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  • 1.
    Andersson, Maria
    et al.
    NIDA, MD 21224 USA.
    Diao, Xingxing
    NIDA, MD 21224 USA.
    Wohlfarth, Ariane
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. NIDA, MD 21224 USA; 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.
    Metabolic profiling of new synthetic cannabinoids AMB and 5F-AMB by human hepatocyte and liver microsome incubations and high-resolution mass spectrometry2016Inngår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, nr 8, s. 1067-1078Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RationaleAMB (methyl (1-pentyl-1H-indazole-3-carbonyl)-L-valinate)) and its fluoro analog 5F-AMB (methyl (1-(5-fluoropentyl)-1H-indazole-3-carbonyl)-L-valinate) are two new synthetic cannabinoids that are structural analogs of AB-PINACA and 5F-AB-PINACA, respectively. 5F-AMB is scheduled as an illicit drug in China, Germany, Singapore and Japan, and no metabolism data are currently available for either drug. The aim of the present work was to investigate the metabolism of AMB and 5F-AMB and propose appropriate markers to identify their intake in clinical or forensic cases. MethodsAMB and 5F-AMB were incubated in human hepatocytes (10 mol/L) to generate phase I and II metabolites, which were identified with a TripleTOF 5600(+) high-resolution mass spectrometer. AMB and 5F-AMB metabolic stability studies also were performed with human liver microsomes (HLM) to evaluate metabolic clearances, and to adequately design the human hepatocyte experiment. ResultsAMB and 5F-AMB were quickly metabolized in HLM with a 1.1 0.1 and 1.0 +/- 0.2min T-1/2, respectively. The predominant metabolic pathway for AMB and 5F-AMB in hepatocytes was ester hydrolysis, and further oxidation and/or glucuronidation. In total, 19 metabolites were identified for AMB and 17 for 5F-AMB. We describe metabolites to differentiate AMB from 5F-AMB, and metabolites that are common to both analytes due to oxidative defluorination of 5F-AMB. ConclusionsFor the first time, AMB and 5F-AMB metabolism profiles were characterized, providing valuable data for identifying these two novel psychoactive substances. The difficulties of differentiating AMB and 5F-AMB from AB-PINACA/5F-AB-PINACA metabolites also were examined. These data improve the interpretation of urinary markers after AMB and 5F-AMB intake. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA

  • 2.
    Arup, Ulf
    et al.
    Botanical Museum, Lund University, Lund, Sweden.
    Ekman, Stefan
    Museum of Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
    Fröberg, Lars
    Frödén, Patrik
    n/a.
    Knutsson, Tommy
    Lättman, Håkan
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Lindblom, Louise
    Department of Biology & Museum of Natural History, University of Bergen, Bergen, Norway..
    Mattsson, Jan-Eric
    School of Life Sciences, Södertörn University, Huddinge, Sweden.
    Thell, Arne
    The Biological Museums, Lund University, Lund, Sweden.
    Westberg, Martin
    Swedish Museum of Natural History, Cryptogamic Botany, Stockholm, Sweden.
    Professor Ingvar Kärnfelt - a birthday tribute2009Inngår i: The Lichenologist, ISSN 0024-2829, E-ISSN 1096-1135, Vol. 41, nr 5, s. 453-456Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    On 19 July 2009 Ingvar Kärnefelt celebrated his 65th birthday. This could have meant that we, his former students, would be celebrating him in his retirement from his position as head of the Biological Museums at Lund University. We are grateful that this is not the case, as Ingvar will carry on, probably for at least one or two more years. Instead, we celebrate Ingvar because he is the main reason for all of us having studied lichenology in Lund. This special issue of The Lichenologist is dedicated to him as a birthday tribute in honour of his long and fruitful lichenological career. The main authors of all the papers in this issue are former students of Ingvar. For several of us he has not only acted as supervisor but later also as the director of the Botanical Museum where we meet him in our daily work.

  • 3.
    Aziz, Abdul Maruf Asif
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.

    The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.

    In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced “hangover” anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats.  Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.

    In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.

    In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for motivation to work for alcohol and reinstatement of alcohol-seeking behavior. Treatment with CYM-9840 (10 mg/kg) potently attenuated alcohol SA, progressive ratio responding and stress-induced reinstatement using yohimbine as the stressor, while alcohol cue-induced reinstatement was unaffected. Moreover, a range of control behaviors including taste sensitivity, locomotor and pharmacological sensitivity to the sedative effects of alcohol remained unaffected by CYM-9840 pretreatment, indicating that its effects are specific to the rewarding and motivational aspects of alcohol-intake and related behaviors. CYM-9840 also reversed acute alcohol withdrawal-induced “hangover” anxiety measured in the EPM and reduced alcohol-intake in the 4 hour limited access two-bottle free choice preference drinking model.

    Finally, in the fourth study (Paper IV), the selective MCH1-R antagonist GW803430 was tested in rat models of escalated alcohol-intake. Pretreatment with GW803430 (effective at 10 & 30 mg/kg) dose-dependently reduced alcohol and food-intake in rats that consumed high amounts of alcohol during IA, while it only decreased food-intake in rats that consumed low amounts of alcohol during IA, likely due to a floor effect. Upon protracted abstinence following IA, GW803430 significantly reduced operant alcohol SA and this was associated with adaptations in MCH and MCH1-R gene-expression. In contrast, GW803430 did not affect escalated alcohol SA induced by chronic alcohol vapor exposure and this was accompanied by no change in MCH or MCH1-R gene expression. Overall, these results suggest that the MCH1-R antagonist affects alcohol-intake through regulation of both motivation for caloric-intake and the rewarding properties of alcohol.

    In conclusion, our results suggest critical roles for these central neuropeptides in the regulation of anxiety and of alcohol reward, making them potential pharmacological targets in the treatment of AUD.

    Delarbeid
    1. The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Åpne denne publikasjonen i ny fane eller vindu >>The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Vise andre…
    2016 (engelsk)Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, nr 19-20, s. 3553-3563Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

    OBJECTIVES: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

    RESULTS: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

    CONCLUSION: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

    sted, utgiver, år, opplag, sider
    Springer, 2016
    Emneord
    Nociception/orphanin FQ, Agonist, Wistar rat, Alcohol, Operant, Reinstatement, Elevated plus-maze
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-132347 (URN)10.1007/s00213-016-4385-8 (DOI)000383672500006 ()27515665 (PubMedID)
    Merknad

    Funding Agencies|National Institutes of Health [R01-DA035055]; Swedish Research Council [2010-3219]

    Tilgjengelig fra: 2016-11-12 Laget: 2016-11-01 Sist oppdatert: 2017-08-21bibliografisk kontrollert
    2. Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Åpne denne publikasjonen i ny fane eller vindu >>Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Vise andre…
    2016 (engelsk)Inngår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, nr 10, s. 2199-2207Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Reward and energy homeostasis are both regulated by a network of hypothalamic neuropeptide systems. The melanin-concentrating hormone (MCH) and its MCH-1 receptor (MCH1-R) modulate alcohol intake, but it remains unknown to what extent this reflects actions on energy balance or reward. Here, we evaluated the MCH1-R in regulation of caloric intake and motivation to consume alcohol in states of escalated consumption.

    Methods: Rats had intermittent access (IA) to alcohol and were divided into high- and low-drinking groups. Food and alcohol consumption was assessed after administration of an MCH1-R antagonist, GW803430. Next, GW803430 was evaluated on alcohol self-administration in protracted abstinence induced by IA in high-drinking rats. Finally, the effect of GW803430 was assessed on alcohol self-administration in acute withdrawal in rats exposed to alcohol vapor. Gene expression of MCH and MCH1-R was measured in the hypothalamus and nucleus accumbens (NAc) in both acute and protracted abstinence.

    Results: High-drinking IA rats consumed more calories from alcohol than chow and GW803430 decreased both chow and alcohol intake. In low-drinking rats, only food intake was affected. In protracted abstinence from IA, alcohol self-administration was significantly reduced by pretreatment with GW803430 and gene expression of both MCH and the MCH1-R were dysregulated in hypothalamus and NAc. In contrast, during acute withdrawal from vapor exposure, treatment with GW803430 did not affect alcohol self-administration, and no changes in MCH or MCH1-R gene expression were observed.

    Conclusions: Our data suggest a dual role of MCH and the MCH1-R in regulation of alcohol intake, possibly through mechanisms involving caloric intake and reward motivation. A selective suppression of alcohol self-administration during protracted abstinence by GW803430 was observed and accompanied by adaptations in gene expression of MCH and MCH1-R. Selective suppression of escalated consumption renders the MCH1-R an attractive target for treatment of alcohol use disorders.

    sted, utgiver, år, opplag, sider
    Wiley-Blackwell, 2016
    Emneord
    Alcohol Escalation, Reward, Motivation, Calorie Intake, Melanin-Concentrating Hormone Receptor-1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-132522 (URN)10.1111/acer.13181 (DOI)000385542900017 ()27579857 (PubMedID)
    Tilgjengelig fra: 2016-11-14 Laget: 2016-11-13 Sist oppdatert: 2018-03-19bibliografisk kontrollert
  • 4.
    Bandyopadhyay, Souvik K.
    et al.
    GlaxoSmithKline Asia Pvt. Ltd., Bangalore, India.
    Azharuddin, Mohammad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten.
    Dasgupta, Anjan K.
    Department of Biochemistry, University of Calcutta, Kolkata, India.
    Ganguli, Bhaswati
    Department of Statistics, University of Calcutta, Kolkata, India.
    SenRoy, Sugata
    Department of Statistics, University of Calcutta, Kolkata, India.
    Patra, Hirak Kumar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Wolfson College, University of Cambridge, Cambridge, United Kingdom; Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom.
    Deb, Suryyani
    Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, Kolkata, India.
    Probing ADP Induced Aggregation Kinetics During Platelet-Nanoparticle Interactions: Functional Dynamics Analysis to Rationalize Safety and Benefits2019Inngår i: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 7, s. 163-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Platelets, one of the most sensitive blood cells, can be activated by a range of external and internal stimuli including physical, chemical, physiological, and/or non-physiological agents. Platelets need to respond promptly during injury to maintain blood hemostasis. The time profile of platelet aggregation is very complex, especially in the presence of the agonist adenosine 5′-diphosphate (ADP), and it is difficult to probe such complexity using traditional linear dose response models. In the present study, we explored functional analysis techniques to characterize the pattern of platelet aggregation over time in response to nanoparticle induced perturbations. This has obviated the need to represent the pattern of aggregation by a single summary measure and allowed us to treat the entire aggregation profile over time, as the response. The modeling was performed in a flexible manner, without any imposition of shape restrictions on the curve, allowing smooth platelet aggregation over time. The use of a probabilistic framework not only allowed statistical prediction and inference of the aggregation signatures, but also provided a novel method for the estimation of higher order derivatives of the curve, thereby allowing plausible estimation of the extent and rate of platelet aggregation kinetics over time. In the present study, we focused on the estimated first derivative of the curve, obtained from the platelet optical aggregometric profile over time and used it to discern the underlying kinetics as well as to study the effects of ADP dosage and perturbation with gold nanoparticles. In addition, our method allowed the quantification of the extent of inter-individual signature variations. Our findings indicated several hidden features and showed a mixture of zero and first order kinetics interrupted by a metastable zero order ADP dose dependent process. In addition, we showed that the two first order kinetic constants were ADP dependent. However, we were able to perturb the overall kinetic pattern using gold nanoparticles, which resulted in autocatalytic aggregation with a higher aggregate mass and which facilitated the aggregation rate.

  • 5.
    Banerjee, Debarshi
    et al.
    Columbia University Medical Center, USA.
    Cieslar-Pobuda, Artur
    University of Oslo, Norway.
    Zhu, Geyunjian Harry
    University of Cambridge, UK.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Patra, Hirak
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Chemical Engineering and Biotechnology, University of Cambridge, UK; Wolfson College, University of Cambridge, UK.
    Adding nanotechnology to the metastasis treatment arsenal2019Inngår i: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 40, nr 6, s. 403-418Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Metastasis is a major cause of cancer-related mortality, accounting for 90% of cancer deaths. The explosive growth of cancer biology research has revealed new mechanistic network information and pathways that promote metastasis. Consequently, a large number of antitumor agents have been developed and tested for their antimetastatic efficacy. Despite their exciting cytotoxic effects on tumor cells in vitro and antitumor activities in preclinical studies in vivo, only a few have shown potent antimetastatic activities in clinical trials. In this review, we provide a brief overview of current antimetastatic strategies that show clinical efficacy and review nanotechnology-based approaches that are currently being incorporated into these therapies to mitigate challenges associated with treating cancer metastasis.

    Fulltekst tilgjengelig fra 2020-05-07 12:06
  • 6.
    Björck, Åke
    et al.
    Linköpings universitet, Matematiska institutionen, Beräkningsmatematik. Linköpings universitet, Tekniska fakulteten.
    Indahl, Ulf G.
    Norwegian University of Life Science, Norway.
    Fast and stable partial least squares modelling: A benchmark study with theoretical comments2017Inngår i: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 31, nr 8, artikkel-id e2898Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Algorithms for partial least squares (PLS) modelling are placed into a sound theoretical context focusing on numerical precision and computational efficiency. NIPALS and other PLS algorithms that perform deflation steps of the predictors (X) may be slow or even computationally infeasible for sparse and/or large-scale data sets. As alternatives, we develop new versions of the Bidiag1 and Bidiag2 algorithms. These include full reorthogonalization of both score and loading vectors, which we consider to be both necessary and sufficient for numerical precision. Using a collection of benchmark data sets, these 2 new algorithms are compared to the NIPALS PLS and 4 other PLS algorithms acknowledged in the chemometrics literature. The provably stable Householder algorithm for PLS regression is taken as the reference method for numerical precision. Our conclusion is that our new Bidiag1 and Bidiag2 algorithms are themethods of choice for problems where both efficiency and numerical precision are important. When efficiency is not urgent, the NIPALS PLS and the Householder PLS are also good choices. The benchmark study shows that SIMPLS gives poor numerical precision even for a small number of factors. Further, the nonorthogonal scores PLS, direct scores PLS, and the improved kernel PLS are demonstrated to be numerically less stable than the best algorithms. PrototypeMATLAB codes are included for the 5 PLS algorithms concluded to be numerically stable on our benchmark data sets. Other aspects of PLS modelling, such as the evaluation of the regression coefficients, are also analyzed using techniques from numerical linear algebra.

  • 7.
    Björkman, Martin
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Maskinkonstruktion.
    Cost analysis of robot families2010Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    During the last decades, the production enterprises have gone through a strong global change in terms of shorter product life cycles, fluctuations in the order income and increased demand of customized products. Basically, a company needs to develop appealing products in terms of cost and quality that are brought to the market in timely manner. As many studies show that over 70% of the total life cycle cost of a product is determined at the early design stage, this thesis work are focused on analyzing how the total cost of robot families can be affected in the early design stage through changing the component commonality level. More specifically, a cost estimation model in excel has been built to see how the total costs of robot family IRB 6640 are affected when choosing different gears for joints one, two and three. Also, a more general analysis has been done where it is investigated how ABB can take benefit of a product configuration system integrated with a robot platform and cost estimation model.The result of this study shows that the traditional opinion on “higher commonality means lower costs” is not applicable in all cases. For instance, considering the commonality of gears within a robot family, the optimal solution out of a cost perspective do no longer exists at the highest commonality possible but at a slightly lower commonality level, lying between 0,7<CI<0,9 using the measurement commonality index (CI). This is because the gears tend to be over dimensioned, and thereby more expensive for certain joints when commonality increases. The analysis also shows that fix and variable costs are not linear to each other, which complicates the situation when trying to describe the change of total costs with one commonality index. Consequently, two different commonality indices are needed: CI to describe the fix costs and CIC (component part commonality index) to describe the variable costs.

  • 8.
    Busardò, Francesco Paolo
    et al.
    a Department of Anatomical, Histological, Forensic and Orthopaedic Sciences , Sapienza University of Rome , Rome , Italy.
    Jones, A Wayne
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Interpreting γ-hydroxybutyrate concentrations for clinical and forensic purposes2019Inngår i: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 57, nr 3, s. 149-163Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9.
    Bäck, Marcus
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    LeVine, Harry III
    University of Kentucky, KY 40536 USA.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Anionic Oligothiophenes Compete for Binding of X-34 but not PIB to Recombinant A beta Amyloid Fibrils and Alzheimers Disease Brain-Derived A beta2016Inngår i: CHEMISTRY-A EUROPEAN JOURNAL, ISSN 0947-6539, Vol. 22, nr 51, s. 18335-18338Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deposits comprised of amyloid- (A) are one of the pathological hallmarks of Alzheimers disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for the diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X-34, a Congo Red analogue, but not Pittsburgh compoundB (PIB) from recombinant A amyloid fibrils and Alzheimers disease brain-derived A. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high-affinity ligands for A pathology only found in human AD brain, targeting a different site than PIB.

  • 10.
    Carlier, Jeremy
    et al.
    NIDA, MD 21224 USA.
    Diao, Xingxing
    NIDA, MD 21224 USA.
    Wohlfarth, Ariane
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. 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 Cannabinoid2017Inngår i: Current Neuropharmacology, ISSN 1570-159X, E-ISSN 1875-6190, Vol. 15, nr 5, s. 682-691Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 11.
    Carlsson, Andreas
    et al.
    Swedish National Forens Centre NFC, SE-58194 Linkoping, Sweden.
    Lindberg, Sandra
    Swedish Def Research Agency, Sweden.
    Wu, Xiongyu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Dunne, Simon
    Swedish National Forens Centre NFC, SE-58194 Linkoping, Sweden.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden.
    Astot, Crister
    Swedish Def Research Agency, Sweden.
    Dahlén, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Prediction of designer drugs: synthesis and spectroscopic analysis of synthetic cannabinoid analogues of 1H-indol-3-yl(2,2,3,3-tetramethylcyclopropyl) methanone and 1H-indol-3-yl(adamantan-1-yl)methanone2016Inngår i: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 8, nr 10, s. 1015-1029Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this work, emergence patterns of synthetic cannabinoids were utilized in an attempt to predict those that may appear on the drug market in the future. Based on this information, two base structures of the synthetic cannabinoid analogues - (1H-indol-3-yl (2,2,3,3-tetramethylcyclopropyl) methanone and 1H-indol-3-yl(adamantan-1-yl)methanone) - together with three substituents butyl, 4-fluorobutyl and ethyl tetrahydropyran - were selected for synthesis. This resulted in a total of six synthetic cannabinoid analogues that to the authors knowledge have not yet appeared on the drug market. Spectroscopic data, including nuclearmagnetic resonance (NMR), mass spectrometry (MS), and Fourier transforminfrared (FTIR) spectroscopy (solid and gas phase), are presented for the synthesized analogues and some additional related cannabinoids. In this context, the suitability of the employed techniques for the identification of unknowns is discussed and the use of GC-FTIR as a secondary complementary technique to GC-MS is addressed. Examples of compounds that are difficult to differentiate by their mass spectra, but can be distinguished based upon their gas phase FTIR spectra are presented. Conversely, structural homologueswhere mass spectra aremore powerful than gas phase FTIR spectra for unambiguous assignments are also exemplified. This work further emphasizes that a combination of several techniques is the key to success in structural elucidations. Copyright (C) 2015 John Wiley amp; Sons, Ltd.

  • 12.
    Carlsson, Andreas
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Swedish Natl Forens Ctr NFC, SE-58194 Linkoping, Sweden.
    Sandgren, Veronica
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Svensson, Stefan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Konradsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Dunne, Simon
    Swedish Natl Forens Ctr NFC, SE-58194 Linkoping, Sweden.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Dahlén, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Prediction of designer drugs: Synthesis and spectroscopic analysis of synthetic cathinone analogs that may appear on the Swedish drug market2018Inngår i: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 10, nr 7, s. 1076-1098Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The use of hyphenated analytical techniques in forensic drug screening enables simultaneous identification of a wide range of different compounds. However, the appearance of drug seizures containing new substances, mainly new psychoactive substances (NPS), is steadily increasing. These new and other already known substances often possess structural similarities and consequently they exhibit spectral data with slight differences. This situation has made the criteria that ensure indubitable identification of compounds increasingly important. In this work, 6 new synthetic cathinones that have not yet appeared in any Swedish drug seizures were synthesized. Their chemical structures were similar to those of already known cathinone analogs of which 42 were also included in the study. Hence, a total of 48 synthetic cathinones making up sets of homologous and regioisomeric compounds were used to challenge the capabilities of various analytical techniques commonly applied in forensic drug screening, ie, gas chromatography-mass spectrometry (GC-MS), gas chromatography-Fourier transform infrared spectroscopy (GC-FTIR), nuclear magnetic resonance (NMR), and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Special attention was paid to the capabilities of GC-MS and GC-FTIR to distinguish between the synthetic cathinones and the results showed that neither GC-MS nor GC-FTIR alone can successfully differentiate between all synthetic cathinones. However, the 2 techniques proved to be complementary and their combined use is therefore beneficial. For example, the structural homologs were better differentiated by GC-MS, while GC-FTIR performed better for the regioisomers. Further, new spectroscopic data of the synthesized cathinone analogs is hereby presented for the forensic community. The synthetic work also showed that cathinone reference compounds can be produced in few reaction steps.

  • 13.
    Cavallo, Joel S.
    et al.
    University of Chicago, IL 60637 USA.
    Mayo, Leah
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN).
    de Wit, Harriet
    University of Chicago, IL 60637 USA.
    Acquisition of Conditioning between Methamphetamine and Cues in Healthy Humans2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 8, s. e0161541-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Environmental stimuli repeatedly paired with drugs of abuse can elicit conditioned responses that are thought to promote future drug seeking. We recently showed that healthy volunteers acquired conditioned responses to auditory and visual stimuli after just two pairings with methamphetamine (MA, 20 mg, oral). This study extended these findings by systematically varying the number of drug-stimuli pairings. We expected that more pairings would result in stronger conditioning. Three groups of healthy adults were randomly assigned to receive 1, 2 or 4 pairings (Groups P1, P2 and P4, Ns = 13, 16, 16, respectively) of an auditory-visual stimulus with MA, and another stimulus with placebo (PBO). Drug-cue pairings were administered in an alternating, counterbalanced order, under double-blind conditions, during 4 hr sessions. MA produced prototypic subjective effects (mood, ratings of drug effects) and alterations in physiology (heart rate, blood pressure). Although subjects did not exhibit increased behavioral preference for, or emotional reactivity to, the MA-paired cue after conditioning, they did exhibit an increase in attentional bias (initial gaze) toward the drug-paired stimulus. Further, subjects who had four pairings reported " liking" the MApaired cue more than the PBO cue after conditioning. Thus, the number of drug-stimulus pairings, varying from one to four, had only modest effects on the strength of conditioned responses. Further studies investigating the parameters under which drug conditioning occurs will help to identify risk factors for developing drug abuse, and provide new treatment strategies.

  • 14.
    Davies Forsman, Lina
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Niward, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Hu, Yi
    Fudan Univ, Peoples R China; Fudan Univ, Peoples R China.
    Zheng, Rongrong
    Xiamen City Ctr Dis Control, Peoples R China.
    Zheng, Xubin
    Fudan Univ, Peoples R China.
    Ke, Ran
    Xiamen City Ctr Dis Control, Peoples R China.
    Cai, Weiping
    Xiamen City Ctr Dis Control, Peoples R China.
    Hong, Chao
    Xiamen City Ctr Dis Control, Peoples R China.
    Li, Yang
    Fudan Univ, Peoples R China.
    Gao, Yazhou
    Fudan Univ, Peoples R China.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Sweden.
    Paues, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Kuhlin, Johanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Simonsson, Ulrika S. H.
    Uppsala Univ, Sweden.
    Eliasson, Erik
    Karolinska Univ Hosp, Sweden.
    Alffenaar, Jan-Willem
    Univ Groningen, Netherlands.
    Mansjo, Mikael
    Publ Hlth Agcy Sweden, Sweden.
    Hoffner, Sven
    Karolinska Inst, Sweden.
    Xu, Biao
    Fudan Univ, Peoples R China.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Kalmar Cty Hosp, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study2018Inngår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, nr 9, artikkel-id e023899Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB. Methods and analysis Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960. Ethics and dissemination This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal. Trial registration number NCT02816931; Pre-results.

  • 15.
    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
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. 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)2017Inngår i: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 35, nr 1, s. 20-32Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16.
    Diao, Xingxing
    et al.
    National Institute Drug Abuse, MD 21224 USA.
    Scheidweiler, Karl B.
    National Institute Drug Abuse, MD 21224 USA.
    Wohlfarth, Ariane
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Pang, Shaokun
    SCIEX Ltd, CA 94404 USA.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Sweden.
    Huestis, Marilyn A.
    National Institute Drug Abuse, MD 21224 USA.
    In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-222016Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 18, nr 2, s. 455-464Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 17.
    Diao, Xingxing
    et al.
    NIDA, USA.
    Scheidweiler, Karl B.
    NIDA, USA.
    Wohlfarth, Ariane
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Zhu, Mingshe
    Bristol Myers Squibb, NJ 08543 USA.
    Pang, Shaokun
    SCIEX Ltd, USA.
    Huestis, Marilyn A.
    NIDA, USA.
    Strategies to distinguish new synthetic cannabinoid FUBIMINA (BIM-2201) intake from its isomer THJ-2201: metabolism of FUBIMINA in human hepatocytes2016Inngår i: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 34, nr 2, s. 256-267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Since 2013, a new drugs-of-abuse trend attempts to bypass drug legislation by marketing isomers of scheduled synthetic cannabinoids (SCs), e.g., FUBIMINA (BIM-2201) and THJ-2201. It is much more challenging to confirm a specific isomers intake and distinguish it from its structural analog because the isomers and their major metabolites usually have identical molecular weights and display the same product ions. Here, we investigated isomers FUBIMINA and THJ-2201 and propose strategies to distinguish their consumption. THJ-2201 was scheduled in the US, Japan, and Europe; however, FUBIMINA is easily available on the Internet. We previously investigated THJ-2201 metabolism in human hepatocytes, but human FUBIMINA metabolism is unknown. We aim to characterize FUBIMINA metabolism in human hepatocytes, recommend optimal metabolites to confirm its consumption, and propose strategies to distinguish between intakes of FUBIMINA and THJ-2201. FUBIMINA (10 mu M) was incubated in human hepatocytes for 3 h, and metabolites were characterized with high-resolution mass spectrometry (HR-MS). We identified 35 metabolites generated by oxidative defluorination, further carboxylation, hydroxylation, dihydrodiol formation, glucuronidation, and their combinations. We recommend 5-OH-BIM-018 (M34), BIM-018 pentanoic acid (M33), and BIM-018 pentanoic acid dihydrodiol (M7) as FUBIMINA specific metabolites. THJ-2201 produced specific metabolite markers 5-OH-THJ-018 (F26), THJ-018 pentanoic acid (F25), and hydroxylated THJ-2201 (F13). Optimized chromatographic conditions to achieve different retention times and careful selection of specific product ion spectra enabled differentiation of isomeric metabolites, in this case FUBIMINA from THJ-2201. Our HR-MS approach should be applicable for differentiating future isomeric SCs, which is especially important when different isomers have different legal status.

  • 18.
    Feasel, Michael G.
    et al.
    US Army, MD 21010 USA.
    Wohlfarth, Ariane
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. NIDA, MD 21224 USA; National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Nilles, John M.
    Excet Inc, VA 22150 USA.
    Pang, Shaokun
    SCIEX Ltd, CA 94404 USA.
    Kristovich, Robert L.
    US Army, MD 21010 USA.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA.
    Metabolism of Carfentanil, an Ultra-Potent Opioid, in Human Liver Microsomes and Human Hepatocytes by High-Resolution Mass Spectrometry2016Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 18, nr 6, s. 1489-1499Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Carfentanil is an ultra-potent synthetic opioid. No human carfentanil metabolism data are available. Reportedly, Russian police forces used carfentanil and remifentanil to resolve a hostage situation in Moscow in 2002. This alleged use prompted interest in the pharmacology and toxicology of carfentanil in humans. Our study was conducted to identify human carfentanil metabolites and to assess carfentanils metabolic clearance, which could contribute to its acute toxicity in humans. We used Simulations Pluss ADMET Predictor (TM) and Molecular Discoverys MetaSite (TM) to predict possible metabolite formation. Both programs gave similar results that were generally good but did not capture all metabolites seen in vitro. We incubated carfentanil with human hepatocytes for up to 1 h and analyzed samples on a Sciex 3200 QTRAP mass spectrometer to measure parent compound depletion and extrapolated that to represent intrinsic clearance. Pooled primary human hepatocytes were then incubated with carfentanil up to 6 h and analyzed for metabolite identification on a Sciex 5600+ TripleTOF (QTOF) high-resolution mass spectrometer. MS and MS/MS analyses elucidated the structures of the most abundant metabolites. Twelve metabolites were identified in total. N-Dealkylation and monohydroxylation of the piperidine ring were the dominant metabolic pathways. Two N-oxide metabolites and one glucuronide metabolite were observed. Surprisingly, ester hydrolysis was not a major metabolic pathway for carfentanil. While the human liver microsomal system demonstrated rapid clearance by CYP enzymes, the hepatocyte incubations showed much slower clearance, possibly providing some insight into the long duration of carfentanils effects.

  • 19. Felini, Usisipho
    et al.
    Beni, Valerio
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Iwuoha, Emanuel
    University of the Western Cape, South Africa.
    Turner, Anthony
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Palladium telluride quantum dots and cytochrome P450 biosensor for the detection of breast cancer drug – tamoxifen.2015Inngår i: Sweden-Japan Seminar on Nanomaterials and Nanotechnology – SJS-Nano, Linköping, Sweden, 10-11 March 2015., Japan Society for the Promotion of Science (JSPS), Stockholm. , 2015Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Tamoxifen is an oral non-steroidal anti-estrogen drug used in the prevention and treatment of all stages of breast cancer. This drug acts by competing with estrogen for binding to the estrogen receptor (ER) and reduces the transcription of estrogen dependent genes. However, approximately 30-50% of ER-positive breast cancer patients either fail to respond or eventually become resistant to tamoxifen resulting in a serious clinical challenge in breast cancer management. This, therefore, calls for new selective and sensitive methods for evaluating individual’s metabolic activities of the drug ensuring in this way reliable dosing of the drug. This paper presents a biosensor system based on the combination of thioglycolic acid-capped palladium telluride (TGA-PdTe) quantum dots (QDs) and cytochrome P450-3A4 or 2D6 (CYP3A4 or CYP2D6) enzymes for the determination of tamoxifen. Preliminary FTIR and UVs studies of the QDs confirmed the presence of the capping agent via the specific COOH and CH2 signature bands; furthermore the adsorption band at ca. 330 nm and the corresponding band gap energy, Eg, value is 3.47 eV (within the Eg value for QDs particles) confirmed the successful synthesis of the TGA-PdTe QDs. Differential pulse voltammetric (DPV) electroanalysis using the Au|Cyst|TGA-PdTeQDs|CYP3A4 (or CYP2D6) biosensor systems indicated a clear catalytic cathodic peak at -0.35 V for the tamoxifen biotransformation reaction; this signal was used, in this work, as the biosensor analytical response. The developed biosensor presented a limit of detection (LOD) of 0.98 and 2.5 ng/mL, for CYP3A4 and CYP2D6 based biosensors, respectively. These are lower than tamoxifen’s maximum steady state plasma concentration (Cmax 40 ng/L) value; these performances make the proposed biosensor a promising platform for monitoring the drug in patients.

  • 20.
    Forsgren, Mikael
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Karlsson, Markus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dahlqvist Leinhard, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dahlström, Nils
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Norén, Bengt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Romu, Thobias
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Ignatova, Simone
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Ekstedt, Mattias
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Lundberg, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Medicinsk strålningsfysik. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Cedersund, Gunnar
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort2019Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, nr 6, artikkel-id e1007157Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.

    Author summary

    Being able to accurately and reliably estimate liver function is important when monitoring the progression of patients with liver disease, as well as when identifying drug-induced liver injury during drug development. A promising method for quantifying liver function is to use magnetic resonance imaging combined with gadoxetate. Gadoxetate is a liver-specific contrast agent, which is taken up by the hepatocytes and excreted into the bile. We have previously developed a mechanistic model for gadoxetate dynamics using averaged data from healthy volunteers. In this work, we extended our model with a non-linear mixed-effects modeling framework to give patient-specific estimates of the gadoxetate transport-rates. We validated the model by recruiting 100 patients with liver disease, covering a range of severity and etiologies. All patients underwent an MRI-examination and provided both blood and liver biopsies. Our validated model provides a new and deeper look into how the mechanisms of liver function varies across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate.

  • 21.
    Fridlund, Jimmy
    et al.
    Kalmar County Hospital, Sweden.
    Woksepp, Hanna
    Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    A microbiological method for determining serum levels of broad spectrum beta-lactam antibiotics in critically ill patients2016Inngår i: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 129, s. 23-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Recent studies show that suboptimal blood levels of beta-lactam antibiotics are present in intensive care unit (ICU) patients. A common reference method for assessing drug concentrations is liquid chromatography coupled with mass-spectrometry (LC-MS) which is highly accurate but rarely available outside reference centres. Thus, our aim was to develop a microbiological method for monitoring beta-lactam antibiotic serum levels which could be used at any hospital with a microbiological laboratory. Methods: The method was developed as a 96-well broth microdilution format to assess the concentrations of cefotaxime (CTX), meropenem (MER), and piperacillin (PIP). Patient serum containing antibiotics were diluted in suspensions of bacteria with known minimal inhibitory concentrations (MICs). Serum antibiotic concentrations were calculated by dividing the MIC with the dilution factor at which the serum inhibited growth of the bacterial suspension. Serum (n = 88) from ICU patients at four hospitals in south-east Sweden were analysed and compared to LC-MS analysis. Results: The overall accuracy and precision for spiked samples and patient samples was within the pre-set target of +/- 20.0% for all drugs. There was a significant correlation between the microbiological assay and LC-MS for the patient samples (CTX: r = 0.86, n = 31; MER: r = 0.96, n = 11; PIP: r = 0.88, n = 39) and the agreement around the clinical cut-off for CTX (4.0 mg/l), MER (2.0 mg/l) and PIP (16.0 mg/l) was 90%, 100% and 87%, respectively. Conclusion: The microbiological method has a performance for determination of serum levels of meropenem, piperacillin and cefotaxime suitable for clinical use. It is an inexpensive method applicable in any microbiology laboratory. (C) 2016 Elsevier B.V. All rights reserved.

  • 22.
    Gorinski, Nataliya
    et al.
    Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Bijata, Monika
    Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany / Cell Biophysics, Nencki Institute, Pasteur Str. 3, 02-093, Warsaw, Poland.
    Prasad, Sonal
    Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Wirth, Alexander
    Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Abdel Galil, Dalia
    Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Zeug, Andre
    Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, German.
    Bazovkina, Daria
    Behavioural Neurogenomics, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia.
    Kondaurova, Elena
    Behavioural Neurogenomics, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia.
    Kulikova, Elizabeth
    Behavioural Neurogenomics, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia.
    Ilchibaeva, Tatiana
    Behavioural Neurogenomics, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia.
    Zareba-Koziol, Monika
    Cell Biophysics, Nencki Institute, Pasteur Str. 3, 02-093, Warsaw, Poland.
    Papaleo, Francesco
    Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genova, Italy.
    Scheggia, Diego
    Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genova, Italy.
    Kochlamazashvili, Gaga
    Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genova, Italy.
    Dityatev, Alexander
    Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genova, Italy / Molecular Neuroplasticity, DZNE, Leipziger Str. 44, 39120, Magdeburg, Germany.
    Smyth, Ian
    Anatomy & Developmental Biology, Monash University, 3800, Melbourne, Australia.
    Krzystyniak, Adam
    Cell Biophysics, Nencki Institute, Pasteur Str. 3, 02-093, Warsaw, Poland.
    Wlodarczyk, Jakub
    Cell Biophysics, Nencki Institute, Pasteur Str. 3, 02-093, Warsaw, Poland.
    Richter, Diethelm W.
    Neuro and Sensory Physiology, University of Göttingen, 37073, Göttingen, Germany.
    Strekalova, Tatyana
    Sechenov First Moscow State Medical University, Moscow, Russia / Neuroscience, Maastricht University, 6229 ER, Maastricht, Netherlands / Laboratory of Psychiatric Neurobiology and Institute of General Pathology and Pathophysiology, Sechenov First Moscow State Medical University, Trubetskaya 8, 119315, Moscow, Russia.
    Sigrist, Stephan
    Institute of Biology, Free University Berlin, Takustr. 6, 14195, Berlin, Germany.
    Bang, Claudia
    Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Hobuß, Lisa
    Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Fiedler, Jan
    Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Thum, Thomas
    Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Naumenko, Vladimir S.
    Behavioural Neurogenomics, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia.
    Pandey, Ghanshyam
    Department of Psychiatry, University of Illinois, 1601 W. Taylor Street, Chicago, IL, 60612, USA.
    Ponimaskin, Evgeni
    Cellular Neurophysiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
    Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors2019Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, nr 1, s. 1-14, artikkel-id 3924Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.

  • 23.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Suleman Khan, Muhammad
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Åvall-Lundqvist, Elisabeth
    Karolinska University of Hospital.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Impact of CYP3A5(*)3 and CYP2C8-HapC on Paclitaxel/Carboplatin-Induced Myelosuppression in Patients with Ovarian Cancer2011Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, nr 10, s. 4205-4209Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8(*)3, CYP2C8-HapC, and CYP3A5(*)3 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5(*)3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p andlt; 0.05) than patients with the wild-type genotype. CYP3A5(*)3/(*)1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than (*)3/(*)3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.

  • 24.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Mirghani, Rajaa A
    Karolinska University .
    Rymark, Per
    Västerås Hospital.
    Åvall Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Karolinska University Hospital.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Tekniska högskolan. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer2009Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 104, nr 2, s. 130-137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.

  • 25.
    Gregers, Jannie
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Childhood acute lymphoblastic leukaemia is the most common type of cancer in children. Improvement in treatment has increased survival to approximately 85 per cent. Pharmacogenetics can influence the disposition of anticancer agents and can ideally be used as tool to further improve treatment based on the individual child’s pharmacogenetic profile.

    The hypothesis in this thesis was that polymorphisms in genes responsible for MTX influx (SLC19A1), efflux (ABCB1, studies with MTX monotherapy have demonstrated effect of variations in this gene) or other MTX pathways (ATIC, MTHFR and SHMT) could have impact on efficacy in childhood acute lymphoblastic leukaemia.

    The uptake of MTX and impact of SLC19A1 80G>A was investigated in vitro and showed that SLC19A1 80GG had decreased uptake in CD+ T cells and B cells caused by reduced capacity on receptor-to-receptor basis.

    In more than 500 patients the clinical effect of SLC19A1 80G>A genotype was evaluated and showed that patients with the SLC19A1 80AA had better survival, more bone marrow toxicity, but less liver toxicity than patients with SLC19A1 80GG or 80GA variants. Furthermore, it was demonstrated that SLC19A1 80G>A interacts with chromosome 21 copy number in the leukemic clone.

    The clinical impact of ABCB1 1199G>A, 1236C>T, 2677G<T/A and 3435C>T on the treatment was evaluated. Patients with either the 1199GA or the 3435CC variant had increased risk of relapse compared to patients with the 1199GG or 3435CT/TT variants, respectively. Toxicity was also affected by the ABCB1 polymorphisms.

    No association between polymorphisms in the ATIC, MTHFR and SHMT genes and outcome was seen. However the 677C>T and 1298 C>A in the MTHFR gene were associated with toxicity.

    The genotype frequencies between healthy donors and patients were compared, but no association to risk of developing cancer was seen in the investigated polymorphisms.

    The results in this thesis emphasise the importance of including pharmacogenetic markers in attempts to improve outcome and reduced side effects in childhood ALL.

    Delarbeid
    1. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
    Åpne denne publikasjonen i ny fane eller vindu >>Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
    2008 (engelsk)Inngår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 47, nr 4, s. 451-453Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.

    METHODS: Mononuclear cells were isolated from peripheral blood of healthy persons. Real-time PCR was used to detect the RFC80 variants. FITC-labelled MTX was added to cells stimulated with Candida albicans or tetanus toxoid, and the uptake of MTX was measured by flow cytometry. A FITC-conjugated monoclonal antibody against RFC was used to detect the cellular RFC expression.

    RESULTS: Antigen-stimulated CD4+ T cells and B cells from individuals with the GG variant (n = 9) exhibited lower uptake of MTX than individuals expressing the AA variant (n = 8), or the GA variant (n = 8). No difference could be demonstrated between the three groups with respect to the expression of RFC by CD4+ T cells and B cells, and CD4+ T cells from individuals homozygous for the G allele exhibited lower uptake of MTX per receptor than CD4+ T cells from individuals homozygous for the A allele.

    CONCLUSION: MTX is taken up more efficiently via the A allele than via the G allele. This difference between the variant forms of RFC suggests that genotyping could be relevant for determining the relevant dosage of MTX in the treatment of neoplastic and autoimmune disease.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77610 (URN)10.1093/rheumatology/ken073 (DOI)18316334 (PubMedID)
    Tilgjengelig fra: 2012-05-24 Laget: 2012-05-24 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    2. The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
    Åpne denne publikasjonen i ny fane eller vindu >>The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
    Vise andre…
    2010 (engelsk)Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 23, s. 4671-4677Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G greater than A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G greater than A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

    sted, utgiver, år, opplag, sider
    American Society of Hematology, 2010
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-58380 (URN)10.1182/blood-2010-01-256958 (DOI)000278635900013 ()
    Merknad
    Original Publication: Jannie Gregers, Ib Jarle Christensen, Kim Dalhoff, Birgitte Lausen, Henrik Schroeder, Steen Rosthoej, Niels Carlsen, Kjeld Schmiegelow and Curt Peterson, The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number, 2010, Blood, (115), 23, 4671-4677. http://dx.doi.org/10.1182/blood-2010-01-256958 Copyright: American Society of Hematology http://www.hematology.org/Tilgjengelig fra: 2010-08-13 Laget: 2010-08-11 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    3. Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
    Vise andre…
    2012 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences pharmacokinetics in several anti-cancer drugs. We hypothesized that 1199G>A, 1236C>T, 2677G>A/T and 3435C>T variants of ABCB1 could affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL), since treatment includes known P-glycoprotein substrates and 3435C/T may affect methotrexate therapy.

    We studied 522 Danish children with ALL treated according to NOPHO ALL92 and ALL2000 protocols, 93% of all those eligible during 1992-2007. Risk of relapse was 2.9-fold increased for 41 patients with the 1199GA variant compared to 477 with 1199GG (p=0.001), and reduced by 61% and 40%, respectively for 421 patients with the 3435CT or 3435TT variants compared to 96 with 3435CC (overall p=0.02).

    Degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was higher in 71 patients with 3435TT variant (median nadirs: hemoglobin 3% and platelets 34/37% lower in3435CT/3435CC) compared to 160 patients with 3435CT/3435CC (Hemoglobin p=0.01 and platelets p<0.0001).

    We observed more liver toxicity after high-dose methotrexate in 109 patients with 3435CC variant versus 3435CT/TT (Median max alanineaminotransferase: 280 versus 142/111 U/L, p=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms and efficacy and toxicity in childhood ALL.

    Emneord
    Acute lymphoblastic leukemia; ABCB1; MDR1; P-glycoprotein; Polymorphism; Relapse; Toxicity
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77618 (URN)
    Tilgjengelig fra: 2012-05-24 Laget: 2012-05-24 Sist oppdatert: 2012-05-24bibliografisk kontrollert
    4. Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
    Vise andre…
    2012 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001).

    In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77622 (URN)
    Tilgjengelig fra: 2012-05-24 Laget: 2012-05-24 Sist oppdatert: 2012-05-24bibliografisk kontrollert
  • 26.
    Gundersen, Per Ole M.
    et al.
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Spigset, Olav
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Natl Forens Ctr, Drug Unit, Linkoping, Sweden.
    Screening, quantification, and confirmation of synthetic cannabinoid metabolites in urine by UHPLC-QTOF-MS2019Inngår i: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 11, nr 1, s. 51-67Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Synthetic cannabinoids are one of the most significant groups within the category new psychoactive substances (NPS) and in recent years new compounds have continuously been introduced to the market of recreational drugs. A sensitive and quantitative screening method in urine with metabolites of frequently seized compounds in Norway (AB-FUBINACA, AB-PINACA, AB-CHMINACA, AM-2201, AKB48, 5F-AKB48, BB-22, JWH-018, JWH-073, JWH-081, JWH-122, JWH-203, JWH-250, PB-22, 5F-PB-22, RCS-4, THJ-2201, and UR-144) using ultra-high pressure liquid chromatography-quadrupole time of flight-mass spectrometry (UHPLC-QTOF-MS) has been developed. The samples were treated with ss-glucuronidase prior to extraction and solid-phase extraction was used. Liquid handling was automated using a robot. Chromatographic separation was achieved using a C18-column and a gradient of water and acetonitrile, both with 0.1% formic acid. Each sample was initially screened for identification and quantification followed by a second injection for confirmation. The concentrations by which the compounds could be confirmed varied between 0.1 and 12 ng/mL. Overall the validation showed that the method fulfilled the set criteria and requirements for matrix effect, extraction recovery, linearity, precision, accuracy, specificity, and stability. One thousand urine samples from subjects in drug withdrawal programs were analyzed using the presented method. The metabolite AB-FUBINACA M3, hydroxylated metabolite of 5F-AKB48, hydroxylated metabolite of AKB48, AKB48 N-pentanoic acid, 5F-PB-22 3-carboxyindole, BB-22 3-carboxyindole, JWH-018 N-(5-hydroxypentyl), JWH-018 N-pentanoic acid, and JWH-073 N-butanoic acid were quantified and confirmed in 2.3% of the samples. The method was proven to be sensitive, selective and robust for routine use for the investigated metabolites.

  • 27.
    Haage, Pernilla
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Forensic Toxicological Aspects of Tramadol: Focus on Enantioselective Drug Disposition and Pharmacogenetics2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    One of the most difficult parts in forensic toxicology is to interpret obtained drug concentrations. Was it therapeutic, toxic or even lethal to the particular individual that the blood sample was drawn from? Concentrations of opioid drugs are especially difficult to interpret, because of large interindividual differences in innate and acquired tolerance.

    Tramadol is a complex drug. Not only is it an opioid, it is also a racemic drug with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. Further, it is metabolized by polymorphic enzymes, which may affect the amounts of metabolites formed and possibly the enantiomer ratios of the parent compound and its metabolites. It has been speculated that particularly the (+)/(-)-enantiomer ratio of O-desmethyltramadol is related to the risk of adverse effects, and it has been shown that the ratio is affected by CYP2D6 genotype.

    The overall aim of the thesis was to evaluate if forensic interpretations of tramadol, regarding toxicity and time since drug administration, may be improved by the use of genotyping and enantioselective concentration determination of tramadol and its three main metabolites.

    To simultaneously quantify the enantiomer concentrations of tramadol, Odesmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol in whole blood, a liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed and validated. Genetic variation in CYP2D6, CYP2B6, CYP3A4 (encoding the tramadol metabolizing enzymes), ABCB1 (encoding a transport protein) and OPRM1 (encoding the μ-opioid receptor) was investigated, using pyrosequencing, xTAG, and TaqMan analysis. The methods were applied to the blood samples of two study populations; 19 healthy volunteers administered a therapeutic, single tramadol dose, and 159 tramadol positive autopsy cases.

    The most important finding was the positive correlations between all four enantiomer ratios and time since tramadol administration in the healthy volunteers. All enantiomer ratios except the one of tramadol was also affected by the CYP2D6 genotype, which was apparent among the autopsy cases as well. Genetic variation in CYP2D6 and possibly CYP2B6 was shown to have an impact on tramadol pharmacokinetics, although no association to neither drug related symptoms nor tramadol related causes of death was found. Tramadol intoxications were predominantly characterized by low age (median 26 years) and male sex, often with a history of substance abuse and with other drugs (at fairly low concentrations) detected in blood.

    In conclusion, enantiomer concentration determination combined with genotyping seems promising regarding estimations of time since drug administration, although is of low value concerning interpretations of toxicity in autopsy cases.

    Delarbeid
    1. Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
    Åpne denne publikasjonen i ny fane eller vindu >>Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
    Vise andre…
    2014 (engelsk)Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, s. 125-132Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

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

    sted, utgiver, år, opplag, sider
    Elsevier, 2014
    Emneord
    Tramadol; Pharmacokinetics; Pharmacodynamics; CYP2D6; ABCB1; OPRM1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-106838 (URN)10.1016/j.forsciint.2014.03.003 (DOI)000334580700025 ()24709712 (PubMedID)
    Tilgjengelig fra: 2014-05-28 Laget: 2014-05-23 Sist oppdatert: 2018-11-09bibliografisk kontrollert
    2. Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.
    Åpne denne publikasjonen i ny fane eller vindu >>Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.
    2016 (engelsk)Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 119, s. 1-9Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

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

    Emneord
    Enantiomer; LC–MS/MS; N, O-didesmethyltramadol; N-desmethyltramadol; O-desmethyltramadol; Tramadol
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-125284 (URN)10.1016/j.jpba.2015.11.012 (DOI)000370211900001 ()26625281 (PubMedID)
    Merknad

    Funding agencies:The National Board of Forensic Medicine in Sweden funded this work.

    Tilgjengelig fra: 2016-02-19 Laget: 2016-02-19 Sist oppdatert: 2018-11-09
    3. Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
    Åpne denne publikasjonen i ny fane eller vindu >>Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
    Vise andre…
    2018 (engelsk)Inngår i: Pharmacology Research & Perspectives, ISSN 2052-1707, Vol. 6, nr 4, artikkel-id e00419Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.

    sted, utgiver, år, opplag, sider
    John Wiley & Sons, 2018
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-152586 (URN)10.1002/prp2.419 (DOI)000442994300006 ()29992026 (PubMedID)2-s2.0-85052511964 (Scopus ID)
    Tilgjengelig fra: 2018-11-09 Laget: 2018-11-09 Sist oppdatert: 2018-12-03bibliografisk kontrollert
  • 28.
    Haage, Pernilla
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Calistri, Simona
    Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands / Scuola di Scienze della Salute Umana, Università degli studi di Firenze, Florence, Italy.
    van Schaik, Ron H N
    Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype2018Inngår i: Pharmacology Research & Perspectives, ISSN 2052-1707, Vol. 6, nr 4, artikkel-id e00419Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.

  • 29.
    Hedna, Khedidja
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Inappropriate prescribing, non-adherence to long-term medications and related morbidities: Pharmacoepidemiological aspects2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Inappropriate use of medications (IUM), in particular inappropriate prescribing and non-adherence to prescribed medications, are important causes of drug-related morbidities (DRMs). They are increasing problems with the ageing populations and the growing burden of chronic conditions. However, research is needed on the association of IUMs with DRMs in outpatient settings and in the general population.

    Aim: The aim of this thesis is to estimate and analyse the burden of potentially inappropriate prescriptions (PIPs) in the elderly and non-adherence to long-term medications among adults across care settings, and to investigate how IUM is associated to DRMs.

    Methods: A meta-analysis summarised the previous evidence on the percentage of adverse drug reactions (ADRs) associated to IUM across healthcare settings (Study I). From a cohort in the general population, using medical records and register data, the prevalence of PIPs in the elderly and its association with ADRs were estimated retrospectively (Study II). From the same cohort, the factors associated with refill non-adherence to antihypertensive therapy, considering the use of multiple medications, and the association between non-adherence and sub-therapeutic effects (STEs) were investigated (Study III). A survey assessed the refill behaviour to antihypertensive, lipid lowering and oral antidiabetic medications (undersupply, adequate supply and oversupply), and its association with perceived ADRs and STEs (Study IV).

    Results: IUM was the cause 52% and 45% of ADRs occurring in adult outpatients and inpatients respectively. Across healthcare settings, 46% of the elderly refilled PIPs over a 6-month period; PIPs were considered the cause of 30% of all ADRs; and the elderly who were prescribed PIPs had increased odds to experience ADRs (OR 2.47, 95% CI 1.65-3.69). In total, 35% was nonadherent to the full multidrug therapy and 13% was non-adherent to any medication (complete non-adherence).  Sociodemographic factors (working age and lower income) were associated with non-adherence to any medication, while clinical factors (use of specialised care, use of multiple medications, and being a new user) with non-adherence to the full multidrug therapy. STEs were associated with non-adherence to any medication a month prior to a healthcare visit (OR 3.27, 95% CI 1.27-8.49), but not with long-term measures of non-adherence. Among survey respondents, 22% of the medications were oversupplied and 12% were undersupplied. Inadequate refill behaviour was not associated with reporting ADRs or STEs (p<0.05).

    Conclusions: A large proportion of ADRs occurring in hospital is caused by IUM, but more knowledge is needed in other settings. PIPs are common in the elderly general population and associated with ADRs. Therefore decreasing PIPs could contribute towards ADR prevention. Considering the use of multiple medications may help to better understand the factors associated with non-adherence to a multidrug therapy for tailoring the interventions to patient needs. Monitoring the adherence prior to a healthcare visit may facilitate interpreting STEs. Yet, the absence of an association between long-term measures of refill non-adherence with clinical and perceived DRMs suggest the need to enhance the knowledge of this association in clinical practice. In summary, this thesis shows a significant potential for improvements of medication use and outcomes.

    Delarbeid
    1. Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions - a meta-analysis
    Åpne denne publikasjonen i ny fane eller vindu >>Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions - a meta-analysis
    2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 3, s. 1-9, artikkel-id e33236Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Numerous observational studies suggest that preventable adverse drug reactions are a significant burden in healthcare, but no meta-analysis using a standardised definition for adverse drug reactions exists. The aim of the study was to estimate the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions in adult outpatients and inpatients.

    METHODS: Studies were identified through searching Cochrane, CINAHL, EMBASE, IPA, Medline, PsycINFO and Web of Science in September 2010, and by hand searching the reference lists of identified papers. Original peer-reviewed research articles in English that defined adverse drug reactions according to WHO's or similar definition and assessed preventability were included. Disease or treatment specific studies were excluded. Meta-analysis on the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions was conducted.

    RESULTS: Data were analysed from 16 original studies on outpatients with 48797 emergency visits or hospital admissions and from 8 studies involving 24128 inpatients. No studies in primary care were identified. Among adult outpatients, 2.0% (95% confidence interval (CI): 1.2-3.2%) had preventable adverse drug reactions and 52% (95% CI: 42-62%) of adverse drug reactions were preventable. Among inpatients, 1.6% (95% CI: 0.1-51%) had preventable adverse drug reactions and 45% (95% CI: 33-58%) of adverse drug reactions were preventable.

    CONCLUSIONS: This meta-analysis corroborates that preventable adverse drug reactions are a significant burden to healthcare among adult outpatients. Among both outpatients and inpatients, approximately half of adverse drug reactions are preventable, demonstrating that further evidence on prevention strategies is required. The percentage of patients with preventable adverse drug reactions among inpatients and in primary care is largely unknown and should be investigated in future research.

    sted, utgiver, år, opplag, sider
    Public Library of Science, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-76102 (URN)10.1371/journal.pone.0033236 (DOI)000303309000014 ()22438900 (PubMedID)
    Tilgjengelig fra: 2012-03-27 Laget: 2012-03-27 Sist oppdatert: 2017-12-07
    2. Potentially inappropriate prescribing and adverse drug reactions in the elderly: a population-based study
    Åpne denne publikasjonen i ny fane eller vindu >>Potentially inappropriate prescribing and adverse drug reactions in the elderly: a population-based study
    Vise andre…
    2015 (engelsk)Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, nr 12, s. 1525-1533Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose

    Potentially inappropriate prescriptions (PIPs) criteria are widely used for evaluating the quality of prescribing in elderly. However, there is limited evidence on their association with adverse drug reactions (ADRs) across healthcare settings. The study aimed to determine the prevalence of PIPs, defined by the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP) criteria, in the Swedish elderly general population and to investigate the association between PIPs and occurrence of ADRs.

    Method

    Persons ≥65 years old were identified from a random sample of 5025 adults drawn from the Swedish Total Population Register. A retrospective cohort study was conducted among 813 elderly with healthcare encounters in primary and specialised healthcare settings during a 3-month period in 2008. PIPs were identified from the Swedish Prescribed Drug Register, medical records and health administrative data. ADRs were independently identified by expert reviewers in a stepwise manner using the Howard criteria. Multivariable logistic regression examined the association between PIPs and ADRs.

    Results

    Overall, 374 (46.0 %) persons had ≥1 PIPs and 159 (19.5 %) experienced ≥1 ADRs during the study period. In total, 29.8 % of all ADRs was considered caused by PIPs. Persons prescribed with PIPs had more than twofold increased odds of experiencing ADRs (OR 2.47; 95 % CI 1.65–3.69). PIPs were considered the cause of 60 % of ADRs affecting the vascular system, 50 % of ADRs affecting the nervous system and 62.5 % of ADRs resulting in falls.

    Conclusion

    PIPs are common among the Swedish elderly and are associated with increased odds of experiencing ADRs. Thus, interventions to decrease PIPs may contribute to preventing ADRs, in particular ADRs associated with nervous and vascular disorders and falls.

    sted, utgiver, år, opplag, sider
    Springer, 2015
    Emneord
    Inappropriate prescribing – Elderly – Adverse drug reactions – Retrospective study – Medical records – Registries
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-121823 (URN)10.1007/s00228-015-1950-8 (DOI)000365179600013 ()26407684 (PubMedID)
    Tilgjengelig fra: 2015-10-08 Laget: 2015-10-08 Sist oppdatert: 2020-01-21bibliografisk kontrollert
    3. Adherence to Antihypertensive Therapy and Elevated Blood Pressure: Should We Consider the Use of Multiple Medications?
    Åpne denne publikasjonen i ny fane eller vindu >>Adherence to Antihypertensive Therapy and Elevated Blood Pressure: Should We Consider the Use of Multiple Medications?
    Vise andre…
    2015 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 9, artikkel-id e0137451Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background

    Although a majority of patients with hypertension require a multidrug therapy, this is rarely considered when measuring adherence from refill data. Moreover, investigating the association between refill non-adherence to antihypertensive therapy (AHT) and elevated blood pressure (BP) has been advocated.

    Objective

    Identify factors associated with non-adherence to AHT, considering the multidrug therapy, and investigate the association between non-adherence to AHT and elevated BP.

    Methods

    A retrospective cohort study including patients with hypertension, identified from a random sample of 5025 Swedish adults. Two measures of adherence were estimated by the proportion of days covered method (PDC≥80%): (1) Adherence to any antihypertensive medication and, (2) adherence to the full AHT regimen. Multiple logistic regressions were performed to investigate the association between sociodemographic factors (age, sex, education, income), clinical factors (user profile, number of antihypertensive medications, healthcare use, cardiovascular comorbidities) and non-adherence. Moreover, the association between non-adherence (long-term and a month prior to BP measurement) and elevated BP was investigated.

    Results

    Non-adherence to any antihypertensive medication was higher among persons < 65 years (Odds Ratio, OR 2.75 [95% CI, 1.18–6.43]) and with the lowest income (OR 2.05 [95% CI, 1.01–4.16]). Non-adherence to the full AHT regimen was higher among new users (OR 2.04 [95% CI, 1.32–3.15]), persons using specialized healthcare (OR 1.63, [95% CI, 1.14–2.32]), and having multiple antihypertensive medications (OR 1.85 [95% CI, 1.25–2.75] and OR 5.22 [95% CI, 3.48–7.83], for 2 and ≥3 antihypertensive medications, respectively). Non-adherence to any antihypertensive medication a month prior to healthcare visit was associated with elevated BP.

    Conclusion

    Sociodemographic factors were associated with non-adherence to any antihypertensive medication while clinical factors with non-adherence to the full AHT regimen. These differing findings support considering the use of multiple antihypertensive medications when measuring refill adherence. Monitoring patients' refill adherence prior to healthcare visit may facilitate interpreting elevated BP.

    sted, utgiver, år, opplag, sider
    ´PLoS, 2015
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-121822 (URN)10.1371/journal.pone.0137451 (DOI)000361043100040 ()26359861 (PubMedID)
    Tilgjengelig fra: 2015-10-08 Laget: 2015-10-08 Sist oppdatert: 2018-01-11
    4. Refill adherence and self-reported adverse drug reactions and sub-therapeutic effects: a population-based study
    Åpne denne publikasjonen i ny fane eller vindu >>Refill adherence and self-reported adverse drug reactions and sub-therapeutic effects: a population-based study
    Vise andre…
    2013 (engelsk)Inngår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 22, nr 12, s. 1317-1325Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    PURPOSE: To assess refill adherence to dispensed oral long-term medications among the adult population and to investigate whether the percentages of self-reported adverse drug reactions (ADRs) and sub-therapeutic effects (STEs) differed for medications with adequate refill adherence, oversupply, and undersupply.

    METHOD: Survey responses on self-reported ADRs and STEs were linked to the Swedish Prescribed Drug Register in a cross-sectional population-based study. Refill adherence to antihypertensive, lipid-lowering, and oral anti-diabetic medications was measured using the continuous measure of medication acquisition (CMA). The percentages of self-reported ADRs and STEs were compared between medications with adequate refill adherence (CMA 0.8-1.2), oversupply (CMA > 1.2), and undersupply (CMA < 0.8).

    RESULTS: The study included 1827 persons, and the refill adherence was measured for 3014 antihypertensive, 839 lipid lowering, and 253 oral anti-diabetic medications. Overall, 65.7% of the medications had adequate refill adherence, 21.9% oversupply, and 12.4% undersupply. The percentages of self-reported ADRs and STEs were respectively 2.6%, 2.7%, and 2.1% (p > 0.5) for ADRs and 1.1%, 1.6%, and 1.5% (p > 0.5) for STEs.

    CONCLUSIONS: Adequate refill adherence was found in two thirds of the medication therapies. ADRs and STEs were unexpectedly equally commonly reported for medications with adequate refill adherence, oversupply, and undersupply. These results suggest that a better understanding of patients' refill behaviors and their perceived medication adverse outcomes is needed and should be considered in improving medication management. The impact of individual and healthcare factors that may influence the association between refill adherence and reported medication adverse outcomes should be investigated in future studies. Copyright © 2013 John Wiley & Sons, Ltd.

    sted, utgiver, år, opplag, sider
    John Wiley & Sons, 2013
    Emneord
    adverse drug reaction, oversupply, pharmacoepidemiology, refill adherence, self-report, therapeutic failure, undersupply
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-99892 (URN)10.1002/pds.3528 (DOI)000327446700010 ()24127242 (PubMedID)
    Tilgjengelig fra: 2013-10-23 Laget: 2013-10-23 Sist oppdatert: 2017-12-06
  • 30.
    Hendry, Gillian
    et al.
    University of Strathclyde.
    Winn, Philip
    University of Strathclyde.
    Wiggins, Sally
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi.
    Turner, Chris
    University of Strathclyde.
    Qualitative evaluation of a practice-based experience pilot program for Master of Pharmacy students in Scotland.2016Inngår i: American Journal of Pharmaceutical Education, Vol. 80, nr 10, s. 165-170Artikkel i tidsskrift (Fagfellevurdert)
  • 31.
    Henriksson, Martin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälso- och sjukvårdsanalys. Linköpings universitet, Medicinska fakulteten. PAREXEL Int, Sweden.
    Jindal, Ramandeep
    PAREXEL Int, India.
    Sternhufvud, Catarina
    AstraZeneca, Sweden.
    Bergenheim, Klas
    AstraZeneca, Sweden.
    Sorstadius, Elisabeth
    AstraZeneca, Sweden.
    Willis, Michael
    Swedish Institute Health Econ, Sweden.
    A Systematic Review of Cost-Effectiveness Models in Type 1 Diabetes Mellitus2016Inngår i: PharmacoEconomics (Auckland), ISSN 1170-7690, E-ISSN 1179-2027, Vol. 34, nr 6, s. 569-585Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Critiques of cost-effectiveness modelling in type 1 diabetes mellitus (T1DM) are scarce and are often undertaken in combination with type 2 diabetes mellitus (T2DM) models. However, T1DM is a separate disease, and it is therefore important to appraise modelling methods in T1DM. This review identified published economic models in T1DM and provided an overview of the characteristics and capabilities of available models, thus enabling a discussion of best-practice modelling approaches in T1DM. A systematic review of Embase(A (R)), MEDLINEA (R), MEDLINEA (R) In-Process, and NHS EED was conducted to identify available models in T1DM. Key conferences and health technology assessment (HTA) websites were also reviewed. The characteristics of each model (e.g. model structure, simulation method, handling of uncertainty, incorporation of treatment effect, data for risk equations, and validation procedures, based on information in the primary publication) were extracted, with a focus on model capabilities. We identified 13 unique models. Overall, the included studies varied greatly in scope as well as in the quality and quantity of information reported, but six of the models (Archimedes, CDM [Core Diabetes Model], CRC DES [Cardiff Research Consortium Discrete Event Simulation], DCCT [Diabetes Control and Complications Trial], Sheffield, and EAGLE [Economic Assessment of Glycaemic control and Long-term Effects of diabetes]) were the most rigorous and thoroughly reported. Most models were Markov based, and cohort and microsimulation methods were equally common. All of the more comprehensive models employed microsimulation methods. Model structure varied widely, with the more holistic models providing a comprehensive approach to microvascular and macrovascular events, as well as including adverse events. The majority of studies reported a lifetime horizon, used a payer perspective, and had the capability for sensitivity analysis. Several models have been developed that provide useful insight into T1DM modelling. Based on a review of the models identified in this study, we identified a set of best in class methods for the different technical aspects of T1DM modelling.

  • 32.
    Hernandez, Aura Rocio
    et al.
    Malmo Univ, Sweden; Univ Nacl Colombia, Colombia.
    Boutonnet, Marine
    Malmo Univ, Sweden.
    Svensson, Birgitta
    Bioglan AB, Sweden.
    Butler, Eile
    Biogaia AB, Sweden.
    Lood, Rolf
    Lund Univ, Sweden.
    Blom, Kristina
    Medibiome AB, Sweden.
    Vallejo, Bibiana
    Univ Nacl Colombia, Colombia.
    Anderson, Chris
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Engblom, Johan
    Malmo Univ, Sweden.
    Ruzgas, Tautgirdas
    Malmo Univ, Sweden.
    Bjorklund, Sebastian
    Malmo Univ, Sweden.
    New concepts for transdermal delivery of oxygen based on catalase biochemical reactions studied by oxygen electrode amperometry2019Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 306, s. 121-129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of formulation concepts for improved skin tissue oxygenation, including methods for measuring oxygen (O-2) transport across biological barriers, are important research topics with respect to all processes that are affected by the O-2 concentration, such as radiation therapy in oncology treatments, wound healing, and the general health status of skin. In this work we approach this topic by a novel strategy based on the antioxidative enzyme catalase, which is naturally present in the skin organ where it enables conversion of the reactive oxygen species hydrogen peroxide (H2O2) into O-2. We introduce various applications of the skin covered oxygen electrode (SCOE) as an in-vitro tool for studies of catalase activity and function. The SCOE is constructed by placing an excised skin membrane directly on an O-2 electrode and the methodology is based on measurements of the electrical current generated by reduction of O-2 as a function of time (i.e. chronoamperometry). The results confirm that a high amount of native catalase is present in the skin organ, even in the outermost stratum corneum (SC) barrier, and we conclude that excised pig skin (irrespective of freeze-thaw treatment) represents a valid model for ex vivo human skin for studying catalase function by the SCOE setup. The activity of native catalase in skin is sufficient to generate considerable amounts of O-2 by conversion from H2O2 and proof-of-concept is presented for catalase-based transdermal O-2 delivery from topical formulations containing H2O2. In addition, we show that this concept can be further improved by topical application of external catalase on the skin surface, which enables transdermal O-2 delivery from 50 times lower concentrations of H2O2. These important results are promising for development of novel topical or transdermal formulations containing low and safe concentrations of H2O2 for skin tissue oxygenation. Further, our results indicate that the O-2 production by catalase, derived from topically applied S. epidermidis (a simple model for skin microbiota) is relatively low as compared to the O-2 produced by the catalase naturally present in skin. Still, the catalase activity derived from S. epidermidis is measurable. Taken together, this work illustrates the benefits and versatility of the SCOE as an in vitro skin research tool and introduces new and promising strategies for transdermal oxygen delivery, with simultaneous detoxification of H2O2, based on native or topically applied catalase.

  • 33.
    Hernandez, Frank J
    et al.
    POLYMAT, University of of Basque Country UPV/EHU, Avda. Tolosa 72, 20018 Donostia-San-Sebastián, Spain.
    Hernandez, Luiza I.
    Nanobiz Ltd., METU Technopark, Ankara 06800, Turkey.
    Kavruk, Murat
    Test and Calibration Center, Turkish Standards Institute (TSE), Gebze Kocaeli 41400, Turkey.
    Arica, Yakup M.
    Biochemical Processing and Biomaterial Research Laboratory, Gazi University, 06500 Teknikokullar, Ankara, Turkey.
    Bayramoǧlu, Gülay
    Biochemical Processing and Biomaterial Research Laboratory, Gazi University, 06500 Teknikokullar, Ankara, Turkey.
    Borsa, Baris A.
    School of Medicine, Istanbul Kemerburgaz University, 34217 Istanbul, Turkey.
    Öktem, Hüseyin A.
    Nanobiz Ltd., METU Technopark, Ankara 06800, Turkey.
    Schäfer, Thomas
    POLYMAT, University of of Basque Country UPV/EHU, Avda. Tolosa 72, 20018 Donostia-San-Sebastián, Spain.
    Özalp, Veli C.
    School of Medicine, Istanbul Kemerburgaz University, 34217 Istanbul, Turkey.
    NanoKeepers: stimuli responsive nanocapsules for programmed specific targeting and drug delivery2014Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 50, nr 67, s. 9489-9492Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bacterial resistance is a high priority clinical issue worldwide. Thus, an effective system that rapidly provides specific treatment for bacterial infections using controlled dose release remains an unmet clinical need. Herein, we report on the NanoKeepers approach for the specific targeting of S. aureus with controlled release of antibiotics based on nuclease activity. This journal is © the Partner Organisations 2014.

  • 34.
    Hernandez, Frank J
    et al.
    Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of of Iowa, Iowa City, IA 52242, United States.
    Hernandez, Luiza I.
    Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of of Iowa, Iowa City, IA 52242, United States.
    Pinto, Alessandro
    NanoBioSeparations Group, POLYMAT, University of of the Basque Country UPV/EHU, Avda. Tolosa 72, Donostia-San-Sebastián, Spain.
    Schäfer, Thomas
    NanoBioSeparations Group, POLYMAT, University of of the Basque Country UPV/EHU, Avda. Tolosa 72, Donostia-San-Sebastián, Spain; Ikerbasque, Basque Foundation for Science, 48011 Bilbao, Spain.
    Özalp, Veli C.
    Nanobiz Ltd. Metu Technopolis, 06800 Ankara, Turkey; Middle East Technical University, Biological Sciences, 06800 Ankara, Turkey.
    Targeting cancer cells with controlled release nanocapsules based on a single aptamer2013Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, nr 13, s. 1285-1287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular gates have received considerable attention as drug delivery systems. More recently, aptamer-based gates showed great potential in overcoming major challenges associated with drug delivery by means of nanocapsules. Based on a switchable aptamer nanovalves approach, we herein report the first demonstration of an engineered single molecular gate that directs nanoparticles to cancer cells and subsequently delivers the payload in a controllable fashion. © 2012 The Royal Society of Chemistry.

  • 35.
    Ingberg, Edvin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Theodorsson, Annette
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurokirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Neurokirurgiska kliniken US.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Ström, Jakob O
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Methods for long-term 17β-estradiol administration to mice2012Inngår i: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, nr 1, s. 188-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within – except on one occasion – the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

  • 36.
    Iredahl, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Assessment of microvascular and metabolic responses in the skin2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The general aim of this project was to develop experimental in vivo models that allow for minimally invasive investigations of responses in the skin to microvascular and metabolic provocations. The cutaneous microvasculature has emerged as a valuable model and been proposed to mirror the microcirculation in other organs. Dysfunction in the cutaneous microcirculation has thus been linked to systemic diseases such as hypertension and diabetes mellitus. Models for investigating skin responses could facilitate the understanding of pathophysiological mechanisms as well as effects of drugs.

    In the first study, three optical measurement techniques (laser Doppler flowmetry (LDF), laser speckle contrast imaging (LSCI) and tissue viability imaging (TiVi)) were compared against each other and showed differences in their ability to detect microvascular responses to provocations in the skin. TiVi was found more sensitive for measurement of noradrenaline-induced vasoconstriction, while LSCI was more sensitive for measurement of vascular occlusion. In the second study, microvascular responses in the skin to iontophoresis of vasoactive drugs were found to depend on the drug delivery protocol. Perfusion half-life was defined and used to describe the decay in the microvascular response to a drug after iontophoresis. In the third study, the role of nitric oxide (NO) was assessed during iontophoresis of insulin. The results showed a NO-dependent vasodilation in the skin by insulin. In the fourth study the vasoactive and metabolic effects of insulin were studied after both local and endogenous administration. Local delivery of insulin increased skin blood flow, paralleled by increased skin concentrations of interstitial pyruvate and lactate, although no change in glucose concentration was observed. An oral glucose load resulted in an increased insulin concentration in the skin paralleled by an increase in blood flow, as measured using the microdialysis urea clearance technique, although no changes in perfusion was measured by LSCI.

    The thesis concludes that when studying skin microvascular responses, the choice of measurement technique and the drug delivery protocol has an impact on the measurement results, and should therefore be carefully considered. The thesis also concludes that insulin has metabolic and vasodilatory effects in the skin both when administered locally and as an endogenous response to an oral glucose load. The vasodilatory effect of insulin in the skin is mediated by nitric oxide.

    Delarbeid
    1. Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations
    Åpne denne publikasjonen i ny fane eller vindu >>Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations
    Vise andre…
    2015 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 8, s. 1-15, artikkel-id e0133760Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Introduction Microvascular changes in the skin due to pharmacological and physiological provocations can be used as a marker for vascular function. While laser Doppler flowmetry (LDF) has been used extensively for measurement of skin microvascular responses, Laser Speckle Contrast Imaging (LSCI) and Tissue Viability Imaging (TiVi) are novel imaging techniques. TiVi measures red blood cell concentration, while LDF and LSCI measure perfusion. Therefore, the aim of this study was to compare responses to provocations in the skin using these different techniques. Method Changes in skin microcirculation were measured in healthy subjects during (1) iontophoresis of sodium nitroprusside (SNP) and noradrenaline (NA), (2) local heating and (3) post-occlusive reactive hyperemia (PORH) using LDF, LSCI and TiVi. Results Iontophoresis of SNP increased perfusion (LSCI: baseline 40.9 +/- 6.2 PU; 10-min 100 +/- 25 PU; pless than0.001) and RBC concentration (TiVi: baseline 119 +/- 18; 10-min 150 +/- 41 AU; p = 0.011). No change in perfusion (LSCI) was observed after iontophoresis of NA (baseline 38.0 +/- 4.4 PU; 10-min 38.9 +/- 5.0 PU; p = 0.64), while RBC concentration decreased (TiVi: baseline 59.6 +/- 11.8 AU; 10-min 54.4 +/- 13.3 AU; p = 0.021). Local heating increased perfusion (LDF: baseline 8.8 +/- 3.6 PU; max 112 +/- 55 PU; pless than0.001, LSCI: baseline 50.8 +/- 8.0 PU; max 151 +/- 22 PU; pless than0.001) and RBC concentration (TiVi: baseline 49.2 +/- 32.9 AU; max 99.3 +/- 28.3 AU; pless than0.001). After 5 minutes of forearm occlusion with prior exsanguination, a decrease was seen in perfusion (LDF: p = 0.027; LSCI: pless than0.001) and in RBC concentration (p = 0.045). Only LSCI showed a significant decrease in perfusion after 5 minutes of occlusion without prior exsanguination (pless than0.001). Coefficients of variation were lower for LSCI and TiVi compared to LDF for most responses. Conclusion LSCI is more sensitive than TiVi for measuring microvascular changes during SNP-induced vasodilatation and forearm occlusion. TiVi is more sensitive to noradrenaline-induced vasoconstriction. LSCI and TiVi show lower inter-subject variability than LDF. These findings are important to consider when choosing measurement techniques for studying skin microvascular responses.

    sted, utgiver, år, opplag, sider
    Public Library of Science, 2015
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-121109 (URN)10.1371/journal.pone.0133760 (DOI)000359492800006 ()26270037 (PubMedID)
    Tilgjengelig fra: 2015-09-07 Laget: 2015-09-07 Sist oppdatert: 2019-04-29
    2. Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols
    Åpne denne publikasjonen i ny fane eller vindu >>Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols
    Vise andre…
    2015 (engelsk)Inngår i: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 22, nr 6, s. 446-453Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective: After iontophoresis of vasoactive drugs into the skin, a decrease in perfusion is commonly observed. We delivered vasoactive drugs by iontophoresis using different delivery protocols to study how these affect this decrease in perfusion as measured using LDF. Methods: We measured skin perfusion during iontophoresis of (ACh), MCh, andNAusing a single pulse or separate pulses at different skin sites, and during repeated delivery of ACh at the same site. Results: Perfusion half-life was 6.1 (5.6-6.6) minutes for ACh and 41 (29-69) minutes for MCh (p less than 0.001). The maximum response with multiple pulses of ACh iontophoresis was lower than with a single pulse, 30 (22-37) PU vs. 43 (36-50) PU, p less than 0.001. Vasoconstriction to NA was more rapid with a single pulse than with multiple pulses. The perfusion half-life of ACh decreased with repeated delivery of ACh at the same site-first 16 (14-18), second 5.9 (5.1-6-9) and third 3.2 (2.9-3.5) minutes, p less than 0.001. Conclusions: The drug delivery protocol affects microvascular responses to iontophoresis, possibly as a result of differences in the dynamics of local drug concentrations. Perfusion half-life may be used as a measure to quantify the rate of perfusion recovery after iontophoresis of vasoactive drugs.

    sted, utgiver, år, opplag, sider
    Informa Healthcare / Wiley: 12 months, 2015
    Emneord
    microcirculation; iontophoresis; acetylcholine; metha choline; noradrenaline; skin
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-121138 (URN)10.1111/micc.12211 (DOI)000359676500002 ()26016387 (PubMedID)
    Tilgjengelig fra: 2015-09-08 Laget: 2015-09-08 Sist oppdatert: 2017-12-04
    3. The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide
    Åpne denne publikasjonen i ny fane eller vindu >>The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide
    Vise andre…
    2013 (engelsk)Inngår i: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 20, nr 8, s. 717-723Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    ObjectiveInsulin has direct effects on blood flow in various tissues, most likely due to endothelial NO production. We investigated whether insulin delivered to the skin by iontophoresis increases microvascular perfusion and whether this effect is partly or completely mediated by the release of NO. MethodsIn healthy subjects, regular insulin and monomeric insulin were delivered to the skin by cathodal iontophoresis. The skin was pretreated either with L-NAME or control solution (PBS) using anodal iontophoresis. Microvascular responses were measured using laser Doppler flowmetry. ResultsA dose-dependent increase in perfusion was observed during iontophoresis of regular and monomeric insulin. The maximum perfusion was significantly elevated compared with control after PBS (regular insulin 53.6 (12.7-95.6) PU vs. 4.2 (3.4-4.8) PU, p = 0.002; monomeric insulin 32.6 (8.9-92.6) PU vs. 5.9 (3.4-56.0) PU, p = 0.03). The microvascular response to insulin was abolished after L-NAME (regular insulin: 25.6 (11.6-54.4) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.15; monomeric insulin 10.9 (5.4-56.8) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.22). ConclusionsThe main finding is that iontophoresis of insulin induces a dose-dependent vasodilation in the skin, which could be suppressed after pretreatment with a NO synthase inhibitor. This suggests that vasodilation in the skin after iontophoresis of insulin is mediated by the NO pathway.

    sted, utgiver, år, opplag, sider
    WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2013
    Emneord
    insulin, transdermal iontophoresis, endothelial function, vasodilation
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-102080 (URN)10.1111/micc.12071 (DOI)000326607600008 ()
    Merknad

    Funding Agencies|Linkoping University||County Council of Ostergotland||

    Tilgjengelig fra: 2013-12-02 Laget: 2013-11-29 Sist oppdatert: 2017-12-06
    4. Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load
    Åpne denne publikasjonen i ny fane eller vindu >>Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load
    Vise andre…
    2016 (engelsk)Inngår i: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 23, nr 7, s. 597-605Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: Insulin causes capillary recruitment in muscle and adipose tissue, but the metabolic and microvascular effects of insulin in the skin have not been studied in detail. The aim of this study was to measure glucose metabolism and microvascular blood flow in the skin during local insulin delivery and after an oral glucose load.

    METHODS: Microdialysis catheters were inserted intracutanously in human subjects. In eight subjects two microdialysis catheters were inserted, one perfused with insulin and one with control solution. First the local effects of insulin was studied, followed by a systemic provocation by an oral glucose load. Additionally, as control experiment, six subjects did not recieve local delivery of insulin or the oral glucose load. During microdialysis the local blood flow was measured by urea clearance and by laser speckle contrast imaging (LSCI).

    RESULTS: Within 15 minutes of local insulin delivery, microvascular blood flow in the skin increased (urea clearance: P=.047, LSCI: P=.002) paralleled by increases in pyruvate (P=.01) and lactate (P=.04), indicating an increase in glucose uptake. An oral glucose load increased urea clearance from the catheters, indicating an increase in skin perfusion, although no perfusion changes were detected with LSCI. The concentration of glucose, pyruvate and lactate increased in the skin after the oral glucose load.

    CONCLUSION: Insulin has metabolic and vasodilatory effects in the skin both when given locally and after systemic delivery through an oral glucose load.

    sted, utgiver, år, opplag, sider
    Wiley-Blackwell, 2016
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-132368 (URN)10.1111/micc.12325 (DOI)000386946300014 ()27681957 (PubMedID)
    Merknad

    Funding agencies: ALF grants; Region Ostergotland; Sinnescentrum; Gronberg Foundation

    Tilgjengelig fra: 2016-11-01 Laget: 2016-11-01 Sist oppdatert: 2018-01-13bibliografisk kontrollert
  • 37.
    Jones, Alan Wayne
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Perspectives in Drug Discovery: Central Nervous System Depressants2014Inngår i: TIAFT Bulletin, ISSN 1103-7660, nr 44, s. 5-16Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    This collection of short essays deal with the history of drug discovery and covers a wide range of pharmaceutical substances, including prescription medication as well as illicit recreational drugs of abuse. Consideration was also given to the plethora of drugs encountered in routine forensic casework, especially in traffic crimes, such as driving under the influence of drugs (DUID) and in post-mortem toxicology when drug poisoning deaths are investigated. The essays were written over a number of years and reflect to a large extent my own interests and reading about the history of pharmacology and toxicology of drugs. Background information about the chemistry and pharmacology of many of the most commonly encountered drugs and poisons is presented and this should prove useful in the training of newly recruited staff as well as students starting their studies in pharmacology and toxicology. One aim of the essays was to highlight the human side of pharmacology in medicine by providing details about the scientists who are credited with making the crucial observation when a new therapeutic agent was discovered. Another aim was to highlight the role of serendipity in drug discovery. Abbreviated versions of the essays are scheduled to appear in consecutive issues of the bulletin of The International Association of Forensic Toxicologists (TIAFT).

  • 38.
    Jones, Alana Wayne
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine.
    Perspectives in Drug Discovery: A Collection of Essays on the Historyand Development of Pharmaceutical Substances2014Rapport (Annet vitenskapelig)
    Abstract [en]

    This collection of short essays deal with the history of drug discovery and covers a wide range of pharmaceutical substances, including prescription medication as well as illicit recreational drugs of abuse. Consideration was also given to the plethora of drugs encountered in routine forensic casework, especially in traffic crimes, such as driving under the influence of drugs (DUID) and in post-mortem toxicology when drug poisoning deaths are investigated. The essays were written over a number of years and reflect to a large extent my own interests and reading about the history of pharmacology and toxicology of drugs. Background information about the chemistry and pharmacology of many of the most commonly encountered drugs and poisons is presented and this should prove useful in the training of newly recruited staff as well as students starting their studies in pharmacology and toxicology. One aim of the essays was to highlight the human side of pharmacology in medicine by providing details about the scientists who are credited with making the crucial observation when a new therapeutic agent was discovered. Another aim was to highlight the role of serendipity in drug discovery. Abbreviated versions of the essays are scheduled to appear in consecutive issues of the bulletin of The International Association of Forensic Toxicologists (TIAFT).

    For those who might be interested in a more in-depth coverage of this subject the book by Walter Sneader entitled ”Drug discovery – a history” is highly recommended. Sneader’s book has received excellent reviews and represents the best single reference source on the subject of drug discovery. It traces the development of drugs and medication from antiquity until the present day. Chemical structures are provided for most of the drugs discussed along with many interesting anecdotes about the individuals involved – chemists, physicians and pharmacologists – and key events in their quest to discover new and improved therapeutic agents. Another excellent and highly recommended text is the book entitled “Pharmaceutical achievers” produced by the Chemical Heritage Foundation in Philadelphia. Of particular note to historians of science is the fact that this book also contains many photographs and biosketches of the men and women who made the discoveries.

    The essays are collected together here to make them more easily available and are published in book-form thanks to support from the Swedish National Board of Forensic Medicine (Rättsmedicinalverket, RMV). Hopefully these essays will be of interest to colleagues within various branches of the RMV organisation who specialise in forensic psychiatry, forensic genetics, forensic medicine and especially forensic toxicology.

    Linköping 2010-10-01

    A.W. Jones

    Perspectives in Drug Discovery

  • 39.
    Jonsson, Anna K.
    et al.
    Natl Board Forens Med, Dept Forens Chem and Genet, Linkoping, Sweden.
    Spigset, Olav
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Reis, Margareta
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Sickle Univ Hosp, Sweden.
    A Compilation of Serum Concentrations of 12 Antipsychotic Drugs in a Therapeutic Drug Monitoring Setting2019Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 41, nr 3, s. 348-356Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: No comprehensive collection of routine therapeutic drug monitoring data for antipsychotic drugs has been published. Methods: In this compilation, data on 12 antipsychotics are presented. The drugs included are amisulpride (n = 506), aripiprazole (n = 1610), clozapine (n = 1189), flupentixol (n = 215), haloperidol (n = 390), olanzapine (n = 10,268), perphenazine (n = 1065), quetiapine (n = 5853), risperidone (n = 3255), sertindole (n = 111), ziprasidone (n = 1235), and zuclopenthixol (n = 691). Because only one sample per patient is included, the number of patients equals the number of samples. For each drug, median serum concentrations as well as that of the 10th and 90th percentiles are given for a range of daily doses. Comparisons are made between males and females, between patients younger than 65 years and 65 years and older, and between those treated with a low and a high dose of each drug. The concentration-to-dose (C/D) ratio is the primary variable used in these comparisons. Coefficients of variation (CVs) for the serum concentrations of each drug within and between subjects are presented. Results: In general, the C/D ratios were higher in females than in males, higher in those 65 years and older than in younger subjects, and lower in those treated with higher doses than in those treated with lower doses. CVs between individuals were larger than within subjects, and the CVs were highest for the drugs with short elimination half-lives. Conclusions: For each antipsychotic drug, the results presented can serve as a reference tool for pharmacokinetic interpretation of the individual patients serum drug level. The compiled serum concentrations and the C/D ratios can support the physicians decision when individualizing dosing and determining treatment strategies for a specific patient.

  • 40.
    Kallen, Bengt
    et al.
    Lund University, Sweden.
    Reis, Margareta
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Skåne University Hospital, Sweden.
    Ongoing Pharmacological Management of Chronic Pain in Pregnancy2016Inngår i: Drugs, ISSN 0012-6667, E-ISSN 1179-1950, Vol. 76, nr 9, s. 915-924Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The article discusses possible effects of the use of analgesics during pregnancy. It summarizes the pertinent literature and reports some previously unpublished data from the Swedish Medical Birth Register. Most likely the use of analgesics does not cause spontaneous abortion. Only small malformation risk increases are seen after the use of opioids and perhaps non-steroid anti-inflammatory drug (NSAID) use. If possible, the latter should be avoided during the first trimester. If exposure has occurred there is no reason to consider an interruption of the pregnancy. Continued use of analgesics may increase the risk of preeclampsia and of preterm birth, especially valid for opioids. Use of acetylsalicylic acid (ASA) in late pregnancy should be avoided because of the risk of bleeding and (valid also for NSAIDs) premature closure of the ductus arteriosus. A small risk for neonatal abstinence syndrome may exist after the use of opioids for chronic pain, notably during the third trimester and long-lasting effects on child development can possibly occur. For a woman with chronic pain, adequate use of pain killers during pregnancy is needed. It is prudent to avoid ASA and NSAIDs towards the end of the pregnancy, while acetaminophen is an acceptable option all through pregnancy. If continued use of opioids is necessary, the associated risks are low. Triptans can be used for migraine during pregnancy. If possible sumatriptan is preferable to other triptans as data for the latter are largely lacking. Ergots are preferably avoided as not enough data are available.

  • 41.
    Karlsson, Markus
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Forsgren, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Dahlström, Nils
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Leinhard Dahlqvist, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten.
    Norén, Bengt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Ekstedt, Mattias
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Lundberg, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Diffuse Liver Disease: Measurements of Liver Trace Metal Concentrations and R2* Relaxation Rates2016Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Introduction

    Over the past decade, several methods for measuring of liver iron content (LIC) non-invasively with MRI have been developed and verified. The most promising methods uses relaxometry, measuring either R2- or R2* relaxation rate in the liver1,2. For instance, several studies have shown that there seems to be a linear relationship between R2* and LIC1. However, few of these studies have measured the liver content of other metals, which could also affect the relaxation rates. The goal of this study was to investigate if any trace metals, other than iron could affect the R2* relaxation rate in liver tissue in a patients with diffuse liver disease.

    Subjects and methods

    75 patients with suspected diffuse liver disease underwent an MRI examination followed by a liver biopsy the same day. The R2* relaxation rate of the water protons in the liver was measured using an axial 3D multi-slice fat-saturated multi-echo turbo field echo sequence (TE=4.60/9.20/13.80/18.40/23.00ms). Regions of interest (ROI) were drawn and R2* was estimated by fitting the mean signal intensity from the ROIs to a mono-exponential decay model. The biopsies were freeze dried and the concentrations of iron, manganese, copper, cobalt and gadolinium were measured using Inductively Coupled Plasma Sector Field Mass Spectrometry (ICP-SFMS). A multiple linear regression analysis was applied to determine which of the measured metals significantly affected the relaxation rate.

    Results

    A linear regression with the LIC and R2* showed a reasonable fit (Figure 1). The multiple linear regression analysis (Table 1) showed that iron as well as manganese had a significant affect on R2*. Unlike iron however, the regression coefficient of manganese was negative, meaning that an increasing manganese concentration gave a shorter R2* relaxation rate. The same trend can be seen when plotting the manganese concentration against R2* (Figure 2).

  • 42.
    Lundberg, Peter
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Karlsson, Markus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten.
    Forsgren, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Dahlström, Nils
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Leinhard Dahlqvist, Olof
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Norén, Bengt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Cedersund, Gunnar
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Ekstedt, Mattias
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Kechagias, Stergios
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Mechanistic modeling of qDCE-MRI data reveals increased bile excretion of Gd-EOB-DTPA in diffuse liver disease patients with severe fibrosis2016Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Introduction

    Over the past decades, several different non-invasive methods for staging hepatic fibrosis have been proposed. One such method is dynamic contrast enhanced MRI (DCE-MRI) using the contrast agent (CA) Gd-EOB-DTPA. Gd-EOB-DTPA is liver specific, which means that it is taken up specifically by the hepatocytes via the OATP3B1/B3 transporters and excreted into the bile via the MRP2 transporter. Several studies have shown that DCE-MRI and Gd-EOBDTPA can separate patients with advanced (F3-F4) from mild (F0-F2) hepatic fibrosis by measuring the signal intensity, where patients with advanced fibrosis have a lower signal intensity than the mild fibrosis cases.1 However, none of the studies up to date have been able to differentiate if the reduced signal intensity in the liver is because of an decreased uptake of CA or an increased excretion. Analyzing the DCE-MRI data with mechanistic mathematical modelling has the possibility of investigating such a differentiation.

    Subjects and methods

    88 patients with diffuse liver disease were examined using DCE-MRI (1.5 T Philips Achieva, two-point Dixon, TR=6.5 ms, TE=2.3/4.6 ms, FA=13) after a bolus injection of Gd-EOB-DTPA, followed by a liver biopsy. Regions of interest were placed within the liver, spleen and veins and a whole-body mechanistic pharmacokinetic model2 was fitted to the data. The fitted parameters in the model correspond to the rate of CA transport between different compartments, e.g. hepatocytes, blood plasma, and bile (Fig. 1).

    Results

    As can be seen in Fig. 2, the parameter corresponding to the transport of CA from the blood plasma to the hepatocytes, kph, is lower for patients with advanced fibrosis (p=0.01). Fig. 3 shows that the parameter corresponding to the CA excretion into the bile, khb, is higher for patients with advanced fibrosis (p<0.01).

    Discussion/Conclusion

    This work shows that the decreased signal intensity in DCE-MRI images in patients with advanced fibrosis depends on both a decreased uptake of CA in the hepatocytes and an increased excretion into the bile. Similar results have also been observed in a rat study3. In that study, rats with induced cirrhosis had a higher MRP2-activity than the healthy control rats.

    References

    1Norén et al: Eur. Radiol, 23(1), 174-181, 2013.

    2Forsgren et al: PloS One, 9(4): e95700, 2014.

    3Tsuda & Matsui: Radiol, 256(3): 767-773, 2010.

  • 43.
    Nakatani, Yoshio
    et al.
    University of Otago, New Zealand; University of Auckland, New Zealand; University of Otago, New Zealand.
    Opel-Reading, Helen K.
    University of Otago, New Zealand.
    Merker, Matthias
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Machado, Diana
    University of Nova Lisboa, Portugal.
    Andres, Sonke
    National TB Reference Lab, Germany.
    Siva Kumar, S.
    National Institute Research TB, India.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Institute, England.
    Coll, Francesc
    London School Hyg and Trop Med, England.
    Perdigao, Joao
    University of Lisbon, Portugal.
    Portugal, Isabel
    University of Lisbon, Portugal.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Kalmar County Hospital, Sweden.
    Nair, Dina
    National Institute Research TB, India.
    Uma Devi, K. R.
    National Institute Research TB, India.
    Kohl, Thomas A.
    Research Centre Borstel, Germany.
    Beckert, Patrick
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Clark, Taane G.
    London School Hyg and Trop Med, England.
    Maphalala, Gugu
    Minist Heatlh, Swaziland.
    Khumalo, Derrick
    Minist Heatlh, Swaziland.
    Diel, Roland
    University Hospital Schleswig Holstein, Germany.
    Klaos, Kadri
    Tartu University Hospital, Estonia.
    Lin Aung, Htin
    University of Otago, New Zealand; University of Auckland, New Zealand.
    Cook, Gregory M.
    University of Otago, New Zealand; University of Auckland, New Zealand.
    Parkhill, Julian
    Wellcome Trust Sanger Institute, England.
    Peacock, Sharon J.
    Wellcome Trust Sanger Institute, England; London School Hyg and Trop Med, England; University of Cambridge, England.
    Swaminathan, Soumya
    Indian Council Medical Research, India.
    Viveiros, Miguel
    University of Nova Lisboa, Portugal.
    Niemann, Stefan
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Krause, Kurt L.
    University of Auckland, New Zealand; University of Otago, New Zealand.
    Koser, Claudio U.
    University of Cambridge, England.
    Role of Alanine Racemase Mutations in Mycobacterium tuberculosis D-Cycloserine Resistance2017Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, nr 12, artikkel-id e01575-17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to D-cycloserine.

  • 44.
    Niward, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Towards individualised treatment of tuberculosis2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Each year, around 10 million of individuals develop active tuberculosis (TB). Worldwide, TB is the leading cause of death from an infectious agent surpassing both malaria and HIV. Current treatment regimens are long and therefore encompass a risk of nonadherence and development of acquired drug-resistance, reflected in the increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Indeed, this calls for prudent use of existing TB drugs and improvement of TB treatment strategies. The aim of this thesis was to investigate the current drug susceptibility testing (DST) breakpoints for Mycobacterium tuberculosis (M. tuberculosis), the pharmacokinetics and pharmacodynamics (PK/PD) of TB treatment and to explore the role of therapeutic drug monitoring (TDM) for optimising TB treatment.

    Drug resistance in M. tuberculosis is expressed over a continuous scale and for some drugs it may be identified as low- and high-level resistance. This has been poorly reflected in currently used binary susceptibility breakpoints for TB drugs. Results from genome sequencing and phenotypic DST of ofloxacin and levofloxacin were compared in study I and current breakpoints were found to misclassify up to 25% of M. tuberculosis isolates with resistance mutations in gyrA as susceptible to fluoroquinolones. This finding may have implications for the classification of XDR-TB, treatment of MDR-TB and the evaluation of fluoroquinolones in clinical studies.

    Study II was a prospective cohort study of susceptible TB in Sweden, where drug concentrations of first-line TB drugs were measured along with the susceptibility level of the bacteria defined by the minimum inhibitory concentration (MIC) of M. tuberculosis. First-line drug concentrations below the reference range (16-42%) were common and most pronounced for rifampicin (13/31, 42%). An exploratory investigation of PK/PD parameters displayed a wide distribution of ratios between drug exposures and MICs. Rifampicin exhibited higher level of individual fluctuations over time during TB treatment compared with isoniazid. In study III the plasma drug concentrations of rifampicin were compared to the tuberculosis drug activity assay (TDA) and results showed that rifampicin drug levels, but not drug levels of the other first-line drugs, correlated with TDA. Patients with rifampicin drug levels below 8 mg/L had significantly lower median TDA. This finding supports the use of TDA as a potential indicator for low rifampicin exposure in resource-constrained settings without access to drug concentration analysis. The study design in study II has been further developed in study IV, which is a prospective cohort study of MDR-TB in China, where drug exposure will be explored in relation to individual bacterial MIC and measurements of treatment outcome.

    In summary, the work in this thesis emphasises the importance of reliable DST of M. tuberculosis and the need to re-evaluate the currently used breakpoints. Therapeutic drug monitoring (TDM) based on drug concentrations and MICs is a useful tool to avoid suboptimal drug exposure and to individualise TB treatments. Such strategies may improve treatment regimens and avoid further development of resistance.

    Delarbeid
    1. Susceptibility testing breakpoints for Mycobacterium tuberculosis categorize isolates with resistance mutations in gyrA as susceptible to fluoroquinolones: implications for MDR-TB treatment and the definition of XDR-TB.
    Åpne denne publikasjonen i ny fane eller vindu >>Susceptibility testing breakpoints for Mycobacterium tuberculosis categorize isolates with resistance mutations in gyrA as susceptible to fluoroquinolones: implications for MDR-TB treatment and the definition of XDR-TB.
    Vise andre…
    2016 (engelsk)Inngår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, nr 2, s. 333-338Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES: Fluoroquinolones (FQs) are important in the treatment of MDR-TB and in the definition of XDR-TB. Our objective was to investigate how discrepancies in the phenotypic and genotypic methods for antimicrobial susceptibility testing could affect the interpretation of antimicrobial susceptibility test results.

    METHODS: We analysed MICs of ofloxacin and levofloxacin in Middlebrook 7H10 broth (7H10) as well as sequencing of the quinolone resistance-determining region of the gyrA gene and the MTBDRsl assay in 75 resistant isolates, including MDR and XDR strains of Mycobacterium tuberculosis.

    RESULTS: Among 75 resistant isolates, 27 had mutations associated with FQ resistance. Among isolates with resistance mutations in gyrA, 26% (seven of 27) were susceptible to levofloxacin and ofloxacin by phenotypic testing at 1 mg/L and 2 mg/L. The most common mutation was in codon 94 and these isolates had significantly increased MICs of levofloxacin (2-8 mg/L) compared with isolates with mutations in codon 90 (0.25-2 mg/L, P < 0.05). The sensitivity and specificity for the MTBDRsl assay compared with gyrA sequencing were 96% and 98%, respectively.

    CONCLUSION: Current critical concentrations may classify up to 26% of isolates with gyrA mutations as susceptible to FQs due to a close relationship between susceptible and resistant populations. These results should be considered while improving clinical breakpoints for M. tuberculosis and may have an impact on the definition of XDR-TB.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-124557 (URN)10.1093/jac/dkv353 (DOI)000372427600008 ()26538509 (PubMedID)
    Merknad

    Funding agencies: Heart and Lung Foundation; Swedish Society of Antimicrobial Chemotherapy (SSAC); Swedish Medical Association; Marianne and Marcus Wallenberg Foundation

    Tilgjengelig fra: 2016-02-03 Laget: 2016-02-03 Sist oppdatert: 2019-04-24
    2. Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
    Åpne denne publikasjonen i ny fane eller vindu >>Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
    Vise andre…
    2018 (engelsk)Inngår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, nr 10, s. 2838-2845Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (amp;lt;8 mg/L), 19% for isoniazid (amp;lt;3 mg/L), 27% for pyrazinamide (amp;lt;35 mg/L) and 16% for ethambutol (amp;lt;2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

    sted, utgiver, år, opplag, sider
    OXFORD UNIV PRESS, 2018
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-153707 (URN)10.1093/jac/dky268 (DOI)000452914200032 ()30124844 (PubMedID)
    Merknad

    Funding Agencies|Research Council of Southeast Sweden; Region of Ostergotland; Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Swedish Research Council; Stockholm County Council [ALF20160331]

    Tilgjengelig fra: 2019-01-07 Laget: 2019-01-07 Sist oppdatert: 2019-05-02
    3. Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
    Åpne denne publikasjonen i ny fane eller vindu >>Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
    Vise andre…
    2018 (engelsk)Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, nr 5, artikkel-id e00218-18Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h post-dose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.

    sted, utgiver, år, opplag, sider
    AMER SOC MICROBIOLOGY, 2018
    Emneord
    pharmacokinetics; Mycobacterium tuberculosis; rifampin; isoniazid
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-147915 (URN)10.1128/AAC.00218-18 (DOI)000431341200022 ()29483112 (PubMedID)
    Merknad

    Funding Agencies|Research Council of Southeast Sweden (FORSS); Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Region of Ostergotland, Sweden; Swedish Research Council

    Tilgjengelig fra: 2018-05-23 Laget: 2018-05-23 Sist oppdatert: 2019-05-01
    4. Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study
    Åpne denne publikasjonen i ny fane eller vindu >>Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study
    Vise andre…
    2018 (engelsk)Inngår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, nr 9, artikkel-id e023899Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Introduction Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB. Methods and analysis Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960. Ethics and dissemination This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal. Trial registration number NCT02816931; Pre-results.

    sted, utgiver, år, opplag, sider
    BMJ Publishing Group Ltd, 2018
    Emneord
    tuberculosis; clinical pharmacology; public health; microbiology
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-153393 (URN)10.1136/bmjopen-2018-023899 (DOI)000450417800153 ()30287613 (PubMedID)2-s2.0-85054436449 (Scopus ID)
    Merknad

    Funding Agencies|Swedish Heart Lung Foundation [20150508]; Swedish National Research Council [540-2013-8797]; National Research Foundation of China [81361138019]

    Tilgjengelig fra: 2018-12-17 Laget: 2018-12-17 Sist oppdatert: 2019-05-01bibliografisk kontrollert
  • 45.
    Niward, Katarina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Davies Forsman, Lina
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Chryssanthou, Erja
    Karolinska Univ Hosp Solna, Sweden; Karolinska Inst, Sweden.
    Carlström, Oskar
    Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Alomari, Teba
    Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Pohanka, Anton
    Karolinska Univ Hosp Huddinge, Sweden.
    Mansjö, Mikael
    Publ Hlth Agcy Sweden, Sweden.
    Jonsson Nordvall, Michaela
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk mikrobiologi.
    Johansson, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk mikrobiologi.
    Eliasson, Erik
    Karolinska Univ Hosp Huddinge, Sweden.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Sweden.
    Paues, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Simonsson, Ulrika S. H.
    Uppsala Univ, Sweden.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Kalmar Cty Hosp, Sweden.
    Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting2018Inngår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, nr 10, s. 2838-2845Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (amp;lt;8 mg/L), 19% for isoniazid (amp;lt;3 mg/L), 27% for pyrazinamide (amp;lt;35 mg/L) and 16% for ethambutol (amp;lt;2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

  • 46.
    Nordenfelt, Patrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Hereditary Angioedema in Sweden: a National Project2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Hereditary angioedema (HAE) due to C1-inhibitor deficiency, type I and II, is a rare disease with an estimated prevalence of 1/50,000. Angioedema in the larynx can be life threatening and angioedema in the abdomen and skin can give severe and disabling pain. Data on patients with HAE in Sweden were scarce before our study.

    Aim: To study the prevalence of HAE, and to investigate clinical manifestations, treatments, and Health-Related Quality of Life (HR-QoL) in adults and children in Sweden.

    Method: In studies, I and II, all patients received a written questionnaire followed by a phone interview with questions about clinical manifestations, medication, sick leave and QoL. In study III the patients completed EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaires for both the attack-free state (EQ5D today), and the last HAE attack (EQ5D attack). Questions were also asked about sick-leave. In study IV all adults received questionnaires with EQ-5D-5L and RAND-36, Angioedema Quality of Life instrument (AE-QoL), and Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication.

    Results: We identified 146 patients, 110 adults and 36 children with HAE, type I (n=136) or II (n=10), giving a minimal HAE prevalence of 1.54/100,000. For adults, the median age at onset of symptoms was 12 years and median age at diagnosis was 22 years. Median age at onset of symptoms for children was 4 years and at diagnosis 3 years. During the previous year, 47% of adults experienced at least 12 attacks, 21% 4-11 attacks, 11% 1-3 attacks, while 22% were asymptomatic. For children, the corresponding figures were about the same. The median number of attacks in those having attacks was 14 in adults and 6 in children last year. Adult females reported on average 19 attacks the previous year versus nine for males. Irrespective of location nine out of 10 reported pain. Trigger factors were experienced in 95 % of adults and 74 % of children. Plasma-derived C1-inhibitor concentrate (pdC1INH) had a very good effect on acute attacks. Long-term prophylaxis with androgens and pdC1INH reduced the annual attack frequency by more than 50 %. Of the children’s parents, 73% had been on parental leave to care for the child due to HAE symptoms. Health and QoL were generally rated as good. In study III 103 of 139 responded and reported an EQ5D today score that was significantly higher than the EQ5D attack score. Attack frequency had a negative effect on EQ5D today. Children had significantly higher EQ-5D-5L than adults. Forty four percent had been absent from work or school during the latest attack. In study IV 64 of 133 adults responded. The most affected HR-QoL dimensions in EQ-5D-5L were pain/discomfort and anxiety/depression, in RAND-36 energy/fatigue, general health, health transition, pain, and in AE-QoL fears/shame and fatigue/mood. Females had significantly lower HR-QoL in RAND-36 for general health and energy/fatigue. There was an association between AAS and EQ-5D-5L/RAND-36 (except physical function) /AEQoL. There was no significant difference in HR-QoL in patients with and without prophylactic medication.

    Conclusion: The minimal prevalence of HAE type I and II in Sweden is 1.54/100,000. Median age at onset was 12 years. Adult females had twice as many attacks as males, adults had also twice as many attacks as children. For acute treatment, pdC1INH had a very good effect. For long term prophylaxis, androgens and pdC1INH had good effect. The most affected HR-QoL dimensions in EQ-5D-5L were pain/discomfort and anxiety/ depression, in RAND-36 energy/fatigue, general health, health transition and pain, and in AE-QoL fears/shame and fatigue/mood. Children reported better HR-QoL than adults. AE-QoL is more disease-specific in HAE than the generic instruments EQ-5D-5L and RAND-36. However, the latter highlights the pain aspect, whereas AE-QoL does not. Patients with high disease activity should thus be considered for more intensive treatment to improve their HR-QoL.

    Delarbeid
    1. Hereditary Angioedema in Swedish Adults: Report From the National Cohort
    Åpne denne publikasjonen i ny fane eller vindu >>Hereditary Angioedema in Swedish Adults: Report From the National Cohort
    Vise andre…
    2016 (engelsk)Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 96, nr 4, s. 540-545Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Hereditary angioedema (HAE) is rare, disabling and sometimes life-threatening. The aim of this study is to describe its prevalence, symptomatology and treatment in Sweden. A total of 146 patients were identified; 110 adults and 36 children with HAE type I (n = 136) or II (n = 10), giving a minimum HAE prevalence of 1.54/100,000. All patients received a written questionnaire followed by a structured telephone interview. This report focuses on the 102 adults who responded. Females reported 19 attacks in the previous year vs. 9 for males (p &lt; 0.01), and females reported 10 days of sick leave vs. 4 days for males (p &lt; 0.05). For all treated acute attacks, plasma-derived Cl-inhibitor concentrate (pdClINH) (used in 27% of patients) had a good effect. For maintenance treatment, 43% used attenuated androgens and 8% used pdClINH, which reduced their attack rate by more than 50%. In conclusion, the minimum HAE prevalence in Sweden was 1.54/100,000. HAE affected females more severely. Attenuated androgens and pdClINH had a good effect on preventing attacks.

    sted, utgiver, år, opplag, sider
    ACTA DERMATO-VENEREOLOGICA, 2016
    Emneord
    Clinhibitor deficiency; census; clinical manifestations; epidemiology; hereditary angioedema; prevalence; Sweden
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-128976 (URN)10.2340/00015555-2274 (DOI)000375741300022 ()26540175 (PubMedID)
    Merknad

    Funding Agencies|Futurum the Academy for Healthcare; Jonkoping County Council; Linkoping University; Karolinska Institutet

    Tilgjengelig fra: 2016-06-09 Laget: 2016-06-07 Sist oppdatert: 2018-03-19
    2. Swedish children with hereditary angioedema report good overall health and quality of life despite symptoms
    Åpne denne publikasjonen i ny fane eller vindu >>Swedish children with hereditary angioedema report good overall health and quality of life despite symptoms
    Vise andre…
    2016 (engelsk)Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, nr 5, s. 529-534Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    AimFew studies have been published on children with hereditary angioedema (HAE), an autosomal dominant disease caused by mutations on chromosome 11. This study explored various aspects of the disease in the Swedish paediatric population. MethodsA retrospective questionnaire was sent to all 36 Swedish children known to have HAE, and a physician carried out follow-up telephone interviews. ResultsMost of the questionnaires were completed by the parents of 31 (86%) children with HAE, with or without their input, at a median age of nine years (range 1-17), and the physician also interviewed 29. HAE symptoms were experienced by 23 children, including abdominal attacks (96%), skin swelling (78%) and swelling in the mouth and/or upper airways (52%). Psychological stress was the most common trigger for abdominal attacks and trauma and sports triggered skin swelling. The majority (n = 19) had access to complement-1 esterase inhibitor concentrate at home. Current health and quality of life were generally rated as good, independent of whether the child had experienced HAE symptoms or not. ConclusionMost children with HAE had experienced abdominal attacks and skin swelling, but their overall health and quality of life were generally perceived to be good.

    sted, utgiver, år, opplag, sider
    WILEY-BLACKWELL, 2016
    Emneord
    Children; Complement-1 esterase inhibitor defects; Epidemiology; Hereditary angioedema; Symptoms
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-127743 (URN)10.1111/apa.13345 (DOI)000373921200028 ()26821285 (PubMedID)
    Merknad

    Funding Agencies|Futurum - the Academy for Health and Care; Region Jonkoping County; Linkoping University; Karolinska Institutet

    Tilgjengelig fra: 2016-05-12 Laget: 2016-05-12 Sist oppdatert: 2017-11-30
    3. Quantifying the burden of disease and perceived health state in patients with hereditary angioedema in Sweden
    Åpne denne publikasjonen i ny fane eller vindu >>Quantifying the burden of disease and perceived health state in patients with hereditary angioedema in Sweden
    Vise andre…
    2014 (engelsk)Inngår i: Allergy and Asthma Proceedings, ISSN 1088-5412, E-ISSN 1539-6304, Vol. 35, nr 2, s. 185-190Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Hereditary angioedema (HAE) due to C1 inhibitor deficiency is a rare disease characterized by attacks of edema, known to impact quality of life (QoL). This study investigates the burden of HAE in Swedish patients, both children and adults. We used a retrospective registry study of Swedish patients with HAE, captured by the Sweha-Reg census. Data were collected using a paper-based survey. Patients completed EuroQoL 5 Dimensions 5 Levels (EQ5D-5L) questionnaires for both the attack-free state (EQ5D today), and the last HAE attack (EQ5D attack). Questions related to patients age and sex and other variables, such as attack location and severity, were included to better understand the burden of HAE. EQ5D-5L values were estimated for the two HAE disease states. Patient-reported sick leave was also analyzed. A total of 103 responses were analyzed from 139 surveys (74% response rate). One hundred one reported an EQ5D today score (mean, 0.825) and 78 reported an EQ5D attack score (mean, 0.512) with significant differences between the two states (p less than 0.0001). This difference was observed for both mild (p less than 0.05), moderate (p less than 0.0001), and severe attacks (p less than 0.0001). Attack frequency had a negative effect on EQ5D today. Patients with greater than30 attacks a year had a significantly lower EQ5D today score than those with less frequent attacks. Of 74 participants, 33 (44.6%) had been absent from work or school during the latest attack and, of those with a severe attack, 81% had been absent. HAE has a significant impact on QoL both during and between attacks and on absenteeism during attacks.

    sted, utgiver, år, opplag, sider
    OceanSide Publications; 1999, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-106024 (URN)10.2500/aap.2014.35.3738 (DOI)000333071700015 ()
    Tilgjengelig fra: 2014-04-17 Laget: 2014-04-17 Sist oppdatert: 2017-12-05
    4. Health-related quality of life in relation to disease activity in adults with hereditary angioedema in Sweden
    Åpne denne publikasjonen i ny fane eller vindu >>Health-related quality of life in relation to disease activity in adults with hereditary angioedema in Sweden
    Vise andre…
    2017 (engelsk)Inngår i: Allergy and Asthma Proceedings, ISSN 1088-5412, E-ISSN 1539-6304, Vol. 38, nr 6, s. 447-455Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Health-related quality of life (HR-QoL) is impaired in patients with hereditary angioedema (HAE) but has not yet been satisfactorily described.

    Objective: To study HR-QoL in patients with HAE by combining different HR-QoL instruments with disease activity assessment. Methods: All adults in the Swedish HAE registry were invited to take part in this questionnaire study, which used the generic HR-QoL instruments, EuroQol 5 Dimensions 5 Level (EQ-5D-5L) and the RAND Corporation Short Form 36 (RAND-36), the disease-specific Angioedema Quality of Life instrument (AE-QoL), the recently introduced Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication.

    Results: Sixty-four of 133 adults (26 men, 38 women) between 18 and 91 years old responded. The most affected HR-QoL dimensions in the EQ-5D-5L were pain/discomfort and anxiety/depression; in the RAND-36, energy/fatigue, general health, pain; and, in the AE-QoL, fears/shame and fatigue/mood. Women had lower HR-QoL in the RAND-36 for general health and energy/fatigue (p < 0.05). Patients who reported any AAS of >0 had significantly impaired HR-QoL. There were significant associations (p < 0.05) between the AAS and EQ-5D-5L, between the AAS and all dimensions of the RAND-36 except physical function, and between the AAS and AE-QoL in all dimensions. Nine of 36 patients who reported sick leave during the previous 4 weeks had significantly impaired HR-QoL in all the instruments (p < 0.05). There was no significant difference in HR-QoL in the patients with and the patients without prophylactic medication, except for the nutrition dimension of the AE-QoL (p < 0.05).

    Conclusion: Comprehensive information is obtained by combining different HR-QoL instruments. Pain, anxiety/depression, and fatigue/mood are important aspects of HAE but the AE-QoL disregards pain. HR-QoL was not significantly affected by prophylaxis. Increased disease activity was associated with impaired HR-QoL, which justifies more active disease management.

    sted, utgiver, år, opplag, sider
    OceanSide Publications, 2017
    Emneord
    AAS; AE-QoL; C1-inhibitor deficiency; EQ-5D-5L; HAE; HR-QoL; RAND-36; Sweden; disease activity; prophylaxis; sex differences; sick leave; the Svensson method
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-142205 (URN)10.2500/aap.2017.38.4087 (DOI)000415839200009 ()28855002 (PubMedID)
    Merknad

    Funding agencies: Karolinska Institutet; Stockholm County Council, Stockholm; Futurum; Jonkoping County Council, Jonkoping; Linkoping University, Linkoping, Sweden; CSL Behring; Shire; Galderma; Novartis

    Tilgjengelig fra: 2017-10-23 Laget: 2017-10-23 Sist oppdatert: 2018-03-28bibliografisk kontrollert
  • 47.
    Nordin, Gunnar
    et al.
    Equalis, Sweden.
    Dybkaer, Rene
    Copenhagen Univ Hosp, Denmark.
    Forsum, Urban
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk mikrobiologi.
    Fuentes-Arderiu, Xavier
    Clin Lab Sci Consulting, Spain.
    Pontet, Francoise
    Vocabulary on nominal property, examination, and related concepts for clinical laboratory sciences (IFCC-IUPAC Recommendations 2017)2018Inngår i: Pure and Applied Chemistry, ISSN 0033-4545, E-ISSN 1365-3075, Vol. 90, nr 5, s. 913-935Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Scientists of disciplines in clinical laboratory sciences have long worked on a common language for efficient and safe request of investigations, report of results, and communication of experience and - scientific achievements. Widening the scope, most scientific disciplines, not only clinical laboratory sciences, rely to some extent on various examinations in addition to measurements. The International vocabulary of - metrology - Basic and general concepts and associated terms (VIM), is designed for metrology, the science of measurement. The aim of this vocabulary is to suggest definitions and explanations of concepts and a selection of terms related to nominal properties, i.e. properties that have no size.

  • 48.
    Ottosson, Nina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Molecular Mechanisms of Resin Acids and Their Derivatives on the Opening of a Potassium Channel2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Voltage-gated ion channels play fundamental roles in excitable cells, such as neurons, where they enable electric signaling. Normally, this signaling is well controlled, but brain damage, alterations in the ionic composition of the extracellular solution, or dysfunctional ion channels can increase the electrical excitability thereby causing epilepsy. Voltage-gated ion channels are obvious targets for antiepileptic drugs, and, as a rule of thumb, excitability is dampened either by closing voltagegated sodium channels (Nav channels) or by opening voltage-gated potassium channels (Kv channels). For example, several classical antiepileptic drugs block the ion-conducting pore of Nav channels. Despite the large number of existing antiepileptic drugs, one third of the patients with epilepsy suffer from intractable or pharmacoresistant seizures.

    Our research group has earlier described how different polyunsaturated fatty acids (PUFAs) open a Kv channel by binding close to the voltage sensor and, from this position, electrostatically facilitate the movement of the voltage-sensor, thereby opening the channel. However, PUFAs affect a wide range of ion channels, making it difficult to use them as pharmaceutical drugs; it would be desirable to find smallmolecule compounds with an electrostatic, PUFA-like mechanism of action. The aim of the research leading to this thesis was to find, characterize, and refine drug candidates capable of electrostatically opening a Kv channel.

    The majority of the experiments were performed on the cloned Shaker Kv channel, expressed in oocytes from the frog Xenopus laevis, and the channel activity was explored with the two-electrode voltage-clamp technique. By systematically mutating the extracellular end of the channel’s voltage sensor, we constructed a highly PUFAsensitive channel, called the 3R channel. Such a channel is a useful tool in the search for electrostatic Kv-channel openers. We found that resin acids, naturally occurring in tree resins, act as electrostatic Shaker Kv channel openers. To explore the structure-activity relationship in detail, we synthesized 120 derivatives, whereof several were potent Shaker Kv channel openers. We mapped a common resin acidbinding site to a pocket formed by the voltage sensor, the channel’s third transmembrane segment, and the lipid membrane, a principally new binding site for small-molecule compounds. Further experiments showed that there are specific interactions between the compounds and the channel, suggesting promises for further drug development. Several of the most potent Shaker Kv channel openers also dampened the excitability in dorsal-root-ganglion neurons from mice, elucidating the pharmacological potency of these compounds. In conclusion, we have found that resin-acid derivatives are robust Kv-channel openers and potential drug candidates against diseases caused by hyperexcitability, such as epilepsy.

    Delarbeid
    1. Drug-induced ion channel opening tuned by the voltage sensor charge profile
    Åpne denne publikasjonen i ny fane eller vindu >>Drug-induced ion channel opening tuned by the voltage sensor charge profile
    2014 (engelsk)Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 143, nr 2, s. 173-182Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseases. Here, we show that arginines on one side of the helical K-channel voltage sensor S4 increased the sensitivity to docosahexaenoic acid (DHA), whereas arginines on the opposing side decreased this sensitivity. Glutamates had opposite effects. In addition, a positively charged DHA-like molecule, arachidonyl amine, had opposite effects to the negatively charged DHA. This suggests that S4 rotates to open the channel and that DHA electrostatically affects this rotation. A channel with arginines in positions 356, 359, and 362 was extremely sensitive to DHA: 70 mu M DHA at pH 9.0 increased the current greater than500 times at negative voltages compared with wild type (WT). The small-molecule compound pimaric acid, a novel Shaker channel opener, opened the WT channel. The 356R/359R/362R channel drastically increased this effect, suggesting it to be instrumental in future drug screening.

    sted, utgiver, år, opplag, sider
    Rockefeller University Press, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-105035 (URN)10.1085/jgp.201311087 (DOI)000330628500006 ()
    Tilgjengelig fra: 2014-03-06 Laget: 2014-03-06 Sist oppdatert: 2018-01-25
    2. Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability
    Åpne denne publikasjonen i ny fane eller vindu >>Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability
    Vise andre…
    2015 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, nr 13278Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.

    sted, utgiver, år, opplag, sider
    Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-121307 (URN)10.1038/srep13278 (DOI)000359905300001 ()26299574 (PubMedID)
    Merknad

    Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; ALF; County Council of Ostergotland

    Tilgjengelig fra: 2015-09-16 Laget: 2015-09-14 Sist oppdatert: 2018-01-25bibliografisk kontrollert
  • 49.
    Patzelt, Alexa
    et al.
    Charite, Germany.
    Cheung Mak, Wing
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Jung, Sora
    Charite, Germany.
    Knorr, Fanny
    Charite, Germany.
    Meinke, Martina C.
    Charite, Germany.
    Richter, Heike
    Charite, Germany.
    Ruehl, Eckart
    Free University of Berlin, Germany.
    Cheung, Kitt
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Tran, Ngo Bich Nga Nathalie
    Charite, Germany.
    Lademann, Juergen
    Charite, Germany.
    Do nanoparticles have a future in dermal drug delivery?2017Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 246, s. 174-182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    More and more investigations confirm that nanoparticles are incapable of overcoming the intact skin barrier in vivo. Do nanoparticles still have a future in dermal drug delivery? Unlike many other topically applied substances, nanoparticles have not been reported to utilize the intercellular penetration pathway and preferentially make use of the follicular penetration pathway. Deep penetration into the follicular ducts has been described for a variety of particles and appears to be strongly influenced by particle size. For targeted drug delivery, smart nanoparticles are required which are able to release their loaded drugs subsequent to internal or external trigger stimuli, and thereby enable the translocation of the active agents into the viable epidermis. In the recent manuscript, three nanoparticles systems are summarized and compared which release their model drugs upon different trigger mechanisms. The BSA hydrogel nanoparticles release their model drug TRITC-dextran by passive diffusion due to a concentration gradient via a porous surface. The protease-triggered controlled release BSA nanoparticles release their model drug if they are applied simultaneously with protease nanoparticles, resulting in an enzymatic degradation of the particles and a release of the model drug FITC. Finally, the IR-triggered controlled release AuNP-doped BSA nanoparticles release their model drug FITC after photoactivation with wIRA. For all three nanoparticle systems, the release of their model drugs could be observed. For the first nanoparticle system, only low follicular penetration depths were found which might by due do an agglomeration effect. For the last two nanoparticle systems, deep follicular penetration and even an uptake by the sebaceous glands were verified. In conclusion, it could be demonstrated that nanoparticles do have a future in dermal drug delivery if smart nanoparticle systems are utilized which are able to release their drug at specific times and locations within the hair follicle. (C) 2016 Elsevier B.V. All rights reserved.

  • 50.
    Perego, Paola
    et al.
    Fdn IRCCS Ist Nazl Tumori, Italy.
    Hempel, Georg
    Westfalische Wilhelms Univ Munster, Germany.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Bradshaw, Tracey D.
    Univ Nottingham, England.
    Larsen, Annette K.
    INSERM U938, France; Sorbonne Univ, France.
    Peters, Godefridus J.
    Vrije Univ Amsterdam, Netherlands.
    Phillips, Roger M.
    Univ Huddersfield, England.
    Cellular pharmacology studies of anticancer agents: recommendations from the EORTC-PAMM group2018Inngår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 81, nr 3, s. 427-441Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    An increasing number of manuscripts focus on the in vitro evaluation of established and novel anti-tumor agents in experimental models. Whilst the design of such in vitro assays is inherently flexible, some of these studies lack the minimum information necessary to critically evaluate their relevance or have been carried out under unsuitable conditions. The use of appropriate and robust methods and experimental design has important implications for generating results that are reliable, relevant, and reproducible. The Pharmacology and Molecular Mechanisms (PAMM) group of the European Organization for Research and Treatment of Cancer (EORTC) is the largest group of academic scientists working on drug development and bundle decades of expertise in this field. This position paper addresses all researchers with an interest in the preclinical and cellular pharmacology of anti-tumor agents and aims at generating basic recommendations for the correct use of compounds to be tested for anti-tumor activity using a range of preclinical cellular models of cancer.

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