Time- and Site-dependent Postmortem Redistribution of Antidepressants and Neuroleptics in Blood and Alternative Matrices

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 samples (lung, kidney, liver, spleen, thigh muscle and adipose tissue) were collected upon admission to the institute utilizing a computed tomography-guided sample collection workflow (t1). Approximately 24 h later (t2; mean 23 ± 9.3 h), samples 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-individual variability.

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

Metabolites ◽

10.3390/metabo11090643 ◽

2021 ◽

Vol 11 (9) ◽

pp. 643

Author(s):

Lana Brockbals ◽

Yannick Wartmann ◽

Dylan Mantinieks ◽

Linda Glowacki ◽

Dimitri Gerostamoulos ◽

...

Keyword(s):

Drugs Of Abuse ◽

Individual Variability ◽

Time Dependent ◽

Postmortem Changes ◽

Knowledge Gain ◽

Mixed Effect ◽

Drug Concentrations ◽

Liquid Chromatography Tandem Mass ◽

Forensic Case ◽

Concentration Changes

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).

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Diffusion in CP Stars: The Quest for Accuracy

Highlights of Astronomy ◽

10.1017/s1539299600018414 ◽

1998 ◽

Vol 11 (2) ◽

pp. 671-673

Author(s):

G. Alecian

Keyword(s):

Computational Methods ◽

Stellar Evolution ◽

Diffusion Processes ◽

Stellar Atmospheres ◽

Time Dependent ◽

Data Bases ◽

Self Consistent ◽

Stellar Envelopes ◽

Better Than

We present a brief review about recent progresses concerning the study of diffusion processes in CP stars. The most spectacular of them concerns the calculation of radiative accelerations in stellar envelopes for which an accuracy better than 30% can now be reached for a large number of ions. This improvement is mainly due to huge and accurate atomic and opacity data bases available since the beginning of the 90’s. Developments of efficient computational methods have been carried out to take advantage of these new data. These progresses have, in turn, led to a better understanding of how the element stratification is building up with time. A computation of self-consistent stellar evolution models, including time-dependent diffusion, can now be within the scope of the next few years. However, the progresses previously mentioned do not apply for stellar atmospheres and upper layers of envelopes.

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Biliary transport of glutathione and methylmercury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1983.244.4.g435 ◽

1983 ◽

Vol 244 (4) ◽

pp. G435-G441 ◽

Cited By ~ 9

Author(s):

N. Ballatori ◽

T. W. Clarkson

Keyword(s):

Bile Flow ◽

Individual Variability ◽

Secretion Rate ◽

Female Rats ◽

Biliary Secretion ◽

Male And Female ◽

Male And Female Rats ◽

Sodium Dehydrocholate ◽

Bile Fluid ◽

Concentration Changes

The hepatobiliary transport of glutathione (GSH) and methylmercury (MM) was investigated in male and female rats anesthetized with pentobarbital sodium. When bile flow was altered with either sodium dehydrocholate (DHC), hypertonic sucrose infusion, or by hypothermia, the absolute rates of GSH and MM secretion into bile were not affected, resulting in parallel concentration changes in the bile fluid for both GSH and MM. Indocyanine green and sulfobromophthalein (BSP), but not BSP-glutathione complex, inhibited the biliary secretion of free GSH. This inhibition was accompanied by a parallel inhibition of MM secretion into bile and occurred without any changes in liver GSH or MM levels. On the other hand, the intravenous administration of cysteine, GSH, and penicillamine was associated with an increase in the secretion rate of reduced sulfhydryl groups into bile and an increase in the biliary secretion rate of MM. The increased biliary secretion rate of MM after phenobarbital pretreatment was also associated with an increased rate of secretion of GSH into bile. In addition, sex differences and individual variability in the biliary secretion of MM were correlated with differing abilities to secrete GSH into bile. The results suggest the presence of a biliary transport system for GSH that determines the biliary secretion of MM.

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Restricted Gompertz-Type Diffusion Processes with Periodic Regulation Functions

Mathematics ◽

10.3390/math7060555 ◽

2019 ◽

Vol 7 (6) ◽

pp. 555 ◽

Cited By ~ 4

Author(s):

Virginia Giorno ◽

Amelia G. Nobile

Keyword(s):

Diffusion Process ◽

Diffusion Processes ◽

First Passage Time ◽

Transition Probability ◽

Passage Time ◽

Time Dependent ◽

Transition Probability Density ◽

Special Boundaries ◽

Special Cases ◽

Regulation Functions

We consider two different time-inhomogeneous diffusion processes useful to model the evolution of a population in a random environment. The first is a Gompertz-type diffusion process with time-dependent growth intensity, carrying capacity and noise intensity, whose conditional median coincides with the deterministic solution. The second is a shifted-restricted Gompertz-type diffusion process with a reflecting condition in zero state and with time-dependent regulation functions. For both processes, we analyze the transient and the asymptotic behavior of the transition probability density functions and their conditional moments. Particular attention is dedicated to the first-passage time, by deriving some closed form for its density through special boundaries. Finally, special cases of periodic regulation functions are discussed.

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Growth-related changes of phosphorus metabolites in VX-2 carcinoma implanted into rabbit thigh muscle: in vivo 31P MR spectroscopy

Indian Journal of Animal Research ◽

10.18805/ijar.v0i0f.3798 ◽

2016 ◽

Author(s):

Hyeong-Kil Kim ◽

Gwang Woo Jeong ◽

Tae-Hoon Kim ◽

Gwang-Won Kim ◽

Jong-Bong Kim

Keyword(s):

Tumor Growth ◽

Intracellular Ph ◽

Tumor Necrosis ◽

Time Course ◽

Ph Value ◽

Thigh Muscle ◽

Ph Values ◽

Concentration Changes ◽

Phosphorus Metabolites

The purpose of this study was to evaluate the usefulness of in vivo 31P magnetic resonance spectroscopy (MRS) for monitoring changes in growth-related phosphate metabolite concentration and intracellular pH value in rabbit thigh muscle implanted with VX-2 carcinoma. The time-course magnetic resonance imaging (MRI) and in vivo 31P MRS were examined weekly in the course of 10 weeks following the onset of a VX-2 carcinoma implantation. The spectra were quantitatively analyzed to obtain vital information on the time course variation of the phosphorus metabolites and intracellular pH value according to the tumor growth. Elevation in the concentrations of phosphormonoesters (PME), inorganic phosphate (Pi), and phosphodiesters (PDE) was observed over the time course of 3-4 weeks after the implantation of VX2 carcinoma, while the rest of the metabolites, PCr and ATP tended to be constant. The concentration changes of PME, Pi, and PDE were positively correlated with the volumes of tumor necrosis. The intracellular pH values decreased with the time course of tumor growth and the volumes of tumor necrosis. In vivo 31P MRS is capable of non-invasive monitoring of intracellular pH values as well as the concentration changes of phosphate metabolites during tumor growth.

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Postmortem Changes in Skeletal Muscle Can Be Expressed by Hounsfield Unit Measurements in Postmortem Computed Tomography—A Murine Model Study

Journal of Medical Imaging and Health Informatics ◽

10.1166/jmihi.2019.2645261 ◽

2019 ◽

Vol 9 (2) ◽

pp. 261-266

Author(s):

Tsuyoshi Yamada ◽

Tamaki Takeuchi ◽

Morihiro Ito

Keyword(s):

Computed Tomography ◽

Skeletal Muscle ◽

Small Animal ◽

Hounsfield Unit ◽

Time Dependent ◽

Histological Evaluation ◽

Postmortem Changes ◽

Postmortem Computed Tomography ◽

Ct Scanner ◽

Histological Images

Purpose: The aim of the present study was to assess time-dependent changes in postmortem images of mouse skeletal muscle that were obtained with a small animal CT scanner. Materials and methods: Mice were euthanized and time-dependent changes in postmortem computed tomography (PMCT) images of skeletal muscle were recorded for 11 elapsed intervals: at the confirmed time of cardiac arrest, and at 0.5, 1, 2, 3, 6, 12, 24, 36, 48, and 72 hours after death. After acquiring PMCT images, skeletal muscle was removed and prepared for histological evaluation. Histological images and PMCT images of the skeletal muscle were then compared. Hounsfield unit (HU) measurements were obtained for the skeletal muscle PMCT images at each interval and time-dependent changes were examined. Results: Time-dependent changes were observed in histological images of skeletal muscle, but not in PMCT images. Time-dependent changes were detectable by HU values of skeletal muscle. Conclusion: Postmortem changes in skeletal muscle tissue appear as decreases in HU values on PMCT.

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Postmortem Changes in Skeletal Muscle Can Be Expressed by Hounsfield Unit Measurements in Postmortem Computed Tomography—A Murine Model Study

Journal of Medical Imaging and Health Informatics ◽

10.1166/jmihi.2019.2645 ◽

2019 ◽

Vol 9 (2) ◽

pp. 261-266

Author(s):

Tsuyoshi Yamada ◽

Tamaki Takeuchi ◽

Morihiro Ito

Keyword(s):

Computed Tomography ◽

Skeletal Muscle ◽

Small Animal ◽

Hounsfield Unit ◽

Time Dependent ◽

Histological Evaluation ◽

Postmortem Changes ◽

Postmortem Computed Tomography ◽

Ct Scanner ◽

Histological Images

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Rheology modulated non-equilibrium fluctuations in time-dependent diffusion processes

Physica A Statistical Mechanics and its Applications ◽

10.1016/j.physa.2016.06.114 ◽

2016 ◽

Vol 462 ◽

pp. 654-666

Author(s):

Debonil Maity ◽

Aditya Bandopadhyay ◽

Suman Chakraborty

Keyword(s):

Diffusion Processes ◽

Time Dependent ◽

Equilibrium Fluctuations ◽

Non Equilibrium

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Ergodicity breaking, ageing, and confinement in generalized diffusion processes with position and time dependent diffusivity

Journal of Statistical Mechanics Theory and Experiment ◽

10.1088/1742-5468/2015/05/p05010 ◽

2015 ◽

Vol 2015 (5) ◽

pp. P05010 ◽

Cited By ~ 28

Author(s):

Andrey G Cherstvy ◽

Ralf Metzler

Keyword(s):

Diffusion Processes ◽

Time Dependent ◽

Ergodicity Breaking

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Histopathologic evaluation of postmortem autolytic changes in bluegill (Lepomis macrohirus) and crappie (Pomoxis anularis) at varied time intervals and storage temperatures

PeerJ ◽

10.7717/peerj.1943 ◽

2016 ◽

Vol 4 ◽

pp. e1943 ◽

Cited By ~ 6

Author(s):

Jami George ◽

Arnaud J. Van Wettere ◽

Blayk B. Michaels ◽

Debbi Crain ◽

Gregory A. Lewbart

Keyword(s):

Lepomis Macrochirus ◽

Postmortem Changes ◽

Sample Collection ◽

Time Intervals ◽

Pomoxis Annularis ◽

Histopathologic Evaluation ◽

Liver And Kidney ◽

Microscopy Data ◽

And Storage ◽

Storage Temperatures

Information is lacking on preserving fish carcasses to minimize postmortem autolysis artifacts when a necropsy cannot be performed immediately. The purpose of this study was to qualitatively identify and score histologic postmortem changes in two species of freshwater fish (bluegill—Lepomis macrochirus; crappie—Pomoxis annularis), at varied time intervals and storage temperatures, to assess the histologic quality of collected samples. A pooled sample of 36 mix sex individuals of healthy bluegill and crappie were euthanized, stored either at room temperature, refrigerated at 4 °C, or frozen at −20 °C, and then necropsied at 0, 4, 24, and 48 h intervals. Histologic specimens were evaluated by light microscopy. Data showed that immediate harvesting of fresh samples provides the best quality and refrigeration would be the preferred method of storage if sample collection had to be delayed for up to 24 h. When sample collection must be delayed more than 24 h, the preferred method of storage to minimize autolysis artifacts is freezing if evaluation of the gastrointestinal tract is most important, or refrigeration if gill histology is most important. The gill arch, intestinal tract, followed by the liver and kidney were the most sensitive organs to autolysis.

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