liu.seSearch for publications in DiVA
Change search
Refine search result
123 1 - 50 of 120
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Almquist, Joachim
    et al.
    AstraZeneca, Sweden; Fraunhofer Chalmers Ctr, Sweden; AstraZeneca, Sweden.
    Rikard, S. Michaela
    Univ Virginia, VA USA.
    Wagberg, Maria
    AstraZeneca, Sweden.
    Bruce, Anthony C.
    Univ Virginia, VA USA.
    Gennemark, Peter
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. AstraZeneca, Sweden.
    Fritsche-Danielson, Regina
    AstraZeneca, Sweden.
    Chien, Kenneth R.
    Karolinska Inst, Sweden.
    Peirce, Shayn M.
    Univ Virginia, VA USA.
    Hansson, Kenny
    AstraZeneca, Sweden.
    Lundahl, Anna
    AstraZeneca, Sweden.
    Model-Based Analysis Reveals a Sustained and Dose-Dependent Acceleration of Wound Healing by VEGF-A mRNA (AZD8601)2020In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 9, no 7, p. 384-394Article in journal (Refereed)
    Abstract [en]

    Intradermal delivery of AZD8601, an mRNA designed to produce vascular endothelial growth factor A (VEGF-A), has previously been shown to accelerate cutaneous wound healing in a murine diabetic model. Here, we develop population pharmacokinetic and pharmacodynamic models aiming to quantify the effect of AZD8601 injections on the dynamics of wound healing. A dataset of 584 open wound area measurements from 131 mice was integrated from 3 independent studies encompassing different doses, dosing timepoints, and number of doses. Evaluation of several candidate models showed that wound healing acceleration is not likely driven directly by time-dependent VEGF-A concentration. Instead, we found that administration of AZD8601 induced a sustained acceleration of wound healing depending on the accumulated dose, with a dose producing 50% of the maximal effect of 92 mu g. Simulations with this model showed that a single dose of 200 mu g AZD8601 can reduce the time to reach 50% wound healing by up to 5 days.

    Download full text (pdf)
    fulltext
  • 2.
    Amini, Mahdi
    et al.
    Department of Obstetrics and Gynecology, Skåne University Hospital, Lund, Sweden.
    Reis, Margareta
    Department of Clinical Chemistry and Pharmacology, Skåne University Hospital, Lund, Sweden.
    Wide-Swensson, Dag
    Department of Obstetrics and Gynecology, Skåne University Hospital, Lund, Sweden.
    A Relative Bioavailability Study of Two Misoprostol Formulations Following a Single Oral or Sublingual Administration2020In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 11, article id 50Article in journal (Refereed)
    Abstract [en]

    Introduction: Misoprostol (Cytotec) was primarily made for treating gastric ulcers. However today it is mostly used for abortion, treating postpartum hemorrhage, and for induction of labor. The tablet contains 200 µg of misoprostol, yet the dosages used for induction of labor are much smaller (25–50 µg), leading to uncertainty of dosage in daily use.

    Aim: To evaluate and compare the relative bioavailability of two misoprostol products (Angusta 25 µg and Cytotec 200 µg tablets) administered orally or sublingually given in a daily clinical setting to women admitted for induction of labor at term.

    Methods: Women carrying a live, singleton fetus in a cephalic position and with a gestational age between 259 and 296 days were included. Blood samples were collected at 0, 5, 10, 20, 30, 40, 50, 75, 100, 120, 180, and 240 minutes. A serum analytical assay was performed and pharmacokinetic parameters were calculated. Patients were assigned to one of three groups.

    Results: A total of 72 patients were included. No significant differences demographic characteristics were found. The ratios for AUC, AUC (0−t), and Cmax were similar in all three groups, but CI-values were outside the required 80–125%. Sublingual administration yielded a 20–30% higher bioavailability and a 50% higher Cmax than compared to the oral route.

    Conclusion: The relative bioavailability between Angusta and Cytotec could not be confirmed as being equal at the 25 µg or 50 µg level because the 90% CI-values when comparing the ratios for AUC, AUC(0−t), and Cmax were wider than accepted. The reason for this could be the real-life, non-standardized circumstances in which the study was conducted. Sublingual administration seems to have higher bioavailability than oral administration. More studies are needed to ascertain an optimal dosage regime balancing both safety and efficacy for mother and child.

    Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02516631.

    Download full text (pdf)
    fulltext
  • 3.
    Andersson, Maria
    et al.
    NIDA, MD 21224 USA.
    Diao, Xingxing
    NIDA, MD 21224 USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. NIDA, MD 21224 USA; National Board Forens Med, 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 spectrometry2016In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, no 8, p. 1067-1078Article in journal (Refereed)
    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

  • 4.
    Andersson, Viktoria
    et al.
    Karolinska Univ Hosp, Sweden.
    Froberg, Gabrielle
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Dahl, Victor
    Aarhus Univ Hosp, Sweden; Aarhus Univ GloHAU, Denmark; Statens Serum Inst, Denmark.
    Chryssanthou, Erja
    Karolinska Univ Hosp, Sweden.
    Giske, Christian
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Schön, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Infectious Diseases. Karolinska Univ Hosp, Sweden.
    Forsman, Lina
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    The In vitro Activity of Carbapenems Alone and in Combination with β-lactamase Inhibitors against Difficult-to-treat Mycobacteria; Mycobacterium tuberculosis, Mycobacterium abscessus, and Mycobacterium avium Complex: A Systematic Review2023In: INTERNATIONAL JOURNAL OF MYCOBACTERIOLOGY, ISSN 2212-5531, Vol. 12, no 3, p. 211-225Article, review/survey (Refereed)
    Abstract [en]

    Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium tuberculosis (MTB), as well as nontuberculous mycobacteria such as the Mycobacterium abscessus complex (MABC) and Mycobacterium avium complex (MAC). Recently, new carbapenems and combinations of carbapenems with beta-lactamase inhibitors have become available, but activity data in vitro against mycobacteria are so far scarce. Therefore, we performed a systematic review collating the minimum inhibitory concentrations (MICs) of carbapenems, with or without a beta-lactamase inhibitors for MTB, MABC, and MAC. The databases PubMed and Web of Science were searched for the relevant articles in English up until September 21, 2022. Screening of studies was performed by two independent reviewers. MIC data by recommended methods with at least five individual MICs were included. Data were reported as MIC range, MIC50, modal MIC, and/or histograms when individual MICs were available. The study protocol was registered at PROSPERO (CRD42021258537). After screening, a total of 75 studies with MIC data for carbapenems with or without beta-lactamase inhibitors were included in the review. For MTB, the oral carbapenem tebipenem combined with the beta-lactamase inhibitor clavulanic acid resulted in the most significant reduction of MICs. For MABC, the addition of avibactam to tebipenem resulted in a 64-fold reduction of modal MIC. Data were insufficient for the analysis of MAC. Carbapenems, and in particular the novel oral compound tebipenem, in combination with clavulanic acid for MTB and avibactam for MABC may be an untapped potential for difficult-to-treat mycobacterial infections.

  • 5.
    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
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    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 tribute2009In: The Lichenologist, ISSN 0024-2829, E-ISSN 1096-1135, Vol. 41, no 5, p. 453-456Article in journal (Other academic)
    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.

  • 6. Order onlineBuy this publication >>
    Aziz, Abdul Maruf Asif
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders2017Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Open this publication in new window or tab >>The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Show others...
    2016 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 19-20, p. 3553-3563Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Springer, 2016
    Keywords
    Nociception/orphanin FQ, Agonist, Wistar rat, Alcohol, Operant, Reinstatement, Elevated plus-maze
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-132347 (URN)10.1007/s00213-016-4385-8 (DOI)000383672500006 ()27515665 (PubMedID)
    Note

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

    Available from: 2016-11-12 Created: 2016-11-01 Last updated: 2017-08-21Bibliographically approved
    2. Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Open this publication in new window or tab >>Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Show others...
    2016 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, no 10, p. 2199-2207Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2016
    Keywords
    Alcohol Escalation, Reward, Motivation, Calorie Intake, Melanin-Concentrating Hormone Receptor-1
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-132522 (URN)10.1111/acer.13181 (DOI)000385542900017 ()27579857 (PubMedID)
    Available from: 2016-11-14 Created: 2016-11-13 Last updated: 2018-03-19Bibliographically approved
    Download full text (pdf)
    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders
    Download (pdf)
    omslag
    Download (jpg)
    presentationsbild
  • 7.
    Bandyopadhyay, Souvik K.
    et al.
    GlaxoSmithKline Asia Pvt. Ltd., Bangalore, India.
    Azharuddin, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. 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 Benefits2019In: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 7, p. 163-Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 8.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Patra, Hirak
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Department of Chemical Engineering and Biotechnology, University of Cambridge, UK; Wolfson College, University of Cambridge, UK.
    Adding nanotechnology to the metastasis treatment arsenal2019In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 40, no 6, p. 403-418Article, review/survey (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 9.
    Barranco, Isabel
    et al.
    Univ Murcia, Spain; Univ Girona, Spain.
    Padilla, Lorena
    Univ Murcia, Spain.
    Perez-Patino, Cristina
    Univ Murcia, Spain.
    Vazquez, Juan M.
    Univ Murcia, Spain.
    Martinez, Emilio A.
    Univ Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Roca, Jordi
    Univ Murcia, Spain.
    Parrilla, Inmaculada
    Univ Murcia, Spain.
    Seminal Plasma Cytokines Are Predictive of the Outcome of Boar Sperm Preservation2019In: Frontiers in Veterinary Science, E-ISSN 2297-1769, Vol. 6, article id 436Article in journal (Refereed)
    Abstract [en]

    Background: Boar seminal plasma is rich in cytokines, which could influence the capability of spermatozoa to tolerate preservation.

    Objectives: To evaluate the involvement of boar seminal plasma cytokines in the changes experienced by boar spermatozoa during their storage, either in liquid or frozen state.

    Materials and Methods: In two separated experiments, semen samples from healthy and fertile boars were split in two aliquots, one centrifuged twice (1,500 ×g for 10 min) to harvest seminal plasma, whereas the other was either commercially extended (3 × 107 sperm/mL) and liquid-stored at 17°C during 144 h (n = 28, Experiment 1) or frozen-thawed using a standard 0.5 mL protocol (n = 27, Experiment 2). Sixteen cytokines were quantified using Luminex xMAP®. Sperm attributes (CASA-evaluated total and progressive motility; flow cytometry-evaluated sperm viability, production of intracellular H2O2 and O2•-" role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">O∙−2O2•- and levels of lipid peroxidation in viable spermatozoa) were evaluated either at 0, 72, or 144 h of liquid storage (Experiment 1) or before freezing and at 30- and 150-min post-thawing (Experiment 2).

    Results: Multiple linear regression models, with Bayesian approach for variable selection, revealed that the anti-inflammatory TGF-β2, TGF-β3, IL-1Ra, and IL-4 and the pro-inflammatory IL-8 and IL-18, predicted changes in sperm motility for liquid-stored semen while the anti-inflammatory IFN-γ was included in the models predicting changes in all sperm attributes for cryopreserved semen.

    Conclusion: Specific boar seminal plasma cytokines would contribute to modulate the structural and metabolic changes shown by spermatozoa during preservation, either in liquid or frozen state.

    Download full text (pdf)
    fulltext
  • 10.
    Belal, Amany
    et al.
    Taif Univ, Saudi Arabia.
    Mahmoud, Rehab
    Beni Suef Univ, Egypt.
    Mohamed, Eman E.
    Beni Suef Univ, Egypt.
    Farghali, Ahmed
    Beni Suef Univ, Egypt.
    El-Ela, Fatma I. Abo
    Beni Suef Univ, Egypt.
    Gamal, Amr
    Beni Suef Univ, Egypt.
    Halfaya, Fatma Mohamed
    Beni Suef Univ, Egypt.
    Khaled, Esraa
    Beni Suef Univ, Egypt.
    Farahat, Abdelbasset A.
    Calif Northstate Univ, CA 95757 USA; Mansoura Univ, Egypt.
    Hassan, Ahmed H. E.
    Mansoura Univ, Egypt; Kyung Hee Univ, South Korea.
    Ghoneim, Mohammed M.
    AlMaarefa Univ, Saudi Arabia.
    Taha, Mohamed
    Beni Suef Univ, Egypt.
    Zaky Khalifa, Mohamed Yassin Zaky
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Beni Suef Univ, Egypt.
    A Novel Hydroxyapatite/Vitamin B-12 Nanoformula for Treatment of Bone Damage: Preparation, Characterization, and Anti-Arthritic, Anti-Inflammatory, and Antioxidant Activities in Chemically Induced Arthritic Rats2023In: Pharmaceuticals, E-ISSN 1424-8247, Vol. 16, no 4, article id 551Article in journal (Refereed)
    Abstract [en]

    The usage of nanomaterials for rheumatoid arthritis (RA) treatment can improve bioavailability and enable selective targeting. The current study prepares and evaluates the in vivo biological effects of a novel hydroxyapatite/vitamin B-12 nanoformula in Complete Freunds adjuvant-induced arthritis in rats. The synthesized nanoformula was characterized using XRD, FTIR, BET analysis, HERTEM, SEM, particle size, and zeta potential. We synthesized pure HAP NPs with 71.01% loading weight percentages of Vit B12 and 49 mg/g loading capacity. Loading of vitamin B-12 on hydroxyapatite was modeled by Monte Carlo simulation. Anti-arthritic, anti-inflammatory, and antioxidant effects of the prepared nanoformula were assessed. Treated arthritic rats showed lower levels of RF and CRP, IL-1 beta, TNF-alpha, IL-17, and ADAMTS-5, but higher IL-4 and TIMP-3 levels. In addition, the prepared nanoformula increased GSH content and GST antioxidant activity while decreasing LPO levels. Furthermore, it reduced the expression of TGF-beta mRNA. Histopathological examinations revealed an improvement in joint injuries through the reduction of inflammatory cell infiltration, cartilage deterioration, and bone damage caused by Complete Freunds adjuvant. These findings indicate that the anti-arthritic, antioxidant, and anti-inflammatory properties of the prepared nanoformula could be useful for the development of new anti-arthritic treatments.

    Download full text (pdf)
    fulltext
  • 11.
    Belal, Amany
    et al.
    Taif Univ, Saudi Arabia.
    Mahmoud, Rehab
    Beni Suef Univ, Egypt.
    Taha, Mohamed
    Beni Suef Univ, Egypt.
    Halfaya, Fatma Mohamed
    Beni Suef Univ, Egypt.
    Hassaballa, Ahmed
    Wayne State Univ, MI 48202 USA; ZeroHarm LC, MI 48333 USA.
    Elbanna, Esraa Salah
    Beni Suef Univ, Egypt.
    Khaled, Esraa
    Beni Suef Univ, Egypt.
    Farghali, Ahmed
    Beni Suef Univ, Egypt.
    Abo El-Ela, Fatma I.
    Beni Suef Univ, Egypt.
    Mahgoub, Samar M.
    Beni Suef Univ, Egypt.
    Ghoneim, Mohammed M.
    AlMaarefa Univ, Saudi Arabia; Al Azhar Univ, Egypt.
    Zaky Khalifa, Mohamed Yassin Zaky
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Beni Suef Univ, Egypt.
    Therapeutic Potential of Zeolites/Vitamin B12 Nanocomposite on Complete Freunds Adjuvant-Induced Arthritis as a Bone Disorder: In Vivo Study and Bio-Molecular Investigations2023In: Pharmaceuticals, E-ISSN 1424-8247, Vol. 16, no 2, article id 285Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis (RA) is a long-term autoimmune disease. As nanotechnology has advanced, a growing number of nanodrugs have been used in the treatment of RA due to their unique physical and chemical properties. The purpose of this study was to assess the therapeutic potential of a novel zeolite/vitamin B12 nanocomposite (Nano ZT/Vit B12) formulation in complete Freunds adjuvant (CFA)-induced arthritis. The newly synthesized Nano ZT/Vit B12 was fully characterized using various techniques such as XRD, FT-IR, BET analysis, HERTEM, SEM, practical size, zeta potential, XRF, and EDX. The anti-arthritic, anti-inflammatory, and antioxidant activities as well as the immunomodulation effect of Nano ZT/Vit B12 on the CFA rat model of arthritis were examined. Histopathologic ankle joint injuries caused by CFA intrapedal injection included synovium hyperplasia, inflammatory cell infiltration, and extensive cartilage deterioration. The arthritic rats Nano ZT/Vit B12 supplementation significantly improved these effects. Furthermore, in arthritic rats, Nano ZT/Vit B12 significantly reduced serum levels of RF and CRP, as well as the levels of IL-1 beta, TNF-alpha, IL-17, and ADAMTS-5, while increasing IL-4 and TIMP-3 levels. Nano-ZT/Vit B12 significantly declined the LPO level and increased antioxidant activities, such as GSH content and GST activity, in the arthritic rats. In arthritic rats, Nano ZT/Vit B12 also reduced TGF-beta mRNA gene expression and MMP-13 protein levels. Collectively, Nano ZT/Vit B12 seems to have anti-arthritic, anti-inflammatory, and antioxidant properties, making it a promising option for RA in the future.

    Download full text (pdf)
    fulltext
  • 12.
    Björck, Åke
    et al.
    Linköping University, Department of Mathematics, Computational Mathematics. Linköping University, Faculty of Science & Engineering.
    Indahl, Ulf G.
    Norwegian University of Life Science, Norway.
    Fast and stable partial least squares modelling: A benchmark study with theoretical comments2017In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 31, no 8, article id e2898Article in journal (Refereed)
    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.

  • 13.
    Björkman, Martin
    Linköping University, Department of Management and Engineering, Machine Design.
    Cost analysis of robot families2010Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    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.

    Download full text (pdf)
    FULLTEXT01
  • 14.
    Brandon, Andrew M.
    et al.
    Univ Dundee, Scotland; Newcastle Univ, England.
    Baginski, Steven R.
    Univ Dundee, Scotland.
    Peet, Caroline
    Univ Dundee, Scotland; Debiopharm, Switzerland.
    Dugard, Pat
    Univ Dundee, Scotland.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Sutcliffe, Oliver B.
    Manchester Metropolitan Univ, England.
    Daeid, Niamh Nic
    Univ Dundee, Scotland.
    Nisbet, Lorna A.
    Univ Dundee, Scotland; Newcastle Univ, England.
    Read, Kevin D.
    Univ Dundee, Scotland.
    McKenzie, Craig
    Univ Dundee, Scotland; Chiron AS, Norway.
    Log D7.4 and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity2023In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611Article in journal (Refereed)
    Abstract [en]

    The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D-7.4 ranging from 2.48 (AB-FUBINACA) to 4.95 (4F-ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB-BUTINACA) to 99.9% (BZO-HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser-bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market.

  • 15.
    Buesker, Soeren
    et al.
    Univ Cologne, Germany; Univ Cologne, Germany.
    Jones, A Wayne
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Hahn, Robert G.
    Sodertalje Hosp, Sweden; Karolinska Inst, Sweden.
    Taubert, Max
    Univ Cologne, Germany; Univ Cologne, Germany.
    Klotz, Ulrich
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Germany.
    Schwab, Matthias
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Germany; Univ Hosp Tubingen, Germany; Univ Hosp Tubingen, Germany.
    Fuhr, Uwe
    Univ Cologne, Germany; Univ Cologne, Germany.
    Population Pharmacokinetics as a Tool to Reevaluate the Complex Disposition of Ethanol in the Fed and Fasted States2023In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 63, p. 681-694Article in journal (Refereed)
    Abstract [en]

    The pharmacokinetics (PK) of ethanol are important in pharmacology and therapeutics because of potential drug-alcohol interactions as well as in forensic science when alcohol-related crimes are investigated. The PK of ethanol have been extensively studied since the 1930s, although some issues remain unresolved, such as the significance of first-pass metabolism, whether zero-order kinetics apply, and the effects of food on bioavailability. We took advantage of nonlinear mixed-effects modeling to describe blood-alcohol concentration (BAC) profiles derived from 3 published clinical studies involving oral, intraduodenal, and intravenous administration of ethanol with and without food. The overall data set included 1510 BACs derived from 72 healthy subjects (60 men, 12 women) aged between 20 and 60 years. Two-compartment models with first-order absorption and Michaelis-Menten elimination kinetics adequately described the BAC profiles. Food intake had 2 separate effects: It reduced the absorption rate constant and accelerated the maximum elimination rate. Estimates of the maximum elimination rate (fasted) and the food effect (as a factor) were 6.31 g/h (95%CI, 6.04-6.59 g/h) and 1.39-fold (95%CI, 1.33-1.46-fold), respectively. Simulations showed that the area under the BAC-time curve (AUC) was smaller with lower input rate of ethanol, irrespective of any first-pass metabolism. The AUC from time 0 to 10 hours for a 75-kg subject was 2.34 g center dot h/L (fed) and 3.83 g center dot h/L (fasted) after an oral dose of 45 g ethanol. This difference was mainly attributable to the food effect on ethanol elimination and depended less on the absorption rate. Our new approach to explain the complex human PK of ethanol may help when BAC predictions are made in clinical pharmacology and forensic medicine.

    Download full text (pdf)
    fulltext
  • 16.
    Busardò, Francesco Paolo
    et al.
    a Department of Anatomical, Histological, Forensic and Orthopaedic Sciences , Sapienza University of Rome , Rome , Italy.
    Jones, A Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Interpreting γ-hydroxybutyrate concentrations for clinical and forensic purposes2019In: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 57, no 3, p. 149-163Article, review/survey (Refereed)
    Abstract [en]

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

    Download full text (pdf)
    fulltext
  • 17.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Appelqvist, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    LeVine, Harry III
    University of Kentucky, KY 40536 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Anionic Oligothiophenes Compete for Binding of X-34 but not PIB to Recombinant A beta Amyloid Fibrils and Alzheimers Disease Brain-Derived A beta2016In: CHEMISTRY-A EUROPEAN JOURNAL, ISSN 0947-6539, Vol. 22, no 51, p. 18335-18338Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 18.
    Cao, Huiming
    et al.
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Zhou, Zhen
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Key Laboratory of Optoelectronic Chemical Materials and Devices, Ministry of Education, School of Chemical and Environmental Engineering, Jianghan University, Wuhan, P. R. China.
    Wang, Ling
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Liu, Guangliang
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Sun, Yuzhen
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Wang, Yawei
    Institute of Environment and Health, Jianghan University, Wuhan, P. R. China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, P. R. China.
    Wang, Thanh
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Örebro universitet, Institutionen för naturvetenskap och teknik.
    Liang, Yong
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Screening of Potential PFOS Alternatives To Decrease Liver Bioaccumulation: Experimental and Computational Approaches2019In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 53, no 5, p. 2811-2819Article in journal (Refereed)
    Abstract [en]

    Perfluorooctanesulfonate (PFOS) is a persistent organic pollutant with significant bioaccumulation potential in liver tissues. Exposure to PFOS could cause increase of liver weight, induce adenomas of the liver, and cause hepatomegaly. Alternatives of PFOS might be designed and synthesized that have significantly lower liver bioaccumulation. In this study, we conducted animal exposure experiments to investigate tissue accumulations of 14 per- and polyfluoroalkyl substances. Correlation analysis demonstrated that accumulation of the compounds in rat liver had strong correlations with their binding affinities of liver fatty acid binding protein (LFABP). Thus, we combined a quantitative structure-activity relationship model with molecular dynamics (MD) simulations to develop computational models to predict the LFABP binding affinities of two newly synthesized alternatives, perfluorodecalin-2-sulfonic acid and N-diperfluorobutanoic acid. The binding characteristics of the PFOS alternatives for LFABP were elaborated to explore how the different structural modifications of molecules influenced the underlying binding mechanisms. Subsequent animal experiments demonstrated that the binding free energy calculations based on the MD simulations provided a good indicator to reflect the relative degree of liver accumulation of the PFOS alternatives in the same exposure doses and durations. Our findings from the combination of experimental exposure and computational model can provide helpful information to design potential alternatives of PFOS with weak LFABP binding capability and low liver accumulation.

  • 19.
    Carlier, Jeremy
    et al.
    NIDA, MD 21224 USA.
    Diao, Xingxing
    NIDA, MD 21224 USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. NIDA, MD 21224 USA; National Board Forens Med, Linkoping, Sweden.
    Scheidweiler, Karl
    NIDA, MD 21224 USA.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA; University of Maryland, MD 21201 USA.
    In Vitro Metabolite Profiling of ADB-FUBINACA, A New Synthetic Cannabinoid2017In: Current Neuropharmacology, ISSN 1570-159X, E-ISSN 1875-6190, Vol. 15, no 5, p. 682-691Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Carlsson, Andreas
    et al.
    Swedish National Forens Centre NFC, SE-58194 Linkoping, Sweden.
    Lindberg, Sandra
    Swedish Def Research Agency, Sweden.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Dunne, Simon
    Swedish National Forens Centre NFC, SE-58194 Linkoping, Sweden.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden.
    Astot, Crister
    Swedish Def Research Agency, Sweden.
    Dahlén, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    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)methanone2016In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 8, no 10, p. 1015-1029Article in journal (Refereed)
    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.

  • 21.
    Carlsson, Andreas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Swedish Natl Forens Ctr NFC, SE-58194 Linkoping, Sweden.
    Sandgren, Veronica
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Svensson, Stefan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Dunne, Simon
    Swedish Natl Forens Ctr NFC, SE-58194 Linkoping, Sweden.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Dahlén, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Prediction of designer drugs: Synthesis and spectroscopic analysis of synthetic cathinone analogs that may appear on the Swedish drug market2018In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 10, no 7, p. 1076-1098Article in journal (Refereed)
    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.

  • 22.
    Cavallo, Joel S.
    et al.
    University of Chicago, IL 60637 USA.
    Mayo, Leah
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN).
    de Wit, Harriet
    University of Chicago, IL 60637 USA.
    Acquisition of Conditioning between Methamphetamine and Cues in Healthy Humans2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 8, p. e0161541-Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 23.
    Chung, Vincent C. H.
    et al.
    Chinese Univ Hong Kong, Peoples R China.
    Ho, Fai Fai
    Chinese Univ Hong Kong, Peoples R China.
    Lao, Lixing
    Virginia Univ Integrat Med, VA USA.
    Liu, Jianping
    Beijing Univ Chinese Med, Peoples R China.
    Lee, Myeong Soo
    Korea Inst Oriental Med, South Korea.
    Chan, Kam Wa
    Univ Hong Kong, Peoples R China.
    Nilsen, Per
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Implementation science in traditional, complementary and integrative medicine: An overview of experiences from China and the United States2023In: Phytomedicine, ISSN 0944-7113, E-ISSN 1618-095X, Vol. 109, article id 154591Article in journal (Refereed)
    Abstract [en]

    Background: The introduction of traditional, complementary and integrative medicine (TCIM) services into health systems has been advocated by the World Health Organization, but there is a paucity of reviews synthesising the experiences of (i) implementing TCIM services in conventional healthcare settings and (ii) introducing evidencebased practice in TCIM. Knowledge of the first issue will assist policymakers to innovate implementation interventions in their own health system contexts. Addressing the second issue will facilitate the closure of the evidence-practice gap in TCIM and improve the translation of research evidence into health outcome benefits. Purpose: The aim of this study was to identify, describe and analyse publications on these two key TCIM policy issues via an overview from an implementation science perspective. Methods: Publications describing international experiences of implementing TCIM services or evidence for TCIM practices were identified by searching MEDLINE, EMBASE and Global Health databases in November 2021. The findings were summarised using a narrative synthesis approach. Results: Sixty-three relevant publications were included in the analysis. Current experiences in China and the United Sates (US) reflect varying policy priorities at different stages of implementing TCIM services. In the US, where TCIM have yet to be introduced into mainstream healthcare settings, implementation interventions were designed to facilitate the provision of specific, evidence-based TCIM modalities via referrals from conventional clinicians. The application of these strategies at the health system, regulatory, financial, community, provider and patient levels provided a comprehensive picture of how TCIM implementation may be facilitated via multilevel interventions. In China, the major form of TCIM is traditional Chinese medicine (TCM), for which service provision has already been adopted at all levels of healthcare. With the high volume of clinical research that has been generated in the past several decades, a key policy question at this stage is how to translate TCM-related clinical evidence into practice. The development of clinical practice guidelines (CPGs) is the main implementation intervention, but adherence by TCM clinicians has been poor, due to the conflict between classical individualised practice and CPG standardisation. While tailoring interventions to facilitate CPG uptake is indicated, concurrent innovations in TCM clinical research methods would improve the compatibility between classical and CPG-based practice. Conclusion: Policymakers managing different stages of TCIM implementation will benefit from the experiences of practitioners in the US and China. Multi-level implementation interventions launched in the US provide ideas for the initial introduction of TCIM into a conventional medicine-dominated health system. As TCIM service provision and related clinical research become more common, Chinas experience will inform how clinical evidence related to TCIM may be disseminated and implemented to improve service quality.

  • 24.
    Das, Alakesh
    et al.
    Chettinad Acad Res & Educ, India.
    Deka, Dikshita
    Chettinad Acad Res & Educ, India.
    Banerjee, Antara
    Chettinad Acad Res & Educ, India.
    Radhakrishnan, Arun Kumar
    Chettinad Acad Res & Educ, India.
    Zhang, Hong
    Orebro Univ, Sweden.
    Sun, Xiao-Feng
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pathak, Surajit
    Chettinad Acad Res & Educ, India.
    A Concise Review on the Role of Natural and Synthetically Derived Peptides in Colorectal Cancer2022In: Current Topics in Medicinal Chemistry, ISSN 1568-0266, E-ISSN 1873-4294, Vol. 22, no 31, p. 2571-2588Article, review/survey (Refereed)
    Abstract [en]

    Colorectal cancer being the second leading cause of cancer-associated deaths has become a significant health concern around the globe. Though there are various cancer treatment approaches, many of them show adverse effects and some compromise the health of cancer patients. Hence, significant efforts are being made for the evolution of a novel biological therapeutic approach with better efficacy and minimal side effects. Current research suggests that the application of peptides in colorectal cancer therapeutics holds the possibility of the emergence of an anticancer reagent. The primary beneficial factors of peptides are their comparatively rapid and easy process of synthesis and the enormous potential for chemical alterations that can be evaluated for designing novel peptides and enhancing the delivery capacity of peptides. Peptides might be utilized as agents with cytotoxic activities or as a carrier of a specific drug or as cytotoxic agents that can efficiently target the tumor cells. Further, peptides can also be used as a tool for diagnostic purposes. The recent analysis aims at developing peptides that have the potential to efficiently target the tumor moieties without harming the nearby normal cells. Additionally, decreasing the adverse effects, and unfolding the other therapeutic properties of potential peptides, are also the subject matter of in-depth analysis. This review provides a concise summary of the function of both natural and synthetically derived peptides in colorectal cancer therapeutics that are recently being evaluated and their potent applications in the clinical field.

  • 25.
    Davies Forsman, Lina
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Niward, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. 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 study2018In: BMJ Open, E-ISSN 2044-6055, Vol. 8, no 9, article id e023899Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 26.
    Diao, Xingxing
    et al.
    NIDA, MD 21224 USA.
    Carlier, Jeremy
    NIDA, MD 21224 USA.
    Zhu, Mingshe
    Bristol Myers Squibb, NJ 08543 USA.
    Pang, Shaokun
    SCIEX Ltd, CA 94065 USA.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Scheidweiler, Karl B.
    NIDA, MD 21224 USA.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA; University of Maryland, MD 21224 USA.
    In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)2017In: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 35, no 1, p. 20-32Article in journal (Refereed)
    Abstract [en]

    In 2014, NM-2201 (CBL-2201), a novel synthetic cannabinoid (SC), was detected by scientists at Russian and US laboratories. It has been already added to the list of scheduled drugs in Japan, Sweden and Germany. Unfortunately, no human metabolism data are currently available, which makes it challenging to confirm its intake, especially given that all SCs investigated thus far have been found to be extensively metabolized. The present study aims to recommend appropriate marker metabolites by investigating NM-2201 metabolism in human hepatocytes, and to confirm the results in authentic human urine specimens. For the metabolic stability assay, 1 A mu M NM-2201 was incubated in human liver microsomes (HLMs) for up to 1 h; for metabolite profiling, 10 A mu M of NM-2201 was incubated in human hepatocytes for 3 h. Two authentic urine specimens from NM-2201-positive cases were subjected to beta-glucuronidase hydrolysis prior to analysis. The identification of metabolites in hepatocyte samples and urine specimens was achieved with high-resolution mass spectrometry via information-dependent acquisition. NM-2201 was quickly metabolized in HLMs, with an 8.0-min half-life. In human hepatocyte incubation samples, a total of 13 NM-2201 metabolites were identified, generated mainly from ester hydrolysis and further hydroxylation, oxidative defluorination and subsequent glucuronidation. M13 (5-fluoro PB-22 3-carboxyindole) was found to be the major metabolite. In the urine specimens, the parent drug NM-2201 was not detected; M13 was the predominant metabolite after beta-glucuronidase hydrolysis. Therefore, based on the results of our study, we recommend M13 as a suitable urinary marker metabolite for confirming NM-2201 and/or 5F-PB-22 intake.

  • 27.
    Diao, Xingxing
    et al.
    National Institute Drug Abuse, MD 21224 USA.
    Scheidweiler, Karl B.
    National Institute Drug Abuse, MD 21224 USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Pang, Shaokun
    SCIEX Ltd, CA 94404 USA.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Sweden.
    Huestis, Marilyn A.
    National Institute Drug Abuse, MD 21224 USA.
    In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-222016In: AAPS Journal, E-ISSN 1550-7416, Vol. 18, no 2, p. 455-464Article in journal (Refereed)
    Abstract [en]

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

  • 28.
    Diao, Xingxing
    et al.
    NIDA, USA.
    Scheidweiler, Karl B.
    NIDA, USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, 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 hepatocytes2016In: Forensic Toxicology, ISSN 1860-8965, E-ISSN 1860-8973, Vol. 34, no 2, p. 256-267Article in journal (Refereed)
    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.

  • 29.
    Feasel, Michael G.
    et al.
    US Army, MD 21010 USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. NIDA, MD 21224 USA; National Board Forens Med, 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 Spectrometry2016In: AAPS Journal, E-ISSN 1550-7416, Vol. 18, no 6, p. 1489-1499Article in journal (Refereed)
    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.

  • 30. Felini, Usisipho
    et al.
    Beni, Valerio
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Iwuoha, Emanuel
    University of the Western Cape, South Africa.
    Turner, Anthony
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Palladium telluride quantum dots and cytochrome P450 biosensor for the detection of breast cancer drug – tamoxifen.2015In: Sweden-Japan Seminar on Nanomaterials and Nanotechnology – SJS-Nano, Linköping, Sweden, 10-11 March 2015., Japan Society for the Promotion of Science (JSPS), Stockholm. , 2015Conference paper (Refereed)
    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.

  • 31.
    Forsgren, Mikael
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Markus
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Romu, Thobias
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort2019In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, no 6, article id e1007157Article in journal (Refereed)
    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.

    Download full text (pdf)
    Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort
  • 32.
    Fridlund, Jimmy
    et al.
    Kalmar County Hospital, Sweden.
    Woksepp, Hanna
    Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    A microbiological method for determining serum levels of broad spectrum beta-lactam antibiotics in critically ill patients2016In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 129, p. 23-27Article in journal (Refereed)
    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.

  • 33.
    Gennemark, Peter
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. AstraZeneca, Sweden.
    Walter, Katrin
    AstraZeneca, Sweden.
    Clemmensen, Niclas
    AstraZeneca, Sweden.
    Rekic, Dinko
    AstraZeneca, Sweden.
    Nilsson, Catarina A. M.
    AstraZeneca, Sweden.
    Knochel, Jane
    AstraZeneca, Sweden.
    Holtta, Mikko
    AstraZeneca, Sweden.
    Wernevik, Linda
    AstraZeneca, Sweden.
    Rosengren, Birgitta
    AstraZeneca, Sweden.
    Kakol-Palm, Dorota
    AstraZeneca, Sweden.
    Wang, Yanfeng
    Ionis Pharmaceut Inc, CA 92010 USA.
    Yu, Rosie Z.
    Ionis Pharmaceut Inc, CA 92010 USA.
    Geary, Richard S.
    Ionis Pharmaceut Inc, CA 92010 USA.
    Riney, Stan J.
    Ionis Pharmaceut Inc, CA 92010 USA.
    Monia, Brett P.
    Ionis Pharmaceut Inc, CA 92010 USA.
    Isaksson, Rikard
    AstraZeneca, Sweden.
    Jansson-Lofmark, Rasmus
    AstraZeneca, Sweden.
    Rocha, Cristina S. J.
    AstraZeneca, Sweden.
    Linden, Daniel
    AstraZeneca, Sweden.
    Hurt-Camejo, Eva
    AstraZeneca, Sweden.
    Crooke, Rosanne
    Ionis Pharmaceut Inc, CA 92010 USA.
    Tillman, Lloyd
    Ionis Pharmaceut Inc, CA 92010 USA.
    Ryden-Bergsten, Tina
    AstraZeneca, Sweden.
    Carlsson, Bjorn
    AstraZeneca, Sweden.
    Andersson, Ulf
    AstraZeneca, Sweden.
    Elebring, Marie
    AstraZeneca, Sweden.
    Tivesten, Anna
    AstraZeneca, Sweden.
    Davies, Nigel
    AstraZeneca, Sweden.
    An oral antisense oligonucleotide for PCSK9 inhibition2021In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 13, no 593, article id eabe9117Article in journal (Refereed)
    Abstract [en]

    Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by &gt;90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.

  • 34.
    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 behaviors2019In: Nature Communications, E-ISSN 2041-1723, Vol. 10, no 1, p. 1-14, article id 3924Article in journal (Refereed)
    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.

    Download full text (pdf)
    Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors
  • 35.
    Green, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Suleman Khan, Muhammad
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Åvall-Lundqvist, Elisabeth
    Karolinska University of Hospital.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Impact of CYP3A5(*)3 and CYP2C8-HapC on Paclitaxel/Carboplatin-Induced Myelosuppression in Patients with Ovarian Cancer2011In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 10, p. 4205-4209Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 36.
    Green, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Rosenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
    Mirghani, Rajaa A
    Karolinska University .
    Rymark, Per
    Västerås Hospital.
    Åvall Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Karolinska University Hospital.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, The Institute of Technology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
    Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer2009In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 104, no 2, p. 130-137Article in journal (Refereed)
    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.

    Download full text (pdf)
    FULLTEXT01
  • 37. Order onlineBuy this publication >>
    Gregers, Jannie
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate2012Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
    Open this publication in new window or tab >>Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
    2008 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 47, no 4, p. 451-453Article in journal (Refereed) 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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-77610 (URN)10.1093/rheumatology/ken073 (DOI)18316334 (PubMedID)
    Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2017-12-07Bibliographically approved
    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
    Open this publication in new window or tab >>The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
    Show others...
    2010 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 23, p. 4671-4677Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-58380 (URN)10.1182/blood-2010-01-256958 (DOI)000278635900013 ()
    Note
    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/Available from: 2010-08-13 Created: 2010-08-11 Last updated: 2017-12-12Bibliographically approved
    3. Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
    Open this publication in new window or tab >>Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
    Show others...
    2012 (English)Manuscript (preprint) (Other academic)
    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.

    Keywords
    Acute lymphoblastic leukemia; ABCB1; MDR1; P-glycoprotein; Polymorphism; Relapse; Toxicity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-77618 (URN)
    Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2020-08-18Bibliographically approved
    4. Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
    Open this publication in new window or tab >>Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
    Show others...
    2012 (English)Manuscript (preprint) (Other academic)
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-77622 (URN)
    Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2012-05-24Bibliographically approved
    Download full text (pdf)
    Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
    Download (pdf)
    omslag
  • 38.
    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
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Natl Forens Ctr, Drug Unit, Linkoping, Sweden.
    Screening, quantification, and confirmation of synthetic cannabinoid metabolites in urine by UHPLC-QTOF-MS2019In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 11, no 1, p. 51-67Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 39. Order onlineBuy this publication >>
    Haage, Pernilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Forensic Toxicological Aspects of Tramadol: Focus on Enantioselective Drug Disposition and Pharmacogenetics2018Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
    Open this publication in new window or tab >>Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
    Show others...
    2014 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, p. 125-132Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    Keywords
    Tramadol; Pharmacokinetics; Pharmacodynamics; CYP2D6; ABCB1; OPRM1
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-106838 (URN)10.1016/j.forsciint.2014.03.003 (DOI)000334580700025 ()24709712 (PubMedID)
    Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2020-08-18Bibliographically approved
    2. Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.
    Open this publication in new window or tab >>Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.
    2016 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 119, p. 1-9Article in journal (Refereed) 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.

    Keywords
    Enantiomer; LC–MS/MS; N, O-didesmethyltramadol; N-desmethyltramadol; O-desmethyltramadol; Tramadol
    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:liu:diva-125284 (URN)10.1016/j.jpba.2015.11.012 (DOI)000370211900001 ()26625281 (PubMedID)
    Note

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

    Available from: 2016-02-19 Created: 2016-02-19 Last updated: 2020-08-18
    3. Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
    Open this publication in new window or tab >>Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
    Show others...
    2018 (English)In: Pharmacology Research & Perspectives, E-ISSN 2052-1707, Vol. 6, no 4, article id e00419Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2018
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:liu:diva-152586 (URN)10.1002/prp2.419 (DOI)000442994300006 ()29992026 (PubMedID)2-s2.0-85052511964 (Scopus ID)
    Available from: 2018-11-09 Created: 2018-11-09 Last updated: 2021-07-01Bibliographically approved
    Download full text (pdf)
    Forensic Toxicological Aspects of Tramadol: Focus on Enantioselective Drug Disposition and Pharmacogenetics
    Download (pdf)
    omslag
    Download (png)
    presentationsbild
  • 40.
    Haage, Pernilla
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    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
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype2018In: Pharmacology Research & Perspectives, E-ISSN 2052-1707, Vol. 6, no 4, article id e00419Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 41. Order onlineBuy this publication >>
    Hedna, Khedidja
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Inappropriate prescribing, non-adherence to long-term medications and related morbidities: Pharmacoepidemiological aspects2015Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions - a meta-analysis
    Open this publication in new window or tab >>Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions - a meta-analysis
    2012 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 3, p. 1-9, article id e33236Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Public Library of Science, 2012
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-76102 (URN)10.1371/journal.pone.0033236 (DOI)000303309000014 ()22438900 (PubMedID)
    Available from: 2012-03-27 Created: 2012-03-27 Last updated: 2021-06-14
    2. Potentially inappropriate prescribing and adverse drug reactions in the elderly: a population-based study
    Open this publication in new window or tab >>Potentially inappropriate prescribing and adverse drug reactions in the elderly: a population-based study
    Show others...
    2015 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 12, p. 1525-1533Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Springer, 2015
    Keywords
    Inappropriate prescribing – Elderly – Adverse drug reactions – Retrospective study – Medical records – Registries
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:liu:diva-121823 (URN)10.1007/s00228-015-1950-8 (DOI)000365179600013 ()26407684 (PubMedID)
    Available from: 2015-10-08 Created: 2015-10-08 Last updated: 2020-01-21Bibliographically approved
    3. Adherence to Antihypertensive Therapy and Elevated Blood Pressure: Should We Consider the Use of Multiple Medications?
    Open this publication in new window or tab >>Adherence to Antihypertensive Therapy and Elevated Blood Pressure: Should We Consider the Use of Multiple Medications?
    Show others...
    2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 9, article id e0137451Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    ´PLoS, 2015
    National Category
    Social and Clinical Pharmacy
    Identifiers
    urn:nbn:se:liu:diva-121822 (URN)10.1371/journal.pone.0137451 (DOI)000361043100040 ()26359861 (PubMedID)
    Available from: 2015-10-08 Created: 2015-10-08 Last updated: 2021-06-14
    4. Refill adherence and self-reported adverse drug reactions and sub-therapeutic effects: a population-based study
    Open this publication in new window or tab >>Refill adherence and self-reported adverse drug reactions and sub-therapeutic effects: a population-based study
    Show others...
    2013 (English)In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 22, no 12, p. 1317-1325Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2013
    Keywords
    adverse drug reaction, oversupply, pharmacoepidemiology, refill adherence, self-report, therapeutic failure, undersupply
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-99892 (URN)10.1002/pds.3528 (DOI)000327446700010 ()24127242 (PubMedID)
    Available from: 2013-10-23 Created: 2013-10-23 Last updated: 2017-12-06
    Download full text (pdf)
    fulltext
    Download (pdf)
    omslag
    Download (jpg)
    presentationsbild
  • 42.
    Henriksson, Martin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences. 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 Mellitus2016In: PharmacoEconomics (Auckland), ISSN 1170-7690, E-ISSN 1179-2027, Vol. 34, no 6, p. 569-585Article, review/survey (Refereed)
    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.

  • 43.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    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 amperometry2019In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 306, p. 121-129Article in journal (Refereed)
    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.

  • 44.
    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 delivery2014In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 50, no 67, p. 9489-9492Article in journal (Refereed)
    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.

  • 45.
    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 aptamer2013In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, no 13, p. 1285-1287Article in journal (Refereed)
    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.

  • 46.
    Hillarp, Andreas
    et al.
    Halland Cty Hosp, Sweden.
    Strandberg, Karin
    Univ and Reg Labs Reg Skane, Sweden.
    Gustafsson, Kerstin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Lindahl, Tomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Unveiling the complex effects of direct oral anticoagulants on dilute Russells viper venom time assays2020In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 18, no 8, p. 1866-1873Article in journal (Refereed)
    Abstract [en]

    Introduction Dilute Russell viper venom time (dRVVT) assays can be affected by direct oral anticoagulants (DOACs), which may cause false-positive results. However, there are conflicting results indicating significant differences between different reagents and DOACs. Objectives To evaluate the effect of DOACs on dRVVT assays. Material and Methods Samples were prepared by adding DOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) to pooled normal plasma in the concentration range 0 to 800 mu g/L. Six integrated dRVVT reagents were used, all composed of a screen assay (low phospholipid content) and a confirm assay (high phospholipid content). The screen/confirm dRVVT results were expressed as normalized ratios. To further evaluate the observed differences between tests and DOACs, addition of synthetic phospholipids was used. Results The dRVVT ratios increased dose dependently for all DOACs, with four of the six tests and the DOAC rivaroxaban having the greatest effect. With one test, the ratios were almost unaffected with increasing DOAC concentration, whereas another test revealed a negative dose dependency for all DOACs. Variable DOAC effects can be explained by different effects on dRVVT screen and confirm clotting time. Adding synthetic phospholipids to samples containing rivaroxaban resulted in greatly reduced screen clotting times and thereby lower calculated dRVVT ratios. Conclusions There is a great variability in the dRVVT test result with different DOACs. The dRVVT ratios are unaffected for some reagents and this can be explained by an equal dose-dependent effect on both screen and confirm assays. The phospholipid type and content of the different reagents may contribute to the observed differences.

    Download full text (pdf)
    fulltext
  • 47.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Methods for long-term 17β-estradiol administration to mice2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 188-193Article in journal (Refereed)
    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.

  • 48. Order onlineBuy this publication >>
    Iredahl, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Assessment of microvascular and metabolic responses in the skin2016Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations
    Open this publication in new window or tab >>Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations
    Show others...
    2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 8, p. 1-15, article id e0133760Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Public Library of Science, 2015
    National Category
    Physiology
    Identifiers
    urn:nbn:se:liu:diva-121109 (URN)10.1371/journal.pone.0133760 (DOI)000359492800006 ()26270037 (PubMedID)
    Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2024-01-10
    2. Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols
    Open this publication in new window or tab >>Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols
    Show others...
    2015 (English)In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 22, no 6, p. 446-453Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Informa Healthcare / Wiley: 12 months, 2015
    Keywords
    microcirculation; iontophoresis; acetylcholine; metha choline; noradrenaline; skin
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-121138 (URN)10.1111/micc.12211 (DOI)000359676500002 ()26016387 (PubMedID)
    Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2024-01-10
    3. The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide
    Open this publication in new window or tab >>The Microvascular Response to Transdermal Iontophoresis of Insulin is Mediated by Nitric Oxide
    Show others...
    2013 (English)In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 20, no 8, p. 717-723Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2013
    Keywords
    insulin, transdermal iontophoresis, endothelial function, vasodilation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102080 (URN)10.1111/micc.12071 (DOI)000326607600008 ()
    Note

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

    Available from: 2013-12-02 Created: 2013-11-29 Last updated: 2024-01-10
    4. Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load
    Open this publication in new window or tab >>Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load
    Show others...
    2016 (English)In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 23, no 7, p. 597-605Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2016
    National Category
    Endocrinology and Diabetes Physiology Clinical Medicine Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:liu:diva-132368 (URN)10.1111/micc.12325 (DOI)000386946300014 ()27681957 (PubMedID)
    Note

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

    Available from: 2016-11-01 Created: 2016-11-01 Last updated: 2024-01-10Bibliographically approved
    Download full text (pdf)
    Assessment of microvascular and metabolic responses in the skin
    Download (pdf)
    omslag
    Download (jpg)
    presentationsbild
  • 49.
    Jones, A Wayne
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Brief history of the alcohol biomarkers CDT, EtG, EtS, 5-HTOL, and PEth2023In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611Article, review/survey (Refereed)
    Abstract [en]

    This article traces the historical development of various biomarkers of acute and/or chronic alcohol consumption. Much of the research in this domain of clinical and laboratory medicine arose from clinics and laboratories in Sweden, as exemplified by carbohydrate deficient transferrin (CDT) and phosphatidylethanol (PEth). Extensive studies of other alcohol biomarkers, such as ethyl glucuronide (EtG), ethyl sulfate (EtS), and 5-hydroxytryptophol (5-HTOL), also derive from Sweden. The most obvious test of recent drinking is identification of ethanol in a sample of the persons blood, breath, or urine. However, because of continuous metabolism in the liver, ethanol is eliminated from the blood at a rate of 0.15 g/L/h (range 0.1-0.3 g/L/h), so obtaining positive results is not always possible. The widow of detection is increased by analysis of ethanols non-oxidative metabolites (EtG and EtS), which are more slowly eliminated from the bloodstream. Likewise, an elevated ratio of serotonin metabolites in urine (5-HTOL/5-HIAA) can help to disclose recent drinking after ethanol is no longer measurable in body fluids. A highly specific biomarker of hazardous drinking is CDT, a serum glycoprotein (transferrin), with a deficiency in its N-linked glycosylation. Another widely acclaimed biomarker is PEth, an abnormal phospholipid synthesized in cell membranes when people drink excessively, having a long elimination half-life (median similar to 6 days) during abstinence. Research on the subject of alcohol biomarkers has increased appreciably and is now an important area of drug testing and analysis.

  • 50.
    Jones, A Wayne
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Comment on Estimates of Non-Alcoholic Food-Derived Ethanol and Methanol in Human2022In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 46, no 1, p. E48-E51Article in journal (Other academic)
123 1 - 50 of 120
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf