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Sökning: WFRF:(Kronstrand Robert)

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1.
  • Hoiseth, G., et al. (författare)
  • Evaluating the hip-flask defence using analytical data from ethanol and ethyl glucuronide. A comparison of two models
  • 2020
  • Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 316
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Claimed intake of alcohol after a traffic incident, called the hip-flask defence, can be objectively assessed by different methods. One of them is the use of two consecutive ethanol concentrations in urine and the ratio between ethanol concentrations in urine and blood. Another one is the concentrations of ethyl glucuronide (EtG) and ethyl sulphate (EtS) in blood and their ratio to ethanol. The experimental basis for both these models is from single dose studies only. The aim of this study was therefore to describe the kinetics of ethanol, EtG and EtS after ingestion of two repeated doses of ethanol and to investigate the usefulness of the different models for the assessment of the hip-flask defence. Methods: Thirty-five subjects ingested a first dose of 0.51 g of ethanol per kilo body weight, and two hours later a second dose (the hip-flask drink) of 0.25, 0.51 or 0.85 g of ethanol per kilo body weight. Ten urine and 17 blood samples were collected and analysed for ethanol, EtG and EtS using fully validated methods. It was investigated if all subjects fulfilled the criteria for recent drinking, according to the two different models, when using the samples collected 180-240 minutes after start of first dose drinking. According to the first model, increase in urinary ethanol concentrations and a ratio UAC/BAC below 1.3 indicated recent drinking. According to the second model, increase in blood EtG concentrations and a ratio ethanol (g/kg)/EtG (mg/L) above 1 indicated recent drinking. Results: All subjects in the high dose group fulfilled all criteria for recent drinking. One subject in the medium dose group and nine subjects in the low dose group failed to show increasing UAC and/or a UAC/ BAC ratio below 1.3. One subject in the low dose group failed to show increasing concentrations of blood EtG, but all subjects showed a ratio ethanol/EtG above 1. Conclusions: The present study showed, by the use of experimental data, that both two models used to investigate the hip-flask defence can be used, but only when the hip-flask dose is sufficiently high. (C) 2020 The Author(s). Published by Elsevier B.V.
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2.
  • Kronstrand, Christoffer, et al. (författare)
  • Evaluating the hip-flask defence in subjects with alcohol on board: An experimental study
  • 2019
  • Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 294, s. 189-195
  • Tidskriftsartikel (refereegranskat)abstract
    • Driving under the influence of alcohol is a major problem for traffic-safety and a popular defence argument is alleged consumption after driving, commonly referred to as the hip-flask defence. Forensic toxicologists are often called as expert witnesses in drinking and driving cases where the suspect has claimed the hip-flask defence, to assess the credibility of the explanation. Several approaches to help the expert have been introduced but the scientific data used to support or challenge this is solely based on data from controlled single doses of ethanol administered during a short time and in abstinent subjects. In reality, we believe that even in drinking after driving cases, the subject many times has alcohol on board at time of the hip-flask drink. This questions the applicability of the data used as basis to investigate the hip-flask defence. To fill this knowledge gap, we aimed to investigate how blood and urine ethanol kinetics vary after an initial drinking session of beer and then a subsequent hip-flask drink of three different doses of whiskey. Fifteen subjects participated in the study and each provided 10 urine samples and 17 blood samples over 7 h. The initial drink was 0.51 g ethanol/kg and the second was either 0.25, 0.51, or 0.85 g/kg. Our data suggested that the difference between the ethanol concentrations in two consecutive urine samples is a more sensitive parameter than the ratio between urine and blood alcohol to detect a recent intake when ethanol from previous intakes are already present in the body. Twelve subjects presented results that fully supported a recent intake using the criteria developed from a single intake of ethanol. Three subjects showed unexpected results that did not fully support a recent intake. We conclude that data from one blood sample and two urine samples provide good evidence for investigating the hip-flask defence even if alcohol was on board at the time of the hip-flask drink. (C) 2018 Elsevier B.V. All rights reserved.
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3.
  • Kronstrand, Robert, et al. (författare)
  • Incidence of opiates, amphetamines, and cocaine in hair and blood in fatal cases of heroin overdose
  • 1998
  • Ingår i: Forensic Science International. - 0379-0738 .- 1872-6283. ; 92:1, s. 29-38
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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4.
  • Kronstrand, Robert, et al. (författare)
  • The metabolism of the synthetic cannabinoids ADB-BUTINACA and ADB-4en-PINACA and their detection in forensic toxicology casework and infused papers seized in prisons
  • 2022
  • Ingår i: Drug Testing and Analysis. - : Wiley. - 1942-7603 .- 1942-7611. ; 14:4, s. 634-652
  • Tidskriftsartikel (refereegranskat)abstract
    • Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC50, 11.5 nM and ADB-4en-PINACA (EC50, 11.6 nM) are similar to that of MDMB-4en-PINACA (EC50, 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation.
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5.
  • Axelsson, Magnus A. B., et al. (författare)
  • Retrospective identification of new psychoactive substances in patient samples submitted for clinical drug analysis
  • 2022
  • Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 131:5, s. 420-434
  • Tidskriftsartikel (refereegranskat)abstract
    • New psychoactive substances (NPS) are life threatening through unpredictable toxicity and limited analytical options for clinicians. We present the retrospective identification of NPS in raw data from a liquid chromatography-high resolution mass spectrometry (LC-HRMS)-based multidrug panel analysis on 14 367 clinical oral fluid samples requested during 2019 mainly by psychiatric and addiction care clinics. Retrospectively analysed NPS included 48 notified originally in 2019 by the European Union Early Warning System (EU EWS) and 28 frequently reported in Sweden. Of 88 included NPS, 34 (mitragynine, flualprazolam, 3F/4F-α-P(i)HP, etizolam, 4F-MDMB-BINACA, cyproheptadine, 5F-MDMB-PICA, isotonitazene, isohexedrone, MDPEP, N-ethylpentedrone, tianeptine, flubromazolam, 4′-methylhexedrone, α-P(i)HP, eutylone, mephedrone, N-ethylhexedrone, 5F-MDMB-PINACA, ADB-BUTINACA, 3-methoxy PCP, 4F-furanylfentanyl, 4F-isobuturylfentanyl, acrylfentanyl, furanylfentanyl, clonazolam, norfludiazepam, 3F-phenmetrazine, 3-MMC, 4-methylpentedrone, BMDP, ethylphenidate, methylone and α-PVP) were identified as 219 findings in 84 patients. Eight NPS notified in 2019 were identified, five before EWS release. NPS occurred in 1.20% of all samples and 1.53% of samples containing traditional drugs, and in 1.87% of all patients and 2.88% of patients using traditional drugs. NPS use was more common in men and polydrug users. Legal (not scheduled) NPS were more used than comparable illegal ones. Retrospective identification could be useful when prioritizing NPS for clinical routine analysis and when studying NPS epidemiology. © 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.
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6.
  • Barmano, Neshro, 1980-, et al. (författare)
  • The association between alcohol consumption, cardiac biomarkers, left atrial size and re-ablation in patients with atrial fibrillation referred for catheter ablation
  • 2019
  • Ingår i: PLOS ONE. - San Francisco, CA, United States : Public Library of Science. - 1932-6203. ; 14:4
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundInformation on alcohol consumption in patients undergoing radiofrequency ablation (RFA) of atrial fibrillation (AF) is often limited by the reliance on self-reports. The aim of this study was to describe the long-term alcohol consumption, measured as ethyl glucuronide in hair (hEtG), in patients undergoing RFA due to AF, and to examine potential associations with cardiac biomarkers, left atrial size and re-ablation within one year after the initial RFA.MethodsThe amount of hEtG was measured in patients referred for RFA, and a cut-off of 7 pg/mg was used. N-terminal pro B-type natriuretic peptide (NT-proBNP) and the mid-regional fragment of pro atrial natriuretic peptide (MR-proANP) were examined and maximum left atrium volume index (LAVI) was measured. The number of re-ablations was examined up to one year after the initial RFA. Analyses were stratified by gender, and adjusted for age, systolic blood pressure, body mass index, presence of heart failure and heart rhythm for analyses regarding NT-proBNP, MR-proANP and LAVI and heart rhythm being replaced by type of AF for analyses regarding re-ablation.ResultsIn total, 192 patients were included in the study. Median (25th– 75th percentile) NT-proBNP in men with hEtG ≥ 7 vs. < 7 pg/mg was 250 (96–695) vs. 130 (49–346) pg/ml (p = 0.010), and in women it was 230 (125–480) vs. 230 (125–910) pg/ml (p = 0.810). Median MR-proANP in men with hEtG ≥ 7 vs. < 7 pg/mg was 142 (100–224) vs. 117 (83–179) pmol/l (p = 0.120) and in women it was 139 (112–206) vs. 153 (93–249) pmol/l (p = 0.965). The median of maximum LAVI was 30.1 (26.7–33.9) vs. 25.8 (21.4–32.0) ml/m2 (p = 0.017) in men, and 25.0 (18.9–29.6) vs. 25.7 (21.7–34.6) ml/m2 (p = 0.438) in women, with hEtG ≥ 7 vs. < 7 pg/ml, respectively. Adjusted analyses showed similar results, except for MR-proANP turning out significant in men with hEtG ≥ 7 vs. < 7 pg/mg (p = 0.047). The odds ratio of having a re-ablation was 3.5 (95% CI 1.3–9.6, p = 0.017) in men with hEtG ≥ 7 vs. < 7 pg/mg, while there was no significant difference in women.ConclusionsIn male patients with AF and hEtG ≥ 7 pg/mg, NT-proBNP and MR-proANP were higher, LA volumes larger, and there was a higher rate of re-ablations, as compared to men with hEtG < 7 pg/mg. This implies that men with an alcohol consumption corresponding to an hEtG-value ≥ 7, have a higher risk for LA remodelling that could potentially lead to a deterioration of the AF situation.
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7.
  • Bastami, Salumeh, et al. (författare)
  • Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • 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.
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8.
  • Bastami, Salumeh, et al. (författare)
  • Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
  • 2014
  • Ingår i: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 238, s. 125-132
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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9.
  • Beck, Olof, et al. (författare)
  • First evaluation of the possibility of testing for drugged driving using exhaled breath sampling
  • 2019
  • Ingår i: Traffic Injury Prevention. - : TAYLOR & FRANCIS INC. - 1538-9588 .- 1538-957X. ; 20:3, s. 238-243
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Driving under the influence of psychoactive drugs causes an increased risk for accidents. In combating this, sobriety tests at the roadside are common practice in most countries. Sampling of blood and urine for forensic investigation cannot be done at the roadside and poses practical problems associated with costs and time. An alternative specimen for roadside testing is therefore warranted and the aerosol particles in exhaled breath are one such alternative.Methods: The present study investigated how the exhaled breath sample compared with the routine legal investigations of blood and urine collected from suspects of drugged driving at 2 locations in Sweden. Exhaled breath was collected using a simple filter collection device and analyzed with state-of-the-art mass spectrometry technique.Results: The total number of cases used for this investigation was 67. In 54 of these cases (81%) the results regarding a positive or negative drug test result agreed and in 13 they disagreed. Out of these, the report from the forensic investigation of blood/urine was negative in 21 cases. In 6 of these, analytical findings were made in exhaled breath and these cases were dominated by the detection of amphetamine. In 7 cases a positive drug test from the forensic investigation was not observed in the breath sample and these cases were dominated by detection of tetrahydrocannabinol in blood. In total, 45 samples were positive with breath testing and the number of positives with established forensic methods was 46.Conclusion: The promising results from this study provide support to exhaled breath as a viable specimen for testing of drugged driving. The rapid, easy, and convenient sampling procedure offers the possibility to collect a drug test specimen at the roadside. The analytical investigation must be done in a laboratory at present because of the need for a highly sensitive instrument, which is already in use in forensic laboratories. The analytical work is not more challenging than for blood or oral fluid and should not cause an increase in cost. However, more studies need to be done before exhaled breath drug testing can be applied routinely for drugged driving investigation.
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10.
  • Bendroth, Peter, et al. (författare)
  • Comparison of ethyl glucuronide in hair with phosphatidylethanol in whole blood as post-mortem markers of alcohol abuse
  • 2008
  • Ingår i: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 176:1, s. 76-81
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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11.
  • Bäckberg, Matilda, et al. (författare)
  • Using in vitro receptor activity studies of synthetic cannabinoids to support the risk assessment of new psychoactive substances – A Swedish strategy to protect public health from harm
  • 2023
  • Ingår i: Forensic Science International. - : Elsevier Ireland Ltd. - 0379-0738 .- 1872-6283. ; 348
  • Tidskriftsartikel (refereegranskat)abstract
    • In the past 15 years, close to 1000 of new psychoactive substances (NPS) have been reported in Europe and globally. At the time of identification, data on safety, toxicity and carcinogenic potential of many NPS are not available or very limited. To work more efficiently, a strategy and collaboration between the Public Health Agency of Sweden (PHAS) and the National Board of Forensic Medicine was established involving in vitro receptor activity assays to demonstrate neurological activity of NPS. This report summarizes the first results on the synthetic cannabinoid receptor agonists (SCRAs), and subsequent actions taken by PHAS. A total of 18 potential SCRAs were selected by PHAS for in vitro pharmacological characterization. 17 compounds could be acquired and investigated for their activity on the human cannabinoid-1 (CB1) receptors expressed together with the AequoScreen system in CHO-K1 cells. Dose-response curves were established using eight different concentrations in triplicates at three occasions with JWH-018 as reference. For the MDMB-4en-PINACA, MMB-022, ACHMINACA, ADB-BUTINACA, 5F-CUMYL-PeGACLONE, 5C-AKB48, NM-2201, 5F-CUMYL-PINACA, JWH-022, 5Cl-AB-PINACA, MPhP-2201, 5F-AKB57 the half maximal effective concentration values ranged from 2.2 nM (5F-CUMYL-PINACA) to 171 nM (MMB-022). EG-018 and 3,5-AB-CHMFUPPYCA were none-active. The results contributed to 14 of these compounds being scheduled as narcotics in Sweden. In conclusion, many of the emerging SCRAs are potent activators of the CB1 receptor in vitro, although some lack activity or are partial agonists. The new strategy proved useful when data on psychoactive effects of the SCRAs under investigation were not available or limited. © 2023 The Authors
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12.
  • Castaneto, Marisol S., et al. (författare)
  • Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry
  • 2015
  • Ingår i: Forensic Toxicology. - : Springer Verlag (Germany). - 1860-8965 .- 1860-8973. ; 33:2, s. 295-310
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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13.
  • Comasco, Erika, et al. (författare)
  • Adolescent alcohol consumption : Biomarkers PEth and FAEE in relation to interview and questionnaire data
  • 2009
  • Ingår i: Journal of Studies on Alcohol and Drugs. - : ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV. - 1937-1888 .- 1938-4114. ; 70:5, s. 797-804
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 influence 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.
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14.
  • Concheiro, Marta, et al. (författare)
  • Simultaneous determination of 40 novel psychoactive stimulants in urine by liquid chromatography-high resolution mass spectrometry and library matching
  • 2015
  • Ingår i: Journal of Chromatography A. - : Elsevier. - 0021-9673 .- 1873-3778. ; 1397, s. 32-42
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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15.
  • Cooper, Gail A A, et al. (författare)
  • Society of Hair Testing guidelines for drug testing in hair
  • 2012
  • Ingår i: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 218:1-3, s. 20-24
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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16.
  • Cooper, Gail, et al. (författare)
  • Current status of accreditation for drug testing in hair
  • 2008
  • Ingår i: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 176:1, s. 9-12
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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17.
  • DeFreitas, Laura, et al. (författare)
  • Fast and Sensitive Method for the Determination of 17 Designer Benzodiazepines in Hair by Liquid Chromatography-Tandem Mass Spectrometry
  • 2022
  • Ingår i: Journal of Analytical Toxicology. - : OXFORD UNIV PRESS INC. - 0146-4760 .- 1945-2403. ; 46:8, s. 852-859
  • Tidskriftsartikel (refereegranskat)abstract
    • In recent years, identification and analysis of designer benzodiazepines have become a challenge in forensic toxicology. These substances are analogs of the classic benzodiazepines, but their pharmacology is not well known, and many of them have been associated with overdoses and deaths. As a result, there has been a surge in efforts to develop analytical methods to determine these compounds in different biological samples. Our aim was to develop and validate a fast, sensitive and specific method for determining 17 designer benzodiazepines (adinazolam, clobazam, clonazolam, delorazepam, deschloroetizolam, diclazepam, etizolam, flualprazolam, flubromazepam, flubromazolam, flunitrazolam, N-desmethylclobazam, nifoxipam, nitrazolam, meclonazepam, pyrazolam and zolazepam) in hair by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Hair samples were decontaminated and pulverized, and a 20 mg aliquot was incubated in methanol in an ultrasound bath (1 h, 25 degrees C). The supernatant was evaporated and reconstituted in 200 mu L of mobile phase, and the extracts were filtered (nano-filter vials) before injection into LC-MS-MS. All analytes were eluted from the chromatographic column in 8 min, and two multiple-reaction monitoring (MRM) transitions were used to identify each compound. The limits of quantification were 5 or 25 pg/mg depending on the analyte, and the calibration functions were linear to 200 pg/mg. Imprecision was <19.2% (n = 15), and bias was from -13.7 to 18.3% (n = 15). All the analytes yielded high extraction efficiencies >70% and displayed ion suppression between -62.8% and -23.9% (n = 10). The method was applied to 19 authentic cases. Five samples were positive for flualprazolam ( 200 pg/mg) and/or etizolam (47.4-88.5 pg/mg). In conclusion, the present validated method has proven to be fast, sensitive, specific and capable of determining 17 designer benzodiazepines in hair using LC-MS-MS.
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18.
  • Diao, Xingxing, et al. (författare)
  • In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)
  • 2017
  • Ingår i: Forensic Toxicology. - : SPRINGER. - 1860-8965 .- 1860-8973. ; 35:1, s. 20-32
  • Tidskriftsartikel (refereegranskat)abstract
    • In 2014, NM-2201 (CBL-2201), a novel synthetic cannabinoid (SC), was detected by scientists at Russian and US laboratories. It has been already added to the list of scheduled drugs in Japan, Sweden and Germany. Unfortunately, no human metabolism data are currently available, which makes it challenging to confirm its intake, especially given that all SCs investigated thus far have been found to be extensively metabolized. The present study aims to recommend appropriate marker metabolites by investigating NM-2201 metabolism in human hepatocytes, and to confirm the results in authentic human urine specimens. For the metabolic stability assay, 1 A mu M NM-2201 was incubated in human liver microsomes (HLMs) for up to 1 h; for metabolite profiling, 10 A mu M of NM-2201 was incubated in human hepatocytes for 3 h. Two authentic urine specimens from NM-2201-positive cases were subjected to beta-glucuronidase hydrolysis prior to analysis. The identification of metabolites in hepatocyte samples and urine specimens was achieved with high-resolution mass spectrometry via information-dependent acquisition. NM-2201 was quickly metabolized in HLMs, with an 8.0-min half-life. In human hepatocyte incubation samples, a total of 13 NM-2201 metabolites were identified, generated mainly from ester hydrolysis and further hydroxylation, oxidative defluorination and subsequent glucuronidation. M13 (5-fluoro PB-22 3-carboxyindole) was found to be the major metabolite. In the urine specimens, the parent drug NM-2201 was not detected; M13 was the predominant metabolite after beta-glucuronidase hydrolysis. Therefore, based on the results of our study, we recommend M13 as a suitable urinary marker metabolite for confirming NM-2201 and/or 5F-PB-22 intake.
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19.
  • Diao, Xingxing, et al. (författare)
  • In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-22
  • 2016
  • Ingår i: AAPS Journal. - : SPRINGER. - 1550-7416. ; 18:2, s. 455-464
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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20.
  • Druid, Henrik, et al. (författare)
  • Evaluation of the role of abstinence in heroin overdose deaths using segmental hair analysis
  • 2007
  • Ingår i: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 168:2-3, s. 223-226
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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21.
  • Elenstal, Emily, et al. (författare)
  • Intralipid as a matrix additive for evaluating hyperlipidemic postmortem blood
  • 2023
  • Ingår i: Journal of Analytical Toxicology. - : OXFORD UNIV PRESS INC. - 0146-4760 .- 1945-2403. ; 47:6, s. 529-534
  • Tidskriftsartikel (refereegranskat)abstract
    • Postmortem whole blood samples can differ greatly in quality where hyperlipemia is a frequent variable that can influence the results of analytical methods. The aim of this study was to investigate the influence of lipemia on postmortem analysis as well as demonstrate the usage of Intralipid in comparison to pooled postmortem lipids as matrix additives for meaningful evaluation and validation of hyperlipidemic postmortem samples. Hyperlipidemic blood samples were simulated by adding different concentrations of Intralipid or pooled authentic postmortem lipids to bovine whole blood. The hyperlipidemic blood samples were spiked with 14 benzodiazepines and five sedative and antianxiety drugs (alprazolam, clonazepam, 7-aminoclonazepam, diazepam, flunitrazepam, 7-aminoflunitrazepam, hydroxyzine, lorazepam, midazolam, nitrazepam, 7-aminonitrazepam, nordazepam, oxazepam, propiomazine, dihydropropiomazine, temazepam, triazolam, zolpidem and zopiclone). Samples were prepared with liquid-Liquid extraction followed by ultra-high performance liquid chromatography-mass spectrometry. The effects of lipemia on the recovery of analytes and internal standards (ISs) were evaluated to determine the effect of, and any differences between, the two additives. Lipemia was found to cause major interference when quantifying the analytes. For most analytes, the ISs could compensate for analyte losses. However, the most hydrophilic analytes (7-amino metabolites), together with the most lipophilic analytes (propiomazine and dihydropropiomazine), were greatly affected by lipemia (<50% recovery), and the IS could not compensate for analyte losses. In general, lower analyte recoveries were observed for samples with Intralipid as a lipemic additive in comparison to those containing pooled postmortem lipids. Both Intralipid and pooled postmortem lipids showed marked effects on the analytical results. Intralipid gave a good indication of the effects of lipemia and could be a useful tool for making a meaningful evaluation of hyperlipidemic postmortem samples during the method development and validation.
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22.
  • Elmsjö, Albert, et al. (författare)
  • Postmortem Metabolomics Reveal Acylcarnitines as Potential Biomarkers for Fatal Oxycodone-Related Intoxication
  • 2022
  • Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 12:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Postmortem metabolomics has recently been suggested as a potential tool for discovering new biological markers able to assist in death investigations. Interpretation of oxycodone concentrations in postmortem cases is complicated, as oxycodone tolerance leads to overlapping concentrations for oxycodone intoxications versus non-intoxications. The primary aim of this study was to use postmortem metabolomics to identify potential endogenous biomarkers that discriminate between oxycodone-related intoxications and non-intoxications. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry data from 934 postmortem femoral blood samples, including oxycodone intoxications and controls positive and negative for oxycodone, were used in this study. Data were processed and evaluated with XCMS and SIMCA. A clear trend in group separation was observed between intoxications and controls, with a model sensitivity and specificity of 80% and 76%. Approximately halved levels of short-, medium-, and long-chain acylcarnitines were observed for oxycodone intoxications in comparison with controls (p < 0.001). These biochemical changes seem to relate to the toxicological effects of oxycodone and potentially acylcarnitines constituting a biologically relevant biomarker for opioid poisonings. More studies are needed in order to elucidate the potential of acylcarnitines as biomarker for oxycodone toxicity and their relation to CNS-depressant effects.
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23.
  • Eriksson, Therese, 1979- (författare)
  • Organelle movement in melanophores: Effects of Panax ginseng, ginsenosides and quercetin
  • 2009
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Panax ginseng is a traditional herb that has been used for over 2000 years to promote health and longevity. Active components of ginseng include ginsenosides, polysaccharides, flavonoids, polyacetylenes, peptides, vitamins, phenols and enzymes, of which the ginsenosides are considered to be the major bioactive constituents. Although widely used, the exact mechanisms of ginseng and its compounds remain unclear. In this thesis we use melanophores from Xenopus laevis to investigate the effects of Panax ginseng extract G115 and its constituents on organelle transport and signalling. Due to coordinated bidirectional movement of their pigmented granules (melanosomes), in response to defined chemical signals, melanophores are capable of fast colour changes and provide a great model for the study of intracellular transport. The movement is regulated by alterations in cyclic adenosine 3’:5’-monophosphate (cAMP) concentration, where a high or low level induce anterograde (dispersion) or retrograde (aggregation) transport respectively, resulting in a dark or light cell. Here we demonstrate that Panax ginseng and its constituents ginsenoside Rc and Rd and flavonoid quercetin induce a concentration-dependent anterograde transport of melanosomes. The effect of ginseng is shown to be independent of cAMP changes and protein kinase A activation. Upon incubation of melanophores with a combination of Rc or Rd and quercetin, a synergistic increase in anterograde movement was seen, indicating cooperation between the ginsenoside and flavonoid parts of ginseng. Protein kinase C (PKC) inhibitor Myristoylated EGF-R Fragment 651-658 decreased the anterograde movement stimulated by ginseng and ginsenoside Rc and Rd. Moreover, ginseng, but not ginsenosides or quercetin, stimulated an activation of 44/42-mitogen activated protein kinase (MAPK), previously shown to be involved in both aggregation and dispersion of melanosomes. PKC-inhibition did not affect the MAPK-activation, suggesting a role for PKC in the ginseng- and ginsenoside-induced dispersion but not as an upstream activator of MAPK.
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24.
  • Forsman, M., et al. (författare)
  • Urinary detection times and excretion patterns of flunitrazepam and its metabolites after a single oral dose
  • 2009
  • Ingår i: Journal of Analytical Toxicology. - 0146-4760 .- 1945-2403. ; 33:8, s. 491-501
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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25.
  • Forsman, Åsa, et al. (författare)
  • Förekomst av droger och läkemedel i trafik i Sverige : resultat från EU-projektet DRUID
  • 2011
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • The prevalence of illicit drugs and medicines in the driving population, i.e. among drivers on the road, was 2.5 per cent between the years 2006 and 2011 in Sweden. The prevalence of alcohol, illicit drugs and medicines among drivers killed in traffic the same years was 31.2 per cent. In comparison with other countries in the EU project DRUID, Sweden has the highest proportion of negative results, i.e. drivers without the presence of alcohol, drugs or medicine. This applies to both drivers on the road and drivers killed in traffic.The studies that form the basis of this report have been performed within the project DRUID - Driving under the influence of drugs, alcohol and medicine, which is a project within the EU's Sixth Framework Programme, which lasted five years (2006-2011). This report presents two sub-studies from the DRUID project. The aims of these studies were: - to study the prevalence of illicit drugs and medicines in the driving population (study among drivers on the road). - to study the prevalence of alcohol, illicit drugs and medicines among killed drivers (study of killed drivers).In the study among drivers on the road, saliva samples were collected. Toxicological results were analysed from 6,199 drivers in Södermanland, Örebro and Östergötland out of 10,223 drivers of passenger cars and vans that were stopped by the police in March 2008- February 2009. In the study of killed drivers we have toxicological results from 157 fatalities out of 178 drivers of passenger cars and vans that were killed in traffic accidents in 2008.
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26.
  • Forsman, Åsa, et al. (författare)
  • Förslag till förbättringar av rattfylleristatistiken i Sverige : underlag till uppdrag att förbättra beskrivningen av vägtrafikolyckornas hälsopåverkan
  • 2008
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • In June 2006, the Swedish Road Administration was mandated by the Government to improve the description of the health effects of road traffic accidents. Under the terms of this mandate, a proposal was to be made as to how the recording of alcohol and drug related accidents can be improved, and how sample surveys of the prevalence of drivers under the influence of alcohol and/or drugs should be performed. This note describes the data used for these parts of the mandate. One common condition for both these parts is that possible screening methods for drivers under the influence of narcotics should be studied. In order to measure the proportion of traffic mileage travelled by drink/drug drivers, the investigation should be organised as a statistical sample survey where the police check drivers at sites selected at random. As regards selection in time, it may be reasonable to use quota sampling. In the present situation, we do not consider that it is possible to carry out regular surveys of drug driving. If the regulations are amended so that routine controls can be performed, and if the police begin to use screening instruments for drug tests, regular surveys can be performed. These surveys can then be integrated with the investigations regarding alcohol, by requiring the stopped drivers to give samples for both alcohol and for drugs.
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27.
  • Guerrieri, Davide, et al. (författare)
  • Acrylfentanyl: Another new psychoactive drug with fatal consequences
  • 2017
  • Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 277, s. E21-E29
  • Tidskriftsartikel (refereegranskat)abstract
    • The European Nordic Countries are the most exposed to opioid-related deaths. Between April and October 2016, a series of forty lethal intoxications occurred in Sweden, in which the presence of the synthetic opioid acrylfentanyl was determined to be the main - or a contributing - cause of death. In the reported cases, the blood concentration of acrylfentanyl - mostly detected in combination with other drugs - ranged from 0.01 ng/g to 5 ng/g; victims were predominantly males (34 males and 6 females), and their age varied between 18 and 53 years. We further describe five cases, representative of the different drug administration route (nasal spray, tablets) and intentions (accidental or voluntary intoxication). Moreover, we address nine cases of non-lethal intoxication, in single (8 cases) or polydrug scenario (1 case). We discuss the present characteristics of the Swedish drug market for fentanyl-analogs in general and acrylfentanyl in particular, reporting a structural difficulty to effectively counteracting the appearance of unscheduled substances due to the constant turnover of new molecules on the recreational drug market. (C) 2017 Published by Elsevier Ireland Ltd.
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28.
  • Guerrieri, Davide, et al. (författare)
  • Postmortem and Toxicological Findings in a Series of Furanylfentanyl-Related Deaths
  • 2017
  • Ingår i: Journal of Analytical Toxicology. - : OXFORD UNIV PRESS INC. - 0146-4760 .- 1945-2403. ; 41:3, s. 242-249
  • Tidskriftsartikel (refereegranskat)abstract
    • Over the course of 4 months in 2015 and 2016, a cluster of seven fatal intoxications involving the opioid-analogue furanylfentanyl occurred in Sweden; toxicological analysis showed presence of furanylfentanyl either as the only drug or in combination with other illicit substances. Previous publications have only reported non-lethal furanylfentanyl intoxications. In the cases presented here, furanylfentanyl intoxication-alone or in combination with other drugs-was determined to be the cause of death by the responsible pathologist. All victims were young (24-37 years old) males, five of which had a well-documented history of drug abuse. Femoral blood concentration of furanylfentanyl ranged from 0.41 ng/g to 2.47 ng/g blood. Five cases presented a complex panel of drugs of abuse and prescription drugs. Moreover, in five cases the concurrent presence of pregabalin corroborates previous observations indicating pregabalin as a possible contributing factor in polydrug intoxications. We conclude that it is difficult to establish a specific lethal concentration of furanylfentanyl, due to incompletely known effects of possible pharmacokinetic and pharmacodynamic interactions with other drugs, as well as to the unknown degree of tolerance to opioids. We suggest that a full toxicological screening-to assess the possibility of drug interactions-together with segmental hair analysis regarding opioids-to estimate the level of opioid tolerance-be carried out to assist in the interpretation of cases involving synthetic opioids such as furanylfentanyl.
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29.
  • Guerrieri, Davide, et al. (författare)
  • Validation and Cross-Reactivity Data for Fentanyl Analogs With the Immunalysis Fentanyl ELISA
  • 2019
  • Ingår i: Journal of Analytical Toxicology. - : OXFORD UNIV PRESS INC. - 0146-4760 .- 1945-2403. ; 43:1, s. 18-24
  • Tidskriftsartikel (refereegranskat)abstract
    • Every year new fentanyl analog compounds, or fentanyls, appear on the drug scene. Development of immunoassays dedicated for screening individual molecules is challenging due to the short-lived presence of these compounds on the recreational drug market. Therefore, we investigated the detecting capabilities of the immunalysis fentanyl direct enzyme-linked immunosorbent assay (ELISA) kit against fentanyl in whole blood, and determined the cross-reactivity of nine fentanyl analogs (2-fluorofentanyl, acetylfentanyl, acrylfentanyl, carfentanil, cyclopropylfentanyl, tetrahydrofuranylfentanyl, furanylfentanyl, ocfentanil, valerylfentanyl) to confirm its validity for the general screening of fentanyls. Immunalysis ELISA assay was used to test whole blood samples fortified with fentanyl on a TECAN Freedom EVOlyzer platform, according to manufacturer specifications. The kit successfully was validated for fentanyl screening with a cutoff set at 0.5 ng/mL, and all tested analogs, with the exclusion of carfentanil, were detected. The lowest cross-reactivity with the kit was obtained with furanylfentanyl (20% +/- 1, 95% confidence intervals (CI)) and 4-fluoroisobutyrfentanyl (25% +/- 1, 95% CI), while the highest was recorded using acetylfentanyl (99% +/- 11, 95% CI) and acrylfentanyl (94% +/- 10, 95% CI). Post-mortem samples containing fentanyl, acrylfentanyl, cyclopropylfentanyl, THF-fentanyl and 4-fluoroisobutyrfentanyl were screened, and sensitivity and specificity of each analog were calculated. Positive screening results were generated by all post-mortem cases containing fentanyl (n = 14), acrylfentanyl (n = 11), cyclopropylfentanyl (n = 14), tetrahydrofuranylfentanyl (n = 13) and 4-fluoroisobutyrfentanyl (n = 10). Concentration of post-mortem fentanyl samples ranged from 0.5 ng/mL (cutoff) to 230 ng/mL, while the range for analogs was 3.4-36 ng/mL (cyclopentylfentanyl), 0.76-370 ng/mL (4-fluoroisobutyrfentanyl), 0.02-12 ng/mL (acrylfentanyl) and 2-26 ng/mL (tetrahydrofuranylfentanyl). The immunalysis fentanyl direct ELISA kit was successfully validated and showed significant cross-reactivity for all tested fentanyls, except carfentanil, making it a suitable technique for fentanyl and fentanyl analogs screening.
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30.
  • Haage, Pernilla, 1982-, et al. (författare)
  • Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
  • 2018
  • Ingår i: Pharmacology Research & Perspectives. - : John Wiley & Sons. - 2052-1707. ; 6:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.
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31.
  • Haage, Pernilla, 1982- (författare)
  • Forensic Toxicological Aspects of Tramadol : Focus on Enantioselective Drug Disposition and Pharmacogenetics
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • One of the most difficult parts in forensic toxicology is to interpret obtained drug concentrations. Was it therapeutic, toxic or even lethal to the particular individual that the blood sample was drawn from? Concentrations of opioid drugs are especially difficult to interpret, because of large interindividual differences in innate and acquired tolerance.Tramadol is a complex drug. Not only is it an opioid, it is also a racemic drug with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. Further, it is metabolized by polymorphic enzymes, which may affect the amounts of metabolites formed and possibly the enantiomer ratios of the parent compound and its metabolites. It has been speculated that particularly the (+)/(-)-enantiomer ratio of O-desmethyltramadol is related to the risk of adverse effects, and it has been shown that the ratio is affected by CYP2D6 genotype.The overall aim of the thesis was to evaluate if forensic interpretations of tramadol, regarding toxicity and time since drug administration, may be improved by the use of genotyping and enantioselective concentration determination of tramadol and its three main metabolites.To simultaneously quantify the enantiomer concentrations of tramadol, Odesmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol in whole blood, a liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed and validated. Genetic variation in CYP2D6, CYP2B6, CYP3A4 (encoding the tramadol metabolizing enzymes), ABCB1 (encoding a transport protein) and OPRM1 (encoding the μ-opioid receptor) was investigated, using pyrosequencing, xTAG, and TaqMan analysis. The methods were applied to the blood samples of two study populations; 19 healthy volunteers administered a therapeutic, single tramadol dose, and 159 tramadol positive autopsy cases.The most important finding was the positive correlations between all four enantiomer ratios and time since tramadol administration in the healthy volunteers. All enantiomer ratios except the one of tramadol was also affected by the CYP2D6 genotype, which was apparent among the autopsy cases as well. Genetic variation in CYP2D6 and possibly CYP2B6 was shown to have an impact on tramadol pharmacokinetics, although no association to neither drug related symptoms nor tramadol related causes of death was found. Tramadol intoxications were predominantly characterized by low age (median 26 years) and male sex, often with a history of substance abuse and with other drugs (at fairly low concentrations) detected in blood.In conclusion, enantiomer concentration determination combined with genotyping seems promising regarding estimations of time since drug administration, although is of low value concerning interpretations of toxicity in autopsy cases.
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32.
  • Haage, Pernilla, et al. (författare)
  • Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.
  • 2016
  • Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 119, s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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33.
  • Hansson, Therese, et al. (författare)
  • Enhetliga analyser av narkotika i urin krävs för rättssäkerheten.
  • 2015
  • Ingår i: Läkartidningen. - 0023-7205. ; 112
  • Tidskriftsartikel (refereegranskat)abstract
    • Drugs of abuse testing is used in various areas of society for detection and follow-up of drug use. In routine laboratory drug testing, immunoassays are employed for initial screening of specimens to indicate the presence of drugs. To confirm a positive screening test, a secondary analysis by mass spectrometry is performed. The »cut-off« is the pre-defined concentration threshold of a drug or drug metabolite above which the sample is considered positive. A reading below this level implies a negative test result. Swedish drug testing laboratories currently employ varying cut-offs to distinguish between a positive and a negative test result. Because a positive drug test may have serious legal consequences to the individual, it is of importance that testing is performed and judged equally, regardless of where it is performed. A national harmonization of cut-offs is therefore warranted. Based on data from four major Swedish drug testing laboratories, and considering the recommendations in international guidelines, a proposal for national harmonization of urine cut-offs for the most common set of drugs of abuse is presented.
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34.
  • Helander, Anders, 1959, et al. (författare)
  • Kreatininkoncentrationen i urin bör mätas vid drogtestning. Riktlinjer för beslutsgräns och tolkning behövs - inte minst för rättssäkerheten
  • 2011
  • Ingår i: Läkartidningen. - 0023-7205. ; 108:24-25, s. 1311-1314
  • Tidskriftsartikel (refereegranskat)abstract
    • Utspädning av urinen är den vanligaste manipulationsmetoden som syftar till att dölja förekomst av droger i provet. Mätning av kreatininkoncentrationen används för att upptäcka urinprov som på grund av utspädning riskerar att testa falskt negativt för droger. Det saknas nationella rekommendationer vad gäller beslutsgräns för kreatininkoncentrationen i urin i samband med drogtestning. Eftersom resultat från drogtestning kan få allvarliga rättsliga konsekvenser bör gemensamma riktlinjer införas i Sverige. Förslaget innebär att 2 mmol/l blir nedre gränsvärde för att indikera ett utspätt urinprov i samband med drogtestning. Ett utspätt urinprov ska dock inte likställas med ett positivt drogtest eftersom det kan finnas andra orsaker än avsiktlig manipulation till en låg kreatininkoncentration.
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35.
  • Hjälmdahl, Magnus, et al. (författare)
  • Effects of d-amphetamine on simulated driving performance before and after sleep deprivation
  • 2012
  • Ingår i: Psychopharmacology. - : Springer Berlin/Heidelberg. - 0033-3158 .- 1432-2072. ; 222:3, s. 401-411
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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36.
  • Hodgins, Sheelagh, et al. (författare)
  • A multisite study of community treatment programs for mentally ill offenders with major mental disorders : Design, measures, and the forensic sample
  • 2007
  • Ingår i: Criminal justice and behavior. - : SAGE Publications. - 0093-8548 .- 1552-3594. ; 34:2, s. 211-228
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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37.
  • Jakobsson, Gerd, et al. (författare)
  • Heroin-Related Compounds and Metabolic Ratios in Postmortem Samples Using LC-MS-MS
  • 2021
  • Ingår i: Journal of Analytical Toxicology. - : Oxford University Press. - 0146-4760 .- 1945-2403. ; 45:3, s. 215-225
  • Tidskriftsartikel (refereegranskat)abstract
    • Analysis of postmortem samples with the presence of morphine can sometimes be challenging to interpret. Tolerance complicates interpretation of intoxications and causes of death due to overlap in therapeutic and fatal concentrations. Determination of metabolites and metabolic ratios can potentially differentiate between abstinence, continuous administration, and perhaps time of administration. The purpose of this study was to (a) develop and validate a method for quantitation of morphine-3 beta-D-glucuronide, morphine-6 beta-D-glucuronide, normorphine, codeine-6 beta-D-glucuronide, norcodeine, codeine, 6-acetylmorphine, and ethylmorphine in urine using liquid chromatography-tandem mass spectrometry; (b) apply the method to opiate related deaths; (c) compare metabolic ratios in urine in different causes of death (CoD) and after different drug intakes and (d) compare heroin intoxications in rapid and delayed deaths. Validation parameters such as precision, bias, matrix effects, stability, process efficiency, and dilution integrity were assessed and deemed acceptable. Lower limits of quantitation ranged from 0.01-0.2 mu g/mL for all analytes. Autopsy cases (n=135) with paired blood and urine samples were analyzed. Cases were divided into three groups based on CoD; opiate intoxication, intoxication with other drugs than opiates, and other CoD. The cases were classified by intake: codeine (n=42), heroin (n=36), morphine (n=49), and ethylmorphine (n=3). Five cases were classified as mixed intakes and excluded. Heroin intoxications (n=35) were divided into rapid (n=15) or delayed (n=20) deaths. Parent drug groups were compared using metabolic ratio morphine-3 beta-D-glucuronide/morphine and significant differences were observed between codeine vs morphine (p=0.005) and codeine vs heroin (p <= 0.0001). Urine and blood concentrations, and metabolic ratios in rapid and delayed heroin intoxications were compared and determined a significant difference for morphine (p=0.001), codeine (p=0.009), 6-acetylmorphine (p=0.02) in urine, and morphine (p=0.02) in blood, but there was no significant difference (p=0.9) between metabolic ratios. Morphine-3 beta-D-glucuronide results suggested a period of abstinence prior to death in 25% of the heroin intoxications.
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38.
  • Jakobsson, Gerd, et al. (författare)
  • Oxycodone Concentrations and Metabolic Ratios in Femoral Blood from Fatal Intoxications and Other Causes of Death using LC-MS-MS
  • 2021
  • Ingår i: Journal of Analytical Toxicology. - : OXFORD UNIV PRESS INC. - 0146-4760 .- 1945-2403. ; 45:2, s. 124-133
  • Tidskriftsartikel (refereegranskat)abstract
    • Oxycodone (OC) is an opioid with strong analgesic effects widely used to treat acute and chronic pain. Interpretation of OC concentrations in postmortem cases is complicated due to tolerance and overlapping concentrations for fatal and non-fatal levels. In this study, our aim was to develop and validate a method for OC and its three metabolites: noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM) in postmortem femoral blood. Our goal was to define reference concentrations for intoxications and non-intoxications and investigate metabolic ratios in different causes of death. A rapid LC-MS-MS method using protein-precipitated postmortem blood was developed. Lower limit of quantitation was 0.005 mu g/g blood for all analytes; upper limit of quantitation was 1.0 mu g/g for OC and NOC and 0.25 mu g/g for OM and NOM. The method displayed high precision (3.3-7.7%) and low bias (-0.3 to 12%). In total, 192 cases were analyzed and concentrations ranged from 0.005 to 13 mu g/g for OC, 0.005 to 2.0 mu g/g for NOC, 0.005 to 0.24 mu g/g for OM, and 0.005 to 0.075 mu g/g for NOM. We found a significant difference in OC concentration between the cases where OC contributed and those where it did not. In spite of that, we do not recommend the use of a specific blood concentration to distinguish fatal intoxications. Instead, the percentiles from our data set suggest that concentrations >0.2 mu g/g are likely to have contributed to toxicity, but that concentrations as high as 0.3 might be tolerated without toxic effects. In addition, we also found that a low NOC/OC ratio could point toward an acute fatal intoxication. In conclusion, the OC concentration alone may not be sufficient to diagnose a fatal intoxication.
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39.
  • Jakobsson, Gerd, et al. (författare)
  • Oxycodone findings and CYP2D6 function in postmortem cases
  • 2021
  • Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 1872-4973 .- 1878-0326. ; 53
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 mu g/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/ oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.
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40.
  • Jakobsson, Gerd, 1981- (författare)
  • Oxycodone in Forensic Toxicology : Analytical Strategies and Interpretation
  • 2022
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Oxycodone is a common finding in forensic casework and widely used as an analgetic. Oxycodone’s pharmacokinetic and pharmacodynamic properties make the interpretation of post mortem oxycodone blood concentrations complicated. Coadministered substances and inter-individual differences in metabolic capacity can alter the oxycodone blood concentration and thereby cause an unexpected pharmacological effect and possibly lead to negative side-effects, respiratory depression, and death. As the level of tolerance often is unknown in post mortem cases the correlation between blood concentration and effect is weak. In this thesis, the overall aim was to increase the ability to determine cause and manner of death in suspected oxycodone intoxications, by studying concentrations of oxycodone and its metabolites, CYP2D6 phenotype, as well as endogenous substances in post mortem cases. Moreover, trends and patterns in prescription and post mortem findings of substances causing pharmacodynamic and pharmacokinetic interactions with oxycodone were studied.In paper I, concentrations of oxycodone, noroxycodone, oxymorphone and noroxymorphone were determined in femoral blood from 192 post mortem cases by LC-MS/MS. Concentrations and the metabolite-to-parent drug ratio were studied in groups separated by cause of death, A) intoxication by oxycodone, B) intoxication caused by oxycodone and additional substance/s, C) intoxication where oxycodone did not contribute, D) other causes of death than intoxication. It was found that concentrations above 0.2 μg/g indicate an oxycodone intoxication but that concentrations up to 0.3 μg/g can be seen in tolerant individuals. The results also demonstrated that a low noroxycodone/oxycodone ratio indicates an oxycodone intoxication. Paper II included LC-MS/MS analysis as in paper I, and in addition, genotyping for CYP2D6 enzyme activity in 174 cases. The metabolite-to-parent drug ratios were compared between poor, intermediate, extensive, and ultra-rapid metabolizers. It was concluded that with knowledge of CYP2D6 activity the oxymorphone/oxycodone ratio could distinguish between oxycodone-related deaths and other causes of deaths. Paper III was a pharmacoepidemiological study where post mortem findings were investigated in combination with prescription records in 1081 cases to evaluate the presence of interacting drugs in oxycodone-related intoxications. One of the main findings was that pharmacodynamically interacting drugs were twice as often prescribed, and five times more common as a co-finding in oxycodone-related intoxications compared to other causes of death. An oxycodone prescription was missing in 34% of all cases, with a trend that individuals, 35 years or below, more often lacked an oxycodone prescription. In paper IV, the post mortem metabolome was explored in 934 cases to reveal possible biomarkers correlated with oxycodone intoxications. The results showed that levels of acylcarnitines, a group of endogenous substances involved in mitochondrial metabolism, were significantly decreased in oxycodone-related intoxications compared to a control group, revealing post mortem metabolome analysis as a possible complemental approach of interpretation in post mortem toxicology.In conclusion, this thesis emphasizes the importance of including metabolites in the toxicological analytical strategy to improve the interpretation in post mortem case work. Also, the applicability of pharmacogenetic analysis is highly useful in certain cases. Furthermore, the use of post mortem metabolomics is a possible future promising strategy to the early identification of oxycodone-related deaths.
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41.
  • Jakobsson, Gerd, 1981-, et al. (författare)
  • Oxycodone-Related Deaths : The Significance of Pharmacokinetic and Pharmacodynamic Drug Interactions
  • 2022
  • Ingår i: European journal of drug metabolism and pharmacokinetics. - : Springer France. - 0378-7966 .- 2107-0180. ; 47, s. 259-270
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Objectives Oxycodone is frequently prescribed as well as detected in postmortem cases. Concurrent use of pharmacodynamically or pharmacokinetically interacting drugs can cause adverse effects or even fatal intoxication. The aims of this study were to investigate differences in prescriptions for and toxicological findings of pharmacodynamically and pharmacokinetically interacting drugs in fatal oxycodone-related intoxications and other causes of death. We also aimed to investigate the differences in prevalence of oxycodone prescriptions, and the detected postmortem oxycodone concentrations between fatal oxycodone-related intoxications and other causes of death. Methods Forensic autopsy cases (2012-2018) where oxycodone was identified in femoral blood (n = 1236) were included. Medical history and prescription data were retrieved from national databases and linked to the forensic toxicology findings. Results Oxycodone-related deaths were found to have higher blood concentrations of oxycodone (median 0.30 mu g/g vs. 0.05 mu g/g) and were less likely to have a prescription for oxycodone (OR 0.62) compared to nonintoxication deaths. Pharmacodynamically interacting drugs were prescribed in 79% and found in blood in 81% of the cases. Pharmacokinetically interacting drugs were rarely prescribed (1%). Oxycodone-related deaths were more likely to have prescriptions for a pharmacodynamically interacting drug (OR 1.7) and more often have co-findings of one or multiple pharmacodynamically interacting drugs (OR 5.6). Conclusion The results suggest that combined use of oxycodone and pharmacodynamically interacting drugs is associated with oxycodone-related death and that non-medical use of oxycodone is a potential risk factor for oxycodone-related intoxication.
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42.
  • Jakobsson, Gerd, et al. (författare)
  • Segmental analysis of amphetamines in hair using a sensitive UHPLC-MS/MS method
  • 2014
  • Ingår i: Drug Testing and Analysis. - : John Wiley & Sons. - 1942-7603 .- 1942-7611. ; 6, s. 22-29
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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43.
  • Johansen, Sys Stybe, et al. (författare)
  • Temporal patterns of tramadol in hair after a single dose
  • 2020
  • Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 316
  • Tidskriftsartikel (refereegranskat)abstract
    • This controlled study aimed to measure concentrations of tramadol (TRA) and its two main metabolites, N-desmethyltramadol (NDMT) and O-desmethyltramadol (ODMT), in hair following a single dose ingestion and to investigate the distribution patterns in hair by segmental analysis of hair samples taken at several sampling time points after ingestion. An oral dose (50 or 100 mg) of TRA was administered to 17 healthy volunteers. Hair samples were collected prior to drug administration and 14, 30, 60 and 120 days after ingestion. Each sample was segmented in 5 mm segments and washed. The analytes were extracted from pulverized hair by incubation in extraction media for 18 h at 37 degrees C. A validated UHPLC-MS/MS method was used to quantify the analytes at a LLOQ of 0.001 ng/mg. Hair segments corresponding to the time of ingestion were positive for TRA and the metabolites of each sampling time point, although neighboring segments also showed positive results. The highest concentrations for both dosage groups were observed in the proximal segment of hair collected 14 days after ingestion for all subjects: 0.061-0.95 ng TRA/mg, 0.012-0.86 ng NDMT/mg and 0.009-0.17 ng ODMT/mg (n = 16). Generally, the TRA concentration was higher than the metabolites concentrations but depended on the CYP2D6 phenotype. The metabolite to TRA ratios were stable within a subject over the sampling time points, however it varied greatly between subjects. No significant differences in hair concentrations were found between the two dosage groups at each sampling time. Several confounding factors were identified such as hair pigmentation and internal sweat. We showed that analysis of 5 mm segments improved the determination of the exposure time after a single ingestion of TRA. In addition, in the later sampling time points the analytes were spread more between segments and the total drug amount of each later sampling time point declined up to a 100% (median: 75%) due to wash out. The presented results are important additions to the sparse literature reporting single dose of psychoactive drugs in hair. (C) 2020 Elsevier B.V. All rights reserved.
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44.
  • Johansson, Anna, et al. (författare)
  • A non-fatal intoxication and seven deaths involving the dissociative drug 3-MeO-PCP
  • 2017
  • Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 275, s. 76-82
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: 3-methoxyphencyclidine (3-MeO-PCP) appeared on the illicit drug market in 2011 and is an analogue of phencyclidine, which exhibits anesthetic, analgesic and hallucinogenic properties. In this paper, we report data from a non-fatal intoxication and seven deaths involving 3-MeO-PCP in Sweden during the period March 2014 until June 2016. Case descriptions: The non-fatal intoxication case, a 19-year-old male with drug problems and a medical history of depression, was found awake but tachycardic, hypertensive, tachypnoeic and catatonic at home. After being hospitalized, his condition worsened as he developed a fever and lactic acidosis concomitant with psychomotor agitation and hallucinations. After 22 h of intensive care, the patient had made a complete recovery. During his hospitalization, a total of four blood samples were collected at different time points. The seven autopsy cases, six males and one female, were all in their twenties to thirties with psychiatric problems and/or an ongoing drug abuse. Methods: 3-MeO-PCP was identified with liquid chromatography (LC)/time-of-flight technology and quantified using LC-tandem mass spectrometry. Results: In the clinical case, the concentration of 3-MeO-PCP was 0.14 mu g/g at admission, 0.08 mu g/g 2.5 h after admission, 0.06 mu g/g 5 h after admission and 0.04 mu g/g 17 h after admission. The half-life of 3-MeO-PCP was estimated to 11 h. In the autopsy cases, femoral blood concentrations ranged from 0.05 mu g/g to 0.38 mu g/g. 3-MeO-PCP was the sole finding in the case with the highest concentration and the cause of death was established as intoxication with 3-MeO-PCP. In the remaining six autopsy cases, other medications and drugs of abuse were present as well. Conclusion: Despite being scheduled in January 2015, 3-MeO-PCP continues to be abused in Sweden. Exposure to 3-MeO-PCP may cause severe adverse events and even death, especially if the user does not receive life-supporting treatment.
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45.
  • Johansson, Anna, et al. (författare)
  • Quantitation of seven sedative and analgesic drugs in whole blood from intensive care patients using liquid chromatography mass spectrometry
  • 2021
  • Ingår i: TOXICOLOGIE ANALYTIQUE ET CLINIQUE. - : Elsevier. - 2352-0078 .- 2352-0086. ; 33:4, s. 327-337
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of clonidine, dexmedetomidine, fentanyl, ketamine, ketobemidone, midazolam and morphine in whole blood. These are drugs predominately used in intensive care units (ICUs) but they are also encountered in forensic investigations. The analytes were recovered from 0.25 g of blood by protein precipitation with a mixture of acetonitrile and ethanol. Separation was performed on a BEH phenyl column. Mobile phases consisted of 0.05% formic acid in 10 mM ammonium formate and 0.05% formic acid in methanol, respectively, and the flow rate was 600 mu L/min. The mass spectrometer was operated in positive electrospray ionization mode with multiple reaction monitoring. Validation included selectivity, qualitative matrix effects, calibration model, limit of detection, lower limit of quantification, within- and between-day accuracy and precision, process efficiency, dilution integrity, carry over and stability. Selectivity was high and no ion suppression or enhancementwas observed in the areas were the analytes eluted. Calibration curves were linear over arange of 0.25-50 ng/g for dexmedetomidine, 0.05-50 ng/g for fentanyl and 5.0-500 ng/g formorphine and quadratic over a range of 0.5-50 ng/g for clonidine, 50-5000 ng/g for ketamine, 5.0-500 ng/g for ketobemidone and midazolam. The method showed acceptable within- and betweenday accuracies and precisions. All analytes were stable in whole blood for three weeksat 4. C. Concentrations in patient samples ranged between 42-760 ng/g for midazolam (n = 15), 0.3-1.5 ng/g for dexmedetomidine (n = 13), 0.6-6.4 ng/g for clonidine (n = 13), 8-62 ng/g for morphine (n = 16), 5-19 ng/g for ketobemidone (n = 5), 0.07-3.1 ng/g for fentanyl (n = 43), and 562000 ng/g for ketamine (n = 10). We conclude that the method was successfully validatedand applied to ante-mortem and post-mortem blood samples from critically ill adult patientsin a general ICU.
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46.
  • Jones, A Wayne, et al. (författare)
  • Concentration-Time Profiles of Gamma-Hydroxybutyrate in Blood After Recreational Doses are Best Described by Zero-Order Rather Than First-Order Kinetics
  • 2009
  • Ingår i: Journal of Analytical Toxicology. - 0146-4760 .- 1945-2403. ; 33:6, s. 332-335
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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47.
  • Karlsson, Louise, et al. (författare)
  • Mephedrone, Methylone and 3,4-Methylenedioxypyrovalerone (MDPV) Induce Conditioned Place Preference in Mice
  • 2014
  • Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley: 12 months. - 1742-7835 .- 1742-7843. ; 115:5, s. 411-416
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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48.
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49.
  • Kronstrand, Robert, et al. (författare)
  • A Cluster of Deaths Involving 5-(2-Aminopropyl)Indole(5-IT)
  • 2013
  • Ingår i: Journal of Analytical Toxicology. - : Oxford University Press (OUP): Policy F. - 0146-4760 .- 1945-2403. ; 37:8, s. 542-546
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  •  
50.
  • Kronstrand, Robert, et al. (författare)
  • A Screening Method for 30 Drugs in Hair Using Ultrahigh-Performance Liquid Chromatography Time-of-Flight Mass Spectrometry
  • 2013
  • Ingår i: Therapeutic Drug Monitoring. - : Lippincott, Williams and Wilkins. - 0163-4356 .- 1536-3694. ; 35:3, s. 288-295
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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