challenging, in particular due to postmortem redistribution (PMR) phenomena. Recent studies have shown that computed tomography (CT)-guided collection of biopsy s les using a robotic arm (virtobot) provides a valuable tool for systematic studies on time-dependent PMR. Utilizing this strategy, several cases involving opioid use such as methadone, fentanyl, tramadol, codeine, oxycodone and hydrocodone were evaluated for time-dependent concentration changes and potential redistribution mechanisms. Upon admission to the institute (t1), blood (femoral and right ventricle heart blood) and tissue biopsy s les (lung, kidney, liver, spleen, thigh muscle and adipose tissue) were collected utilizing CT-guided biopsy. Approximately 24 h later (t2 mean 28 ± 15 h), during the autopsy, s les from the same body regions were collected manually and in addition brain tissue, gastric content, urine and left ventricle heart blood. Analysis was conducted with liquid chromatography tandem mass spectrometry. Significant time-dependent methadone concentration increases in femoral blood (pB) indicate the occurrence of PMR, however, ultimately not relevant for forensic interpretation. The main metabolite of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), showed a less significant trend for PMR. Redistribution by passive diffusion along the muscle-to-pB concentration gradient seems likely for methadone, but not for EDDP. Results for fentanyl suggest extensive PMR. Other opioids such as tramadol, codeine, hydrocodone and oxycodone showed no consistent trend for significant PMR. Overall, CT-guided biopsy s ling proved to be a valuable tool for the investigation of PMR mechanisms.
Publisher: Wiley
Date: 27-10-2022
DOI: 10.1002/WFS2.1449
Abstract: Clinical toxicology (CT) and forensic toxicology (FT) represent two disciplines of toxicology dedicated to the qualitative and quantitative analysis and respective interpretation of alcohol, drugs of abuse (DOA), over the counter (OTC), and prescription drugs or poisons, mainly in humans. Analytical challenges, such as the transient occurrence of new psychoactive substances (NPS) on the (il)legal drug market, insufficiently long detection windows of some DOAs, or the lack of objective measures to unambiguously proof s le manipulation as well as interpretative issues, for instance, the difficulty to discriminate occasional users from chronic/addictive ones still require further evaluation and research, though. Metabolomics is a rather new research field, aiming for qualitative, and quantitative analysis of endogenous compounds (small molecules with a molecular weight 1000 Da) in an organism to identify changes related to a certain stimulus, for ex le, a drug intake. Over the last years, metabolomics has been established as a valuable tool in different disciplines, including very recently CT and FT. Analytical techniques usually applied include nuclear magnetic resonance and majorly hyphenated high‐resolution mass spectrometry (HR‐MS), similar to the instrumentation used in CT and FT. We will summarize practical considerations for each step of a typical untargeted metabolome workflow (experimental set‐up, s le collection and storage, analysis, data processing, statistics, and identification) in CT and FT, provide an update on the current applications of untargeted metabolome profiling and will critically discuss its benefits or lack thereof within the particular field. This article is categorized under: Toxicology Analytical Toxicology Metabolomics Toxicology New Psychoactive Substances
Publisher: MDPI AG
Date: 20-09-2021
Abstract: Postmortem redistribution (PMR) can result in artificial drug concentration changes following death and complicate forensic case interpretation. Currently, no accurate methods for PMR prediction exist. Hence, alternative strategies were developed investigating the time-dependent postmortem behavior of diazepam, nordiazepam, morphine, codeine, mirtazapine and citalopram. For 477 authentic postmortem cases, femoral blood s les were collected at two postmortem time-points. All s les were quantified for drugs of abuse (targeted liquid chromatography-tandem mass spectrometry LC-MS/MS) and characterized for small endogenous molecules (untargeted gas chromatography-high resolution MS (GC-HRMS). Trends for significant time-dependent concentration decreases (diazepam (n = 137), nordiazepam (n = 126)), increases (mirtazapine (n = 55), citalopram (n = 50)) or minimal median postmortem changes (morphine (n = 122), codeine (n = 92)) could be observed. Robust mathematical mixed effect models were created for the generalized postmortem behavior of diazepam and nordiazepam, which could be used to back-calculate drug concentrations towards a time-point closer to the estimated time of death (caution: inter-in idual variability). Significant correlations between time-dependent concentration changes of morphine, mirtazapine and citalopram with in idual endogenous molecules could be determined no correlation was deemed strong enough for successful a posteriori estimation on the occurrence of PMR for specific cases. The current dataset did successfully lead to a significant knowledge gain in further understanding the time-dependent postmortem behavior of the studied drugs (of abuse).
Publisher: Wiley
Date: 03-2023
DOI: 10.1002/DTA.3463
Abstract: Along with the recent acknowledgement of the World Anti‐Doping Agency to use dried blood spot (DBS) s les for routine doping control purposes, there have been propositions to use DBS as a matrix that allows regular proactive remotely supervised self‐s ling, providing potential longitudinal monitoring of an athlete's exposure to doping agents. However, several organizational aspects have to be considered before implementation, such as the verification of the s le collections time point. Based on a previous untargeted proteomics workflow utilizing liquid chromatography–high‐resolution mass spectrometry (LC–HRMS) to identify protein eptide markers to define the time since deposition of a bloodstain, the aim of the current study was to develop a targeted LC–HRMS/MS analytical method for promising peptidic target analytes. A long‐term DBS storage experiment was carried out over a 3‐month period (s le collection time points: 0, 2, 4, 7, 14, 21, 28, 42, 56, 70, 84 and 91 days) with DBS s les of 10 volunteers for longitudinal investigation of signal abundance changes of targeted peptide sequences at different storage temperatures (room temperature [RT], 4°C and −20°C). Prior to experimental analysis, LC–HRMS/MS method characteristics were successfully assessed, including intraday precision, carryover and s le extract stability. For estimation of DBS s le collection time points, ratios of two peptides that originate from the same protein prior to tryptic digestion were created. Two targeted peptide area ratios were found to significantly increase after being stored at RT for 28 days, representing potential markers for future use in routine doping controls that contribute to advancing complementary avenues in anti‐doping.
Publisher: Wiley
Date: 06-2020
DOI: 10.1002/DTA.2814
Publisher: Springer Science and Business Media LLC
Date: 22-11-2019
DOI: 10.1007/S00216-019-02258-3
Abstract: Metabolomics studies that aim to qualitatively and quantitatively characterize the entirety of small endogenous biomolecules in an organism are widely conducted in the clinical setting. They also become more and more popular in the field of forensics (toxicology), e.g., to assist in postmortem investigations by objective postmortem interval estimation. However, other issues in postmortem toxicology, such as the phenomenon of (time-dependent) postmortem redistribution, have not yet been tackled by metabolomics studies. Hence, the aim of the current study was to develop an (un)targeted gas chromatography-high-resolution mass spectrometry-based method for endogenous metabolites as a tool for large-scale (un)targeted human postmortem metabolomics investigations (e.g., to objectively assess PMR) with thorough analytical evaluation of this method to ensure fitness-to-purpose in terms of reliability and robustness. This was achieved by using a targeted metabolite subset (n = 56) and a targeted processing workflow. Evaluation experiments have shown that using an artificial matrix (revised simulated body fluid (rSBF) + 5% bovine serum albumin (BSA)) for calibration purposes, all parameters lay within the scope of the method (sensitivity, selectivity, calibration model, accuracy, precision, processed s le stability, and extraction efficiency). When applying this method to large-scale studies, s les should be run in randomized order if analysis time is expected to exceed 18-24 h and potential biomarkers that are found with this method should be verified by a specialized, targeted method (e.g., by using standard addition in authentic matrix for quantification purposes). Overall, the current method can be successfully used for conduction of time-dependent postmortem metabolomics investigations. Graphical abstract.
Publisher: Wiley
Date: 14-03-2014
Publisher: Oxford University Press (OUP)
Date: 22-07-2020
DOI: 10.1093/JAT/BKAA092
Abstract: Postmortem redistribution (PMR) leads to challenges in postmortem case interpretation. Particularly antidepressants and neuroleptics are expected to undergo PMR based on their physico-chemical properties. For the current study, time- and site-dependent PMR of 20 antidepressants and neuroleptics were investigated in humans (authentic cases) five of which are discussed in detail (citalopram, mirtazapine, quetiapine, risperidone and venlafaxine) along with two metabolites (9-OH-risperidone and O-desmethylvenlafaxine). Blood [femoral (pB) and heart blood (HB)] and tissue biopsy s les (lung, kidney, liver, spleen, thigh muscle and adipose tissue) were collected upon admission to the institute utilizing a computed tomography-guided s le collection workflow (t1). Approximately 24 h later (t2 mean 23 ± 9.3 h), s les from the same body regions were collected manually. Liquid chromatography–tandem mass spectrometry was used for quantification. Most antidepressants and neuroleptics showed significant time-dependent concentration changes indicating the occurrence of PMR. For the first time, two phases of redistribution in pB for quetiapine were proposed (concentration decreases in the early postmortem phase, followed by concentration increases) and contrasting existing literature, both concentration increases and decreases in pB overtime were observed for risperidone and 9-OH-risperidone. Venlafaxine and its metabolite only showed minimal concentration changes, while citalopram exhibited a trend for concentration increases and mirtazapine for concentration decreases in pB overtime. Based on time-dependent tissue data, passive diffusion processes along the muscle-to-pB, liver-to-HB and lung-to-HB concentration gradients could be proposed along with bacterial degradation. Overall, no case interpretation had to be adjusted, which suggests that PMR changes of antidepressants and neuroleptics do not seem to be relevant for forensic case interpretation within the 24 h period that was investigated. However, limitations of the current study (e.g., temperature-controlled storage of the bodies) could have led to an underestimation of occurring postmortem changes, hence, interpretation of postmortem results should always be conducted with care, considering PMR phenomena and inter-in idual variability.
Publisher: American Society for Clinical Investigation
Date: 26-07-2018
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.FORSCIINT.2018.11.007
Abstract: A growing number of fatal overdoses involving opioid drugs, in particular involving fentanyl and its analogues, pose an immense threat to public health. Postmortem casework of forensic toxicologists in such cases is challenging, as data on pharmacodynamic and pharmacokinetic properties as well as reference values for acute toxicities and data on potential postmortem redistribution (PMR) mechanisms often do not exist. A fatal case involving cyclopropylfentanyl was investigated at the Zurich Institute of Forensic Medicine and the Zurich Forensic Science Institute an unknown powder found at the scene was reliably identified as cyclopropylfentanyl by gas chromatography-infrared spectroscopy (GC-IR). Femoral blood s les were collected at two time points after death 11h postmortem (t1) and during the medico-legal autopsy 29h after death (t2). At the autopsy, additional s les from the heart blood, urine and gastric content were collected. Cyclopropylfentanyl was quantified using a validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Femoral blood concentration of cyclopropylfentanyl at autopsy was 19.8ng/mL (t1=15.7ng/mL heart blood concentration at autopsy=52.4ng/mL). In the light of the current literature and under the exclusion that no other morphological findings could explain the cause of death, contribution of cyclopropylfentanyl to death was proposed (polydrug use). Significant postmortem concentration increases of cyclopropylfentanyl in femoral blood during 18h after the first s ling were observed, thus indicating a relevant potential to undergo PMR. A central-to-peripheral blood concentration ratio of 2.6 supports this. Consequently, the current case suggests that postmortem cyclopropylfentanyl concentration should always be interpreted with care.
Publisher: Frontiers Media SA
Date: 10-05-2019
Location: Switzerland
No related grants have been discovered for Andrea Eva Steuer.