liu.seSearch for publications in DiVA
Change search
Refine search result
12 1 - 50 of 55
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the 'Create feeds' function.
  • 1.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Haage, Pernilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik C.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamicsManuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.

    Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.

    Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the  variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.

    Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.

  • 2.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Haage, Pernilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Zackrisson, Anna-Lena
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose2014In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, 125-132 p.Article in journal (Refereed)
    Abstract [en]

    The major purpose of this study was to elucidate if genotyping can facilitate interpretations of tramadol (TRA) in forensic case work, with special regard to the estimation of the time of drug intake and drug related symptoms (DRS). The association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA was studied. Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report DRS during the experimental day. We found a positive correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA and the time after drug intake for both CYP2D6 intermediate metabolizers and extensive metabolizers. For the only poor metabolizer with detectable ODT levels the metabolic ratio was almost constant. Significant associations were found between the area under the concentration-time curve (AUC) and three of the investigated ABCB1 single nucleotide polymorphisms for TRA, but not for ODT and only in the 50 mg dosage group. There was great interindividual variation in DRS, some subjects exhibited no symptoms at all whereas one subject both fainted and vomited after a single therapeutic dose. However, no associations could be found between DRS and investigated polymorphisms. We conclude that the metabolic ratio of ODT/TRA may be used for estimation of the time of drug intake, but only when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study.

  • 3.
    Bendroth, Peter
    et al.
    Department of Forensic Medicine, Lund, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Genetics. Linköping University, Faculty of Health Sciences.
    Helander, Anders
    Department of Clinical Neuroscience, Alcohol Laboratory, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.
    Greby, Jesper
    Department of Forensic Medicine, Lund, Sweden.
    Stephanson, Nikolai
    Department of Clinical Pharmacology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Krantz, Peter
    Department of Forensic Medicine, Lund, Sweden.
    Comparison of ethyl glucuronide in hair with phosphatidylethanol in whole blood as post-mortem markers of alcohol abuse2008In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 176, no 1, 76-81 p.Article in journal (Refereed)
    Abstract [en]

    Ethyl glucuronide (EtG) is a direct metabolite of ethanol and has been used as a marker of alcohol abuse in both urine and hair. This study investigated the value of EtG testing in post-mortem hair for diagnostic improvement of alcohol abuse in forensic medicine. Material from 70 consecutive medico-legal autopsies was collected in accordance with the recommendations on ethics by the Swedish National Board of Forensic Medicine. A method for determination of EtG in hair samples was developed using ultra performance liquid chromatography/electrospray tandem mass spectrometry (UPLC/ESI-MS/MS; LOQ, 2.5 pg/mg). The result of the EtG analysis was compared with the findings of phosphatidylethanol (PEth) in femoral whole blood, as measured by high performance liquid chromatography with an evaporative light-scattering detector (HPLC–ELSD; LOQ, 0.22 μmol/l). Evaluation of liver histology and anamnestic evidence of alcohol abuse of the deceased were taken in consideration for the interpretation. Measurable levels of EtG were present in 49 of the 70 autopsy cases whereas PEth was present in 36. Thirty-nine cases had EtG levels above the cutoff limit (≥30 pg/mg) compared with 29 for PEth (≥0.7 μmol/l). Fifteen cases had EtG as exclusive indicator for alcohol abuse compared with four cases for PEth. These findings suggest that measurements of EtG in hair may provide improved diagnostic information on alcohol abuse, due to a long retrospective time-window for detection and stability of EtG in hair in the decaying cadaver. However, an EtG level below the cutoff does not completely exclude previous alcohol abuse.

  • 4.
    Castaneto, Marisol S.
    et al.
    NIDA, MD 21224 USA; University of Maryland, MD 21201 USA.
    Wohlfarth, Ariane
    NIDA, MD 21224 USA.
    Pang, Shaokun
    SCIEX Ltd, CA USA.
    Zhu, Mingshe
    Bristol Myers Squibb Co, NJ USA.
    Scheidweiler, Karl B.
    NIDA, MD 21224 USA.
    Kronstrand, Robert
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA.
    Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry2015In: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 33, no 2, 295-310 p.Article in journal (Refereed)
    Abstract [en]

    AB-FUBINACA, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide, is an indazole synthetic cannabinoid identified in drug seizures around the world. Few metabolism data are available, despite the need for human urinary markers to detect AB-FUBINACA intake. Our main objective was to identify suitable analytical targets by analyzing human hepatocyte incubation samples with high-resolution mass spectrometry (HRMS) and to confirm the results in authentic urine specimens. We also determined AB-FUBINACAs metabolic stability in human liver microsomes (HLMs) and compared hepatocyte and urine results with in silico predictions. The metabolic stability of AB-FUBINACA was determined in pooled HLMs (1 A mu mol/l, up to 1 h). The metabolite profile of human hepatocytes (10 A mu mol/l, 1 and 3 h) and urine samples from two subjects were determined by HRMS using information-dependent tandem-mass spectrometry (MS-MS) acquisition. Data were analyzed with MetabolitePilot (TM) software utilizing different processing algorithms, including generic peak finding, mass defect filtering, neutral loss, and product ion filtering. In silico metabolite prediction was performed with MetaSite (TM) software. AB-FUBINACAs half-life in HLMs was 62.6 +/- A 4.0 min. AB-FUBINACA produced 11 metabolites (2 glucuronides) in human hepatocytes and 10 were identified in authentic human urine. Major metabolic pathways were terminal amide hydrolysis, acyl glucuronidation and hydroxylation at the aminooxobutane moiety. Epoxidation followed by hydrolysis, hydroxylation at the indazole moiety and dehydrogenation were minor pathways. Defluorination did not occur. Seventeen first-generation metabolites were predicted in silico, of which seven were observed in vitro and eight in vivo. We recommend AB-FUBINACA carboxylic acid, hydroxy AB-FUBINACA carboxylic acid, dihydrodiol AB-FUBINACA and dihydrodiol AB-FUBINACA carboxylic acid as suitable urinary markers.

  • 5.
    Comasco, E.
    et al.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Centre for Clinical Research, Uppsala University, Central Hospital, Västerås, Sweden.
    Nordquist, N.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Section of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Leppert, J.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Centre for Clinical Research, Uppsala University, Central Hospital, Västerås, Sweden.
    Oreland, L.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Section of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Alling, C.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Department of Laboratory Medicine, Division of Clinical Chemistry and, Lund University Hospital, Lund, Sweden.
    Nilsson, K.W.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Centre for Clinical Research, Uppsala University, Central Hospital, Västerås, Sweden.
    Adolescent alcohol consumption: Biomarkers PEth and FAEE in relation to interview and questionnaire data2009In: Journal of Studies on Alcohol and Drugs, ISSN 1937-1888, E-ISSN 1938-4114, Vol. 70, no 5, 797-804 p.Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to investigate the congruence of biomarkers, questionnaires, and interviews as instruments to assess adolescent alcohol consumption. Method: The methodology used was a cross-sectional study with a randomized sample. Four different methods were used to estimate high adolescent alcohol consumption. The concordance of the results was investigated. Surveys were performed, and biological specimens were collected at all schools in the county of Västmanland, Sweden, in 2001. Eighty-one boys and 119 girls from a population of 16- and 19-year-old adolescents were randomly selected from quartiles of volunteers representing various degrees of psychosocial risk behaviors. Using a questionnaire (for a 1-hour session) and in-depth interviews, subjects were assessed regarding their alcohol-use habits. Blood and hair samples were analyzed for phosphatidylethanol (PEth) and fatty acid ethyl esters (FAEEs), respectively. Results: High alcohol consumption was underreported in the questionnaire compared with the interviews. PEth and FAEE analyses weakly confirmed the self-reports, and the results of the two biochemical tests did not overlap. The PEth blood test was the most specific but the least sensitive, whereas the FAEE hair test revealed low specificity and an overrepresentation of positive results in girls. Conclusions: The expected higher self-report of high alcohol consumption by interview rather than by questionnaire was confirmed partly because of the infl uence of a bogus pipeline procedure. The absence of overlap between PEth and FAEE results and their poor agreement with self-reports suggested that biomarkers are unsuitable as screening tools for alcohol consumption in adolescents.

  • 6.
    Concheiro, Marta
    et al.
    NIDA, MD 21224 USA.
    Castaneto, Marisol
    NIDA, MD 21224 USA; University of Maryland Baltimore County, MD 21228 USA.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA.
    Simultaneous determination of 40 novel psychoactive stimulants in urine by liquid chromatography-high resolution mass spectrometry and library matching2015In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1397, 32-42 p.Article in journal (Refereed)
    Abstract [en]

    The emergence of novel psychoactive substances is an ongoing challenge for analytical toxicologists. Different analogs are continuously introduced in the market to circumvent legislation and to enhance their pharmacological activity. Although detection of drugs in blood indicates recent exposure and link intoxication to the causative agent, urine is still the most preferred testing matrix in clinical and forensic settings. We developed a method for the simultaneous quantification of 8 piperazines, 4 designer amphetamines and 28 synthetic cathinones and 4 metabolites, in urine by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Data were acquired in full scan and data dependent MS2 mode. Compounds were quantified by precursor ion exact mass, and confirmed by product ion spectra library matching, taking into account product ions exact mass and intensities. One-hundred pi, urine was subjected to solid phase cation exchange extraction (SOLA SCX). The chromatographic reverse-phase separation was achieved with gradient mobile phase of 0.1% formic acid in water and in acetonitrile in 20 min. The assay was linear from 2.5 or 5 to 500 mu g/L. Imprecision (n = 15) was less than15.4%, and accuracy (n = 15) 84.2-118.5%. Extraction efficiency was 51.2-111.2%, process efficiency 57.7-104.9% and matrix effect ranged from -41.9% to 238.5% (CV less than 23.3%, except MDBZP CV less than 34%). Authentic urine specimens (n = 62) were analyzed with the method that provides a comprehensive confirmation for 40 new stimulant drugs with specificity and sensitivity.

  • 7.
    Cooper, Gail A A
    et al.
    Forensic Medicine and Science, University of Glasgow, Glasgow Scotland.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kintz, Pascal
    X-Pertise Consulting, Oberhausbergen, France.
    Society of Hair Testing guidelines for drug testing in hair2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 218, no 1-3, 20-24 p.Article in journal (Refereed)
    Abstract [en]

    The Society of Hair Testing (SoHT) Guidelines for Drug Testing in Hair provide laboratories with recommended best practice guidelines whether they are currently offering drug testing in hair, or plan to offer a hair testing service in the future. The guidelines include reference to recommended sample collection and storage procedures, through sample preparation, pre-treatment and analysis and the use of cut-offs.

  • 8.
    Cooper, Gail
    et al.
    Forensic Medicine and Science, University of Glasgow, Scotland, United Kingdom.
    Moeller, Manfred
    Saarland University Hospital, Homburg/SAAR, Germany.
    Kronstrand, Robert
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Genetics. Linköping University, Faculty of Health Sciences.
    Current status of accreditation for drug testing in hair2008In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 176, no 1, 9-12 p.Article in journal (Refereed)
    Abstract [en]

    At the annual meeting of the Society of Hair Testing in Vadstena, Sweden in 2006, a committee was appointed to address the issue of guidelines for hair testing and to assess the current status of accreditation amongst laboratories offering drug testing in hair.

    A short questionnaire was circulated amongst the membership and interested parties. Fifty-two responses were received from hair testing laboratories providing details on the amount and type of hair tests they offered and the status of accreditation within their facilities.

    Although the vast majority of laboratories follow current guidelines (83%), only nine laboratories were accredited to ISO/IEC 17025 for hair testing. A significant number of laboratories reporting that they were in the process of developing quality systems with a view to accrediting their methods within 2–3 years. This study provides an insight into the status of accreditation in hair testing laboratories and supports the need for guidelines to encourage best practice.

  • 9.
    Diao, Xingxing
    et al.
    National Institute Drug Abuse, MD 21224 USA.
    Scheidweiler, Karl B.
    National Institute Drug Abuse, MD 21224 USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Pang, Shaokun
    SCIEX Ltd, CA 94404 USA.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Sweden.
    Huestis, Marilyn A.
    National Institute Drug Abuse, MD 21224 USA.
    In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-222016In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 18, no 2, 455-464 p.Article in journal (Refereed)
    Abstract [en]

    In 2014, FDU-PB-22 and FUB-PB-22, two novel synthetic cannabinoids, were detected in herbal blends in Japan, Russia, and Germany and were quickly added to their scheduled drugs list. Unfortunately, no human metabolism data are currently available, making it challenging to confirm their intake. The present study aims to identify appropriate analytical markers by investigating FDU-PB-22 and FUB-PB-22 metabolism in human hepatocytes and confirm the results in authentic urine specimens. For metabolic stability, 1 mu M FDU-PB-22 and FUB-PB-22 was incubated with human liver microsomes for up to 1 h; for metabolite profiling, 10 mu M was incubated with human hepatocytes for 3 h. Two authentic urine specimens from FDU-PB-22 and FUB-PB-22 positive cases were analyzed after beta-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was accomplished by high-resolution mass spectrometry using information-dependent acquisition. Both FDU-PB-22 and FUB-PB-22 were rapidly metabolized in HLM with half-lives of 12.4 and 11.5 min, respectively. In human hepatocyte samples, we identified seven metabolites for both compounds, generated by ester hydrolysis and further hydroxylation and/or glucuronidation. After ester hydrolysis, FDU-PB-22 and FUB-PB-22 yielded the samemetabolite M7, fluorobenzylindole-3-carboxylic acid (FBI-COOH). M7 and M6 (hydroxylated FBI-COOH) were the major metabolites. In authentic urine specimens after beta-glucuronidase hydrolysis, M6 and M7 also were the predominant metabolites. Based on our study, we recommend M6 (hydroxylated FBI-COOH) and M7 (FBI-COOH) as suitable urinary markers for documenting FDU-PB-22 and/or FUB-PB-22 intake.

  • 10.
    Druid, Henrik
    et al.
    Department of Forensic Medicine, Karolinska Institutet, Stockholm, Sweden.
    Strandberg, Joakim J.
    Department of Forensic Medicine, Karolinska Institutet, Stockholm, Sweden.
    Alkass, Kanar
    Department of Forensic Medicine, Karolinska Institutet, Stockholm, Sweden.
    Nyström, Ingrid
    Department of Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Department of Forensic Medicine, Karolinska Institutet, Stockholm, Sweden.
    Kronstrand, Robert
    Department of Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Evaluation of the role of abstinence in heroin overdose deaths using segmental hair analysis2007In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 168, no 2-3, 223-226 p.Article in journal (Refereed)
    Abstract [en]

    In the body heroin is rapidly metabolized to 6-acetylmorphine and morphine. Victims of lethal heroin overdose often present with fairly low blood concentrations of morphine. Reduced tolerance due to abstinence has been proposed to account for this finding. The aim of the present study was to examine the role of abstinence in drug-related deaths by comparing recent and past exposure to opioids using segmental hair analysis with the postmortem blood morphine concentrations in deceased heroin users. The study included 60 deceased drug addicts in the Stockholm area, Sweden. In 32 cases, death was not related to heroin intake. In 18 of the 28 heroin fatalities, opioids were absent in the most recent hair segment, suggesting a reduced tolerance to opioids. However, the blood morphine levels were similar to those found in the 10 subjects that showed continuous opioid use. Hair and blood analysis disclosed an extensive use of additional drugs that directly or indirectly may influence the opioid system. The results suggest that abstinence is not a critical factor for heroin overdose death. Obviously tolerant subjects die after intake of similar doses. Other factors, particularly polydrug use, seem to be more causally important for these deaths.

  • 11.
    Forsman, M.
    et al.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Nystrom, I.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Roman, M.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Berglund, L.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Urinary detection times and excretion patterns of flunitrazepam and its metabolites after a single oral dose2009In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 33, no 8, 491-501 p.Article in journal (Refereed)
    Abstract [en]

    We investigated the excretion profiles of flunitrazepam metabolites in urine after a single dose. Sixteen volunteers received either 0.5 or 2.0 mg flunitrazepam. Urine samples were collected after 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 240, and 336 h. Samples were screened using CEDIA (300 µg/L cutoff) and quantitated using liquid chromatography-tandem mass spectrometry. The cutoff was 0.5 µg/L for flunitrazepam, N-desmethylflunitrazepam, 7-aminoflunitrazepam, 7-aminodesmethylflunitrazepam, 7-acetamidoflunitrazepam, and 7-acetamidodesmethylflunitrazepam. None of the subjects receiving 0.5 mg were screened positive, and only 23 of 102 samples from the subjects given 2.0 mg were positive with CEDIA. The predominant metabolites were 7-aminoflunitrazepam and 7-aminodesmethylflunitrazepam. For all subjects given the low dose, 7-aminoflunitrazepam was detected up to 120 h, and for two subjects for more than 240 h. Seven subjects given the high dose were positive up to 240 h for 7-aminoflunitrazepam. We conclude that the ratio 7-aminodesmethylflunitrazepam to 7-aminoflunitrazepam increased with time, independent of dose, and may be used to estimate the time of intake. For some low-dose subjects, the metabolite concentrations in the early samples were low and a chromatographic method may fail to detect the intake. We think laboratories should consider this when advising police and hospitals about sampling as well as when they set up strategies for analysis.

  • 12.
    Haage, Pernilla
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping Sweden.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping Sweden.
    Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.2016In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 119, 1-9 p.Article in journal (Refereed)
    Abstract [en]

    The analgesic drug tramadol and its metabolites are chiral compounds, with the (+)- and (-)-enantiomers showing different pharmacological and toxicological effects. This novel enantioselective method, based on LC-MS/MS in reversed phase mode, enabled measurement of the parent compound and its three main metabolites O-desmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol simultaneously. Whole blood samples of 0.5g were fortified with internal standards (tramadol-(13)C-D3 and O-desmethyl-cis-tramadol-D6) and extracted under basic conditions (pH 11) by liquid-liquid extraction. Chromatography was performed on a chiral alpha-1-acid glycoprotein (AGP) column preceded by an AGP guard column. The mobile phase consisted of 0.8% acetonitrile and 99.2% ammonium acetate (20mM, pH 7.2). A post-column infusion with 0.05% formic acid in acetonitrile was used to enhance sensitivity. Quantitation as well as enantiomeric ratio measurements were covered by quality controls. Validation parameters for all eight enantiomers included selectivity (high), matrix effects (no ion suppression/enhancement), calibration model (linear, weight 1/X(2), in the range of 0.25-250ng/g), limit of quantitation (0.125-0.50ng/g), repeatability (2-6%) and intermediate precision (2-7%), accuracy (83-114%), dilution integrity (98-115%), carry over (not exceeding 0.07%) and stability (stable in blood and extract). The method was applied to blood samples from a healthy volunteer administrated a single 100mg dose and to a case sample concerning an impaired driver, which confirmed its applicability in human pharmacokinetic studies as well as in toxicological and forensic investigations.

  • 13.
    Hjalmdahl, Magnus
    et al.
    Swedish Road and Transport Research Institute, Linköping.
    Vadeby, Anna
    Swedish Road and Transport Research Institute, Linköping.
    Forsman, Asa
    Swedish Road and Transport Research Institute, Linköping.
    Fors, Carina
    Swedish Road and Transport Research Institute, Linköping.
    Ceder, Gunnel
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Woxler, Per
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Effects of d-amphetamine on simulated driving performance before and after sleep deprivation2012In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 222, no 3, 401-411 p.Article in journal (Refereed)
    Abstract [en]

    Stimulant drugs are commonly abused and also used to promote wakefulness, yet their effects on driving performance during sleep deprivation have not been thoroughly researched in experimental studies. The aims were to assess the effects on fundamental driving parameters during simulated driving of two doses of d-amphetamine and further to assess the interaction between d-amphetamine and sleep deprivation. A double-blind, placebo-controlled experiment including 18 healthy male volunteers was conducted. The participants felt more alert when taking a dose of d-amphetamine than when taking placebo, and the effect was stronger for the higher dose. However, the data did not show any evidence that taking d-amphetamine prevented the subjects from becoming successively sleepier during the night. A significant main effect of the dose was found for three out of the five primary indicators where the lower dose led to improved driving. These indicators were crossing-car reaction time, and coherence and delay from a car-following event. Regarding sleep deprivation, a main effect was found for four of the primary indicators and three of the secondary indicators. The results showed overall impaired driving with respect to standard deviation of lateral position and delay in reaction time when the sleep-deprived conditions were compared to the alert condition. We found no interactions between dose and sleep deprivation for any of the performance indicators. Our results suggest that administration of d-amphetamine does not compensate for impairment of driving due to fatigue. The positive effects of 10 mg were not further improved or even sustained when increasing the dose to 40 mg.

  • 14.
    Hodgins, S.
    et al.
    Institute of Psychiatry, King's College, London.
    Tengstrom, A.
    Tengström, A., Maria-Ungdom Research Centre, Karolinska Institute, Stockholm, Sweden.
    Eriksson, A.
    Maria-Ungdom Research Centre, Karolinska Institute, Stockholm, Sweden.
    Osterman, R.
    Österman, R., Stockholm University, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Eaves, D.
    Eaves, D..
    Hart, S.
    Simon Fraser University, Burnaby, Canada.
    Webster, C.
    Simon Fraser University, Burnaby, Canada.
    Ross, D.
    Riverview Hospital, Coquitlam, Canada.
    Levin, A.
    Vancouver General Hospital, Vancouver, Canada.
    Levander, S.
    University Hospital, MAS, Malmö, Sweden.
    Tuninger, E.
    University Hospital, MAS, Malmö, Sweden.
    Muller-Isberner, R.
    Müller-Isberner, R., Klinik für Forensische Psychiatrie Haina, Haina (Kloster), Germany.
    Freese, R.
    Klinik für Forensische Psychiatrie Haina, Haina (Kloster), Germany.
    Tiihonen, J.
    University of Kuopio, Kuopio, Finland.
    Kotilainen, I.
    University of Kuopio, Kuopio, Finland.
    Repo-Tiihonen, E.
    Niuvanniemi Hospital, Kuopio, Finland.
    Vaananen, K.
    Väänänen, K., Niuvanniemi Hospital, Kuopio, Finland.
    Eronen, M.
    Vanha Vaasa Hospital, Vaasa and Niuvanniemi Hospital, Kuopio, Finland.
    Vokkolainen, A.
    Vanha Vaasa Hospital, Vaasa and Niuvanniemi Hospital, Kuopio, Finland.
    Vartiainen, H.
    Helsinki Central University Hospital, Helsinki, Finland.
    A multisite study of community treatment programs for mentally ill offenders with major mental disorders: Design, measures, and the forensic sample2007In: Criminal justice and behavior, ISSN 0093-8548, E-ISSN 1552-3594, Vol. 34, no 2, 211-228 p.Article in journal (Refereed)
    Abstract [en]

    This article presents reasons for undertaking "The Comparative Study of the Prevention of Crime and Violence by Mentally Ill Persons" and reasons for decisions regarding the study design and choice of measures. A brief portrait of the forensic patients that have been recruited is also presented. Community treatment programs could offer long-term cost-effective care for offenders with major mental disorders (MMDs). The study aims to identify the necessary ingredients of an effective program. Sites are selected in four countries where identification of most, if not all, persons with MMD who commit crimes within the catchment area was possible. Within each site, two samples of patients with MMD are recruited, one from a forensic hospital and one from a general psychiatric hospital. Assessments are completed prior to discharge. Participants are followed during a 5-year period. Comparisons of the forensic patients recruited in the four sites indicate many more similarities than differences. © 2007 American Association for Correctional and Forensic Psychology.

  • 15.
    Jakobsson, Gerd
    et al.
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Segmental analysis of amphetamines in hair using a sensitive UHPLC-MS/MS method2014In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 6, 22-29 p.Article in journal (Refereed)
    Abstract [en]

    A sensitive and robust ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for quantification of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy methamphetamine in hair samples. Segmented hair (10 mg) was incubated in 2M sodium hydroxide (80 degrees C, 10 min) before liquid-liquid extraction with isooctane followed by centrifugation and evaporation of the organic phase to dryness. The residue was reconstituted in methanol:formate buffer pH 3 (20:80). The total run time was 4 min and after optimization of UHPLC-MS/MS-parameters validation included selectivity, matrix effects, recovery, process efficiency, calibration model and range, lower limit of quantification, precision and bias. The calibration curve ranged from 0.02 to 12.5 ng/mg, and the recovery was between 62 and 83%. During validation the bias was less than +/- 7% and the imprecision was less than 5% for all analytes. In routine analysis, fortified control samples demonstrated an imprecision less than13% and control samples made from authentic hair demonstrated an imprecision less than26%. The method was applied to samples from a controlled study of amphetamine intake as well as forensic hair samples previously analyzed with an ultra high performance liquid chromatography time of flight mass spectrometry (UHPLC-TOF-MS) screening method. The proposed method was suitable for quantification of these drugs in forensic cases including violent crimes, autopsy cases, drug testing and re-granting of driving licences. This study also demonstrated that if hair samples are divided into several short segments, the time point for intake of a small dose of amphetamine can be estimated, which might be useful when drug facilitated crimes are investigated.

  • 16.
    Jones, A Wayne
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Eklund, A.
    National Board for Forens Medicine.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Concentration-Time Profiles of Gamma-Hydroxybutyrate in Blood After Recreational Doses are Best Described by Zero-Order Rather Than First-Order Kinetics2009In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 33, no 6, 332-335 p.Article in journal (Refereed)
    Abstract [en]

    The recreational drug gamma-hydroxybutyrate (GHB) has a short plasma elimination half-life (t(1/2)) reported to be about 30-50 min. However, this represents a terminal half-life and therefore might not necessarily apply after large (abuse) doses are taken. Clinical studies with sodium oxybate (sodium salt of GHB) suggest that zero-order rather than first-order kinetics are more appropriate to describe post-peak concentration-time (C-T) profiles. We report the case of a 23-year-old male found unconscious by the police and a blood sample contained 100 mg/L GHB and 0.14 g% ethanol. On regaining consciousness the man admitted drinking alcohol about 6 h earlier but claimed that his drink must have been spiked with GHB. The police wanted to know how much GHB had been administered to account for the man's clinical condition. A back-calculation for 6 h, assuming a GHB half-life of 40 min, gives a very high concentration in blood of approximately 900 mg/L, which would probably have proven fatal. Back-calculating using zero-order kinetics and a proposed elimination rate of 18 mg/L per hour leads to a GHB concentration of 208 mg/L, which is much more realistic. Toxicologists should not arbitrarily apply the principles of first-order kinetics after abuse doses of drugs, when zero-order or saturation kinetics (Michaelis-Menten) are more appropriate.

  • 17.
    Josefsson, M
    et al.
    Nationall Board Forensic Medicine .
    Kronstrand, Robert
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Andersson, J
    Nationall Board Forensic Medicine .
    Roman, M
    Nationall Board Forensic Medicine .
    Evaluation of electrospray ionisation liquid chromatography-tandem mass spectrometry for rational determination of a number of neuroleptics and their major metabolites in human body fluids and tissues2003In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 789, no 1, 151-167 p.Article in journal (Refereed)
    Abstract [en]

    A study of liquid chromatography-triple quadrupole mass spectrometry (LC-MS-MS) with positive electrospray ionisation (ESI) for the determination of selected drugs in human tissues and body fluids such as blood, urine and hair is described. The possibility to screen for and quantify the 19 most commonly prescribed neuroleptics on the Swedish market and determine the presence of their major metabolites within a single LC-MS-MS analysis was evaluated on a PE Sciex API2000 instrument. Chromatographic conditions were optimised and the best separation, with individual retention times for most of the analytes, was obtained on a Zorbax SB-CN column within a 9-min gradient run. The MS-MS fragmentation conditions were optimised for each compound in order to obtain both specific fragments and high signal intensity. Since neuroleptics are a heterogeneous group of compounds, a markedly difference in collision energy needed to achieve fragments of the selected parent ions was seen and the number of fragments achieved varied as well. For sensitive quantification the transition of the most intense fragment of the protonated molecular ion (M + 1)(+) was selected for multiple reaction monitoring analysis. More than 70 transitions were finally included in the assay. Detection levels down to the lower ng/ml level were achieved for all analytes, but between analytes more than a 10-fold difference in signal response was seen. By evaluation of extracted ion chromatograms from the analysis of authentic human blood, urine and hair sample the proposed concept for rational drug analysis was found to be both selective and sensitive for the neuroleptics included. A great number of metabolites could be determined in blood, urine and hair as well. A full method validation was not performed since the objective was to evaluate the method design rather than to validate a final method set-up.

  • 18.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Andersson, Mikael
    National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Mephedrone, Methylone and 3,4-Methylenedioxypyrovalerone (MDPV) Induce Conditioned Place Preference in Mice2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 5, 411-416 p.Article in journal (Refereed)
    Abstract [en]

    During the last decade, there has been a worldwide increase in popularity and abuse of synthetic cathinones. Common ingredients of the so-called bath salts include mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV). Relatively little information about the pharmacology and addiction potential of these drugs is available. We used the conditioned place preference (CPP) paradigm to explore the reinforcing effects of three different synthetic cathinones. The primary aim of this study was to investigate whether mephedrone, methylone and MDPV induce CPP in mice. The secondary aims were to investigate a possible dose-response CPP and whether the synthetic cathinones induce higher CPP than amphetamine at equal dose. C57BL/6 mice were conditioned to mephedrone, methylone, MDPV and amphetamine at doses of 0.5, 2, 5, 10 or 20mg/kg (i.p.). During the conditioning, the mice received two training sessions per day for 4days. All four tested drugs showed a significant place preference compared with controls. Mice conditioned with MDPV (5 and 10mg/kg) displayed a greater preference score compared to mice conditioned with amphetamine (5 and 10mg/kg). Our findings show that mephedrone, methylone and MDPV produce CPP equal or higher than amphetamine strongly suggesting addictive properties. Given the public health concern of abuse, future pharmacological studies are necessary to fully understand the effects of these drugs.

  • 19.
    Kechagias, Stergios
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Dernroth, Dženeta Nezirević
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgren, Anders
    Skåne University Hospital, Lund.
    Hansson, Therese
    Skåne University Hospital, Lund.
    Isaksson, Anders
    Skåne University Hospital, Lund.
    Walther, Lisa
    Skåne University Hospital, Lund.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Nystrom, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Phosphatidylethanol Compared with Other Blood Tests as a Biomarker of Moderate Alcohol Consumption in Healthy Volunteers: A Prospective Randomized Study.2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50, no 4, 399-406 p.Article in journal (Refereed)
    Abstract [en]

    AIM: It is generally agreed that traditional alcohol biomarkers lack in sensitivity to detect hazardous alcohol consumption. The present study was undertaken to evaluate the ability of phosphatidylethanol (PEth) and traditional alcohol markers to detect moderate alcohol consumption and to distinguish between moderate alcohol consumption and abstinence.

    METHODS: Forty-four subjects, 32 females and 12 males, were included in the study. They were randomized to alcohol abstention or to alcohol consumption. Female participants consumed 150 ml of red wine (equivalent to 16 g of alcohol) per 24 h and the male participants double the amount. The study lasted for 3 months. Blood samples were drawn at the start and at the end of the study period. Blood samples were analysed for PEth, carbohydrate-deficient transferrin (CDT), mean corpuscular volume (MCV), γ-glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

    RESULTS: ROC curves for the various biochemical markers were plotted in order to assess their ability to discriminate between abstention and moderate daily consumption of alcohol. PEth and CDT were the only markers with AUROCs significantly higher than 0.5, and PEth was detected in all participants randomized to alcohol consumption.

    CONCLUSION: PEth was the only marker that could detect moderate intake and the present results also indicate that PEth probably can distinguish moderate alcohol consumption from abstinence.

  • 20.
    Kronstrand, Robert
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Analytical and Toxicological Aspects of Drug Incorporation into Human Hair2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall purpose of this thesis was to develop analytical methods for the determination of drugs and melanin content of human hair for practical use in forensic and clinical toxicology. The thesis consists of five papers, two of which are controlled single dose studies where codeine or selegiline were administered to healthy volunteers. One patient study, looked at the concentrations of selegiline metabolites in both pigmented and senile white hairs as well as plasma. Another study involved forensic autopsy cases where the occurrence of drugs of abuse in post-mortem blood, urine and hair were compared. Finally, one in vitro study investigated the binding of [3H]-flunitrazepam to melanin. To our knowledge, the controlled dosage studies are the first to quantitatively determine the relationship between drug concentration in human hair and melanin content.

    The results demonstrated that pigmentation was an important factor for the incorporation of codeine, methamphetamine, and amphetamine into human hair. The relationships could be described by exponential functions with correlations coefficients r2>0.8. We have shown that the pigmented portion of hair from grey-haired patients incorporated more methamphetamine and amphetamine than the non-pigmented portion. The mean pigmented/white-hair ratios were 3.7±1.9 and 3.0±1.2 for methamphetamine and amphetamine respectively. Segmental hair analysis showed decreasing drug-concentrations over three months as a sign of noncompliance or of instability of the drugs in hair owing to cosmetic treatment of hair or wear. In the controlled studies, we demonstrated that the drug concentration in hair was fairly constant up to one month. In the study on autopsy cases, we found that hair analysis revealed patterns of multi-drug use not found by analysis of a single blood sample. Also, in 6 of 19 cases of heroin overdose, no opiates could be detected in hair. This suggested "first" or only occasional use of heroin, which might have been a contributing factor to the overdose death, because of lack of tolerance. The results from the in vitro study showed that binding of flunitrazepam to eumelanin occurs by two mechanisms, a Langmuir-like binding and a diffusion limited binding. We propose that these are expressions of an initial binding to the melanin surface (surface binding) followed by the diffusion of drug molecules into the melanin granule (bulk binding).

    Hair as a specimen for toxicological analysis has hitherto not been investigated in Sweden. This thesis address questions raised by international research on the incorporation of drugs into hair and its implications for clinical and forensic toxicology.

    Melanin has been established as an important factor for incorporation and binding of certain drugs into human hair and methods that allow correction for this are presented. Together, the results from the various studies provide a framework for both future research and the start of drug analysis in hair for forensic and clinical applications in Sweden.

    List of papers
    1. Incidence of opiates, amphetamines, and cocaine in hair and blood in fatal cases of heroin overdose
    Open this publication in new window or tab >>Incidence of opiates, amphetamines, and cocaine in hair and blood in fatal cases of heroin overdose
    1998 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 92, no 1, 29-38 p.Article in journal (Refereed) Published
    Abstract [en]

    The purpose of the present study was to investigate the occurrence in hair, of some drugs of abuse in deaths caused by heroin overdose, in comparison to findings in blood. Blood, urine and hair samples were obtained during routine post mortem examinations. Samples were analysed for amphetamines, opiates, and cocaine. Immunometric drug screening was performed in urine and positive results confirmed with gas chromatography–mass spectrometry (GC–MS) of blood samples. All hair samples were analyzed with GC–MS. Hair samples were either incubated with methanol for determination of opiates and cocaine, or dissolved in sodium hydroxide for determination of amphetamines. All 19 blood samples were positive for morphine (0.04–0.4 μg g−1) and ten were also positive for 6-acetylmorphine (0.003–0.02 μg g−1). Thirteen of the hair samples were positive for 6-acetylmorphine and seven of which were positive also for morphine. Concentrations ranged from 0.3–7.4 and 0.3–1.3 (ng mg), respectively. Amphetamine was found in three blood samples (0.04–1.2 μg g−1) and in eleven hair samples (0.4–18.3 ng mg). Cocaine was determined in one blood sample (0.03 μg g−1) and two hair samples (0.7–6.5 ng mg). Out of the nineteen cases studied, eight showed chronic multi drug use on the basis of the results of hair analysis. In six subjects no opiates could be detected in hair, suggesting; “first” or occasional intake of heroin, which could be a contributing factor to the overdose death, because of lack of tolerance. We conclude that analysis of hair can be a useful complement to analysis of more conventional autopsy material, especially when investigating overdose deaths and previous histories of drug use and abuse.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80902 (URN)10.1016/S0379-0738(98)00003-6 (DOI)
    Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2017-12-07Bibliographically approved
    2. Codeine Concentration in Hair after Oral Administration Is Dependent on Melanin Content
    Open this publication in new window or tab >>Codeine Concentration in Hair after Oral Administration Is Dependent on Melanin Content
    Show others...
    1999 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 45, no 9, 1485-1494 p.Article in journal (Refereed) Published
    Abstract [en]

    Background: Analysis of drugs in hair has been used on a qualitative basis to estimate earlier exposure to drugs. Clinical applications are rare because of the lack of dose–response relationships in the studies performed to date, and questions remain regarding the mechanisms of drug incorporation into hair. Several human studies have shown differences in drug accumulation between pigmented and nonpigmented hair. However, the melanin concentration in hair was not determined and correlated to the amount of drug incorporated.

    Methods: Nine human subjects were given codeine as a single oral dose, and plasma codeine concentrations were determined for 24 h, using gas chromatography–mass spectrometry. Hair samples were obtained weekly for a month. Total melanin, eumelanin, and codeine were measured quantitatively in hair samples by spectrophotometry, HPLC, and gas chromatography–mass spectrometry, respectively.

    Results: There was an exponential relationship between codeine and melanin concentrations in hair, (r2 = 0.95 with total melanin and r2 = 0.83 with eumelanin). After normalizing the results by the area under the curve for codeine in plasma, we obtained r2 = 0.86 for codeine vs total melanin and r2 = 0.90 vs eumelanin.

    Conclusions: Our results stress the importance of melanin determination when measuring drugs in hair. We postulate that analysis of drug concentration in hair may be worthwhile in the monitoring of drug compliance if the results are normalized for melanin content.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25184 (URN)9623 (Local ID)9623 (Archive number)9623 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    3. Incorporation of Selegiline Metabolites into Hair after Oral Selegiline Intake
    Open this publication in new window or tab >>Incorporation of Selegiline Metabolites into Hair after Oral Selegiline Intake
    2001 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 25, no 7, 594-601 p.Article in journal (Refereed) Published
    Abstract [en]

    We have previously shown that melanin in human hair has a great impact on the incorporation of codeine into hair. The present study on 10 subjects was performed to investigate whether or not these findings could also be extrapolated to other therapeutic drugs. We chose selegiline because it metabolizes to two commonly abused central stimulants, methamphetamine and amphetamine. The results would therefore also be of interest when studying the intake of such drugs and their incorporation into human hair. Selegiline and metabolites were determined by gas chromatography-mass spectrometry, total melanin by spectrophotometry, and pyrroletricarboxylic acid by high-performance liquid chromatography with ultraviolet detection. Our results show strong positive exponential relationships (y = ex) between melanin and the metabolites, which for methamphetamine improved by normalizing for plasma area under the curve. We conclude that the major metabolites of selegiline can be detected in hair up to four weeks after a single oral dose and that the incorporation closely relates to the melanin contents.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25186 (URN)10.1093/jat/25.7.594 (DOI)9625 (Local ID)9625 (Archive number)9625 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Quantitative Analysis of Desmethylselegiline, Methamphetamine, and Amphetamine in Hair and Plasma from Parkinson Patients on Long-Term Selegiline Medicatio
    Open this publication in new window or tab >>Quantitative Analysis of Desmethylselegiline, Methamphetamine, and Amphetamine in Hair and Plasma from Parkinson Patients on Long-Term Selegiline Medicatio
    2003 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 27, no 3, 135-141 p.Article in journal (Refereed) Published
    Abstract [en]

    Hair and plasma from patients on long-term selegiline medication were analyzed to evaluate the relationships between plasma and hair melanin concentrations and the incorporation of the selegiline metabolites methamphetamine and amphetamine in hair, and to evaluate hair analyses for determining compliance in medication. Analyses were performed on both the whole hairs, as well as pigmented and non-pigmented hairs from gray-haired patients. Melanin was quantitated by spectrophotometry, and metabolites were quantitated by gas chromatography-mass spectrometry. Concentrations in pigmented and non-pigmented hairs differed significantly for both methamphetamine (p < 0.01) and amphetamine (p < 0.02), with mean concentration ratios being 3.69 ± 1.88 and 2.95 ± 1.16 for methamphetamine and amphetamine, respectively. Segmental analysis indicated that some patients had not been compliant with medication. We concluded that the incorporation of methamphetamine and amphetamine into hair of single individuals shows a preference for pigmented hairs over white hairs and that segmental analysis of hair may he useful when measuring compliance with medication.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26747 (URN)10.1093/jat/27.3.135 (DOI)11342 (Local ID)11342 (Archive number)11342 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2018-01-12Bibliographically approved
    5. Characterization of [3H]flunitrazepam binding to melanin
    Open this publication in new window or tab >>Characterization of [3H]flunitrazepam binding to melanin
    Show others...
    2001 (English)In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 298, no 2, 259-264 p.Article in journal (Refereed) Published
    Abstract [en]

    In both clinical and forensic toxicology, the analysis of hair for drugs is an important tool to determine drug use in the past or to verify abstinence from illegal drugs during extended periods. Melanin is proposed as one of the factors that influences drug incorporation to hair and we have characterized the binding of the drug flunitrazepam to melanin in vitro. The drug was 3H labeled and melanin granules from cuttlefish, Sepia officinalis, were used according to the suggested standard for melanin studies. We observed a rapid Langmuir-like binding followed by a slower diffusion-limited binding that may be interpreted as an initial surface binding followed by deeper bulk binding. From three concentrations of melanin, with a 60-min incubation time, a mean saturation value of 180 ± 20 pmol/mg was calculated. The binding of a group of benzodiazepines and tranquilizers was compared to the binding of [3H]flunitrazepam by means of displacement experiments. These drugs showed binding characteristics similar to [3H]flunitrazepam except phenobarbital, which had a lower affinity to melanin. The method presented in this study allowed measurements with low melanin and drug concentrations and it has the strength of directly measuring the amount of drug bound to melanin, in contrast to previous indirect methods.

    Keyword
    Affinity, Benzodiazepines, Binding, Hair, Melanin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-47156 (URN)10.1006/abio.2001.5364 (DOI)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
  • 21.
    Kronstrand, Robert
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care.
    Using urine and hair to assess drug and medication use in mentally ill patients2002In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 17, 27S-27S p.Conference paper (Other academic)
  • 22.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology. Linköping University, Faculty of Health Sciences.
    Dizdar (Dizdar Segrell), Nil
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology. Linköping University, Faculty of Health Sciences.
    Larsson, Göran
    Sahlgrenska University Hospital, Department of Clinical Chemistry and Transfusion Medicine, Göteborg, Sweden.
    Quantitative Analysis of Desmethylselegiline, Methamphetamine, and Amphetamine in Hair and Plasma from Parkinson Patients on Long-Term Selegiline Medicatio2003In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 27, no 3, 135-141 p.Article in journal (Refereed)
    Abstract [en]

    Hair and plasma from patients on long-term selegiline medication were analyzed to evaluate the relationships between plasma and hair melanin concentrations and the incorporation of the selegiline metabolites methamphetamine and amphetamine in hair, and to evaluate hair analyses for determining compliance in medication. Analyses were performed on both the whole hairs, as well as pigmented and non-pigmented hairs from gray-haired patients. Melanin was quantitated by spectrophotometry, and metabolites were quantitated by gas chromatography-mass spectrometry. Concentrations in pigmented and non-pigmented hairs differed significantly for both methamphetamine (p < 0.01) and amphetamine (p < 0.02), with mean concentration ratios being 3.69 ± 1.88 and 2.95 ± 1.16 for methamphetamine and amphetamine, respectively. Segmental analysis indicated that some patients had not been compliant with medication. We concluded that the incorporation of methamphetamine and amphetamine into hair of single individuals shows a preference for pigmented hairs over white hairs and that segmental analysis of hair may he useful when measuring compliance with medication.

  • 23.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Andersson, Maria Choi
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Larson, Göran
    Sahlgrenska University Hospital, Department of Clinical Chemistry and Transfusion Medicine, Göteborg, Sweden.
    Incorporation of Selegiline Metabolites into Hair after Oral Selegiline Intake2001In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 25, no 7, 594-601 p.Article in journal (Refereed)
    Abstract [en]

    We have previously shown that melanin in human hair has a great impact on the incorporation of codeine into hair. The present study on 10 subjects was performed to investigate whether or not these findings could also be extrapolated to other therapeutic drugs. We chose selegiline because it metabolizes to two commonly abused central stimulants, methamphetamine and amphetamine. The results would therefore also be of interest when studying the intake of such drugs and their incorporation into human hair. Selegiline and metabolites were determined by gas chromatography-mass spectrometry, total melanin by spectrophotometry, and pyrroletricarboxylic acid by high-performance liquid chromatography with ultraviolet detection. Our results show strong positive exponential relationships (y = ex) between melanin and the metabolites, which for methamphetamine improved by normalizing for plasma area under the curve. We conclude that the major metabolites of selegiline can be detected in hair up to four weeks after a single oral dose and that the incorporation closely relates to the melanin contents.

  • 24.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Brinkhagen, Linda
    National Board for Forensic Medicine, Linkoping, Sweden .
    Birath-Karlsson, Carolina
    National Board for Forensic Medicine, Linkoping, Sweden .
    Roman, Markus
    National Board for Forensic Medicine, Linkoping, Sweden .
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine2014In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 406, no 15, 3599-3609 p.Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to compare the performance of an immunoassay screening for synthetic cannabinoids with a newly developed confirmation method using liquid chromatography quadrupole time-of-flight mass spectrometry. The screening included metabolites from JWH-018, JWH-073, and AM-2201. The confirmation included metabolites from AM-2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, JWH-398, MAM-2201, RCS-4, and UR-144. The immunoassay was tested and found to have no cross-reactivity with UR-144 metabolites but considerable cross-reactivity with MAM-2201 and JWH-122 metabolites. Sensitivity and specificity for the immunoassay were evaluated with 87 authentic urine samples and found to be 87 % and 82 %, respectively. With a cutoff at 2 ng/ml, the confirmation showed 80 positive findings in 38 cases. The most common finding was JWH-122 5-OH-pentyl, followed by JWH-018 5-OH-pentyl. There were 9 findings of UR-144 metabolites and 3 of JWH-073 metabolites. In summary, the immunoassay performed well, presenting both high sensitivity and specificity for the synthetic cannabinoids present in the urine samples tested. The rapid exchange of one cannabinoid for another may pose problems for immunoassays as well as for confirmation methods. However, we consider time-of-flight mass spectrometry to be superior since new metabolites can be quickly included and identified.

  • 25.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linkoping, Sweden.
    Brinkhagen, Linda
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linkoping, Sweden.
    Nyström, Fredrik
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Ethyl glucuronide in human hair after daily consumption of 16 or 32 g of ethanol for 3 months2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 215, no 1-3, 51-55 p.Article in journal (Refereed)
    Abstract [en]

    The overall objectives of the study were to develop a sensitive method for ethyl glucuronide (EtG) determination in hair and then investigate if a low or moderate intake of ethanol could be differentiated from total abstinence. Forty-four subjects were included in the study, 12 males (7 drinkers and 5 abstinent) and 32 females (14 drinkers and 18 abstinent). The study lasted 3 months and the female drinkers consumed one glass (16 g of ethanol) and the males consumed two glasses (32 g of ethanol) of wine (13.5-14%) daily. Hair samples were collected as close as possible above the skin and the proximal 2 cm were analyzed for EtG. Hair was cut into pieces of about 0.5 cm length and washed before incubation overnight in water and then extracted on Clean Screen EtG Carbon columns. The LC/MS/MS system consisted of a Waters ACQUITY UPLC connected to an API 4000 triple quadrupole instrument. Two transitions for EtG and one for the internal standard EtG-D-5 were measured. The method was linear from 60 to 10,000 pg/sample. Imprecision studies were performed at three levels as well as with an authentic sample. Total imprecision was 16% at 200 pg/sample, 8% at 1000 pg/sample, 6% at 8000 pg/sample and 13% at 29 pg/mg in the authentic sample. Of those who drank two glasses of wine every day, four had measurable amounts of EtG in their hair (5-11 pg/mg), and in only one of the females drinking one glass of wine EtG was quantified (3 pg/mg). Among the 23 abstinent subjects two had traces of EtG in the hair. We conclude that persons who ingested 16 or 32 g of ethanol daily for 3 months presented with low concentrations of EtG in hair, well below the proposed threshold for overconsumption set at 30 pg/mg. In addition, none of those who ingested 16 g/day had concentrations over the proposed abstinence threshold of 7 pg/mg.

  • 26.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Forsman, Malin
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden .
    Roman, Markus
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden .
    A Screening Method for 30 Drugs in Hair Using Ultrahigh-Performance Liquid Chromatography Time-of-Flight Mass Spectrometry2013In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 35, no 3, 288-295 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: The objectives of this study were to develop and to validate a qualitative screening method that met the new Society of Hair Testing (SoHT) guideline criteria for thresholds. less thanbrgreater than less thanbrgreater thanMethods: Extraction of 20 mg hair was performed by a previously validated procedure using overnight incubation in a mixture of methanol:acetonitrile:formiate buffer pH 3 (10:10:80). Analysis was performed on an Agilent 6540 quadrupole time-of-flight mass spectrometer in combination with an Agilent 1290 Infinity ultrahigh-performance liquid chromatography system. Separation was achieved with a 12-minute linear gradient chromatography on a high-strength silica T3 column at acidic conditions. An in-house database containing 30 compounds from the groups amphetamines, opiates, opioids, cocaine, benzodiazepines, and other sedatives including 6 deuterated internal standards was built by analyzing solutions from certified standards. Data were extracted using mass accuracy of +/- 10 ppm, retention time deviation of +/- 0.15 minutes, and area of andgt;= 30,000 counts. Identification was based on scoring of retention time, accurate mass measurement, and isotopic pattern. Validation included selectivity, repeatability of analyte area, and the scoring parameters at the proposed thresholds and a method comparison with the present liquid chromatography-mass spectrometry-mass spectrometry method using 50 authentic hair samples. A daily cutoff calibrator was used to identify positive samples. less thanbrgreater than less thanbrgreater thanResults: All cutoffs could be met with imprecisions of less than 5% for most parameters and analytes. Hair from drug-free subjects did not produce any positive results and the method comparison agreed in more than 90% of the cases. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that the developed method meets the criteria of the new SoHT guidelines for screening cutoffs. Even though no thresholds have been suggested for benzodiazepines, we conclude that thresholds between 0.05 and 0.1 ng/mg should be sufficient to determine regular use of these substances.

  • 27.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Förstberg-Peterson, Sophie
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Kågedal, Bertil
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Larsson, Göran
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Codeine Concentration in Hair after Oral Administration Is Dependent on Melanin Content1999In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 45, no 9, 1485-1494 p.Article in journal (Refereed)
    Abstract [en]

    Background: Analysis of drugs in hair has been used on a qualitative basis to estimate earlier exposure to drugs. Clinical applications are rare because of the lack of dose–response relationships in the studies performed to date, and questions remain regarding the mechanisms of drug incorporation into hair. Several human studies have shown differences in drug accumulation between pigmented and nonpigmented hair. However, the melanin concentration in hair was not determined and correlated to the amount of drug incorporated.

    Methods: Nine human subjects were given codeine as a single oral dose, and plasma codeine concentrations were determined for 24 h, using gas chromatography–mass spectrometry. Hair samples were obtained weekly for a month. Total melanin, eumelanin, and codeine were measured quantitatively in hair samples by spectrophotometry, HPLC, and gas chromatography–mass spectrometry, respectively.

    Results: There was an exponential relationship between codeine and melanin concentrations in hair, (r2 = 0.95 with total melanin and r2 = 0.83 with eumelanin). After normalizing the results by the area under the curve for codeine in plasma, we obtained r2 = 0.86 for codeine vs total melanin and r2 = 0.90 vs eumelanin.

    Conclusions: Our results stress the importance of melanin determination when measuring drugs in hair. We postulate that analysis of drug concentration in hair may be worthwhile in the monitoring of drug compliance if the results are normalized for melanin content.

  • 28.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Grundin, Robert
    National Board of Forensic Medicine, Department of Forensic Medicine, Solna, Sweden.
    Jonsson, John
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Incidence of opiates, amphetamines, and cocaine in hair and blood in fatal cases of heroin overdose1998In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 92, no 1, 29-38 p.Article in journal (Refereed)
    Abstract [en]

    The purpose of the present study was to investigate the occurrence in hair, of some drugs of abuse in deaths caused by heroin overdose, in comparison to findings in blood. Blood, urine and hair samples were obtained during routine post mortem examinations. Samples were analysed for amphetamines, opiates, and cocaine. Immunometric drug screening was performed in urine and positive results confirmed with gas chromatography–mass spectrometry (GC–MS) of blood samples. All hair samples were analyzed with GC–MS. Hair samples were either incubated with methanol for determination of opiates and cocaine, or dissolved in sodium hydroxide for determination of amphetamines. All 19 blood samples were positive for morphine (0.04–0.4 μg g−1) and ten were also positive for 6-acetylmorphine (0.003–0.02 μg g−1). Thirteen of the hair samples were positive for 6-acetylmorphine and seven of which were positive also for morphine. Concentrations ranged from 0.3–7.4 and 0.3–1.3 (ng mg), respectively. Amphetamine was found in three blood samples (0.04–1.2 μg g−1) and in eleven hair samples (0.4–18.3 ng mg). Cocaine was determined in one blood sample (0.03 μg g−1) and two hair samples (0.7–6.5 ng mg). Out of the nineteen cases studied, eight showed chronic multi drug use on the basis of the results of hair analysis. In six subjects no opiates could be detected in hair, suggesting; “first” or occasional intake of heroin, which could be a contributing factor to the overdose death, because of lack of tolerance. We conclude that analysis of hair can be a useful complement to analysis of more conventional autopsy material, especially when investigating overdose deaths and previous histories of drug use and abuse.

  • 29.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Jones, A Wayne
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Concentration Ratios of Codeine-to-Morphine in Plasma after a Single Oral Dose (100 mg) of Codeine Phosphate2001In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 25, no 6, 486-487 p.Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 30.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Nystrom, Ingrid
    National Board for Forens Medicine.
    Forsman, Malin
    National Board for Forens Medicine.
    Kall, Kerstin
    National Board for Forens Medicine.
    Hair analysis for drugs in drivers license regranting. A Swedish pilot study2010In: FORENSIC SCIENCE INTERNATIONAL, ISSN 0379-0738, Vol. 196, no 1-3, 55-58 p.Article in journal (Refereed)
    Abstract [en]

    When being convicted for petty drug offence or driving under the influence of drugs in Sweden, the driving license may be suspended. To regain the license, the person has to prove that he or she has been drug free during an observation period. This is controlled by urine samples taken at several occasions. However, the risk of manipulation and the risk of false negative urine samples are high. In addition, many people find it difficult or embarrassing to urinate when observed. Hair sampling might therefore be a welcome option to this procedure, with its easy sampling and minimal risk of manipulation. The longer detection window may also provide better information to the physician. The aim of this work was to evaluate if clients preferred hair samples to urine and to investigate practical and interpretive problems or advantages with hair samples. Ninety-nine hair samples and 198 urine samples were collected from 84 clients during the 12 month study period. Hair samples were divided into either one segment (0-3 cm) or two segments (0-3 and 3-6 cm) depending on the length. The hair samples were screened with LC-MS-MS for 20 drugs and confirmation of positive results were performed with GC-MS or LC-MS-MS. The results were compared to urine samples taken at two occasions during the observation period. To cover the timeframe of the urine samples hair was collected 2 weeks after the second sample. The urine samples were analysed with immunochemical screening and positive results confirmed with GC-MS or LC-MS-MS. Seventy-four clients presented with negative results in both urine and hair. Hair analysis identified illegal drugs at seven different occasions whereas urine failed to identify any illegal drugs. However the thresholds used may still be too high to find sporadic use as clients that admitted to use drugs sporadically presented with drug concentrations lower than the agreed thresholds but above the limit of detection. This implicates that the physician must have an understanding and knowledge of the limitations of the screening methods used. Another important outcome was that the clients approved of hair sampling considering it a better means to prove their drug abstinence. In addition, both the clients and the clinicians thought hair sampling easier than urine sampling. We believe that hair analysis can offer several advantages compared to urine analysis for clinicians working with driving license regranting.

  • 31.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Nystrom, Ingrid
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Strandberg, Joakim
    Karolinska Institutet.
    Druid, Henrik
    Karolinska Institutet.
    Screening for drugs of abuse in hair with ion spray LC-MS-MS2004In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 145, no 02-Mar, 183-190 p.Article in journal (Refereed)
    Abstract [en]

    Analyzing hair for many substances can be tedious and expensive, and a rapid screening method should prove helpful. Generally, screening has been performed using immunological tests, mainly in workplace drug testing, where the number of samples has been high. The aim of this study was to develop an LC-MS-MS method for the simultaneous analysis of several drugs of abuse in human hair as an alternative to immunological screening tests. In 75 randomly selected autopsy cases, hair was analyzed in addition to the usual specimens of blood and urine. The method included nicotine, cotinine, morphine, codeine, 6-acetylmorphine, ethylmorphine, amphetamine, methamphetamine, MDA, MDMA, benzoylecgonine, cocaine, 7-aminoflunitrazepam and diazepam. The LC-MS-MS analysis was performed on a SCIEX API 2000 MS-MS instrument equipped with an electrospray interface. To 20-50 mg of hair, 0.5 ml of mobile phase A (acetonitril:methanol: 20 mM formate buffer, pH 3.0 (10:10:80)) and 25 mul of internal standard were added and the sample was incubated in a water bath at 37degreesC during 18 h. Using a threshold of 20 ng/ sample, equivalent to 1 ng/mg if 20 mg hair is used, 26 positive results were found in 16 cases. Three of the 26 positive detections could not be confirmed by GC-MS. Two of the cases were not previously known as drug users. Of the 59 negative cases, only one case had a positive blood sample showing 0.01 and 0.07 mug/g femoral blood of 6-acetylmorphine and morphine, respectively. This might indicate drug abstinence resulting in decreased tolerance or even a "first time" use of heroin resulting in death. We conclude that the use of hair analysis in postmortem cases can reveal both unknown drug use, as well as confirm a period of drug abstinence prior to an acute fatal overdose. The proposed LC-MS-MS method showed high sensitivity, was very easy to perform and seemed appropriate for screening purposes.

  • 32.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Nyström, Ingrid
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Hodgins, Sheilagh
    Department of Psychology, Université de Montréal, Québec, Canada.
    Segmental Ion Spray LC-MS-MS Analysis of Benzodiazepines in Hair of Psychiatric Patients2002In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 26, no 7, 479-484 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the analysis of benzodiazepines in human hair. The method was tested by analyzing hair samples from forensic and clinical psychiatric patients where benzodiazepines had been prescribed during hospitalization and after care. Hair samples were obtained at discharge from the clinic and then after six months. Two-centimeter segments of the hair samples (10–30 mg) were washed once with isopropanol, three times with phosphate buffer, and again with isopropanol, dried, weighed, and digested with proteinase K before solid-phase extraction with BondElut Certify columns. Diazepam, nordiazepam, oxazepam, alprazolam, OH-alprazolam, nitrazepam, 7-aminonitrazepam, flunitrazepam, 7-aminoflunitrazepam, clonazepam, and 7-aminoclonazepam were quantitated in MRM mode using one transition for each analyte and deuterated internal standard. The calibration range was 0.125–5 ng/mg for diazepam, nordiazepam, and oxazepam and 0.025–1.0 ng/mg for the other compounds. In the hair samples analyzed, diazepam, flunitrazepam, nitrazepam, and clonazepam was detected together with their metabolites. Alprazolam was not detected in any sample. Segmental hair analysis revealed differences in drug deposition in hair before and after release from psychiatric treatment. Both increases and decreases of hair drug concentrations were seen after release even though the prescribed dose was the same. This was taken as an indication of noncompliance during the after-care period. We conclude that the extraction and LC-MS-MS procedures were adequate to detect benzodiazepines in hair and that the results indicated that segmental hair analysis might provide retrospective information about medication intake.

  • 33.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Roman, Markus
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Andersson, Mikael
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Eklund, Arne
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Toxicological Findings of Synthetic Cannabinoids in Recreational Users2013In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 37, no 8, 534-541 p.Article in journal (Refereed)
    Abstract [en]

    In recent years, several synthetic cannabinoid compounds have become popular recreational drugs of abuse because of their psychoactive properties. This paper presents toxicological findings of synthetic cannabinoids in whole blood from some cases of severe intoxication including quantitative data from recreational users and a fatal intoxication. Samples were analyzed by liquid chromatography-tandem mass spectrometry in a scheduled multiple reaction mode after a basic liquid extraction. Twenty-nine synthetic cannabinoids were included in the method. In our data set of similar to 3000 cases, 28% were found positive for one or more synthetic cannabinoid(s). The most common finding was AM-2201. Most of the analytes had median concentrations of andlt;0.5 ng/g in agreement with other published data. The emerging drugs MAM-2201 (n = 151) and UR-144 (n = 181) had mean (median) concentrations of 1.04 (0.37) and 1.26 (0.34), respectively. The toxicity of the synthetic cannabinoids seems to be worse than that of natural cannabis, probably owing to the higher potency and perhaps also to the presence of several different cannabinoids in the smoked incense and the difficulties of proper dosing. The acute toxic effects may under certain circumstances contribute to death.

  • 34.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Roman, Markus
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Dahlgren, Maria
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Thelander, Gunilla
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Wikström, Maria
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Druid, Henrik
    Department of Forensic Medicine, National Board of Forensic Medicine, Linköping and Department of Oncology–Pathology, Karolinska Institutet, Stockholm, Sweden.
    A Cluster of Deaths Involving 5-(2-Aminopropyl)Indole(5-IT)2013In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 37, no 8, 542-546 p.Article in journal (Refereed)
    Abstract [en]

    During 2012, the designer drug 5-(2-aminopropyl)indole emerged in Sweden, and became available at different web sites under the name 5-IT or 5-API. This compound is an indole derivative and a positional isomer of alpha-methyltryptamine. In this paper, we report the pathology and toxicology from 15 deaths involving 5-IT. Routine postmortem toxicology was performed in femoral blood, using a targeted screening for pharmaceuticals and drugs of abuse with liquid chromatography time-of-flight technology, and positive results were quantified using chromatographic techniques. For 5-IT, a new method was developed using ultra-high-performance liquid chromatography and tandem mass spectrometry. In 11 cases, intoxication was the cause of death. Two cases were signed out as causa ignota, and they were considered to be natural deaths. All determinations of 5-IT were performed in femoral blood and the concentrations ranged from 0.7 to 18.6 mg/g. Two cases had 5-IT as the only drug identified, while the others presented with other psychotropic drugs or medications in the blood as well. Shortly after this series of deaths, 5-IT was scheduled as a hazardous substance according to the regulation Certain Goods Dangerous to Health on 18 September 2012 prohibiting the handling and selling of the drug. Since then, no positive cases have been found.

  • 35.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Roman, Markus
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Thelander, Gunilla
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Eriksson, Anders
    Section of Forensic Medicine, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden.
    Unintentional Fatal Intoxications with Mitragynine and O-Desmethyltramadol from the Herbal Blend Krypton2011In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 35, no 4, 242-247 p.Article in journal (Refereed)
    Abstract [en]

    The leaves of Kratom, a medicinal plant in Southeast Asia, have been used as an herbal drug for a long time. At least one of the alkaloids present in Kratom, mitragynine, is a mu-receptor agonist. Both Kratom and an additional preparation called Krypton are available via the internet. It seems to consist of powdered Kratom leaves with another mu-receptor agonist, O-desmethyltramadol, added. O-Desmethyltramadol is an active metabolite of tramadol, a commonly prescribed analgesic.We present nine cases of intoxication, occurring in a period of less than one year, where both mitragynine and O-desmethyltramadol were detected in the postmortem blood samples. Neither tramadol nor N-desmethyltramadol was present in these samples, which implies that the ingested drug was O-desmethyltramadol. The blood concentrations of mitragynine, determined by ultra-performance liquid chromatography-tandem mass spectrometry, ranged from 0.02 to 0.18 µg/g, and O-desmethyltramadol concentrations, determined by gas chromatography with nitrogen-specific detection, ranged from 0.4 to 4.3 µg/g. We believe that the addition of the potent mu-receptor agonist O-desmethyltramadol to powdered leaves from Kratom contributed to the unintentional death of the nine cases presented and conclude that intake of Krypton is not as harmless as it often is described on internet websites.

  • 36.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Seldén, Tor
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Josefsson, M
    National Board Forensic Medicine .
    Analysis of buprenorphine, norbuprenorphine, and their glucuronides in urine by liquid chromatography-mass spectrometry2003In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 27, no 7, 464-470 p.Article in journal (Refereed)
    Abstract [en]

    Buprenorphine is used for the treatment of chronic pain and also in treatment of heroin addiction as an alternative to methadone. As the availability of buprenorphine increases, so does the risk for abuse and the pressure on forensic and clinical laboratories to analyze for it. Buprenorphine and its dealkylated metabolite are excreted in urine, almost exclusively as glucuronides. The aim of the present study was to evaluate electrospray liquid chromatography tandem mass spectrometry (LC-MS-MS) for the rapid screening and quantitation of buprenorphine and its metabolites in urine. Three approaches were evaluated: (1) direct injection of diluted urine for measurement of glucuronides, (2) direct injection of diluted urine after enzymatic hydrolysis for the quantitation of buprenorphine and norbuprenorphine, and (3) quantitation of buprenorphine and norbuprenorphine after enzymatic hydrolysis and solid-phase extraction (SPE). One hundred six samples were subjected to procedure 1 and, when positive, further quantitated using procedure 2. Only samples with low analyte concentrations (< 20 microg/L) were subject to SPE. Concentrations of buprenorphine and norbuprenorphine in patients (N = 16) ranged between 31 and 1080 microg/L and 48-2050 microg/L, respectively. In suspected abusers (N = 33), the ranges were 2.3-796 microg/L and 5.0-2580 microg/L. In four of the authentic samples, both the buprenorphine and norbuprenorphine concentrations were below the 20- micro g/L cutoff. We concluded that LC-MS-MS analysis of the glucuronides provided an adequate screening method, but that the direct method for quantitation sometimes had to be complemented with a concentration by SPE, providing increased sensitivity, thus lowering the cutoff from 20 to 1 microg/L urine.

  • 37.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Linköping, Sweden.
    Thelander, G.
    National Board of Forensic Medicine, Linköping, Sweden.
    Lindstedt, D.
    National Board of Forensic Medicine, Linköping, Sweden.
    Roman, M.
    National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Linköping, Sweden.
    Fatal intoxications associated with the designer opioid AH-79212014In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 38, no 8, 599-604 p.Article in journal (Refereed)
    Abstract [en]

    AH-7921 (3,4-dichloro-N-[(1-dimethylamino) cyclohexylmethyl] benzamide) is a designer opioid with similar to 80% of morphines m-agonist activity. Over a 6-month period, we encountered nine deaths where AH-7921 was involved and detected in blood from the deceased. Shortly after the last death, on August 1 2013, AH-7921 was scheduled as a narcotic and largely disappeared from the illicit market in Sweden. AH-7921 was measured by a selective liquid chromatography- MS-MS method and the concentrations of AH-7921 ranged from 0.03 to 0.99 mu g/g blood. Six of our cases had other drugs of abuse on board and most had other medications such as benzodiazepines, antidepressants and analgesics. However, the other medicinal drugs encountered were present in postmortem therapeutic concentrations and unlikely to have contributed to death. In addition to the parent compound, we identified six possible metabolites where two N-demethylated dominated and four mono-hydroxylated were found in trace amounts in the blood. In conclusion, deaths with AH-7921 seem to occur both at low and high concentrations, probably a result of different tolerance to the drug. Hence, it is reasonable to assume that no sharp dividing line exists between lethal and non-lethal concentrations. Further, poly-drug use did not seem to be a major contributing factor for the fatal outcome.

  • 38.
    Morland, Jørg
    et al.
    Norwegian Institute of Public Health, Division of Forensic Toxicology and Drug Abuse, Nydalen, Oslo, Norway.
    Steentoft, Anni
    Department of Forensic Medicine, Section of Forensic Chemistry, Faculty of Health Sciences, University of Copenhagen, Denmark.
    Wiese Simonsen, Kirsten
    Department of Forensic Medicine, Section of Forensic Chemistry, Faculty of Health Sciences, University of Copenhagen, Denmark.
    Ojanperä, Ilkka
    Hjelt Institute, Department of Forensic Medicine, University of Helsinki, Finland.
    Vuori, Erkki
    Hjelt Institute, Department of Forensic Medicine, University of Helsinki, Finland.
    Magnusdottir, Kristin
    Department of Pharmacology and Toxicology, University of Iceland, Iceland.
    Kristinsson, Jakob
    Department of Pharmacology and Toxicology, University of Iceland, Iceland.
    Ceder, Gunnel
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Christophersen, Asbjørg
    Norwegian Institute of Public Health, Division of Forensic Toxicology and Drug Abuse, Nydalen, Oslo, Norway.
    Drugs related to motor vehicle crashes in northern European countries: A study of fatally injured drivers2011In: Accident Analysis and Prevention, ISSN 0001-4575, E-ISSN 1879-2057, Vol. 43, no 6, 1920-1926 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to find which drugs and drug combinations were most common in drivers who died, in particular, in single vehicle crashes where the responsibility for the crash would be referred to the driver killed. The study included all available blood samples from drivers, who died within 24h of the accident, in the years 2001 and 2002 in the five Nordic countries (total population about 24 million inhabitants). The samples were analysed for more than 200 different drugs in addition to alcohol, using a similar analytical programme and cut-off limits in all countries. In three countries (Finland, Norway and Sweden) blood samples were available for more than 70% of the drivers, allowing representative prevalence data to be collected. 60% of the drivers in single vehicle crashes had alcohol and/or drug in their blood samples, compared with 30% of drivers killed in collisions with other vehicles. In single vehicle accidents, 66% of the drivers under 30 years of age had alcohol and/or drugs in their blood (alcohol only - 40%; drugs only - 12%; alcohol and drugs - 14%). The drugs found were mostly illicit drugs and psychoactive medicinal drugs with warning labels (in 57% and 58% respectively of the drivers under 30 with drugs present). Similar findings were obtained for drivers 30-49 years of age (63% with alcohol and/or drugs). In drivers aged 50 years and above, killed in single vehicle crashes (48% with alcohol and/or drugs) illicit drugs were found in only one case, and psychoactive medicinal drugs were detected less frequently than in younger age groups. In 75% of single vehicle crashes, the driver was under 50 years. Thus, the majority of accidents where the drivers must be considered responsible, occurred with drivers who had recently used alcohol, or drugs, alone or in combination. The drugs involved were often illicit and/or psychoactive drugs with warning labels. Therefore a large proportion of single vehicle accidents appear to be preventable, if more effective measures against driving after intake of alcohol and drugs can be implemented.

  • 39.
    Nilsson, Gunnel
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Influence of pre-analytical conditions on the interpretation of zopiclone concentrations in whole blood2011In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 207, no 1-3, 35-39 p.Article in journal (Refereed)
    Abstract [en]

    Zopiclone is a short-acting hypnotic drug used for treatment of insomnia and its stability has been described in some detail. However, data especially on short-term pre-analytical stability is missing. This study investigated zopiclone stability differences between spiked and authentic whole blood from subjects dosed with zopiclone. In this way influence from physiological factors such as drug interactions, matrix composition and plasma protein levels were minimized. Nine volunteers participated in the study. Whole blood was obtained before and after oral administration of 10 mg Imovane®. Aliquots of 1 g of authentic and spiked blood were after initial measuring, stored at 20°C during 5 days, 5°C or -20°C during 3 months, and zopiclone was measured by gas chromatography with nitrogen phosphorus detection. The results showed no stability differences between authentic and spiked blood but confirmed the very short stability in whole blood at ambient temperature. In summary, the stability was less than 1 day at 20°C, less than 2 weeks at 5°C, but stable for 3 months at -20°C. This study demonstrates the importance of controlling pre-analytical conditions from sampling to analysis to avoid misinterpretation of toxicological results.

  • 40.
    Nilsson, Gunnel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Quantitative Analysis of Zopiclone, N-desmethylzopiclone, Zopiclone N-oxide and 2-Amino-5-chloropyridine in Urine Using LC-MS-MS2014In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 38, no 6, 327-334 p.Article in journal (Refereed)
    Abstract [en]

    A simple LC-MS/MS method was validated to allow determination of zopiclone (ZOP), Ndesmethylzopiclone (NDZOP), zopiclone N-oxide (ZOPNO) and 2-amino-5 chloropyridine (ACP) in urine at concentrations up to 3000 ng/mL within 3.5 min. This method was used for quantitative analysis of the analytes in authentic urine samples obtained 10 h after oral administration of zopiclone (Imovane®) and in aliquots of the same urine samples after different storage conditions. Additionally, pH of each studied urine sample was measured over time. The results showed that formation of ACP occurred at elevated pH and/or temperature by degradation of ZOP, NDZOP and ZOPNO. This method was also applied to samples obtained from two female victims of drug-facilitated assault. One sample had been exposed to long-term storage conditions at different temperatures and at pH>8.2, which resulted in high concentrations of ACP. The other sample, which was exposed to pH <6.5, showed no formation of ACP. ACP is formed both from ZOP and from its metabolites NDZOP and ZOPNO depending on the pH of the urine, time of storage and/or the temperature conditions. For correct interpretation in forensic cases ZOP, its major metabolites and ACP should be analyzed. When ACP is identified in urine the concentrations of ZOP, NDZOP and ZOPNO should be interpreted with great caution.

  • 41.
    Nilsson, Gunnel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Validation of an LC-MS/MS method for the determination of zopiclone, N-desmethylzopiclone and 2-amino-5-chloropyridine in whole blood and its application to estimate the original zopiclone concentration in stored specimens2015In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 129, no 2, 269-277 p.Article in journal (Refereed)
    Abstract [en]

    2-amino-5-chloropyridine (ACP) is a degradation product of zopiclone (ZOP) and may be formed when blood specimens are stored. ZOP instability in blood makes interpretation of concentrations difficult especially in cases of prolonged sample storage. This study investigated how ACP could be used to estimate the original concentration of ZOP in authentic samples. For that purpose, an analytical LC-MS/MS method for the quantitation of ACP, ZOP and the metabolite Ndesmethylzopiclone (NDZOP) in blood was validated. The method was then applied to investigate ACP formation, ZOP and NDZOP degradation in stored ZOP post-dosed authentic whole blood and two mathematical models were used to calculate the original concentration of ZOP. During storage, ACP was formed in amounts equimolar to the ZOP and NDZOP degradation. Results from samples in which ACP had been formed were used to test two models to estimate the original ZOP concentration. The correlation tests of the models showed strong correlations to the original ZOP concentration (r=0.960 and r=0.955) with p<0.01. This study showed that the equimolar degradation of ZOP and NDZOP to ACP could be used to estimate the original concentration of the unstable ZOP.

  • 42.
    Nilsson, Gunnel
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Stability tests of zopiclone in whole blood2010In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 200, no 01-Mar, 130-135 p.Article in journal (Refereed)
    Abstract [en]

    Zopiclone is a common drug in forensic cases and it is frequently analyzed in biological materials using different analytical methods. Zopiclone is unstable in certain solvents and depending on storage conditions unstable in biological fluids; however its stability in human whole blood has not yet been established in detail. Therefore, the following investigation was performed to study the stability of zopiclone in both spiked and authentic human blood. First, spiked blood samples were stored at -20 degrees C, 5 degrees C and 20 degrees C and the degradation of zopiclone was investigated. Second, authentic and spiked blood samples were stored at 5 degrees C and differences in zopiclone stability were studied. Third, processed sample stability and effect of freeze/thaw cycles were evaluated. Analyses were performed by GC-NPD and zopiclone concentrations were measured at selected time intervals. The study showed that zopiclone degrades in human blood depending on time and temperature and may not be detected after long-term storage. 2-amino-5-chloropyridine was identified as the primary degradation product from zopiclone. At refrigerator temperature zopiclone was stable less than 1 month in both spiked and authentic human blood samples. The best storage condition was at -20 degrees C even at short storage times, as freeze-thaw had no influence on the results. In butyl acetate extracts, zopiclone was stable at least 2 days when kept in the autosampler at ambient temperature. We conclude that preanalytical factors have great impact on analytical results and should be addressed when interpreting whole blood zopiclone concentrations.

  • 43.
    Nilsson, Kent W
    et al.
    Uppsala University.
    Oreland, Lars
    Uppsala University.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Leppert, Jerzy
    Uppsala University.
    Smoking as a product of gene-environment interaction2009In: UPSALA JOURNAL OF MEDICAL SCIENCES, ISSN 0300-9734, Vol. 114, no 2, 100-107 p.Article in journal (Refereed)
    Abstract [en]

    A strong hereditary influence on smoking has been demonstrated. As one of the candidate genes in relation to smoking, the serotonin transporter gene (5-HTTLPR) has been suggested, however with conflicting results. In recent studies, it has been shown that genotypic and environmental (G*E) factors interact in the shaping of a variety of phenotypic expressions. The objective of the present study was to investigate the interaction between a variation in the 5-HTTLPR and family environment in relation to smoking habits, nicotine dependence, and nicotine and cotinine levels in hair samples. A random Swedish adolescent population sample (n = 785), from which 200 individuals were stratified regarding behaviour, was genotyped for 5-HTTLPR and assessed with semi-structured interviews, a questionnaire, and hair analyses of nicotine and cotinine. The 5-HTTLPR gene interacted with a poor family environment to predict smoking habits, as well as nicotine and cotinine levels. The risk of being a smoker was increased 13 times for an individual with a combination of the 5-HTTLPR LS genotype and a poor family environment in comparison with the Homozygous Long-Long (LL) genotype and a good family environment.

  • 44.
    Nyström, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Trygg, Tomas
    Woxler, Per
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Quantitation of R-(−)- and S-(+)-Amphetamine in Hair and Blood by Gas Chromatography-Mass Spectrometry: An Application to Compliance Monitoring in Adult-Attention Deficit Hyperactivity Disorder Treatment2005In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 29, no 7, 682-688 p.Article in journal (Refereed)
    Abstract [en]

    Amphetamine has been used in Attention Deficit Hyperactivity Disorder (ADHD), narcolepsy, and as an appetite suppressant either as the racemate or in different proportions of its enantiomers. In Linköping, Sweden, the Department for Drug Dependence has successfully treated drug abusers also diagnosed with Adult ADHD with Metamina® [S-(+)-amphetamine]. Because of the high risk of relapse into drug abuse, a strategy involving the analysis of amphetamine enantiomers in blood and hair was investigated for the assessment of compliance as well as abstinence from street amphetamine. Four patients were included: one patient was treated with racemic amphetamine, and three with Metamina. Blood and hair samples were obtained as a part of the treatment. A basic extraction of the analytes into iso-octane was used. Hair was dissolved in sodium hydroxide before extraction. Chiral derivatization was performed by reaction with S-(−)-N-(trifluoroacetyl)prolyl chloride. Quantitation of R-(−)- and S-(+)-amphetamine was performed by gas chromatography-mass spectrometry in selected ion monitoring. Both blood and hair sample results showed good compliance for patients 1 and 2. Patient 3 and 4 showed different percentages of S-(+)-amphetamine in hair together with varying total concentrations, suggesting intake of additional racemic illicit amphetamine. During treatment, these patients also showed other signs of noncompliance, and one was temporarily withdrawn from treatment. We conclude that the method is suitable to detect therapeutic concentrations of R-(−)- and S-(+)-amphetamine in both blood and hair and that hair reveals noncompliance not shown by concentrations or enantiomer ratios in blood.

  • 45.
    Roman, M.
    et al.
    National Board for Forensic Medicine.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Lindstedt, D.
    National Board for Forensic Medicine.
    Josefsson, M.
    National Board for Forensic Medicine.
    Quantitation of seven low-dosage antipsychotic drugs in human postmortem blood using LC-MS-MS2008In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 32, no 2, 147-155 p.Article in journal (Refereed)
    Abstract [en]

    In forensic toxicology, antipsychotic drugs are of considerable interest because of their abuse potential and their involvement in intoxications and suicides. In recent years, several new drugs dosed at low levels have entered the market and have put further demands on assays used. The aim of this work was to develop a validated liquid chromatography-tandem mass spectrometry assay for the quantitation of the low-dosage antipsychotic drugs buspirone, fluphenazine, flupenthixol, perphenazine, risperidone, ziprasidone, and zuclopenthixol in human postmortem blood. After liquid-liquid extraction using methyl t-butyl ether, compounds were separated on a Zorbax SB-CN column. Calibration curves were linear in the range 0.8-100 microg/L (r > 0.998) for all drugs. Both within- and between-day coefficients of variation were lower than 25% for all drugs at the LOQ, and extraction recoveries ranged between 58 and 112%. The possible presence of matrix effects was closely investigated. Fifty-four authentic samples were analyzed within the routine postmortem investigation, which resulted in the diagnosis of three fatal intoxications. Even though only a few intoxications were identified, the assay may present valuable information on suicidal deaths in psychotic patients where a true negative result implies noncompliance and a higher susceptibility for suicide. Without a sensitive enough method, this conclusion cannot be drawn. Therefore, we believe that antipsychotic drugs must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases

  • 46.
    Seldén, Tor
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Druid, Henrik
    Department of Forensic Medicine, National Board of Forensic Medicine, Linköping, Sweden and Department of Oncology–Pathology, Karolinska Institutet, Stockholm, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 220, no 1-3, 284-290 p.Article in journal (Refereed)
    Abstract [en]

    Buprenorphine is considered to have little respiratory side effects at therapeutic doses and the partial agonistic properties should produce a "ceiling effect for respiratory depression at higher doses. Still, there are several reports on buprenorphine related deaths. Most deaths involve drug users and the co-administration of other CNS depressant drugs as well as reduced tolerance have been suggested to be risk factors. The primary aims were to investigate if lack of tolerance and/or co-ingestion of other psychotropic drugs are significant risk factors in buprenorphine fatalities. From July 2005 to September 2009, all autopsy cases where buprenorphine or norbuprenorphine had been detected in femoral blood and where analysis of buprenorphine had been performed in urine were selected. Results from the postmortem examination and toxicology were compiled. Postmortem toxicology was performed using the routine methodology at the laboratory. In total, 97 subjects were included in the study. These were divided into four groups; Intoxication with buprenorphine (N = 41), Possible intoxication with buprenorphine (N = 24), Control cases where buprenorphine was not the cause of death (N = 14), and Unclear (N = 18). The metabolite to parent compound ratios in both blood and urine in the Intoxication group were significantly different from those in the Control and Unclear groups. An extensive poly-drug use was seen in all groups with several additional opioids in the Possible group (54%) and in the Unclear group (78%) and hypnotics or sedatives in more than 75% of the Intoxication, Possible, and Unclear cases. Illicit drugs were present in all groups but not to a great extent with amphetamine and tetrahydrocannabinol as the main findings. Interestingly, 4 cases in the Intoxication group presented with no other significant drugs in blood other than buprenorphine. We conclude that a lethal concentration of buprenorphine in blood cannot be defined. Instead the analysis of blood as well as urine can be an important tool to show that the drug was taken shortly before death and to rule out a continuous use of buprenorphine supporting the notion that abstinence is an important risk factor. The presence of alprazolam in more than 40% of the Intoxications and the presence of hypnotics and sedatives in 75% of the Intoxications suggests that these drugs interact with buprenorphine producing toxic effects that buprenorphine alone would not have produced. Still, in 10% of the Intoxications no other drugs were found indicating that under certain circumstances buprenorphine alone may produce respiratory depression resulting in death.

  • 47.
    Seldén, Tor
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Roman, Markus
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Druid, Henrik
    National Board of Forensic Medicine, Department of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    LC-MS-MS analysis of buprenorphine and norbuprenorphine in whole blood from suspected drug users2011In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 209, no 1-3, 113-119 p.Article in journal (Refereed)
    Abstract [en]

    A liquid chromatography tandem mass spectrometry method is described for the analysis of buprenorphine and norbuprenorphine in whole blood. Linearity was achieved between 0.2-5 ng/g for buprenorphine and 0.5-5 ng/g for norbuprenorphine. Stability studies on spiked whole blood and an authentic sample showed no degradation of buprenorphine- and norbuprenorphine-glucuronide to their respective aglycones. Buprenorphine and norbuprenorphine showed some degradation when stored at 4 degrees C for three weeks, but was stable when stored at -20 degrees C for 4 weeks. The method was applied to forensic cases of driving under the influence of drugs (DUID) and petty drug offences (PDO) during 2007-2009. Out of 2459 cases analyzed, 322 were positive for both buprenorphine and norbuprenorphine (13%), 219 for buprenorphine only (9%), and 12 for norbuprenorphine only (0.5%). The mean and median concentrations (N = 322) were 1.7 and 1.0 ng/g, respectively, for buprenorphine and norbuprenorphine. The mean and median norbuprenorphine/buprenorphine ratios were 1.5 and 1.1, respectively. There was no significant difference in concentration ratios for DUID and PDO cases (p andgt; 0.05). We conclude that the described method for analysis of buprenorphine and norbuprenorphine in whole blood could be used to investigate use or misuse of buprenorphine but that many of the cases presented with very low concentrations of buprenorphine. We also conclude that analysis should be performed within two weeks unless samples are stored frozen prior to analysis.

  • 48.
    Stephanson, Nikolai
    et al.
    Karolinska Institute.
    Josefsson, Martin
    National Board for Forensic Medicine.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Beck, Olof
    Karolinska Institute.
    Accurate identification and quantification of 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid in urine drug testing: Evaluation of a direct high efficiency liquid chromatographic-mass spectrometric method2008In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 871, no 1, 101-108 p.Article in journal (Refereed)
    Abstract [en]

    A direct liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for measurement of urinary Delta(9)-tetrahydrocannabinol carboxylic acid (THCA) was developed. The method involved dilution of the urine sample with water containing H-2(9)-deuterated analogue as internal standard, hydrolysis with ammonia, reversed phase chromatography using a Waters ultra-performance liquid chromatography (UPLC (TM)) equipment with gradient elution, negative electrospray ionization, and monitoring of two product ions in selected reaction monitoring mode. The measuring range was 2-1000 ng/mL for THCA, and the intra- and inter-assay imprecision, expressed as the coefficient of variation, was below 5%. Influence from urine matrix on ionization efficiency was noted in infusion experiments, but was compensated for by the internal standard. Comparison with established gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry methods in authentic patient samples demonstrated accuracy in both qualitative and quantitative results. A small difference in mean ratios (similar to 15%) may be explained by the use of different hydrolysis procedures between methods. In conclusion, the high efficiency LC-MS/MS method was capable of accurately identify and quantify THCA in urine with a capacity of 14 samples per hour.

  • 49.
    Swortwood, Madeleine J.
    et al.
    NIDA, MD 21224 USA.
    Carlier, Jeremy
    NIDA, MD 21224 USA.
    Ellefsen, Kayla N.
    NIDA, MD 21224 USA; University of Maryland, MD 21201 USA.
    Wohlfarth, Ariane
    NIDA, MD 21224 USA; National Board Forens Med, Linkoping, Sweden.
    Diao, Xingxing
    NIDA, MD 21224 USA.
    Concheiro-Guisan, Marta
    NIDA, MD 21224 USA; CUNY John Jay Coll Criminal Justice, NY 10019 USA.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA.
    In vitro, in vivo and in silico metabolic profiling of -pyrrolidinopentiothiophenone, a novel thiophene stimulant2016In: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 8, no 1, 65-82 p.Article in journal (Refereed)
    Abstract [en]

    Background: Little or no pharmacological or toxicological data are available for novel psychoactive substances when they first emerge, making their identification and interpretation in biological matrices challenging. Materials & methods: A new synthetic cathinone, alpha-pyrrolidinopentiothiophenone (alpha-PVT), was incubated with hepatocytes and samples were analyzed using liquid chromatography coupled to a Q Exactive(TM) Orbitrap mass spectrometer. Authentic urine specimens from suspected -PVT cases were also analyzed. Scans were data mined with Compound Discoverer for identification and structural elucidation of metabolites. Results/conclusion: Seven alpha-PVT metabolites were identified in hepatocyte incubations, and in the authentic urine samples, also with an additional monohydroxylated product and a glucuronide of low intensity. alpha-PVT dihydroxypyrrolidinyl, alpha-PVT 2-ketopyrrolidinyl, alpha-PVT hydroxythiophenyl and alpha-PVT thiophenol had the most intense in vivo signals.

  • 50.
    Swortwood, Madeleine J.
    et al.
    NIDA, USA.
    Ellefsen, Kayla N.
    NIDA, USA; University of Maryland, USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. NIDA, USA; National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Diao, Xingxing
    NIDA, USA.
    Concheiro-Guisan, Marta
    NIDA, USA; CUNY John Jay Coll Criminal Justice, NY 10019 USA.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Huestis, Marilyn A.
    NIDA, USA; University of Maryland Baltimore, USA.
    First metabolic profile of PV8, a novel synthetic cathinone, in human hepatocytes and urine by high-resolution mass spectrometry2016In: Analusis, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 408, no 18, 4845-4856 p.Article in journal (Refereed)
    Abstract [en]

    Novel psychoactive substances (NPS) are ever changing on the drug market, making it difficult for toxicology laboratory methods to stay current with so many new drugs. Recently, PV8, a synthetic pyrrolidinophenone, was detected in seized products in Japan (2013), The Netherlands (2014), and Germany (2014). There are no controlled PV8 administration studies, and no pharmacodynamic and pharmacokinetic data. The objective was to determine PV8s metabolic stability in human liver microsome (HLM) incubation and its metabolism following human hepatocyte incubation and high-resolution mass spectrometry (HRMS) with a Thermo Scientific Q-Exactive. Data were acquired with a full-scan data-dependent mass spectrometry method. Scans were thoroughly data mined with different data processing algorithms and analyzed in WebMetaBase. PV8 exhibited a relatively short 28.8 min half-life, with an intrinsic 24.2 mu L/min/mg microsomal clearance. This compound is predicted to be an intermediate clearance drug with an estimated human 22.7 mL/min/kg hepatic clearance. Metabolic pathways identified in vitro included: hydroxylation, ketone reduction, carboxylation, N-dealkylation, iminium formation, dehydrogenation, N-oxidation, and carbonylation. The top three in vitro metabolic pathways were di-hydroxylation amp;gt; ketone reduction amp;gt; gamma-lactam formation. Authentic urine specimen analyses revealed the top three metabolic pathways were aliphatic hydroxylation amp;gt; ketone reduction + aliphatic hydroxylation amp;gt; aliphatic carboxylation, although the most prominent peak was parent PV8. These data provide useful urinary metabolite targets (aliphatic hydroxylation, aliphatic hydroxylation + ketone reduction, aliphatic carboxylation, and di-hydroxylation) for forensic and clinical testing, and focus reference standard companies synthetic efforts to provide commercially available standards needed for PV8 biological specimen testing.

12 1 - 50 of 55
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf