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Postmortem Metabolomics: Strategies to Assess Time-Dependent Postmortem Changes of Diazepam, Nordiazepam, Morphine, Codeine, Mirtazapine and Citalopram.

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 samples were collected at two postmortem time-points. All samples 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-individual variability). Significant correlations between time-dependent concentration changes of morphine, mirtazapine and citalopram with individual 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).

SUBMITTER: Brockbals L

PROVIDER: S-EPMC8466227 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThis study aimed to investigate cohort effects in selected opioids use and determine whether cohort differences were associated with changes in risk factors for use over time.DesignThis study presents secondary analyses of a longitudinal survey panel of the general population that collected data biannually.SettingData from the Canadian Longitudinal National Population Health Survey 1994-2011.PopulationThis study included 12 542 participants from the following birth cohorts: post-World War I (born 1915-1924), pre-World War II (born 1925-1934), World War II (born 1935-1944), Older Baby Boom (born 1945-1954), Younger Baby Boom (born 1955-1964), Older Generation X (born 1965-1974) and Younger Generation X (born 1975-1984).Main outcomeResponses to a single question asking about the use of codeine, morphine or meperidine in the past month (yes/no) were examined.ResultsOver and above age and period effects, there were significant cohort differences in selected opioids use: each succeeding recent cohort had greater use than their predecessors (eg, Gen Xers had greater use than younger baby boomers). Selected opioids use increased significantly from 1994 to 2002, plateauing between 2002 and 2006 and then declining until 2011. After accounting for cohort and period effects, there was a decline in use of these opioids with increasing age. Although pain was significantly associated with greater selected opioids use (OR=3.63, 95% CI 3.39 to 3.94), pain did not explain cohort differences. Cohort and period effects were no longer significant after adjusting for the number of chronic conditions. Cohort differences in selected opioids use mirrored cohort differences in multimorbidity. Use of these opioids was significantly associated with taking antidepressants or tranquillisers (OR=2.52, 95% CI 2.27 to 2.81 and OR=1.60, 95% CI 1.46 to 1.75, respectively).ConclusionsThe findings underscore the need to consider multimorbidity including possible psychological disorders and associated medications when prescribing opioids (codeine, morphine, meperidine), particularly for recent birth cohorts. Continued efforts to monitor prescription patterns and develop specific opioid use guidelines for multimorbidity appear warranted.

Project description:The combined use of multiple omics allows to study complex interrelated biological processes in their entirety. We applied a combination of metabolomics, lipidomics and proteomics to human bones to investigate their combined potential to estimate time elapsed since death (i.e., the postmortem interval [PMI]). This 'ForensOMICS' approach has the potential to improve accuracy and precision of PMI estimation of skeletonized human remains, thereby helping forensic investigators to establish the timeline of events surrounding death. Anterior midshaft tibial bone was collected from four female body donors before their placement at the Forensic Anthropology Research Facility owned by the Forensic Anthropological Center at Texas State (FACTS). Bone samples were again collected at selected PMIs (219-790-834-872days). Liquid chromatography mass spectrometry (LC-MS) was used to obtain untargeted metabolomic, lipidomic, and proteomic profiles from the pre- and post-placement bone samples. The three omics blocks were investigated independently by univariate and multivariate analyses, followed by Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies (DIABLO), to identify the reduced number of markers describing postmortem changes and discriminating the individuals based on their PMI. The resulting model showed that pre-placement metabolome, lipidome and proteome profiles were clearly distinguishable from post-placement ones. Metabolites in the pre-placement samples suggested an extinction of the energetic metabolism and a switch towards another source of fuelling (e.g., structural proteins). We were able to identify certain biomolecules with an excellent potential for PMI estimation, predominantly the biomolecules from the metabolomics block. Our findings suggest that, by targeting a combination of compounds with different postmortem stability, in the future we could be able to estimate both short PMIs, by using metabolites and lipids, and longer PMIs, by using proteins.

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Postmortem Metabolomics: Strategies to Assess Time-Dependent Postmortem Changes of Diazepam, Nordiazepam, Morphine, Codeine, Mirtazapine and Citalopram.

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