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Postmortem toxicology: aspects on interpretation
Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Postmortem toxicology is a matter of analytical chemistry and the consequent interpretation of the results. Thus, both parts are of great importance to come to the right conclusion or the most probable explanation of the analytical results. When interpreting toxicological results there are a lot of different aspects to consider, such as: were the analytical methods used appropriate and with acceptable accuracy, what specimen was analyzed and how was it collected and stored before the analysis, what concentration of a drug can be considered normal or "therapeutic" and which concentration is fatal. Other circumstance to consider is the stability of the drug substances, the pharmacokinetics and pharmacodynamics of the drugs, possible drug interactions, pharmacogenetics and postmortem redistribution.

One crucial question in interpretation of postmortem toxicology results is to find reliable data on the significance of different drug concentrations. Instead of comparing concentrations found in postmortem blood with so called therapeutic concentrations in serum or plasma from the clinical setting, an inappropriate way that will lead to erroneous results, a new approach was used. Data was collected on drug concentrations in femoral blood from autopsy cases where the cause of death by certain not was intoxication and where the diseased was not incapacitated. These concentrations does not reflect any "therapeutic" concentration, which seldom is the key issue in postmortem toxicology, but represents concentrations which could be regarded as normally found and not associated with a fatal outcome. Applying this way to get reference concentrations, errors can be reduced and the problem associated with drug redistribution can be diminished.

Normally samples are stored for one year or more and for a variety of drugs no concentration changes in femoral blood were noted when stored at -20° C with the exception of e.g. ethanol, tetrahydrocannabinol (THC) and zopiclone. Vitreous humor (VH) can be used as an alternative specimen to blood and there exists a correlation between the concentration in VH compared to the blood concentration and the degree of protein binding of the substances. VH can also be used to estimate the corresponding blood concentration under certain circumstances.

Several drugs exist as racemate, containing two or several enantiomers. Chiral analysis can provide additional information about the time that has passed between intake of a drug and the time of death, thus improving the possibilities to predict whether an acute or chronic intake is at hand.

Pharmacokinetic and pharmacodynamic interactions are issues of great importance and have a great impact on interpretation in postmortem toxicology. Pharmacogenetics is another issue that attracts more and more attention in forensic toxicology. Awareness and knowledge of these factors are of utmost importance in order to produce accurate interpretations of postmortem toxicology results.

Place, publisher, year, edition, pages
Linköping: Linköping Universitet , 2004. , 61 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 862
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24323Local ID: 3946ISBN: 91-7373-834-4 (print)OAI: oai:DiVA.org:liu-24323DiVA: diva2:244641
Public defence
2004-10-15, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-11-01Bibliographically approved
List of papers
1. A compilation of fatal and control concentrations of drugs in postmortem femoral blood
Open this publication in new window or tab >>A compilation of fatal and control concentrations of drugs in postmortem femoral blood
1997 (English)In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 42, no 1, 79-87 p.Article in journal (Refereed) Published
Abstract [en]

A compilation of postmortem femoral blood concentrations of drugs is presented. The samples are collected from cases in which the cause of death was: A) certified intoxication by one substance alone, B) certified intoxication by more than one substance and/or alcohol, and C) certified other cause of death without incapacitation due to drugs. The concentrations were compared with blood concentrations detected in suspected drugged drivers (D), and with previously published fatal and therapeutic concentrations. The special features of this compilation are: 1) exclusively femoral blood concentrations are quoted, 2) all analyses are based on samples handled according to a standardized, quality-controlled procedure, 3) two control groups are included, and 4) one-substance-only intoxications are separated from other intoxications. The material is based on a selection of 15,800 samples sent to the Department of Forensic Chemistry in Linkoping, Sweden, during 1992 to 1995 from the six forensic pathology units in Sweden, and the list includes 83 drugs. The compilation includes drugs, where previously published data are scarce. Furthermore, the data gathered from cases with other cause of death than intoxication (group C) constitute a new kind of reference information, which probably offers a better estimate of obviously non fatal levels in postmortem blood than any compilation of therapeutic concentrations in living subjects. The possible factors influencing postmortem drug concentrations are discussed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85073 (URN)8988577 (PubMedID)
Available from: 2012-11-01 Created: 2012-11-01 Last updated: 2017-12-07
2. Stability of drugs in stored postmortem femoral blood and vitreous humor
Open this publication in new window or tab >>Stability of drugs in stored postmortem femoral blood and vitreous humor
2004 (English)In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 49, no 4, 820-825 p.Article in journal (Refereed) Published
Abstract [en]

The stability of 46 drugs in postmortem femoral blood stored for one year at -20°C was investigated. The drugs included benzodiazepines, antidepressants, analgetics and hypnotics. For seven drugs we found a significant change in the concentration between the first and second analysis. Five substances; ethanol, desmethylmianserin, 7-amino-nitrazepam, THC and zopiclone showed a decrease in the concentration whereas the concentrations of two substances; ketobemidone and thioridazine increased. However, the changes observed were not of such an order that it would affect the interpretation in normal forensic casework. We also investigated the possible influence of potassium fluoride on the concentrations of the 46 drugs in vitreous humor after storage for one year. For two substances, ethanol and zopiclone, there were significantly lower concentrations in the samples without potassium fluoride. Furthermore, we also studied the correlation between the concentrations in femoral blood and vitreous humor. For 23 substances there was a significant difference between the concentrations in the vitreous humor and femoral blood. Significant correlations between the concentrations in these two specimens were found for 23 substances, indicating that vitreous humor can be an alternative specimen when blood samples are not available, provided that such correlation exists for the particular substance. Statistical analysis also revealed a correlation between the degree of protein binding of the different drugs and percentage of vitreous/femoral blood concentrations.

Keyword
forensic science; postmortem toxicology; stability; stored samples; vitreous humor; femoral blood
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53524 (URN)10.1520/JFS2003433 (DOI)
Available from: 2010-01-25 Created: 2010-01-25 Last updated: 2017-12-12
3. Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19
Open this publication in new window or tab >>Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19
Show others...
2004 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 28, no 2, 94-104 p.Article in journal (Refereed) Published
Abstract [en]

Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S- and R- enantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral high-performance liquid chromatography (HPLC) method. The mean (± standard deviation) S/R ratio for citalopram was 0.67 ± 0.25 and for desmethylcitalopram, 0.68 ± 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13692 (URN)10.1093/jat/28.2.94 (DOI)
Available from: 2003-06-20 Created: 2003-06-20 Last updated: 2017-12-13
4. Drug interactions: a challenge in interpreting postmortem toxicology results and a problem in the clinical practice
Open this publication in new window or tab >>Drug interactions: a challenge in interpreting postmortem toxicology results and a problem in the clinical practice
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: Multiple drug intake is a problem in tbe clinical setting with potential to adverse drug reactions and certainly a problem in interpretation of forensic toxicology results. The aims of this investigation were to study the incidence of concomitant drugs in autopsy cases where citalopram or zopiclone were detected in femoral blood and to evaluate the potential of drug interactions.

Methods: All medico-legal autopsy cases in Sweden during 1992 to 2003 where citalopram or zopiclone were detected in femoral blood at the toxicological analyses were selected. The number and occurrences of concomitant drugs were recorded together with the concentrations as well as the cause of death.

Results: In the 2405 cases with citalopram, 123 different drugs, metabolites excluded, were detected 4679 times giving an average of 1.9 concomitant drugs and 1099 different dmg combinations were identified. The corresponding figures for the cases with zopiclone were 1557 cases, 118 different drugs detected 3984 times giving an average of 2.6 concomitant drugs and 977 different combinations. We found a strong positive correlation between the number of drugs detected and the frequency of cases judged to be intoxication.

Conclusions: Pharmacokinetic and pharmacodynamic interactions are a potential problem when interpreting forensic toxicological results and the conclusions about the cause and manner of death in the single case must be based on all available information from the investigation and tbe autopsy and on tbe knowledge of tbe pharmacology of included drugs. A better control of prescriptions of what different drugs an individual is given together with a comprehensive therapy control may reduce the risks of adverse drug reactions and unintended or accidental intoxications.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85074 (URN)
Available from: 2012-11-01 Created: 2012-11-01 Last updated: 2012-11-01

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