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  • 51.
    Björn, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vergote, Ignace
    Leuven Canc Inst, Belgium.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 3, p. 277-287Article in journal (Refereed)
    Abstract [en]

    The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199Gamp;gt;A (rs2229109), 1236Camp;gt;T (rs1128503), 2677Gamp;gt;T/A (rs2032582), 3435Camp;gt;T (rs1045642) in ABCB1, and 1196Aamp;gt;G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol((R)) (Arm B, n=265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR=0.590) and in Arm B (HR=0.627), as well as increased OS in All (HR=0.443) and in Arm A (HR=0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p=0.039) and less neutrophil decrease in All (p=0.048) and in Arm B (p=0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.

  • 52.
    Björn, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Pradhananga, S.
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Sigurgeirsson, B.
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
    Lundberg, J.
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Sahlén, P
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples2018In: Journal of Next Generation Sequencing & Applications, ISSN 2469-9853, Vol. 5, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Whole exome sequencing (WES) has been extensively used in genomic research. As sequencing costs decline it is being replaced by whole genome sequencing (WGS) in large-scale genomic studies, but more comparative information on WES and WGS datasets would be valuable. Thus, we have extensively compared variant calls obtained from WGS and WES of matched germline DNA samples from 96 lung cancer patients. WGS provided more homogeneous coverage with higher genotyping quality, and identified more variants, than WES, regardless of exome coverage depth. It also called more reference variants, reflecting its power to call rare variants, and more heterozygous variants that met applied quality criteria, indicating that WGS is less prone to allelic drop outs. However, increasing WES coverage reduced the discrepancy between the WES and WGS results. We believe that as sequencing costs further decline WGS will become the method of choice even for research confined to the exome.

  • 53.
    Björn, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Sigurgeirsson, Benjamín
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden / School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
    Svedberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Pradhananga, Sailendra
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden / Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden / Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Lewensohn, Rolf
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    de Petris, Luigi
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Apellániz-Ruiz, Maria
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Rodríguez-Antona, Cristina
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Lundeberg, Joakim
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia2019In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150Article in journal (Refereed)
    Abstract [en]

    Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

    The full text will be freely available from 2020-04-15 13:16
  • 54.
    Björnström-Karlsson, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Turina, Dean
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Eintrei, Christina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Orexin A Inhibits Propofol-Induced Neurite Retraction by a Phospholipase D/Protein Kinase C-epsilon-Dependent Mechanism in Neurons2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e0097129-Article in journal (Refereed)
    Abstract [en]

    Background: The intravenous anaesthetic propofol retracts neurites and reverses the transport of vesicles in rat cortical neurons. Orexin A (OA) is an endogenous neuropeptide regulating wakefulness and may counterbalance anaesthesia. We aim to investigate if OA interacts with anaesthetics by inhibition of the propofol-induced neurite retraction. Methods: In primary cortical cell cultures from newborn rats brains, live cell light microscopy was used to measure neurite retraction after propofol (2 mu M) treatment with or without OA (10 nM) application. The intracellular signalling involved was tested using a protein kinase C (PKC) activator [phorbol 12-myristate 13-acetate (PMA)] and inhibitors of Rho-kinase (HA-1077), phospholipase D (PLD) [5-fluoro-2-indolyl des-chlorohalopemide (FIPI)], PKC (staurosporine), and a PKC epsilon translocation inhibitor peptide. Changes in PKC epsilon Ser(729) phosphorylation were detected with Western blot. Results: The neurite retraction induced by propofol is blocked by Rho-kinase and PMA. OA blocks neurite retraction induced by propofol, and this inhibitory effect could be prevented by FIPI, staurosporine and PKC epsilon translocation inhibitor peptide. OA increases via PLD and propofol decreases PKC epsilon Ser(729) phosphorylation, a crucial step in the activation of PKC epsilon. Conclusions: Rho-kinase is essential for propofol-induced neurite retraction in cortical neuronal cells. Activation of PKC inhibits neurite retraction caused by propofol. OA blocks propofol-induced neurite retraction by a PLD/PKC epsilon-mediated pathway, and PKC epsilon maybe the key enzyme where the wakefulness and anaesthesia signal pathways converge.

  • 55.
    Blomstrand, Hakon
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Scheibling, Ursula
    Ryhov Cty Hosp, Sweden.
    Bratthall, Charlotte
    Kalmar Cty Hosp, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Real world evidence on gemcitabine and nab-paclitaxel combination chemotherapy in advanced pancreatic cancer2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 40Article in journal (Refereed)
    Abstract [en]

    BackgroundIn the recent phase III trial MPACT the combination of gemcitabine and nab-paclitaxel (Gem/NabP) showed increased overall survival compared to gemcitabine alone in the treatment of advanced pancreatic ductal adenocarcinoma (aPDA). Until now there has been limited information on the clinical benefit and toxicity of the combination regimen in a real world setting. In addition the value for patients with locally advanced rather than metastatic aPDA has been unclear, since the former category of patients was not included in the MPACT trial.MethodsA multicentre retrospective observational study in the South Eastern Region of Sweden was performed, with the first 75 consecutive patients diagnosed with aPDA (both locally advanced and metastatic disease) who received first-line treatment with Gem/NabP.ResultsIn the overall population median progression free survival (PFS) and overall survival (OS) were 5.2 (3.4-7.0 95% CI) and 10.9 (7.8-14.0 95% CI) months, respectively. Patients with metastatic disease displayed a median OS of 9.4 (4.9-13.9) and a median PFS of 4.5 (3.3-5.7) months whereas the same parameters in the locally advanced subgroup were 17.1 (7.6-26.6) and 6.8 (5.2-8.4) months, respectively. Grade 3-4 hematologic toxicity was recorded: Neutropenia, leukopenia, thrombocytopenia, and anaemia were observed in 23, 20, 5, and 4% of patients, respectively. Dose reductions were performed in 80% of the patients.ConclusionThis study confirms the effectiveness and safety of first-line Gem/NabP in both locally advanced and metastatic PDA in a real world setting.

  • 56.
    Boiso, Samuel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Karlsson, Louise
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Tillmar, Andreas
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden .
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    ABCB1 gene polymorphisms are associated with suicide in forensic autopsies2013In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, no 9, p. 463-469Article in journal (Refereed)
    Abstract [en]

    Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

  • 57.
    Borendal Wodlin, Ninnie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Kjölhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Snabbspår har fördelar vid elektiv gynekologisk kirurgi.2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 25-26, p. 2-7Article in journal (Refereed)
    Abstract [en]

    Fast-track is a multimodal strategy aimed at achieving an improved and accelerated postoperative recovery. The strategy combines unimodal evidence-based interventions concerning preoperative preparation, peroperative principles and postoperative care. There is substantial evidence for the benefits of following fast-track concepts in general elective surgery to enhance postoperative recovery. The main findings of this review are that there are benefits likewise within elective gynecological surgery, but studies of quality of life, patient satisfaction and health economics are needed. Studies of fast-track within non-elective surgery and gynaecological oncology surgery are lacking. Widespread information and education is needed to improve the rate of implementation of fast-track. Comprehensive involvement of the entire staff dealing with the patient in the perioperative period is crucial to ensure implementation and development of surgical care aiming for enhanced postoperative recovery.

  • 58.
    Bragde, Hanna
    et al.
    Ryhov County Hospital, Sweden.
    Jansson, Ulf
    Ryhov County Hospital, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Soederman, Jan
    Ryhov County Hospital, Sweden.
    Potential blood-based markers of celiac disease2014In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 14, no 176Article in journal (Refereed)
    Abstract [en]

    Background: Blood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers. Methods: We investigated the levels of messenger RNA (mRNA) in whole blood (n = 49) and protein in plasma (n = 22) from cases with active CD (n = 20), with confirmed CD and normalized histology (n = 15), and without a CD diagnosis (n = 14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann-Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis. Results: CXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-kappa B complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone. Conclusions: The CD markers identified in this study further emphasize the significance of components related to NF-kappa B regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-kappa B interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD.

  • 59.
    Bragde, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Jansson, Ulf
    Ryhov Cty Hosp, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Division of Forensic Genetics & Forensic Toxicology National Board of Forensic Medicine Linköping, Sweden.
    Söderman, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies2018In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 75, no 23, p. 4385-4401Article in journal (Refereed)
    Abstract [en]

    Establishing a celiac disease (CD) diagnosis can be difficult, such as when CD-specific antibody levels are just above cutoff or when small intestinal biopsies show low-grade injuries. To investigate the biological pathways involved in CD and select potential biomarkers to aid in CD diagnosis, RNA sequencing of duodenal biopsies from subjects with either confirmed Active CD (n=20) or without any signs of CD (n=20) was performed. Gene enrichment and pathway analysis highlighted contexts, such as immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. Twenty-nine potential CD biomarkers were selected based on differential expression and biological context. The biomarkers were validated by real-time polymerase chain reaction of eight RNA sequencing study subjects, and further investigated using an independent study group (n=43) consisting of subjects not affected by CD, with a clear diagnosis of CD on either a gluten-containing or a gluten-free diet, or with low-grade intestinal injury. Selected biomarkers were able to classify subjects with clear CD/non-CD status, and a subset of the biomarkers (CXCL10, GBP5, IFI27, IFNG, and UBD) showed differential expression in biopsies from subjects with no or low-grade intestinal injury that received a CD diagnosis based on biopsies taken at a later time point. A large number of pathways are involved in CD pathogenesis, and gene expression is affected in CD mucosa already in low-grade intestinal injuries. RNA sequencing of low-grade intestinal injuries might discover pathways and biomarkers involved in early stages of CD pathogenesis.

  • 60.
    Brinkman, D. J.
    et al.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Tichelaar, J.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Schutte, T.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Benemei, S.
    University of Florence, Italy.
    Böttiger, Ylva
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Chamontin, B.
    University of Toulouse, France.
    Christiaens, T.
    University of Ghent, Belgium.
    Likic, R.
    University of Zagreb, Croatia.
    Maciulaitis, R.
    Lithuanian University of Health Science, Lithuania.
    Marandi, T.
    University of Tartu, Estonia.
    Monteiro, E. C.
    NOVA Medical Sch, Portugal.
    Papaioannidou, P.
    Aristotle University of Thessaloniki, Greece.
    Pers, Y. M.
    University of Montpellier, France.
    Pontes, C.
    Autonomous University of Barcelona, Spain.
    Raskovic, A.
    University of Novi Sad, Serbia.
    Regenthal, R.
    University of Leipzig, Germany.
    Sanz, E. J.
    University of La Laguna, Spain.
    Tamba, B. I.
    Gr T Popa University of Medical and Pharm, Romania.
    Wilson, K.
    University of Manchester, England.
    de Vries, T. P.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Richir, M. C.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    van Agtmael, M. A.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Essential Competencies in Prescribing: A First European Cross-Sectional Study Among 895 Final-Year Medical Students2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 101, no 2, p. 281-289Article in journal (Refereed)
    Abstract [en]

    European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.

  • 61.
    Bro, Tomas
    et al.
    Hoglandssjukhuset, Sweden; Futurum, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Futurum, Sweden.
    Worth changing? Clinical effects of switching treatment in neovascular age-related macular degeneration from intravitreal ranibizumab and aflibercept to bevacizumab in a region in southern Sweden2019In: European Journal of Ophthalmology, ISSN 1120-6721, E-ISSN 1724-6016, article id UNSP 1120672119883602Article in journal (Refereed)
    Abstract [en]

    Purpose: To examine the clinical effects of switching intravitreal drug treatment from the approved vascular endothelial growth factor inhibitors, ranibizumab and aflibercept, to off label use of bevacizumab in patients with wet age-related macular degeneration. Methods: This retrospective study scrutinized medical records of patients with wet age-related macular degeneration who switched therapy to bevacizumab due to a policy decision. Best corrected visual acuity, central retinal thickness, and number of injections before and 1 year after the switch was compared. The non-inferiority margin of best corrected visual acuity was five Early Treatment Diabetic Retinopathy Study letters. Results: A switch from ranibizumab was evaluable in 93 eyes and from aflibercept in 19 eyes. Neither of the groups had a significant non-inferior visual acuity 16 month after the switch. Mean best corrected visual acuity in Early Treatment Diabetic Retinopathy Study letters was 63.8 (95% confidence interval: 61.3-66.4) before and 62.2 (95% confidence interval: 59.3-65.1) after in the ranibizumab group and 68.2 (95% confidence interval: 63.3-73.1) before and 67.7 (95% confidence interval: 62.8-72.6) after in the aflibercept group. Mean central retinal thickness in micrometers decreased from 254 (95% confidence interval: 247-261) to 250 (95% confidence interval: 225-275) in the ranibizumab group and from 265 (95% confidence interval: 255-276) to 262 (95% confidence interval: 251-273) in the aflibercept group. The treatment was changed again after the switch in 18% of the patients in the ranibizumab group and 19% in the aflibercept group and these subjects were excluded from the analyses. Conclusion: In patients with neovascular age-related macular degeneration, a switch from ranibizumab or aflibercept to bevacizumab seems possible without a significant decrease in visual acuity in most patients.

  • 62.
    Brodin, Ola
    et al.
    Karolinska Institute, Sweden.
    Eksborg, Staffan
    Karolinska Institute, Sweden.
    Wallenberg, Marita
    Karolinska Institute, Sweden.
    Asker-Hagelberg, Charlotte
    Medical Prod Agency, Sweden; Karolinska Institute, Sweden.
    Larsen, Erik H.
    Technical University of Denmark, Denmark.
    Mohlkert, Dag
    Karolinska University Hospital Sodersjukhuset, Sweden.
    Lenneby-Helleday, Clara
    Karolinska Institute, Sweden.
    Jacobsson, Hans
    Karolinska University Hospital, Sweden.
    Linder, Stig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Misra, Sougat
    Karolinska Institute, Sweden.
    Bjornstedt, Mikael
    Karolinska Institute, Sweden.
    Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study2015In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 7, no 6, p. 4978-4994Article in journal (Refereed)
    Abstract [en]

    Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

  • 63.
    Buono, Roberta
    et al.
    IRCCS Osped San Raffaele, Italy.
    Briganti, Alberto
    IRCCS Osped San Raffaele, Italy.
    Freschi, Massimo
    IRCCS Osped San Raffaele, Italy.
    Villa, Luca
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    La Croce, Giovanni
    IRCCS Osped San Raffaele, Italy; Lund University, Sweden.
    Moschini, Marco
    IRCCS Osped San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Castiglione, Fabio
    University of Vita Salute San Raffaele, Italy; Lund University, Sweden.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Silodosin and tadalafil have synergistic inhibitory effects on nerve-mediated contractions of human and rat isolated prostates2014In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 744, p. 42-51Article in journal (Refereed)
    Abstract [en]

    Lower urinary tract symptoms (CUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction. Alpha-1-adrenoceptor antagonists are effective drugs for treating symptomatic BPH. Clinical data show improvements in LUIS by phosphodiesterase 5 inhibitors. This study aimed to evaluate effects of siloclosin, a highly selective alpha(1A)-adrenoceptor antagonist, alone or in combination with the phosphocliesterase 5 inhibitor tadalafil on contractions of isolated human and rat prostates. In organbath studies, effects of increasing concentrations of siloclosin (1 nM-1 mu M) and tadalafil (100 nM-100 mu M) on contractions by electrical field stimulation or phenylephrine of human and rat prostate strip preparations were investigated. The combination silodosin and tadalafil reduced electrically-induced contractions of human prostate preparations better than single drugs alone. At any frequencies (1-32 Hz), inhibitory effects of combined therapy (P-values vs single drug) in human tissue were 26-42% (1 nM silodosin+100 nM tadalafil; P less than 0.05), 40-58% (10 nM silodosin+1 mu M tadalafil; P less than 0.001-0.05), 56-67% (100 nM silodosin+10 mu M tadalafil; P less than 0.01-0.05), and 33-55% (1 mu M silodosin+100 mu M tadalafil P less than 0.01-0.05), Similar findings were obtained in rat prostate preparations. In human and rat prostate tissue, the drug combination exerted similar inhibitory effect on phenylephrine contractions as silodosin alone. Silodosin plus tadalafil had greater potency than each drug alone to inhibit prostate contractions to electrical field stimulation but not to phenylephrine. This study supports the clinical application of a combination of an (alpha(1A)-adrenoceptor antagonist and a phosphodiesterase 5 inhibitor for symptomatic BPH and suggests that the drug combination requires endogenous nerve-activity for optimal effect.

  • 64.
    Busardo, Francesco P.
    et al.
    University of Roma La Sapienza, Italy.
    Jones, A Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    GHB Pharmacology and Toxicology: Acute Intoxication, Concentrations in Blood and Urine in Forensic Cases and Treatment of the Withdrawal Syndrome2015In: Current Neuropharmacology, ISSN 1570-159X, E-ISSN 1875-6190, Vol. 13, no 1, p. 47-70Article in journal (Refereed)
    Abstract [en]

    The illicit recreational drug of abuse, gamma-hydroxybutyrate (GHB) is a potent central nervous system depressant and is often encountered during forensic investigations of living and deceased persons. The sodium salt of GHB is registered as a therapeutic agent (Xyrem (R)), approved in some countries for the treatment of narcolepsy-associated cataplexy and (Alcover (R)) is an adjuvant medication for detoxification and withdrawal in alcoholics. Trace amounts of GHB are produced endogenously (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter.-aminobutyric acid (GABA). Available information indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, especially via binding to the GABA-B receptor subtype. Although GHB is listed as a controlled substance in many countries abuse still continues, owing to the availability of precursor drugs, gamma-butyrolactone (GBL) and 1,4-butanediol (BD), which are not regulated. After ingestion both GBL and BD are rapidly converted into GHB (t1/2 similar to 1 min). The Cmax occurs after 20-40 min and GHB is then eliminated from plasma with a half-life of 30-50 min. Only about 1-5% of the dose of GHB is recoverable in urine and the window of detection is relatively short (3-10 h). This calls for expeditious sampling when evidence of drug use and/or abuse is required in forensic casework. The recreational dose of GHB is not easy to estimate and a concentration in plasma of similar to 100 mg/L produces euphoria and disinhibition, whereas 500 mg/L might cause death from cardiorespiratory depression. Effective antidotes to reverse the sedative and intoxicating effects of GHB do not exist. The poisoned patients require supportive care, vital signs should be monitored and the airways kept clear in case of emesis. After prolonged regular use of GHB tolerance and dependence develop and abrupt cessation of drug use leads to unpleasant withdrawal symptoms. There is no evidence-based protocol available to deal with GHB withdrawal, apart from administering benzodiazepines.

  • 65.
    Busardò, Francesco Paolo
    et al.
    a Department of Anatomical, Histological, Forensic and Orthopaedic Sciences , Sapienza University of Rome , Rome , Italy.
    Jones, A Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Interpreting γ-hydroxybutyrate concentrations for clinical and forensic purposes2019In: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 57, no 3, p. 149-163Article in journal (Refereed)
    Abstract [en]

    ?-Hydroxybutyric acid is an endogenous substance, a therapeutic agent, and a recreational drug of abuse. This psychoactive substance acts as a depressant of the central nervous system and is commonly encountered in clinical and forensic practice, including impaired drivers, poisoned patients, and drug-related intoxication deaths.

  • 66.
    Börjeson, Sussanne
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Hursti, T J
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Peterson, C
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
    Fredikson, M
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Fürst, C J
    Stockholms Sjukhem, Stockholm, Sweden.
    Avall-Lundqvist, E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Dept. of Gynaecological Oncology, Karolinska Hospital, Stockholm, Sweden.
    Steineck, G
    Clinical Epidemiology, Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
    Similarities and differences in assessing nausea on a verbal category scale and a visual analogue scale.1997In: Cancer Nursing, ISSN 0162-220X, E-ISSN 1538-9804, Vol. 20, no 4, p. 260-266Article in journal (Refereed)
    Abstract [en]

    The use of verbal category scales in assessing patient symptoms is evolving, but the extent to which reliability and precision are lost in using them as opposed to a visual analogue scale (VAS) remains uncertain. The present study analyzed the concordance between a four-point verbal category scale and a VAS in assessing nausea intensity in patients undergoing chemotherapy. The analysis of a total of 348 simultaneous ratings by 104 women over four cycles revealed good concordance between the scales. The means of the VAS ratings (range 0-100 mm) corresponding to the four verbal categories divided the scale in four almost equally large parts (no nausea = 0.7, mild = 24.8, moderate = 48.3, severe = 75.1). However, the VAS ranges were wide. On an individual level a one-step change in the verbal category was associated with an average change of 20 mm on the VAS. The choice of scale to use should be based on the need in the particular situation. When measuring intensity of nausea in patients, the VAS is a reasonable choice due to its possibly greater ability to detect changes over time. On the group level, findings on a four-point category scale and a VAS on the average seem similar.

  • 67.
    Böttiger, Ylva
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Laine, Kari
    Medbase Ltd, Finland; Univ Turku, Finland.
    Korhonen, Tuomas
    Medbase Ltd, Finland; Univ Turku, Finland.
    Lahdesmaki, Janne
    Medbase Ltd, Finland; Turku Univ Hosp, Finland; Univ Turku, Finland.
    Shemeikka, Tero
    Stockholm Cty Council, Sweden.
    Julander, Margaretha
    Stockholm Cty Council, Sweden.
    Edlert, Maria
    Stockholm Cty Council, Sweden.
    Andersson, Marine L.
    Karolinska Univ Hosp, Sweden.
    Development and pilot testing of PHARAO-a decision support system for pharmacological risk assessment in the elderly2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 3, p. 365-371Article in journal (Refereed)
    Abstract [en]

    The aims of this study are to describe the development of PHARAO (Pharmacological Risk Assessment Online), a decision support system providing a risk profile for adverse events, associated with combined effects of multiple medicines, and to present data from a pilot study, testing the use, functionality, and acceptance of the PHARAO system in a clinical setting. About 1400 substances were scored in relation to their risk to cause any of nine common and/or serious adverse effects. Algorithms for each adverse effect score were developed to create individual risk profiles from the patients list of medication. The system was tested and integrated to the electronic medical record, during a 4-month period in two geriatric wards and three primary healthcare centers, and a questionnaire was answered by the users before and after the test period. A total of 732 substances were tagged with one or more of the nine risks, most commonly with the risk of sedation or seizures. During the pilot, the system was used 933 times in 871 patients. The most common signals generated by PHARAO in these patients were related to the risks of constipation, sedation, and bleeding. A majority of responders considered PHARAO easy to use and that it gives useful support in performing medication reviews. The PHARAO decision support system, designed as a complement to a database on drug-drug interactions used nationally, worked as intended and was appreciated by the users during a 4-month test period. Integration aspects need to be improved to minimize unnecessary signaling.

  • 68.
    Carlier, Jeremy
    et al.
    NIDA, MD 21224 USA.
    Diao, Xingxing
    NIDA, MD 21224 USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. NIDA, MD 21224 USA; National Board Forens Med, Linkoping, Sweden.
    Scheidweiler, Karl
    NIDA, MD 21224 USA.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA; University of Maryland, MD 21201 USA.
    In Vitro Metabolite Profiling of ADB-FUBINACA, A New Synthetic Cannabinoid2017In: Current Neuropharmacology, ISSN 1570-159X, E-ISSN 1875-6190, Vol. 15, no 5, p. 682-691Article in journal (Refereed)
    Abstract [en]

    Background: Metabolite profiling of novel psychoactive substances (NPS) is critical for documenting drug consumption. N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1-Hindazole-3-carboxamide (ADB-FUBINACA) is an emerging synthetic cannabinoid whose toxicological and metabolic data are currently unavailable. Methods: We aimed to determine optimal markers for identifying ADB-FUBINACA intake. Metabolic stability was evaluated with human liver microsome incubations. Metabolites were identified after 1 and 3 h incubation with pooled human hepatocytes, liquid chromatography-high resolution mass spectrometry in positive-ion mode (5600(+) TripleTOF (R), Sciex) and several data mining approaches (MetabolitePilot (TM), Sciex). Results: Metabolite separation was achieved on an Ultra Biphenyl column (Restek (R)); full-scan TOF-MS and information-dependent acquisition MS/MS data were acquired. ADB-FUBINACA microsomal half-life was 39.7 min, with a predicted hepatic clearance of 9.0 mL/min/kg and a 0.5 extraction ratio (intermediate-clearance drug). Twenty-three metabolites were identified. Major metabolic pathways were alkyl and indazole hydroxylation, terminal amide hydrolysis, subsequent glucuronide conjugations, and dehydrogenation. Conclusion: We recommend ADB-FUBINACA hydroxyalkyl, hydroxydehydroalkyl and hydroxylindazole metabolites as ADB-FUBINACA intake markers. N-dealkylated metabolites are not specific ADB-FUBINACA metabolites and should not be used as definitive markers of consumption. This is the first ADB-FUBINACA in vitro metabolism study; in vivo experiments enabling pharmacokinetic and pharmacodynamics studies or urine from authentic clinical/forensic cases are needed to confirm our results.

  • 69.
    Carlsson, Per
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Hoffman, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Nätverk för läkemedelsepidemiologi (NEPI).
    Levin, Lars-Åke
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Sandman, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences. Högskolan i Borås, Institutionen för vårdvetenskap.
    Wiss, Johanna
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Prioritering av läkemedel för behandling av patienter med sällsynta sjukdomar2014In: Läkemedel för djur, maskinell dos och sällsynta tillstånd: hantering och prissättning. Slutbetänkande av Läkemedels- och apoteksutredningen, Stockholm: Fritzes, 2014, p. 639-699Chapter in book (Other academic)
    Abstract [sv]

    I vilken utsträckning kan särskilda hänsyn tas vid prioritering av särläkemedel och läkemedel för behandling av sällsynta tillstånd? Bör man i vissa speciella situationer kunna acceptera sämre kostnadseffektivitet och lägre krav på vetenskapligt underlag? Om så, vad är det för villkor/kriterier som då bör vara uppfyllda? Hur stämmer ett sådant undantag med den etiska plattformen för prioriteringar? Finns det andra argument som talar för eller mot en särbehandling av sällsynta tillstånd? Detta är frågor som vi diskuterar i denna rapport som tagits fram på uppdrag av Läkemedels- och apoteksutredningen.

    I rapporten konstaterar vi att särläkemedel är en relativt heterogen grupp av läkemedel och att det finns andra läkemedel med motsvarande egenskaper som inte ansökt eller kunnat ansöka om status som särläkemedel. Ur prioriteringssynpunkt är det därför mer relevant att fokusera på alla typer av läkemedel, som används för sällsynta tillstånd, när vi diskuterar vilka principer för prioriteringar som bör gälla.

    Utifrån litteratur och erfarenheter i andra länder, som formulerat kriterier för en särskild hantering av läkemedel vid sällsynta sjukdomar, drar vi den preliminära slutsatsen att samhället bör kunna betala mer per hälsovinst (kostnad per kvalitetsjusterat levnadsår (QALY)) och acceptera lägre krav på vetenskapligt underlag vid prioritering av läkemedel för behandling av sällsynta sjukdomar om samtliga följande villkor är uppfyllda:

    • att behandlingen har en hög kostnad per hälsovinst som en konsekvens av att den omfattar endast få patienter,
    • att det rör sig om ett tillstånd med mycket stor svårighetsgrad,
    • att det behandlingsalternativ som övervägs på goda grunder ska antas ha en väsentlig effekt,
    • att det inte finns någon alternativ behandling med en väsentlig effekt som förväntas förebygga, bota, fördröja försämring eller lindra det aktuella tillståndet.

    Om dessa kriterier anses uppfyllda kan läkemedlet bedömas i relation till ett förhöjt tröskelvärde för kostnadseffektivitet. Hur högt detta värde kan vara för att anses rimligt tar vi inte ställning till i rapporten, men en viktig ståndpunkt är att det måste finnas en övre gräns för hur hög kostnad per QALY samhället kan acceptera. Detta bör gälla även om ovanstående kriterier är uppfyllda, annars riskerar det uppstå oacceptabla undanträngningseffekter av andra prioriterade åtgärder. Även lägre krav på vetenskapligt underlag skakunna accepteras....

  • 70.
    Castaneto, Marisol S.
    et al.
    NIDA, MD 21224 USA; University of Maryland, MD 21201 USA.
    Wohlfarth, Ariane
    NIDA, MD 21224 USA.
    Pang, Shaokun
    SCIEX Ltd, CA USA.
    Zhu, Mingshe
    Bristol Myers Squibb Co, NJ USA.
    Scheidweiler, Karl B.
    NIDA, MD 21224 USA.
    Kronstrand, Robert
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA.
    Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry2015In: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 33, no 2, p. 295-310Article in journal (Refereed)
    Abstract [en]

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

  • 71.
    Castiglione, Fabio
    et al.
    University of Leuven, Belgium; IRCCS Osped San Raffaele, Italy.
    Dewulf, Karel
    University of Leuven, Belgium.
    Hakim, Lukman
    University of Leuven, Belgium; Airlangga University, Indonesia.
    Weyne, Emmanuel
    University of Leuven, Belgium.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy.
    Russo, Andrea
    IRCCS Osped San Raffaele, Italy.
    Boeri, Luca
    IRCCS Osped San Raffaele, Italy.
    Bivalacqua, Trinity J.
    Johns Hopkins Medical Institute, MD 21205 USA.
    De Ridder, Dirk
    University of Leuven, Belgium.
    Joniau, Steven
    University of Leuven, Belgium.
    Albersen, Maarten
    University of Leuven, Belgium.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Lund University, Sweden.
    Adipose-derived Stem Cells Counteract Urethral Stricture Formation in Rats2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 6, p. 1032-1041Article in journal (Refereed)
    Abstract [en]

    Background: A medical treatment for urethral stricture (US) is not yet available. Objective: To evaluate if local injection of human adipose tissue-derived stem cells (hADSC) prevents urethral fibrosis in a rat model of US. Design, setting, and participants: Male rats were divided into three groups: sham, US, and hADSC (n = 12 each). Sham rats received a vehicle injection in the urethral wall. US and hADSCs were incised and injected with the fibrosis-inducer transforming growth factor-beta 1 in the urethral wall. Intervention: One day later, hADSCs were injected in the urethral wall of hADSC rats whereas sham and US rats were injected with the vehicle. After 4 wk, the rats underwent cystometries and tissues were then harvested for functional and molecular analyses. Outcome measurements and statistical analysis: Cystometry, microultrasound, histochemistry, organ bath studies, reverse transcription polymerase chain reaction, and western blot. Results and limitations: US rats exhibited 49-51% shorter micturition intervals, 35-51% smaller micturition volumes and bladder capacity, 33-62% higher threshold pressures and flow pressures, and 35-37% lower bladder filling compliance compared with hADSC-treated rats and sham rats (p amp;lt; 0.05). By ultrasound, US rats had hyperechogenic and thick urethral walls with narrowed lumen compared with sham rats, whereas hADSC rats displayed less extensive urethral changes. Isolated detrusor from US rats exhibited 34-55% smaller contractions than detrusor from sham rats (p amp;lt; 0.05). Corresponding values were 11-35% for isolated detrusors from hADSC rats. Collagen and elastin protein expression were increased in the penile urethras of US rats compared with sham and hADSC groups (p amp;lt; 0.05). Endothelial and inducible nitric oxide synthase expressions were higher (p amp;lt; 0.05) in the hADSC group. Compared with US rats, hADSC rats demonstrated decreased expression of several fibrosis-related genes. Administration of hADSCs was performed at an early stage of US development, which we consider a limitation of the study. Conclusions: Local injection of hADSCs prevents stricture formation and urodynamic complications in a new rat model for US. Patient summary: Stem cell therapy is effective for preventing urethral stricture in an experimental setting. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  • 72.
    Castiglione, Fabio
    et al.
    University of Vita Salute San Raffaele, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics. University of Vita Salute San Raffaele, Italy .
    Van der Aa, Frank
    University of Louvain, Belgium .
    Bivalacqua, Trinity J.
    Johns Hopkins Medical Institute, MD USA .
    Rigatti, Patrizio
    University of Vita Salute San Raffaele, Italy .
    Van Poppel, Hein
    University of Louvain, Belgium .
    Montorsi, Francesco
    University of Vita Salute San Raffaele, Italy .
    De Ridder, Dirk
    University of Louvain, Belgium .
    Albersen, Maarten
    University of Vita Salute San Raffaele, Italy .
    Correction: Intratunical Injection of Human Adipose Tissue-derived Stem Cells Prevents Fibrosis and Is Associated with Improved Erectile Function in a Rat Model of Peyronies Disease (vol 63, pg 551, 2013)2013Other (Refereed)
    Abstract [en]

    n/a

  • 73.
    Castiglione, Fabio
    et al.
    Univ Leuven, Belgium; Univ Coll London Hosp, England; IRCCS Osped San Raffaele, Italy.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Lund Univ, Sweden.
    Weyne, Emanuel
    Univ Leuven, Belgium.
    Hakim, Lukman
    Univ Leuven, Belgium; Airlangga Univ, Indonesia.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy.
    Bivalacqua, Trinity J.
    Johns Hopkins Med Inst, MD 21205 USA.
    De Ridder, Dirk
    Univ Leuven, Belgium.
    Milenkovic, Uros
    Univ Leuven, Belgium.
    Ralph, David
    Univ Coll London Hosp, England.
    Garaffa, Giulio
    Univ Coll London Hosp, England.
    Muneer, Asif
    Univ Coll London Hosp, England.
    Joniau, Steven
    Univ Leuven, Belgium.
    Intratunical Injection of Human Adipose Tissue-Derived Stem Cells Restores Collagen III/IRatio in a Rat Model of Chronic Peyronies Disease2019In: SEXUAL MEDICINE, ISSN 2050-1161, Vol. 7, no 1, p. 94-103Article in journal (Refereed)
    Abstract [en]

    Introduction: Previous studies have shown that the injection of adipose tissue-derived stem cells (ADSCs) into the tunica albuginea (TA) during the active phase of Peyronies disease (PD) prevents the development of fibrosis. Aim: To investigate, using an animal model, whether local injection of human ADSCs (hADSCs) can alter the degree of fibrosis in the chronic phase of PD. Methods: 27 male, 12-week-old rats were divided into 3 equal groups: sham, PD without treatment, and PD treated with hADSCs 1 month after disease induction. Sham rats underwent 2 injections of vehicle into the TA 1 month apart. PD rats underwent transforming growth factor beta 1 (TGF beta 1) injection and injection of vehicle 1 month later. PD-hADSC rats underwent TGF beta 1 injection followed by 1 million hADSCs 1 month later. 1 week after treatment, n = 3 animals/group were euthanized, and the penises were harvested for quantitative polymerase chain reaction. 1 month after treatment, the other animals, n = 6 per group, underwent measurement of intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrostimulation of the cavernous nerve. After euthanasia, penises were again harvested for histology and Western blot. Main Outcome Measure: The primary outcome measures included (a) gene expression at one week post-injection; (b) measurement of ICP/MAP upon cavernous nerve stimulation as a measure of erectile function; (c) elastin, collagen I and III protein expression; and (d) Histomorphometric analysis of the penis. Means where compared by analysis of variance (ANOVA) followed by a Student-Newman-Keuls test for post hoc comparisons or Mann-Whitney test when applicable. Results: No significant difference was noted in ICP or ICP/MAP in response to cavernous nerve electrostimulation between the 3 groups at 2.5, 5, and 7.5 V (Pamp;gt;.05 for all voltages). PD animals developed tunical and subtunical areas of fibrosis with a significant upregulation of collagen III protein. The collagen III/I ratio was higher in the PD (4.6 +/- 0.92) group compared with sham (0.66 +/- 0.18) and PD-hADSC (0.86 +/- 0.06) groups (Pamp;lt;.05) These fibrotic changes were prevented when treated with hADSCs. Compared with PD rats, PD-hADSC rats demonstrated a decreased expression of several fibrosis-related genes. Conclusion: Injection of hADSCs reduces collagen III expression in a rat model of chronic PD. Copyright (C) 2018, International Society for Sexual Medicine. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  • 74.
    Castiglione, Fabio
    et al.
    Univ Leuven, Belgium; Univ Coll London Hosp, England; IRCCS Osped San Raffaele, Italy.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Lund Univ, Sweden.
    Weyne, Emmanuel
    Univ Leuven, Belgium.
    Hakim, Lukman
    Univ Leuven, Belgium; Airlangga Univ, Indonesia.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy.
    Salonia, Andrea
    IRCCS Osped San Raffaele, Italy.
    Bivalacqua, Trinity J.
    Johns Hopkins Med Inst, MD 21205 USA.
    De Ridder, Dirk
    Univ Leuven, Belgium.
    Milenkovic, Uros
    Univ Leuven, Belgium.
    Ralph, David
    Univ Coll London Hosp, England.
    Garaffa, Giulio
    Univ Coll London Hosp, England.
    Muneer, Asif
    Univ Coll London Hosp, England.
    Joniau, Steven
    Univ Leuven, Belgium.
    Albersen, Maarten
    Univ Leuven, Belgium.
    Intratunical injection of stromal vascular fraction prevents fibrosis in a rat model of Peyronies disease2019In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 124, no 2, p. 342-348Article in journal (Refereed)
    Abstract [en]

    Objective To investigate whether local injection of autologous adipose stromal vascular fraction (SVF) can prevent the development of fibrosis and elastosis in the tunica albuginea (TA) using a rat model of the acute phase of Peyronies disease (PD). Methods A total of 24 male 12-week-old Sprague-Dawley rats were divided into three equal groups: sham; PD without treatment (transforming growth factor-beta [TGF -beta]); and PD treated with SVF 1 day after disease induction. Sham rats received two injections of vehicle into the TA 1 day apart. TGF -beta rats received TGF- beta 1 injection and injection of vehicle 1 day later. SVF rats received TGF-beta 1 injection, followed by SVF 1 day later. One month after treatment, all rats underwent measurement of intracavernosal pressure and mean arterial pressure during electrostimulation of the cavernous nerve. The rats were then killed and penises were harvested for histology and Western blot analysis. Results Erectile function was moderately reduced in the TGF-beta group and was significantly improved after SVF treatment (P amp;lt; 0.05). PD rats developed areas of fibrosis with a significant upregulation of collagen III, collagen I and elastin protein expression. These fibrotic changes were prevented when treated with SVF. Conclusions Local injection of SVF may represent treatment for the acute phase of PD.

  • 75.
    Chaabane, Wiem
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Interconnections between apoptotic and autophagic pathways during thiopurine-induced toxicity in cancer cells: the role of reactive oxygen species2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 46, p. 75616-75634Article in journal (Refereed)
    Abstract [en]

    Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are a class of genotoxic drugs extensively used in the treatment of various illnesses including leukemia. Their underlying molecular mechanism of action involves the activation of apoptosis and autophagy but remains widely unclear. Here we present evidence that autophagy induction by thiopurines is a survival mechanism that antagonizes apoptosis and is involved in degrading damaged mitochondria through mitophagy. On the other hand, apoptosis is the main cell death mechanism by thiopurines as its inhibition prohibited cell death. Thus a tight interplay between apoptosis and autophagy controls cell fate in response to thiopurine treatment. Moreover, thiopurines disrupt mitochondrial function and induce a loss of the mitochondrial transmembrane potential. The involvement of the mitochondrial pathway in thiopurine-induced apoptosis was further confirmed by increased formation of reactive oxygen species (ROS). Inhibiting oxidative stress protected the cells from thiopurine-induced cell death and ROS scavenging prohibited autophagy induction by thiopurines. Our data indicate that the anticarcinogenic effects of thiopurines are mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.

  • 76.
    Chalise, Jaya Prakash
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Pallotta, Maria Teresa
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Chenna Narendra, Sudeep
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Iacono, Alberta
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Boon, Louis
    EPIRUS Biopharmaceuticals, Utrecht, Netherlands.
    Grohmann, Ursula
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritisManuscript (preprint) (Other academic)
    Abstract [en]

    Interferon-α (IFN-α) prevents antigen-induced arthritis (AIA) in mice by an unknown mechanism. Indoleamine 2, 3 dioxygenase 1 (IDO1) is an immunoregulator via enzymatic as well as signalling activity, which can be activated by TGF-β and further mediated via non canonical NF-κB signalling. We here investigated whether IDO1 and TGF-β are involved in IFN-α protective effects in AIA. Arthritis was induced in wt, Ido1-/- or Ifnar-/- mice, treated or not with IFN-α or kynurenine, the main IDO1 product, and antibodies neutralizing TGF-β or 1-methyltryptophan (1-MT), an inhibitor of IDO1 catalytic activity. IDO1 expression and enzymatic activity were determined by RT-PCR and HPLC, respectively. Proliferation was measured by 3H-Thymidine incorporation. Non-canonical NF-κB signalling was evaluated by ELISA and Western blot in plasmacytoid DCs (pDCs) from treated mice. Protective effects of IFN-α in AIA were associated with increased IDO1 expression and kynurenine production in spleen cells, particularly at the time of mBSA sensitization. Lack of IDO1 ablated IFN-α protection and kynurenine prevented AIA in an IFNAR-independent manner. The IDO1 catalytic activity was crucial for IFN-α effects at the sensitization but not effector phase of AIA. The disease effector phase in mice treated with IFN-α was instead characterized by sustained IDO1 and TGF-β expression and activation of the noncanonical NF-κB pathway in pDCs. IFN-α protective effects in AIA involves IDO1 enzymatic and signalling activity in the disease sensitization and effector phase, respectively. Kynurenine, the main IDO1 metabolite, can be used as an alternative treatment to IFN-α in protecting mice from AIA.

  • 77.
    Chen, Chang
    et al.
    Huazhong University of Science and Technology, Peoples R China.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Linköping, Sweden.
    Xu, Hui
    Maternal and Child Health Hospital Hubei Prov, Peoples R China.
    Su, Dan
    Jiangxi University of Tradit Chinese Med, Peoples R China.
    Wang, Xin
    MassDefect Technology, NJ 08540 USA.
    Jiang, Hongliang
    Huazhong University of Science and Technology, Peoples R China.
    Feng, Yulin
    Jiangxi University of Tradit Chinese Med, Peoples R China.
    Zhu, Mingshe
    Bristol Myers Squibb, NJ 08543 USA.
    Untargeted screening of unknown xenobiotics and potential toxins in plasma of poisoned patients using high-resolution mass spectrometry: Generation of xenobiotic fingerprint using background subtraction2016In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 944, p. 37-43Article in journal (Refereed)
    Abstract [en]

    A novel analytical workflow was developed and applied for the detection and identification of unknown xenobiotics in biological samples. High-resolution mass spectrometry (HRMS)-based data-independent MSE acquisition was employed to record full scan MS and fragment spectral datasets of test and control samples. Then, an untargeted data-mining technique, background subtraction, was utilized to find xenobiotics present only in test samples. Structural elucidation of the detected xenobiotics was accomplished by database search, spectral interpretation, and/or comparison with reference standards. Application of the workflow to analysis of unknown xenobiotics in plasma samples collected from four poisoned patients led to generation of xenobiotic profiles, which were regarded as xenobiotic fingerprints of the individual samples. Among 19 xenobiotics detected, 11 xenobiotics existed in a majority of the patients plasma samples, thus were considered as potential toxins. The follow-up database search led to the tentative identification of azithromycin (X5), alpha-chaconine (X9) and penfluridol (X12). The identity of X12 was further confirmed with its reference standard. In addition, one xenobiotic component (Y5) was tentatively identified as a penfluridol metabolite. The remaining unidentified xenobiotics listed in the xenobiotic fingerprints can be further characterized or identified in retrospective analyses after their spectral data and/or reference compounds are available. This HRMS-based workflow may have broad applications in the detection and identification of unknown xenobiotics in individual biological samples, such as forensic and toxicological analysis and sport enhancement drug screening. (C) 2016 Elsevier B.V. All rights reserved.

  • 78.
    Chermá, Maria D.
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Rydberg, Irene
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Woxler, Per
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Dependency in Linköping.
    Trygg, Tomas
    Region Östergötland, Local Health Care Services in Central Östergötland, Department of Dependency in Linköping.
    Hollertz, Olle
    Department of General Psychiatry, Västervik Hospital, Västervik, Sweden.
    Gustafsson, Per A.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Methylphenidate for Treating ADHD: A Naturalistic Clinical Study of Methylphenidate Blood Concentrations in Children and Adults With Optimized Dosage.2017In: European journal of drug metabolism and pharmacokinetics, ISSN 0378-7966, E-ISSN 2107-0180, Vol. 42, no 2, p. 295-307Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Methylphenidate (MPH), along with behavioral and psychosocial interventions, is the first-line medication to treat attention-deficit hyperactivity disorder (ADHD) in Sweden. The dose of MPH for good symptom control differs between patients. However, studies of MPH concentration measurement in ADHD treatment are limited.

    OBJECTIVE: To describe blood and oral fluid (OF) concentrations of MPH after administration of medication in patients with well-adjusted MPH treatment for ADHD, and to identify the most suitable matrix for accurate MPH concentration during treatment.

    METHODS: Patients were recruited from Child and Adolescent Psychiatry (CAP), General Psychiatry (GP), and the Department of Dependency (DD). Blood and OF samples were collected in the morning before MPH administration as well as 1 and 6 h after administration of the prescribed morning dose of MPH.

    RESULTS: Fifty-nine patients aged between 9 and 69 years, 76 % males. The daily dose of MPH varied from 18 to 180 mg, but the median daily dose per body weight was similar, approximately 1.0 mg/kg body weight. The median MPH concentration in blood 1 and 6 h after the morning dose was 5.4 and 9.3 ng/mL, respectively. Highly variable OF-to-blood ratios for MPH were found at all time points for all three groups.

    CONCLUSIONS: Weight is a reliable clinical parameter for optimal dose titration. Otherwise, MPH blood concentration might be used for individual dose optimization and for monitoring of the prescribed dose. Relying only on the outcome in OF cannot be recommended for evaluation of accurate MPH concentrations for treatment monitoring.

  • 79.
    Chesnaye, Nicholas C.
    et al.
    Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, Netherlands.
    Szummer, Karolina
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Cardiology Huddinge, Karolinska University Hospital, Stockholm, Sweden.
    Bárány, Peter
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Heimbürger, Olof
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Magin, Hasan
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Almquist, Tora
    Division of Nephrology, Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Uhlin, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Centre of Biomedical Engineering, Department of Health Technologies, School of Informatics, Tallinn University of Technology, Tallinn, Estonia.
    Dekker, Friedo W.
    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
    Wanner, Christoph
    Division of Nephrology, University Hospital of Wurzburg, Germany.
    Jager, Kitty J.
    Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, Netherlands.
    Evans, Marie
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients2019In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 8, no 21, article id e013091Article in journal (Refereed)
    Abstract [en]

    Background

    People with reduced glomerular filtration rate (GFR) often have elevated cardiac troponin T (cTnT) levels. It remains unclear how cTnT levels develop over time in those with chronic kidney disease (CKD). The aim of this study was to prospectively study the association between cTnT and GFR over time in older advanced‐stage CKD patients not on dialysis.

    Methods and Results

    The EQUAL (European Quality Study) study is an observational prospective cohort study in stage 4 to 5 CKD patients aged ≥65 years not on dialysis (incident estimated GFR, <20 mL/min/1.73 m²). The EQUAL cohort used for the purpose of this study includes 171 patients followed in Sweden between April 2012 and December 2018. We used linear mixed models, adjusted for important groups of confounders, to investigate the effect of both measured GFR and estimated GFR on high‐sensitivity cTnT (hs‐cTnT) trajectory over 4 years. Almost all patients had at least 1 hs‐cTnT measurement elevated above the 99th percentile of the general reference population (≤14 ng/L). On average, hs‐cTnT increased by 16%/year (95% CI, 13–19; P<0.0001). Each 15 mL/min/1.73 m2 lower mean estimated GFR was associated with a 23% (95% CI, 14–31; P<0.0001) higher baseline hs‐cTnT and 9% (95% CI, 5–13%; P<0.0001) steeper increase in hs‐cTnT. The effect of estimated GFR on hs‐cTnT trajectory was somewhat lower than a previous myocardial infarction (15%), but higher than presence of diabetes mellitus (4%) and male sex (5%).

    Conclusions

    In CKD patients, hs‐cTnT increases over time as renal function decreases. Lower CKD stage (each 15 mL/min/1.73 m2 lower) is independently associated with a steeper hs‐cTnT increase over time in the same range as other established cardiovascular risk factors.

  • 80.
    Chew, Michelle
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Dalesjö, Lina
    Hallands Hosp Halmstad, Sweden.
    Life-threatening ketoacidosis in a lactating woman2018In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 35, no 12, p. 984-986Article in journal (Other academic)
    Abstract [en]

    n/a

  • 81.
    Chew, Michelle
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    Rehn, Marius
    Oslo Univ Hosp, Norway; Norwegian Air Ambulance Fdn, Norway; Univ Stavanger, Norway.
    Olkkola, Klaus T.
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Sverrisson, Kristinn Orn
    Landspitali Univ Hosp, Iceland.
    Yli-Hankala, Arvi
    Tampere Univ Hosp, Finland; Univ Tampere, Finland.
    Moller, Morten Hylander
    Rigshosp, Denmark.
    Clinical practice guideline on prevention of rhabdomyolysis induced acute kidney injury: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine2019In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576Article, review/survey (Refereed)
    Abstract [en]

    The Scandinavian Society of Anaesthesiology and Intensive Care Medicine Clinical Practice Committee endorses the recent DASAIM/DSIT guideline for prevention of rhabdomyolysis-induced acute kidney injury. However, we emphasize the low quality of evidence with only weak recommendations for all interventions, highlighting that further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimates.

  • 82.
    Chew, Michelle S
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Walder, Bernhard
    University Hospital Geneva, Switzerland.
    Improving perioperative outcome: time to update protocols2017In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 34, no 4, p. 185-188Article in journal (Other academic)
    Abstract [en]

    n/a

  • 83.
    Clavarino, Giovanna
    et al.
    Ctr Hosp Univ Grenoble Alpes, France; Univ Grenoble Alpes, France.
    Gauthier, Arnaud
    Ctr Hosp Univ Grenoble Alpes, France.
    Hellmark, Thomas
    Lund Univ, Sweden.
    Carron, Pierre-Louis
    Ctr Hosp Univ Grenoble Alpes, France.
    Giovannini, Diane
    Ctr Hosp Univ Grenoble Alpes, France.
    Colliard, Sophie
    Ctr Hosp Univ Grenoble Alpes, France.
    Dragon-Durey, Marie-Agnes
    Hop Europeen Georges Pompidou, France.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Cesbron, Jean-Yves
    Ctr Hosp Univ Grenoble Alpes, France; Univ Grenoble Alpes, France.
    Dumestre-Perard, Chantal
    Ctr Hosp Univ Grenoble Alpes, France; Univ Grenoble Alpes, France.
    Letter: Routinely used immunoassays do not detect circulating anti-GBM antibodies against native NC1 hexamer and EA epitope of the 3 chain of type IV collagen in EUROPEAN JOURNAL OF IMMUNOLOGY, vol 48, issue 6, pp 1082-10842018In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 48, no 6, p. 1082-1084Article in journal (Other academic)
    Abstract [en]

    n/a

  • 84.
    Coleman, Jamie J.
    et al.
    Univ Birmingham, England; Univ Hosp Birmingham NHS Fdn Trust, England; City Hosp, England.
    Samer, Caroline
    Geneva Univ Hosp HUG, Switzerland.
    Zeitlinger, Markus
    Med Univ Vienna, Austria.
    van Agtmael, Michiel
    Univ Amsterdam, Netherlands.
    Rongen, Gerard A.
    Radboudumc, Netherlands.
    Marquet, Pierre
    Univ Limoges, France.
    Simon, Tabassome
    Pierre and Marie Curie Univ, France.
    Singer, Donald
    11 Chandos St, England.
    Manolopoulos, Vangelis G.
    Democritus Univ Thrace, Greece.
    Böttiger, Ylva
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    The European Association for Clinical Pharmacology and Therapeutics25years young and going strong2019In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 75, no 6, p. 743-750Article in journal (Refereed)
    Abstract [en]

    Clinical pharmacology as a scientific discipline and medical specialty was unarguably born in the twentieth century. Whilst pharmacologythe science behind the treatment of diseasehad been in evolution since at least medieval times, the clinical discipline of pharmacology has had a more recent genesis and rather insidious evolution. During the 1900s, there were some clear father (parent) figures of clinical pharmacology in Europe that emerged and were responsible for the development of the specialty in this continent. This was a time when there were parallel developments in geographically dispersed academic departments (around the globe), during an age of excitement in drug discovery and clinical application of new therapeutic agents. It was the meeting of minds of some of these progenitors of the specialty that led to the development of the European Association for Clinical Pharmacology and Therapeutics (EACPT) 25years ago arising from a working party supported by the World Health Organization in Europe. The EACPT now includes all major national organizations for clinical pharmacology in Europe, representing over 4000 individual professionals interested in clinical pharmacology and therapeutics. The EACPT has a major interest in promoting the safe use of medicines across Europe and internationally and has supported these aims since 1995, through biennial international scientific congresses and summer schools with delegates and presenters from around the world as well as various working group activities. In this article, the current executive committee members of EACPT recall this history, describe the evolution of the association over the last quarter of a century, and provide an update on the activities and ambitions of the association today.

  • 85.
    Comasco, E.
    et al.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Centre for Clinical Research, Uppsala University, Central Hospital, Västerås, Sweden.
    Nordquist, N.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Section of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Leppert, J.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Centre for Clinical Research, Uppsala University, Central Hospital, Västerås, Sweden.
    Oreland, L.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Section of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Alling, C.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Department of Laboratory Medicine, Division of Clinical Chemistry and, Lund University Hospital, Lund, Sweden.
    Nilsson, K.W.
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Box 593, 751 24 Uppsala, Sweden, Centre for Clinical Research, Uppsala University, Central Hospital, Västerås, Sweden.
    Adolescent alcohol consumption: Biomarkers PEth and FAEE in relation to interview and questionnaire data2009In: Journal of Studies on Alcohol and Drugs, ISSN 1937-1888, E-ISSN 1938-4114, Vol. 70, no 5, p. 797-804Article in journal (Refereed)
    Abstract [en]

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

  • 86.
    Cooper, Gail A A
    et al.
    Forensic Medicine and Science, University of Glasgow, Glasgow Scotland.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kintz, Pascal
    X-Pertise Consulting, Oberhausbergen, France.
    Society of Hair Testing guidelines for drug testing in hair2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 218, no 1-3, p. 20-24Article in journal (Refereed)
    Abstract [en]

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

  • 87.
    Coulthard, Sally A
    et al.
    Newcastle University.
    Redfern, Christopher P F
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hall, Andrew G
    Newcastle University.
    Taylor, Gordon A
    Newcastle University.
    Hogarth, Linda A
    Newcastle University.
    Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers2011In: MOLECULAR CANCER THERAPEUTICS, ISSN 1535-7163, Vol. 10, no 3, p. 495-504Article in journal (Refereed)
    Abstract [en]

    The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dG(s)) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP(-)) transfected to express MTAP constitutively (A549-MTAP(+)). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP(-) conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dG(s) incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP.

  • 88.
    D'Arcy, Padraig
    et al.
    Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
    Wang, Xin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
    Linder, Stig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
    Deubiquitinase inhibition as a cancer therapeutic strategy2015In: Pharmacology and Therapeutics, ISSN 0163-7258, E-ISSN 1879-016X, Vol. 147, p. 32-54Article, review/survey (Refereed)
    Abstract [en]

    The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing α,β-unsaturated ketones have indeed been demonstrated to inhibit cellular DUB activity. Inhibition of proteasomal cysteine DUB enzymes (i.e. USP14 and UCHL5) can be predicted to be particularly cytotoxic to cancer cells as it leads to blocking of proteasome function and accumulation of proteasomal substrates. We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity.

  • 89.
    Davids, Mariska
    et al.
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands, .
    Swieringa, Eliane
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Smith, Desirée E C
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
    Smulders, Yvo M
    Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
    Scheffer, Peter G
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands.
    Blom, Henk J
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands.
    Teerlink, Tom
    Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Institute for Cardiovascular Research (ICaR-VU), Amsterdam, The Netherlands.
    Simultaneous determination of asymmetric and symmetric dimethylarginine, l-monomethylarginine, l-arginine, and l-homoarginine in biological samples using stable isotope dilution liquid chromatography tandem mass spectrometry2012In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 900, p. 38-47Article in journal (Refereed)
    Abstract [en]

    Production of the endogenous vasodilator nitric oxide (NO) from l-arginine by NO synthase is modulated by l-homoarginine, l-monomethylargine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Here we report on a stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of these metabolites in plasma, cells and tissues. After addition of the internal standards (D(7)-ADMA, D(4)-l-homoarginine and (13)C(6)-l-arginine), analytes were extracted from the samples using Waters Oasis MCX solid phase extraction cartridges. Butylated analytes were separated isocratically on a Waters XTerra MS C18 column (3.5μm, 3.9mm×100mm) using 600mg/L ammonium formate in water - acetonitrile (95.5:4.5, v/v) containing 0.1vol% formic acid, and subsequently measured on an AB Sciex API 3000 triple quadrupole mass spectrometer. Multiple reaction monitoring in positive mode was used for analyte quantification. Validation was performed in plasma. Calibration lines were linear (r(2)≥0.9979) and lower limits of quantification in plasma were 0.4nM for ADMA and SDMA and 0.8nM for the other analytes. Accuracy (% bias) was <3% except for MMA (<7%), intra-assay precision (expressed as CV) was <3.5%, inter-assay precision <9.6%, and recovery 92.9-103.2% for all analytes. The method showed good correlation (r(2)≥0.9125) with our previously validated HPLC-fluorescence method for measurement in plasma, and was implemented with good performance for measurement of tissue samples. Application of the method revealed the remarkably fast (i.e. within 60min) appearance in plasma of stable isotope-labeled ADMA, SDMA, and MMA during infusion of D(3)-methyl-1-(13)C-methionine in healthy volunteers.

  • 90.
    de Geer, Lina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Engvall, Jan
    Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Oscarsson Tibblin, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Strain echocardiography in septic shock - a comparison with systolic and diastolic function parameters, cardiac biomarkers and outcome2015In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 19, no 1, article id 122Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Myocardial dysfunction is a well-known complication in septic shock but its characteristics and frequency remains elusive. Here, we evaluate global longitudinal peak strain (GLPS) of the left ventricle as a diagnostic and prognostic tool in septic shock.

    METHODS: Fifty adult patients with septic shock admitted to a general intensive care unit were included. Transthoracic echocardiography was performed on the first day, and repeated during and after ICU stay. Laboratory and clinical data and data on outcome were collected daily from admission and up to 7 days, shorter in cases of death or ICU discharge. The correlation of GLPS to left ventricular systolic and diastolic function parameters, cardiac biomarkers and clinical data were compared using Spearman's correlation test and linear regression analysis, and the ability of GLPS to predict outcome was evaluated using a logistic regression model.

    RESULTS: On the day of admission, there was a strong correlation and co-linearity of GLPS to left ventricular ejection fraction (LVEF), mitral annular motion velocity (é) and to amino-terminal pro-brain natriuretic peptide (NT-proBNP) (Spearman's ρ -0.70, -0.53 and 0.54, and R(2) 0.49, 0.20 and 0.24, respectively). In LVEF and NT-proBNP there was a significant improvement during the study period (analysis of variance (ANOVA) with repeated measures, p = 0.05 and p < 0.001, respectively), but not in GLPS, which remained unchanged over time (p = 0.10). GLPS did not correlate to the improvement in clinical characteristics over time, did not differ significantly between survivors and non-survivors (-17.4 (-20.5-(-13.7)) vs. -14.7 (-19.0 - (-10.6)), p = 0.11), and could not predict mortality.

    CONCLUSIONS: GLPS is frequently reduced in septic shock patients, alone or in combination with reduced LVEF and/or é. It correlates with LVEF, é and NT-proBNP, and remains affected over time. GLPS may provide further understanding on the character of myocardial dysfunction in septic shock.

  • 91.
    de Geer, Lina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Oscarsson, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Engvall, Jan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Variability in echocardiographic measurements of left ventricular function in septic shock patients2015In: Cardiovascular Ultrasound, ISSN 1476-7120, E-ISSN 1476-7120, Vol. 13, no 1, p. 19-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Echocardiography is increasingly used for haemodynamic evaluation and titration of therapy in intensive care, warranting reliable and reproducible measurements. The aim of this study was to evaluate the observer dependence of echocardiographic findings of left ventricular (LV) diastolic and systolic dysfunction in patients with septic shock.

    METHODS: Echocardiograms performed in 47 adult patients admitted with septic shock to a general intensive care unit (ICU) were independently evaluated by one cardiologist and one intensivist for the following signs: decreased diastolic tissue velocity of the base of the LV septum (e), increased early mitral inflow (E) to e ratio (E/e), decreased LV ejection fraction (EF) and decreased LV global longitudinal peak strain (GLPS). Diastolic dysfunction was defined as e <8.0cm/s and/or E/e [greater than or equal to]15 and systolic dysfunction as EF <50% and/or GLPS>15%. Ten randomly selected examinations were re-analysed two months later. Pearson’s r was used to test the correlation and Bland-Altman plots to assess the agreement between observers. Kappa statistics were used to test the consistency between readers and intraclass correlation coefficients (ICC) for inter- and intraobserver variability.

    RESULTS: In 44 patients (94%), image quality was sufficient for echocardiographic measurements. The agreement between observers was moderate (k=0.60 for e, k=0.50 for E/e and k=0.60 for EF) to good (k=0.71 for GLPS). Pearson’s r was 0.76 for e, 0.85 for E/e, 0.78 for EF and 0.84 for GLPS (p<0.001 for all four). The ICC between observers for e was very good (0.85; 95% confidence interval (CI) 0.73-0.92), good for E/e (0.70; 95% CI 0.45 - 0.84), very good for EF (0.87; 95% CI 0.77 - 0.93), excellent for GLPS (0.91; 95% CI 0.74 - 0.95), and very good for all measures repeated by one of the observers. On Bland-Altman analysis, the mean differences and 95% limits of agreement for e, E/e, EF and GLPS were 0.01 (0.04 - 0.07), 2.0 (14.2 - 18.1), 0.86 (16 - 14.3) and 0.04 (5.04 - 5.12), respectively.

    CONCLUSIONS: Moderate observer-related differences in assessing LV dysfunction were seen. GLPS is the least user dependent and most reproducible echocardiographic measurement of LV function in septic shock.

  • 92.
    de Geer, Lina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Oscarsson, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Gustafsson, Mikael
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Lung ultrasound in quantifying lung water in septic shock patients2015In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 19, no 1, p. 140-Article in journal (Refereed)
    Abstract [en]

    Quantification of lung ultrasound (LUS) artifacts (B-lines) is used to assess pulmonary congestion in emergency medicine and cardiology [1,2]. We investigated B-lines in relation to extravascular lung-water index (EVLWI) from invasive transpulmonary thermodilution in septic shock patients. Our aim was to evaluate the role of LUS in an intensive care setting.

  • 93.
    de Geer, Lina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Oscarsson Tibblin, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Walther, Sten M.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    No association with cardiac death after sepsis: A nationwide observational cohort study2019In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 63, no 3, p. 344-351Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cardiac dysfunction is a well-known complication of sepsis, but its long-term consequences and implications for patients remain unclear. The aim of this study was to investigate cardiac outcome in sepsis by assessing causes of death up to 2 years after treatment in an Intensive Care Unit (ICU) in a nationwide register-based cohort collected from the Swedish Intensive Care Registry.

    METHODS: A cohort of 13 669 sepsis and septic shock ICU patients from 2008 to 2014 was collected together with a non-septic control group, matched regarding age, sex and severity of illness (n = 6582), and all without preceding severe cardiac disease. For a large proportion of the severe sepsis and septic shock patients (n = 7087), no matches were found. Information on causes of death up to 2 years after ICU admission was sought in the Swedish National Board of Health and Welfare's Cause of Death Registry.

    RESULTS: Intensive Care Unit mortality was nearly identical in a matched comparison of sepsis patients to controls (24% in both groups) but higher in more severely ill sepsis patients for whom no matches were found (33% vs 24%, P < 0.001). There was no association of sepsis to cardiac deaths in the first month (OR 1.03, 95%CI 0.87 to 1.20, P = 0.76) nor up to 2 years after ICU admission (OR 1.01, 95%CI 0.82 to 1.25, P = 0.94) in an adjusted between-group comparison.

    CONCLUSIONS: There was no association with an increased risk of death related to cardiac disease in patients with severe sepsis or septic shock when compared to other ICU patients with similar severity of illness.

  • 94.
    De Hert, Stefan
    et al.
    Univ Ghent, Belgium.
    Staender, Sven
    Reg Hosp Mannedorf Zurich, Switzerland; Paracelsus Med Univ Salzburg, Austria.
    Fritsch, Gerhard
    Paracelsus Med Univ Salzburg, Austria; AUVA Traumactr Vienna, Austria.
    Hinkelbein, Jochen
    Univ Hosp Cologne, Germany.
    Afshari, Arash
    Univ Copenhagen, Denmark.
    Bettelli, Gabriella
    Univ San Marino, San Marino.
    Bock, Matthias
    Paracelsus Med Univ Salzburg, Austria; Merano Hosp Franz Tappeiner, Italy.
    Chew, Michelle
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Coburn, Mark
    Rhein Westfal TH Aachen, Germany.
    De Robertis, Edoardo
    Univ Naples Federico II, Italy.
    Drinhaus, Hendrik
    Univ Hosp Cologne, Germany.
    Feldheiser, Aarne
    Charite Univ Med Berlin, Germany.
    Geldner, Gotz
    RKH Klinikum Ludwigsburg, Germany.
    Lahner, Daniel
    AUVA Traumactr Vienna, Austria; Ludwig Boltzmann Inst Expt and Clin Traumatol, Austria.
    Macas, Andrius
    Lithuanian Univ Hlth Sci, Lithuania.
    Neuhaus, Christopher
    Univ Hosp Heidelberg, Germany.
    Rauch, Simon
    Merano Hosp Franz Tappeiner, Italy; EURAC Res, Italy.
    Santos-Ampuero, Maria Angeles
    Hosp Schwyz, Switzerland.
    Solca, Maurizio
    Danube Univ Krems, Austria.
    Tanha, Nima
    Not Found:Linkoping Univ, Linkoping Univ Hosp, Dept Anaesthesia and Intens Care, Linkoping, Sweden; Linkoping Univ, Linkoping Univ Hosp, Dept Med and Hlth Sci, Linkoping, Sweden.
    Traskaite, Vilma
    Lithuanian Univ Hlth Sci, Lithuania.
    Wagner, Gernot
    Danube Univ Krems, Austria.
    Wappler, Frank
    Univ Witten Herdecke, Germany.
    Pre-operative evaluation of adults undergoing elective noncardiac surgery Updated guideline from the European Society of Anaesthesiology2018In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 35, no 6, p. 407-465Article in journal (Refereed)
    Abstract [en]

    The purpose of this update of the European Society of Anaesthesiology (ESA) guidelines on the pre-operative evaluation of the adult undergoing noncardiac surgery is to present recommendations based on the available relevant clinical evidence. Well performed randomised studies on the topic are limited and therefore many recommendations rely to a large extent on expert opinion and may need to be adapted specifically to the healthcare systems of individual countries. This article aims to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthesiologists all over Europe to integrate - wherever possible - this knowledge into daily patient care. The Guidelines Committee of the ESA formed a task force comprising members of the previous task force, members of ESA scientific subcommittees and an open call for volunteers was made to all individual active members of the ESA and national societies. Electronic databases were searched from July 2010 (end of the literature search of the previous ESA guidelines on pre-operative evaluation) to May 2016 without language restrictions. A total of 34066 abtracts were screened from which 2536 were included for further analysis. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the level of evidence and to grade recommendations. The final draft guideline was posted on the ESA website for 4 weeks and the link was sent to all ESA members, individual or national (thus including most European national anaesthesia societies). Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

  • 95.
    Dessap, Armand Mekontso
    et al.
    Hop Univ Henri Mondor, France; Univ Paris Est Creteil, France.
    Chew, Michelle
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Cardiac tamponade2018In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 44, no 6, p. 936-939Article in journal (Other academic)
    Abstract [en]

    n/a

  • 96.
    Dhanani, Jayesh A
    et al.
    Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia. jadhanani@hotmail.com; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia. jadhanani@hotmail.com; Critical Care Research Group, The University of Queensland, Brisbane, Australia.
    Cohen, Jeremy
    Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia.
    Parker, Suzanne L
    Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia.
    Chan, Hak-Kim
    Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
    Tang, Patricia
    Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
    Ahern, Benjamin J
    Faculty of Science, School of Veterinary Science, The University of Queensland, Gatton, Australia.
    Khan, Adeel
    Faculty of Science, School of Veterinary Science, The University of Queensland, Gatton, Australia.
    Bhatt, Manoj
    Department of Nuclear Medicine and Specialised PET Services Queensland, Royal Brisbane and Womens Hospital, Herston, Queensland, Australia; School of Medicine, Faculty of Health Sciences, University of Queensland, St Lucia, Queensland, Australia.
    Goodman, Steven
    Department of Nuclear Medicine and Specialised PET Services Queensland, Royal Brisbane and Womens Hospital, Herston, Queensland, Australia.
    Diab, Sara
    Critical Care Research Group, The University of Queensland, Brisbane, Australia.
    Chaudhary, Jivesh
    Critical Care Research Group, The University of Queensland, Brisbane, Australia.
    Lipman, Jeffrey
    Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia; Faculty of Health, Queensland University of Technology, Brisbane, Australia.
    Wallis, Steven C
    Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia.
    Barnett, Adrian
    Institute of Health and Biomedical Innovation and School of Public Health and Social Work, Queensland University of Technology, Kelvin Grove, Brisbane, Australia.
    Chew, Michelle S
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Fraser, John F
    Critical Care Research Group, The University of Queensland, Brisbane, Australia.
    Roberts, Jason A
    Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia; Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia; Department of Pharmacy, Royal Brisbane and Womens Hospital, Brisbane, Australia.
    A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models2018In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 6, no 1, article id 17Article in journal (Refereed)
    Abstract [en]

    Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic.

  • 97.
    Dhanani, Jayesh A.
    et al.
    Univ Queensland, Australia; Royal Brisbane and Womens Hosp, Australia.
    Diab, Sara
    Univ Queensland, Australia.
    Chaudhary, Jivesh
    Univ Queensland, Australia.
    Cohen, Jeremy
    Univ Queensland, Australia; Royal Brisbane and Womens Hosp, Australia.
    Parker, Suzanne L.
    Univ Queensland, Australia.
    Wallis, Steven C.
    Univ Queensland, Australia.
    Boidin, Clement
    Univ Queensland, Australia; Civil Hosp Lyon, France; Claude Bernard Univ Lyon 1, France.
    Barnett, Adrian
    Queensland Univ Technol, Australia; Queensland Univ Technol, Australia.
    Chew, Michelle
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    Roberts, Jason A.
    Univ Queensland, Australia; Royal Brisbane and Womens Hosp, Australia; Royal Brisbane and Womens Hosp, Australia.
    Fraser, John F.
    Univ Queensland, Australia.
    Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model2019In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 131, no 2, p. 344-355Article in journal (Refereed)
    Abstract [en]

    Editors PerspectiveWhat We Already Know about This Topic For most bacterial pneumonia, the lung interstitium is considered to be the site of infection, and adequate antibiotic concentrations are important for drug effect Despite systemic antibiotic therapy, therapeutic failure is common, perhaps due to poor lung penetration, and resulting low interstitial space fluid antibiotic concentrations Increasing systemic antibiotic doses in order to increase interstitial space fluid antibiotic concentrations could lead to toxicities such as nephrotoxicity What This Article Tells Us That Is New In a mechanically ventilated healthy large animal model, nebulized tobramycin produced higher peak lung interstitial space fluid concentrations, as well as higher initial epithelial lining fluid concentrations, with lower plasma concentrations than were observed after intravenous administration due to more extensive lung penetration Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. Results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P amp;lt; 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P amp;lt; 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P amp;lt; 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P amp;lt; 0.001). Conclusions: Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.

  • 98.
    Dhanani, Jayesh A
    et al.
    Burns, Trauma and Critical Care Research Centre, The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD 4029, Australia; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia.
    Parker, Suzanne L
    Burns, Trauma and Critical Care Research Centre, The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD 4029, Australia.
    Lipman, Jeffrey
    Burns, Trauma and Critical Care Research Centre, The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD 4029, Australia; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia; Faculty of Health, Queensland University of Technology, Brisbane, Australia.
    Wallis, Steven C
    Burns, Trauma and Critical Care Research Centre, The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD 4029, Australia.
    Cohen, Jeremy
    Burns, Trauma and Critical Care Research Centre, The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD 4029, Australia; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia.
    Fraser, John
    Critical Care Research Group, The University of Queensland, Brisbane, Australia.
    Barnett, Adrian
    Institute of Health and Biomedical Innovation and School of Public Health and Social Work, Queensland University of Technology, Kelvin Grove, Brisbane, Australia.
    Chew, Michelle S
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Roberts, Jason A
    Burns, Trauma and Critical Care Research Centre, The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD 4029, Australia; Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Brisbane, Australia; School of Pharmacy, The University of Queensland, Brisbane, Australia; Department of Pharmacy, Royal Brisbane and Womens Hospital, Brisbane, Australia.
    Recovery rates of combination antibiotic therapy using in vitro microdialysis simulating in vivo conditions2018In: Journal of pharmaceutical analysis, ISSN 2214-0883, Vol. 8, no 6, p. 407-412Article in journal (Refereed)
    Abstract [en]

    Microdialysis is a technique used to measure the unbound antibiotic concentration in the interstitial spaces, the target site of action. In vitro recovery studies are essential to calibrating the microdialysis system for in vivo studies. The effect of a combination of antibiotics on recovery into microdialysate requires investigation. In vitro microdialysis recovery studies were conducted on a combination of vancomycin and tobramycin, in a simulated in vivo model. Comparison was made between recoveries for three different concentrations and three different perfusate flow rates. The overall relative recovery for vancomycin was lower than that of tobramycin. For tobramycin, a concentration of 20µg/mL and flow rate of 1.0µL/min had the best recovery. A concentration of 5.0µg/mL and flow rate of 1.0µL/min yielded maximal recovery for vancomycin. Large molecular size and higher protein binding resulted in lower relative recoveries for vancomycin. Perfusate flow rates and drug concentrations affected the relative recovery when a combination of vancomycin and tobramycin was tested. Low perfusate flow rates were associated with higher recovery rates. For combination antibiotic measurement which includes agents that are highly protein bound, in vitro studies performed prior to in vivo studies may ensure the reliable measurement of unbound concentrations.

  • 99.
    Di Gennaro, Antonio
    et al.
    Karolinska Inst, Sweden.
    Araujo, Ana Carolina
    Karolinska Inst, Sweden.
    Busch, Albert
    Karolinska Inst, Sweden; Tech Univ Munich, Germany.
    Jin, Hong
    Karolinska Inst, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Caidahl, Kenneth
    Karolinska Inst, Sweden; Gothenburg Univ, Sweden.
    Eriksson, Per
    Karolinska Inst, Sweden.
    Samuelsson, Bengt
    Karolinska Inst, Sweden.
    Maegdefessel, Lars
    Karolinska Inst, Sweden; Tech Univ Munich, Germany.
    Haeggstrom, Jesper Z.
    Karolinska Inst, Sweden.
    Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 8, p. 1907-1912Article in journal (Refereed)
    Abstract [en]

    Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (amp;gt;50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.

  • 100.
    Diao, Xingxing
    et al.
    NIDA, MD 21224 USA.
    Carlier, Jeremy
    NIDA, MD 21224 USA.
    Zhu, Mingshe
    Bristol Myers Squibb, NJ 08543 USA.
    Pang, Shaokun
    SCIEX Ltd, CA 94065 USA.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Scheidweiler, Karl B.
    NIDA, MD 21224 USA.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA; University of Maryland, MD 21224 USA.
    In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)2017In: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 35, no 1, p. 20-32Article in journal (Refereed)
    Abstract [en]

    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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