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  • 201.
    Kingbäck, Maria
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Louise
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Zackrisson, Anna-Lena
    National Board of Forensic Medicine, Linköping, Sweden.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Linköping, Sweden.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, Fredrik C
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood2012Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, nr 1-3, s. 124-134Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.

  • 202. Kjellgren, K.I.
    et al.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Saljo, R.
    Antihypertensive treatment and patient autonomy - The follow-up appointment as a resource for care2000Inngår i: Patient Education and Counseling, ISSN 0738-3991, E-ISSN 1873-5134, Vol. 40, nr 1, s. 39-49Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Since hypertension is a chronic condition which generally requires long-term commitment to pharmacological therapy as well as alterations of patient lifestyle, the patient-physician communication in the clinical setting is an important determinant of the quality of care and health outcome. The aim of the present study was to explore the structure and content of the communication between the patient and the physician, and the process of decision-making at a routine follow-up appointment for hypertension. The study was based on 51 audio-recordings of authentic consultations. Most patients had a passive role in the consultations, and initiated few topics of conversation. The few topics that the patients initiated were usually not about hypertension. Patients' questions about medication mainly referred to unwanted effects of the drugs. Little time was invested in discussing risks related to hypertension. A collaborative shared decision-making was seldom observed in the consultations. Copyright (C) 2000 Elsevier Science Ireland Ltd.

  • 203.
    Kronstrand, Robert
    et al.
    RMV Linköping.
    Nyström, Ingrid
    RMV Linköping.
    Andersson, Malin
    RMV Linköping.
    Gunnarsson, Lina
    RMV Linköping.
    Hägg, Staffan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Josefsson, Martin
    RMV Linköping.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Urinary Detection Times and Metabolites/Parent Compound ratios After a Single Dose of Buprenorphine2008Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 32, nr 8, s. 586-593Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

       

  • 204.
    Kronstrand, Robert
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Seldén, Tor
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Josefsson, M
    National Board Forensic Medicine .
    Analysis of buprenorphine, norbuprenorphine, and their glucuronides in urine by liquid chromatography-mass spectrometry2003Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 27, nr 7, s. 464-470Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 205.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Disposition of the enantiomers of citalopram and its demethylated metabolites in rats2003Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, nr 4, s. 163-Konferansepaper (Annet vitenskapelig)
  • 206.
    Kurz, Tino
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Grant, Derek
    GE Healthcare, Oslo, Norway.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Robertson, Towart
    Audacter Consulting, Helensburgh, Scotland.
    De Cesare, Michelandrea
    Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milano, Italy.
    Karlsson, Jan Olof G.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Effects of MnDPDP andICRF-187 on Doxorubicin-Induced Cardiotoxicityand Anticancer Activity12012Inngår i: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 5, nr 4, s. 252-259Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidative stress participates in doxorubicin (Dx)–induced cardiotoxicity. The metal complex MnDPDP and its metaboliteMnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice wereinjected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, theleft atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility wasmeasured for 60 minutes. In parallel experiments, 10 μM MnDPDP or MnPLED was added directly into the organbath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780)was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP,and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuatedthe negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLEDattenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the antitumoractivity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed anin vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized toMnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotectiontakes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest thatthe previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP.

    Translational Oncology (2012) 5, 252–259

  • 207.
    Kutlu, Omer
    et al.
    James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
    Ross, Ashley E.
    James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA..
    Schaeffer, Edward M.
    James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA..
    Gratzke, Christian
    University of Munich, Germany.
    Stief, Christian G.
    University of Munich, Germany.
    Strong, Travis D.
    Johns Hopkins School of Medicine, Baltimore, USA.
    Burnett, Arthur L.
    Johns Hopkins School of Medicine, Baltimore, USA.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bivalacqua, Trinity J.
    Johns Hopkins School of Medicine, Baltimore, USA.
    Increased expression of nestin in the major pelvic ganglion following cavernous nerve injury2012Inngår i: International journal of impotence research, ISSN 0955-9930, E-ISSN 1476-5489, Vol. 24, nr 2, s. 84-90Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In an effort to identify neuronal repair mechanisms of the major pelvic ganglion (MPG), we evaluated changes in the expression of nestin, an intermediate filament protein and neural stem cell marker following cavernous nerve crush injury (CNI). We utilized two groups of Sprague Dawley rats: (i) sham and (ii) bilateral CNI. Erectile responses to cavernous nerve stimulation (CNS) were determined at 48 h in a subset of rats. The MPG was isolated and removed at 48 h after CNI, and nestin immunolocalization, protein levels and RNA expression were evaluated. At 48 h, erectile responses to CNS in CNI rats were substantially reduced (P<0.05; ∼70% decrease in intracavernous pressure/mean arterial pressure) compared with sham surgery controls. This coincided with a dramatic 10-fold increase (P<0.05) in nestin messenger RNA expression and protein levels in the MPG of rats with CNI. Immunoflourescence microscopy demonstrated that nestin upregulation after CNI occurred within the ganglion cell bodies and nerve fibers of the MPG. In conclusion, CNI induces nestin in the MPG. These data suggest that nestin may be involved in the regenerative process of the cavernous nerve following crush injury.

  • 208.
    Kågedal, Bertil
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Lindqvist, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin.
    Farnebäck, Malin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Lenner, Liselotte
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Failure of the PAXgene™ Blood RNA System to maintain mRNA stability in whole blood2005Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 43, nr 11, s. 1190-1192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In multicentre studies of malignant and inflammatory diseases, whole blood, cell or tissue samples are often collected for analyses of gene expression to predict or monitor treatment effects. For correct analysis, sample stability during handling and transport is crucial. In developing the logistics for multicentre studies in malignant melanoma and inflammatory bowel disease, we found poor stability of a number of transcripts using the PAXgene™ Blood RNA System, which was advertised to maintain RNA stability for several days at room temperature. The results indicate that general statements on sample stability are not reliable and have to be verified for the specific transcripts of interest. © 2005 by Walter de Gruyter. Berlin.

  • 209.
    Landen, Mikael
    et al.
    Karolinska Institute.
    Erlandsson, Helena
    University of Gothenburg.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Andersch, Bjorn
    University of Gothenburg.
    Eriksson, Elias
    University of Gothenburg.
    Short Onset of Action of a Serotonin Reuptake Inhibitor When Used to Reduce Premenstrual Irritability2009Inngår i: NEUROPSYCHOPHARMACOLOGY, ISSN 0893-133X, Vol. 34, nr 3, s. 585-592Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several studies suggest that serotonin reuptake inhibitors (SRIs) exert a more rapid effect when used for the treatment of symptoms such as anger and irritability then when used for depression, obsessive-compulsive disorder, or anxiety. In line with this, premenstrual irritability can be effectively dampened by intermittent administration of an SRI, from ovulation to menstruation, indicating an onset of action of 10 days or less. How fast this effect appears, in terms of hours or days, is of considerable theoretical interest, but has previously not been studied in detail. To explore this issue, 22 women with marked premenstrual irritability, who previously had responded to paroxetine, were given this compound during two menstrual cycles and placebo during one cycle in a double-blind, cross-over fashion. The women were asked to start medication in the midst of the luteal phase when irritability had been intense for 2 days. The paroxetine cycles differed significantly from the placebo cycle as early as 14 h after drug intake with respect to the number of subjects experiencing sustained reduction in irritability. When the different cycles were compared with respect to irritability-rating scores for each time of assessment, the difference was significant at day 3. The side effect nausea had an even more rapid onset (4 h), but usually disappeared within 4 days. To summarize, this controlled trial shows that an SRI reduces premenstrual irritability already within a few days after the onset of treatment.

  • 210.
    Leandro-Garcia, Luis J
    et al.
    Spanish National Cancer Research Centre, Spain .
    Leskelae, Susanna
    Spanish National Cancer Research Centre, Spain .
    Jara, Carlos
    Fdn Hospital Alcorcon, Spain .
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Karolinska Institute, Sweden .
    Wheeler, Heather E
    University of Chicago, IL 60637 USA .
    Dolan, M Eileen
    University of Chicago, IL 60637 USA .
    Inglada-Perez, Lucia
    Spanish National Cancer Research Centre, Spain CIBERER, Spain .
    Maliszewska, Agnieszka
    Spanish National Cancer Research Centre, Spain .
    de Cubas, Aguirre A
    Spanish National Cancer Research Centre, Spain .
    Comino-Mendez, Inaki
    Spanish National Cancer Research Centre, Spain .
    Mancikova, Veronika
    Spanish National Cancer Research Centre, Spain .
    Cascon, Alberto
    Spanish National Cancer Research Centre, Spain CIBERER, Spain .
    Robledo, Mercedes
    Spanish National Cancer Research Centre, Spain CIBERER, Spain .
    Rodriguez-Antona, Cristina
    Spanish National Cancer Research Centre, Spain CIBERER, Spain .
    Regulatory Polymorphisms in beta-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy2012Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, nr 16, s. 4441-4448Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through beta-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in beta-tubulin genes. less thanbrgreater than less thanbrgreater thanExperimental Design: We measured variation in gene expression of three beta-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with beta-tubulin expression as measured by Affymetrix exon array. less thanbrgreater than less thanbrgreater thanResults: We found a 63-fold variation in beta-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. less thanbrgreater than less thanbrgreater thanConclusions: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a beta-tubulin gene.

  • 211.
    Lee, Tack
    et al.
    Lund University Hospital.
    Andersson, Karl-Erik
    Wake Forest University, Winston Salem, North Carolina.
    Streng, Torni
    Lund University Hospital.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Simultaneous registration of intraabdominal and intravesical pressures during cystometry in conscious rats-effects of bladder outlet obstruction and intravesical PGE(2)2008Inngår i: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 27, nr 1, s. 88-95Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: A method was developed and evaluated to simultaneously register intraabdominal pressure (IAP) and intravesical pressure (IVP) during cystometry in conscious rats. In addition, IAP and IVP were recorded in rats with experimental detrusor overactivity (DO).

    METHODS: Sprague Dawley rats (n = 24) were used. Six female rats were subjected to partial bladder outlet obstruction for 2 weeks. A catheter was implanted into the bladder to record the IVP, and a balloon-fitted catheter was positioned in the abdominal cavity to record the IAP. PGE(2) was given intravesically to induce DO. Detrusor pressure (DP) was defined as the IVP corrected for IAP.

    RESULTS: Recorded as increases in IAP, all rats of both sexes exhibited abdominal straining during every void. In controls, a maximal IAP of 6.0 +/- 1.4 cmH(2)O (range 3-15 cmH(2)O) was registered (n = 12) at the time of the flow pressure (FP). Intravesical administration of PGE(2) or BOO did not affect the IAP at basal pressure, FP or micturition pressure. Changes in IAP due to movement or non-voiding-related straining were subtracted from IVP to generate DP and to visualize DO after BOO or intravesical PGE(2).

    CONCLUSIONS: The conscious rat uses abdominal straining during voiding, and maximal IAP is recorded at the onset of urinary flow. Simultaneous registration of IAP and IVP during the micturition cycle in conscious rats is a convenient method for accurate quantification of pressures inside the bladder and for studying "true" DO without interference from movement artifacts

  • 212.
    Lee, Tack
    et al.
    Korea.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Newgreen, Donald
    USA.
    Urodynamic effects of a novel EP, receptor antagonist in normal rats and rats with bladder outlet obstruction2007Inngår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 177, s. 1562-1567Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose

    Prostaglandin E2 and its EP1 receptor were suggested as endogenous modulators of bladder function in the normal physiological state and under pathophysiological conditions. We investigated if the new EP1 receptor antagonist PF-2907617-02 would influence the regulation of normal micturition in rats, and if it affects bladder function in animals with partial bladder outlet obstruction.

    Materials and Methods

    The study was performed in normal female Sprague-Dawley rats and in rats with moderate, experimentally induced bladder outlet obstruction 2 weeks in duration. All animals underwent continuous cystometry in the awake state. PF-2907617-02 was given intravenously at doses of 0.1 and 1.0 mg/kg–1 in normal rats, and at 1.0 mg/kg–1 in bladder outlet obstructed animals. In a group of normal rats detrusor overactivity was produced by intravesical instillation of prostaglandin E2.

    Results

    In normal rats PF-2907617-02 (1 mg/kg–1) significantly increased bladder capacity, micturition volume and the micturition interval but it had no effect on other urodynamic parameters. The lower dose of PF-2907617 (0.1 mg/kg–1) showed no effect. Intravesical prostaglandin E2 (50 μM) induced detrusor overactivity. The antagonist significantly decreased the stimulatory effects of prostaglandin E2 at 0.1 and 1.0 mg/kg–1. In obstructed animals PF-2907617-02 significantly increased the micturition interval but not bladder capacity and residual volume. The drug also decreased the frequency and amplitude of nonvoiding contractions.

    Conclusions

    EP1 receptor is involved in initiation of the micturition reflex in normal rats and in animals with bladder outlet obstruction. It may also contribute to the generation of detrusor overactivity after bladder outlet obstruction. Thus, EP1 receptor antagonists may have potential as treatment for detrusor overactivity in humans.

  • 213.
    Li, Wei
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Johnson, Henrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Yuan, Ximing
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Jonasson, Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärtcentrum, Kardiologiska kliniken.
    7-beta-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destalization.2009Konferansepaper (Fagfellevurdert)
  • 214.
    Lind, Anna-Britta
    et al.
    Uppsala University.
    Reis, Margareta
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Jonzier-Perey, Michele
    University of Lausanne.
    Powell, Golay K.
    University of Lausanne.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Baumann, P.
    University of Lausanne.
    Dahl, M.-L.
    Uppsala University.
    Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour2009Inngår i: Clinical Pharmacokinetics, ISSN 0312-5963, Vol. 48, nr 1, s. 63-70Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and objective: Mirtazapine is a tetracyclic antidepressant drug available as a racemic mixture of S(+)- and R(-)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S(+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N-desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. Subjects and methods: The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders - 4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles*3, *4,*5 and*6 and gene duplication. Results: Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6. The median trough serum concentrations of S(+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S(+)/R(-) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S(+)-N-desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S(+)-8-hydroxymirtazapine and S(+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S(+)-mirtazapine, the mirtazapine S(+)/R(-) ratio and S(+)-N- desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R(-)-N-desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(-) ratio (0.28 vs 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. Conclusions: This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.

  • 215.
    Lindberg, Malou
    et al.
    Linköpings universitet, Institutionen för hälsa och samhälle, Allmänmedicin. Linköpings universitet, Hälsouniversitetet.
    Ekstrom, Tommy
    Linköpings universitet, Institutionen för medicin och vård, Lungmedicin. Linköpings universitet, Hälsouniversitetet.
    Moller, Margareta
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Asthma care and factors affecting medication compliance: the patient's point of view2001Inngår i: International Journal for Quality in Health Care, ISSN 1353-4505, E-ISSN 1464-3677, Vol. 13, nr 5, s. 375-383Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. To identify important factors that can influence patient compliance with prescribed medication and to elucidate aspects of asthma care from the patient's point of view.

    Design. Field investigation; the interviewer used a semi‐structured questionnaire.

    Setting. Patients with asthma in primary health care settings in Sweden.

    Study participants. A sample of 77 patients was randomly selected from 11 primary health care centres in southern Sweden; 63 of these patients participated in the study.

    Conclusion. The factors of importance for self‐reported compliance with prescribed medication were age, gender, duration of the disease, the attitude of the staff and information/education about asthma. The patients expressed important aspects of care, and these are in accordance with how an asthma nurse practice functions in Sweden.

  • 216.
    Lindh-Åstrand, Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Brynhildsen, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Hoffman, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hammar, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Vasomotor symptoms usually reappear after cessation of postmenopausal hormone therapy: a Swedish population-based study.2009Inngår i: Menopause (New York, N.Y.), ISSN 1530-0374Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:: The purpose of this study was to investigate the extent of reappearance of vasomotor symptoms after cessation of postmenopausal hormone therapy (HT) in women who started HT because of hot flashes. METHODS:: A cross-sectional postal survey was conducted. A validated questionnaire was sent to all women 53 to 54 years old living in Linköping, Sweden (n = 1,733), including questions about menopause, HT, and vasomotor symptoms. Pearson's chi test and logistic regression were used for statistical analyses. RESULTS:: Response rate after one reminder was 77.3%. After omitting incomplete answers, 72.9% remained for analysis. In all women, 319 (25.3%) were current users of HT, 242 (19.2%) were previous users, and 702 (55.6%) were never-users. Of the 242 previous users, 165 (69%) women stated that they had vasomotor symptoms before starting HT. Vasomotor symptoms recurred after cessation of HT in 143 (87%) of these 165 women. We found no significant difference in symptom recurrence in comparisons of the three groups based on usage of HT for 0 to 1, 2 to 4, or 5 years or more. CONCLUSIONS:: Most women who had vasomotor symptoms when they initiated HT reported recurrence of symptoms after cessation of HT (87%), although the flashes were usually reported to be less frequent and bothersome than they were before HT. Effective and safe treatment approaches for women with recurrence of vasomotor symptoms are needed.

  • 217.
    Lindh-Åstrand, Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Brynhildsen, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
    Hoffmann, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Liffner, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Hammar, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Attitudes towards the menopause and hormone therapy over the turn of the century2007Inngår i: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 56, nr 1, s. 12-20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To assess attitudes and beliefs about the menopausal transition in a population of peri- and postmenopausal women, and if these attitudes differed before and after publication of studies on risks and benefits with hormone therapy (HT).

    Material and methods: In 1999 and 2003 all women aged 53 and 54 years in the community of Linköping, Sweden, were sent a questionnaire about use of HT, menopausal status and attitudes regarding menopause and HT.

    Results: Most women regarded menopause as a natural process characterized by both hormonal deficiency and aging and these views did not differ between 1999 and 2003. A majority of women thought that significant climacteric symptoms were a good reason to use HT, but not that women without symptoms should use HT. The fraction of women who supported HT use was, however, significantly lower in 2003 than in 1999. Most women agreed that menopause leads to increased freedom and that it is a relief not to have to think about contraception and pregnancies.

    Conclusions: Most Swedish women had a mainly biological view on menopause but nevertheless they thought that only women with climacteric symptoms should use HT. Women’s attitudes towards HT have changed after recent reports on risks from long-term use of HT whereas the attitudes towards the menopausal transition were stable. Other factors than attitudes towards menopause affect women’s actual use of HT. Probably women’s and health care provider’s apprehension of the risk-benefit balance of HT use is one such factor.

  • 218.
    Lindh-Åstrand, Lotta
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Hoffmann, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hammar, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Kjellgren, Karin I.
    Faculty of Health and Caring Sciences, Institute of Nursing, The Sahlgrenska Academy, Göteborg, Sweden.
    Women’s conception of the menopausal transition – a qualitative study2007Inngår i: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 16, nr 3, s. 509-517Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To explore, with a qualitative approach, whether the conception of menopause varies between women seeking medical advice due to climacteric symptoms and, if so, to describe these different conceptions.

    Background: For many women, the menopausal transition is a troublesome period of life, often associated with decreased well-being and a number of symptoms. Besides the hormonal changes, many other factors such as psychological, sociological and lifestyle factors affect how women perceive their menopause.

    Method: Semi-structured interviews were held with 20 women after their first-time visits at outpatient clinics of gynaecology for discussion of climacteric symptoms. The interviews were audio-taped, transcribed and analysed using a phenomenographic approach.

    Results: A wide variation of conceptions was revealed. Two main categories were identified including different physical changes with varying symptoms and both positive and negative psychological changes. The menopausal transition was also described as a natural process and as a developmental phase of life.

    Conclusion and relevance to clinical practice: Women’s conceptions of the menopausal transition were individual and contained both physical and psychological symptoms but also expressed a more holistic view of the menopausal transition. The transition was described as a natural process affected by endocrine and life-style factors as well as by the psychosocial situation and by aging per se. It is important that health care providers are aware of women’s conceptions about the menopausal transition to be able to communicate optimally, support and empower middle-aged women in different health care situations and thereby optimise the result of care.

  • 219.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Berg, Jonathan
    City Hospital, England .
    Duley, John
    University of Queensland, Australia .
    Evans, William E.
    St Jude Childrens Research Hospital, TN USA .
    Kennedy, Martin A:
    University of Otago, New Zealand .
    Lennard, Lynne
    University of Sheffield, England .
    Marinaki, Tony
    Guys and St Thomas Hospital, England .
    McLeod, Howard L.
    University of N Carolina, NC USA .
    Relling, Mary V.
    St Jude Childrens Research Hospital, TN USA .
    Schaeffeler, Elke
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany .
    Schwab, Matthias
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany .
    Weinshilboum, Richard
    Mayo Clin, MN USA .
    Yeoh, Allen E J
    National University of Singapore, Singapore .
    McDonagh, Ellen M.
    Stanford University, CA USA .
    Hebert, Joan M.
    Stanford University, CA USA .
    Klein, Teri E.
    Stanford University, CA USA .
    Coulthard, Sally A.
    Newcastle University, England .
    Nomenclature for alleles of the thiopurine methyltransferase gene2013Inngår i: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, nr 4, s. 242-248Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (Gandgt;A) from TPMT*24 to TPMT*30 and position 611 (Tandgt;C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. Pharmacogenetics and Genomics 23: 242-248

  • 220.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hertervig, Erik
    Gastroenterologi, Lunds universitetssjukhus.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Explaining TPMT genotype/phenotype discrepancy by identification of a novel sequence variant, TPMT*262008Konferansepaper (Fagfellevurdert)
  • 221.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Skoglund, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Karlgren, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Kidhall, Irene
    Danderyds sjukhus.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Explaining TPMT genotype/phenotype discrepancy by haplotyping of TPMT*3A and identification of a novel sequence variant, TPMT*232007Inngår i: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 17, nr 10, s. 891-895Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurine drugs. Owing to polymorphisms in the TPMT gene (TPMT*2-*22), the enzyme activity varies interindividually. Patients with reduced TPMT activity may develop adverse reactions when treated with standard doses of thiopurines. This work focuses on a TPMT genotype/phenotype discrepancy found in a patient during routine testing. The patient displayed very low TPMT enzyme activity and she was genotyped by pyrosequencing as being heterozygous for the 460G>A and 719A>G polymorphisms (TPMT*3A). Complete sequencing in combination with haplotyping of the TPMT gene revealed a novel sequence variant, 500C>G, on one allele and TPMT*3A on the other allele, giving rise to the novel genotype TPMT*3A/*23. When investigating the patient's relatives, they too had the TPMT*3A/*23 genotype in combination with low enzyme activity. We conclude that this novel variant allele affects enzyme activity, as the individuals carrying it had almost undetectable TPMT activity. © 2007 Lippincott Williams & Wilkins, Inc.

  • 222.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wennerstrand, Patricia
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Hertervig, Erik
    Department of Gastroenterology, Lund University.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Characterization of a novel sequence variant, TPMT*28, in the human thiopurine methyltransferase gene2010Inngår i: Pharmacogenetics and genomics, ISSN 1744-6880, Vol. 20, nr 11, s. 700-707Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The activity of the human enzyme thiopurine methyltransferase (TPMT) varies greatly between individuals because of genetic polymorphism. TPMT is involved in the detoxification and activation of thiopurines such as 6-mercaptopurine, 6-thioguanine, and azathioprine. These drugs are used in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. A total of 29 sequence variants have been identified so far in the TPMT gene. However, most of these variants are rare and not fully characterized. METHODS AND RESULTS: In this study, we describe the identification and characterization of a novel TPMT sequence variant, originally found in a Swedish man of Italian origin. Sequencing of the variable number tandem repeats region of the TPMT promoter and exons III-X revealed a T-to-C transition at nucleotide 611, causing an amino acid substitution from isoleucine to threonine at amino acid 204, positioned in an α-helix, approximately 16 Å from the active site. This new variant was found in the patient and in his son. Both had intermediate enzyme activity (8.1 U/ml packed red blood cells and 8.8 U/ml packed red blood cells, respectively) and neither carried other variants in the coding region of the gene. To be able to study this variant in more detail, the TPMT*28 variant was expressed in Escherichia coli, and an in-vitro characterization of the variant revealed that the protein was destabilized and showed a stronger tendency towards degradation at 37°C than the wild-type protein. The individuals carrying the TPMT*28 variant had less TPMT protein and lower TPMT activity in both red and white blood cells compared with a wild-type control. CONCLUSIONS: We present a detailed in-vivo and in-vitro characterization of a novel TPMT sequence variant (TPMT*28) causing decreased TPMT activity. Individuals carrying TPMT*28 might have an increased risk for developing severe side effects if treated with conventional doses of thiopurines.

  • 223.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wennerstrand, Patricia
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lars-Göran, Mårtensson
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Hertervig, Erik
    Lund University Hospital, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Explaining TPMT genotype/phenotype discrepancy by identification of a novel sequence variant, TPMT*272009Inngår i: 13th International Symposium on Purine and Pyrimidine metabolism in man, 2009Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurine drugs. Owing to polymorphisms in the TPMT gene (TPMT*2-*22), the enzyme activity varies interindividually. Patients with reduced TPMT activity may develop adverse reactions when treated with standard doses of thiopurines. This work focuses on a TPMT genotype/phenotype discrepancy found in a patient during routine testing. The patient displayed very low TPMT enzyme activity and she was genotyped by pyrosequencing as being heterozygous for the 460G>A and 719A>G polymorphisms (TPMT*3A). Complete sequencing in combination with haplotyping of the TPMT gene revealed a novel sequence variant, 500C>G, on one allele and TPMT*3A on the other allele, giving rise to the novel genotype TPMT*3A/*23. When investigating the patient's relatives, they too had the TPMT*3A/*23 genotype in combination with low enzyme activity. We conclude that this novel variant allele affects enzyme activity, as the individuals carrying it had almost undetectable TPMT activity.

  • 224.
    Ljungberg, Liza
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Fysiologi. Linköpings universitet, Hälsouniversitetet.
    Persson, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Eriksson, Andreas
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Whiss, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013Inngår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, nr 2, s. 932-938Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent.

    The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets.

    None of the metabolites cotinine, cotinine-N-oxide, nicotine-1′-N-oxide or trans-3′-hydroxycotinine (0.1–10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3′-hydroxycotinine (0.1 μM) and nicotine-1′-N-oxide (1–10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor.

    Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 225.
    Lofgren, C.
    et al.
    Löfgren, C., Department of Clinical Hematology, Karolinska University Hospital, Stockholm, Sweden, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden, Hematology Center Karolinska, M 54 Huddinge, Karolinska University Hospital, S-141 86 Stockholm, Sweden.
    Albertioni, Freidoun
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Paul, C.
    Department of Clinical Hematology, Karolinska University Hospital, Stockholm, Sweden, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    High activity and incomplete cross resistance of nucleoside analogues cladribine and fludarabine versus ara-C on leukemic cells from patients with AML2005Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 27, nr 5, s. 641-646Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The in vitro activity and cross-resistance pattern of the purine analogues cladribine and fludarabine and the pyrimidine analogue cytarabine on leukemic cells from 170 patients with AML was evaluated using a bioluminescence assay. In in vivo mimicking concentrations, cladribine (50 nmol/L) and fludarabine (2 µmol/L) were more cytotoxic than cytarabine (0.5 µmol/L). The cytotoxic effect of fludarabine correlated weakly to cytarabine (r = 0.37, P < 0.001). The cytotoxic effect of cladribine correlated better to cytarabine (r = 0.49, P = 0.0002) but best to fludarabine (r = 0.82, P < 0.001). There was an absence of correlation between either cladribine or fludarabine and daunorubicin (0.2 µmol/L). Of 45 highly Ara-C-resistant samples, cladribine exerted high or intermediate effect in 54% and fludarabine in 52%. These in vitro data indicate that cladribine and fludarabine are active drugs in the treatment of AML. The cross resistance to cytarabine was not complete, and the drugs can be valuable either as alternatives to Ara-C or in combination therapy for treatment of leukemia resistant to standard therapy. Copyright © 2005 by Lippincott Williams & Wilkins.

  • 226. Lofti, K.
    et al.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Juliusson, G.
    Lund Strategic Centre for Stem Cell Biology and Therapy, Department of Hematology, Lund University Hospital, Lund, Sweden.
    Monitoring oral cyclosporine therapy [1]2005Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 36, nr 4, s. 367Annet (Annet vitenskapelig)
    Abstract [en]

    [No abstract available]

  • 227.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Albertioni, Freidoun
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Pharmacological basis for cladribine resistance2003Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 44, nr 10, s. 1705-1712Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The inherent or acquired resistance of leukemic cells to cytostatic agents is a major clinical challenge. The purpose of this review was to elucidate and analyse the available data concerning mechanisms of resistance of cladribine with emphasis on recent advances in the characterization of activating and inactivating enzymes in the induction of resistance to cladribine. All available in vitro and clinical data on cladribine was undertaken. Cladribine, unlike many other drugs, is toxic to both dividing and indolent lymphoid malignancies. Cladribine is a prodrug and must be phosphorylated intracellularly to cladribine-monophosphate (MP) by the nuclear/cystosol enzyme deoxycytidine kinase (dCK) and the mitochondrial enzyme deoxyguanosine kinase. The cytotoxicity mainly depends on the accumulation of cladribine-triphosphates (TP) after phosphorylation of cladribine-MP by nucleoside monophosphate kinase and nucleoside diphosphate kinase. 5'-Nucleotidase (5'-NT) dephosphorylates cladribine-MP and the accumulation of cladribine-TP depends on the ratio of dCK and 5'-NT in the cells. The mechanisms underlying cladribine resistance are multifactorial, e.g. decreased nucleoside transport, decreased activity or deficiency of dCK, altered intracellular pools of competing nucleotides, altered regulation of ribonucleotide reductase and increased drug inactivation by 5'-NT. Finally, cladribine resistance may be a consequence of a defective induction of apoptosis. In spite of the fact that more than one mechanism can contribute to a cladribine resistance phenotype, a reduction in dCK activity is probably the major determinant of cladribine resistance. Insight into the mechanism of action and resistance to cladribine is crucial for its optimal use as well as for the development of newer analogues.

  • 228.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Karlsson, Karin
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Fyrberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Juliusson, Gunnar
    Lund University Hospital.
    Jonsson, Viggo
    Oslo University.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Eriksson, Staffan
    Swedish University of Agricultural Sciences, The Biomedical Center, Uppsala.
    Albertioni, Freidoun
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    The pattern of deoxycytidine- and deoxyguanosine kinase activity in relation to messenger RNA expression in blood cells from untreated patients with B-cell chronic lymphocytic leukemia2006Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 71, nr 6, s. 882-890Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) catalyze the first step in the intracellular cascade of fludarabine (2-fluoroadenine-β- d-arabinofuranoside) and cladribine (2-chlorodeoxyadenosine) phosphorylation, which leads to activation of these prodrugs, commonly used for treatment of chronic lymphocytic leukemia (CLL). Thus, resistance to nucleoside analogues may primarily be due to low levels of deoxynucleoside kinase activity. The purpose of this study was to investigate the activity profiles of dCK and dGK and characterize the possible relationship between the levels of dCK enzymatic activities and mRNA levels in B-CLL cells from untreated patient samples in an attempt to determine the best approach for predicting sensitivity to nucleoside analogues and thereby optimizing treatment of CLL. For this purpose, dCK and dGK analyses were done in blood cells from 59 untreated symptomatic patients with CLL. The dGK activity towards 2-chlorodeoxyadenosine was significantly lower than of dCK (median 73 pmol/mg protein/min (85-121, 95% CI) versus 353 pmol/mg protein/min (331-421)). The median dCK mRNA level was 0.107 (0.096-0.120, 95% CI). There was a lack of correlation between the activities of dCK and dGK, which indicates that these proteins are regulated independently. We also found that the dCK and dGK activity measurement towards their endogenous substrates were comparable to the nucleoside analogues tested. Such variations in enzyme activities and mRNA levels may well explain differences in clinical responses to treatment. There was no correlation between the levels of dCK mRNAs and enzymatic activities using a quantitative real-time PCR procedure. Sequencing of dCK mRNA did not reveal alternate splicing or mutations in the coding region. The relation between activity and mRNA levels was studied by short interfering RNA (siRNA) method, which showed that in the siRNA treated cells the down-regulation of dCK expression, and activity followed each other. However, in control cells the mRNA levels remained stable but the protein activity markedly decreased. These data demonstrate that the dCK activity is not reflected by dCK mRNA expression that indicates a post-translational mechanism(s). © 2005 Elsevier Inc. All rights reserved.

  • 229.
    Lovborg, H.
    et al.
    n/a.
    Jacobsson, I.
    Regionalt biverkningscentrum.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Hostmedicin förstärkte effekten av warfarin: Cocillana-Etyfin höjde PK(INR)-värdet2009Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, nr 45, s. 2968-2969Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    De i artikeln beskrivna fallen visar på en potentiell interaktion mellan Cocillana-Etyfin och warfarin, med risk för allvarliga blödningar som följd. Stor vaksamhet och rapportering av misstänkta biverkningar och interaktioner är av stor vikt för att säkerställa en säker och rationell läkemedelsanvändning.

  • 230.
    Lyth, Johan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Frodin, U
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Pain assessments during autologous stem cell transplantation in BONE MARROW TRANSPLANTATION, vol 46, issue , pp S450-S4512011Inngår i: BONE MARROW TRANSPLANTATION, Nature Publishing Group , 2011, Vol. 46, s. S450-S451Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 231.
    Lövborg, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Burman, Robert
    Department of Medicinal Chemistry, Uppsala University.
    Gullbo, Joachim
    Division of Clinical Pharmacology, Uppsala University Hospital.
    Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug.2009Inngår i: BMC research notes, ISSN 1756-0500, Vol. 2, s. 114-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ABSTRACT: BACKGROUND: N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N''-4-pyridyl guanidine) (CHS 828) is the first candidate drug from a novel group of anti-tumour agents - the pyridyl cyanoguanidines, shown to be potent compounds interfering with cellular metabolism (inhibition of nicotinamide phosphoribosyl transferase) and NF-kappaB signalling. Substituted cyanoguanidines are also found in anti-hypertensive agents such as the potassium channel opener pinacidil (N-cyano-N'-(4-pyridyl)-N''-(1,2,2-trimethylpropyl)guanidine) and histamine-II receptor antagonists (e.g. cimetidine, N-cyano-N'-methyl-N''-[2-[[(5-methylimidazol-4-yl]methyl]thio]ethyl)guanidine). In animal studies, CHS 828 has shown very promising activity, and phase I and II studies resulted in further development of a with a water soluble prodrug. FINDINGS: To study the structural requirements for cyanoguanidine cytotoxicity a set of 19 analogues were synthesized. The cytotoxic effects were then studied in ten cell lines selected for different origins and mechanisms of resistance, using the fluorometric microculture cytotoxicity assay (FMCA). The compounds showed varying cytotoxic activity even though the dose-response curves for some analogues were very shallow. Pinacidil and cimetidine were found to be non-toxic in all ten cell lines. Starting with cyanoguanidine as the crucial core it was shown that 4-pyridyl substitution was more efficient than was 3-pyridyl substitution. The 4-pyridyl cyanoguanidine moiety should be linked by an alkyl chain, optimally a hexyl, heptyl or octyl chain, to a bulky end group. The exact composition of this end group did not seem to be of crucial importance; when the end group was a mono-substituted phenyl ring it was shown that the preferred position was 4-substitution, followed by 3- and, finally, 2-substitution as the least active. Whether the substituent was a chloro, nitro or methoxy substituent seemed to be of minor importance. Finally, the activity patterns in the ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients. CONCLUSION: According to this structure-activity relationship (SAR) study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.

  • 232.
    Lövborg, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Jönsson, Anna K
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    A fatal outcome after unintentional overdosing of rivastigmine patches2012Inngår i: Current drug safety, ISSN 2212-3911, Vol. 7, nr 1, s. 30-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Rivastigmine is an acetylcholine esterase inhibitor used in the treatment of dementia. Patches with rivastigmine for transdermal delivery have been used to increase compliance and to reduce side effects.

    CASE REPORT: We describe an 87-year old male with dementia treated with multiple rivastigmine patches (Exelon 9,5 mg/24 h) who developed nausea, vomiting and renal failure with disturbed electrolytes resulting in death. The symptoms occurred after six rivastigmine patches had concomitantly been erroneously applied by health care personnel on two consecutive days. The terminal cause of death was considered to be uremia from an acute tubular necrosis that was assessed as a result of dehydration through vomiting. The rivastigmine intoxication was assessed as having caused or contributed to the dehydrated condition. The medication error occurred at least partly due to ambiguous labeling. The clinical signs were not initially recognized as adverse effects of rivastigmine.

    DISCUSSION: The presented case is a description of a rivastigmine overdose due to a medication error involving patches. This case indicates the importance of clear and unambiguous instructions to avoid administration errors with patches and to be vigilant to adverse drug reactions for early detection and correction of drug administration errors. In particular, instructions clearly indicating that only one patch should be applied at a time are important.

  • 233.
    Lövborg, Henrik
    et al.
    Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Ring Eriksson, Linda
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Jonsson, Anna K
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bradley, Thomas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    A prospective analysis of the preventability of adverse drug reactions reported in Sweden2012Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, nr 8, s. 1183-1189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adverse drug reactions (ADRs) are a major patient safety issue, and a substantial proportion of ADRs are, in fact, preventable. The aim of this study was to describe the proportion and pattern of preventable ADRs in spontaneously reported suspected ADRs and to study the feasibility of using data from an ADR reporting system for this purpose. less thanbrgreater than less thanbrgreater thanAll reports of ADRs, except those in which a vaccine was the suspected drug, submitted to the regional pharmacovigilance center of southeastern Sweden between 2008 and 2009 were analyzed. Causality between the suspected ADR and the medication was assessed using the World Health Organization (WHO) criteria, and preventability was assessed using Hallas criteria. less thanbrgreater than less thanbrgreater thanDuring the study period, 1,290 ADRs were received and 1,255 were classified as having at least a possible causality between a reaction and a drug. Of these, 172 (14%) ADRs were considered preventable, 35 (20%) were classified as definitely preventable, and 137 (80%) as possibly preventable. Of all preventable ADRs, 96 (56%) were related to prescribing, 35 (20%) to administration, and 41 (24%) to clinical and laboratory monitoring of treatment. Warfarin, oxycodone, and ioversol were the most common drugs with preventable ADRs. less thanbrgreater than less thanbrgreater thanThis study found that a substantial part of reported ADRs are preventable. Most of these are related to drug prescription, suggesting that interventions aiming to reduce preventable ADRs should focus on this process. Moreover, systems for ADR reporting may be useful in the mission of reducing the unsafe use of drugs.

  • 234.
    Masquelier, M
    et al.
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Vitols, S
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Palsson, M
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Mars, U
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Larsson, BS
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Low density lipoprotein as a carrier of cytostatics in cancer chemotherapy: Study of stability of drug-carrier complexes in blood2000Inngår i: Journal of drug targeting (Print), ISSN 1061-186X, E-ISSN 1029-2330, Vol. 8, nr 3, s. 155-164Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several solid tumour and leukemia cell types have a higher low density lipoprotein (LDL) uptake than the corresponding normal cells. We are investigating the possibilities to use LDL as a drug carrier to increase the selectivity of antineoplastic drugs in cancer chemotherapy. We have developed a method to incorporate lipophilic cytotoxic agents without interfering with the in vitro and in vivo properties of LDL, In this study, we examined the stability of some drug-LDL complexes in blood and plasma as this is an important prerequisite to achieve a selective therapy. The in vitro dialysis of N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD-32-LDL) against plasma revealed a slow dissociation of the complex. The same method showed a fast and total leakage of paclitaxel from paclitaxel-LDL into the plasma chamber. The dissociation of paclitaxel was confirmed by an autoradiographic study of the distribution of paclitaxel-LDL in tumour-bearing mice. In patients with leukemia the rapid plasma dissociation of AD-32 from LDL illustrated a much higher in vivo instability of this complex. With this method, cholesteryl-linoleate only could be incorporated into LDL in a stable manner as shown by dialysis and autoradiography results. The incorporation of cytotoxic drug derivatives, containing lipophilic anchors, is now under study in order to obtain LDL complexes with better plasma stability.

  • 235.
    Milovanovic, Micha
    et al.
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Hälsa, Aktivitet, Vård (HAV). Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Hallert, Claes
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Hälsa, Aktivitet, Vård (HAV). Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Medicinkliniken ViN.
    Järemo, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Medicinkliniken ViN.
    Platelet Density Distribution in Essential Thrombocythemia2010Inngår i: Pathophysiology of Haemostasis and Thrombosis, ISSN 1424-8832, E-ISSN 1424-8840, Vol. 37, nr 1, s. 35-42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Essential thrombocythemia (ET) is characterized by high platelet counts and a slightly increased bleeding risk. Why severe hemorrhage does not occur more frequently is not known. Variations of platelet density (kg/l) depend mainly on cell organelle content in that high-density platelets contain more alpha and dense granules. This study compares ET patients (n = 2) and healthy volunteers (n = 2) with respect to platelet density subpopulations. A linear Percoll gradient containing prostaglandin E(1) was employed to separate platelets according to density. The platelet population was subsequently divided by density into 16 or 17 subpopulations. Determination of platelet counts was carried out. In each density fraction, platelet in vivo activity, i.e. platelet-bound fibrinogen, was measured using a flow cytometer. To further characterize platelet subpopulations, we determined intracellular concentrations of CD40 ligand (CD40L) and P-selectin in all fractions. Patients and controls demonstrated similar density distributions, i.e. 1 density peak. High-density platelets had more surface-bound fibrinogen in conjunction with signs of platelet release reactions, i.e. with few exceptions they contained less CD40L and P-selectin. Peak density platelets showed less surface-bound fibrinogen. These platelets contained less CD40L and P-selectin than nearby denser populations. The light platelets had more surface-bound fibrinogen than peak platelets together with elevated concentrations of CD40L. In ET, the malignant platelet production could exist together with platelets originating from normal megakaryocytes. It is also possible that clonal megakaryocytes produce platelets covering the entire density span. The 'normal' density distribution offers a tenable explanation as to why serious bleedings do not occur more frequently.

     

  • 236.
    Minhage, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet.
    Wilde Larsson, Bodil
    Division for Health and Caring Sciences, Karlstad University, Karlstad, Sweden.
    Gustafsson, Gunnel
    Institute of Gerontology, University of Jönköping, Jönköping, Sweden.
    Hamrin, Elisabeth
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Psychometric testing of the Swedish version of the Philadelphia Geriatric Center Multilevel Assessment Instrument2007Inngår i: International Journal of Nursing Practice, ISSN 1322-7114, Vol. 13, nr 3, s. 139-150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We examined whether the Swedish adaptation of the Philadelphia Geriatric Center Multilevel Assessment Instrument (PGCMAI) developed by Lawton meets criteria for reliability and validity in an elderly Swedish population with locomotor disability. Data were collected, using the mid-length version of the instrument, from 199 elderly people with locomotor disability in two Swedish counties. Reliability was determined by Cronbach's alpha and construct validity was tested by means of exploratory factor analysis. Comparison was made with the Standardized Practical Equipment (SPE) test. Factor analysis identified eight factors, which were comparable to the original eight domains. There was a logical correlation between the PGCMAI and the SPE test. Further psychometric testing is recommended on other groups of elderly people.

  • 237.
    Minhage, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet.
    Wilde Larsson, Bodil
    Department of Nursing, Karlstad University, Karlstad.
    Gustafsson, Gunnel
    Institute of Gerontology, University of Jönköping, Jönköping.
    Hamrin, Elisabeth
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    The Swedish Version of the Philadelphia Geriatric Center Multilevel Assessment Instrument, by age and gender in an old-age swedish population, especially related to locomotor disability2008Inngår i: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, Vol. 22, nr 3, s. 478-484Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to explore the pattern of the Swedish version of the Philadelphia Geriatric Center Multilevel Assessment Instrument (PGCMAI), in respect of age and gender, in a sample of old people with locomotor disability from a population aged 60 years and older in Sweden and compare it with other studies in the same area for the purpose of further validation. The participants (n = 199) were selected from a population (n = 3469), age ≥60 years, in two counties in Sweden and were visited in their own homes. The measure was carried out with two instruments, the Swedish version of PGCMAI, used as an interview, and the Standardized Practical Equipment test consisting of practical tasks. We found that these two instruments distinguished the functional pattern among old men and women where women had deteriorated most with age. This is in agreement with other studies.

  • 238.
    N Fransson, Martin
    et al.
    Karolinska Institute.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Litton, Jan-Eric
    Karolinska Institute.
    Friberg, Lena E
    Uppsala University.
    Influence of Cremophor EL and Genetic Polymorphisms on the Pharmacokinetics of Paclitaxel and Its Metabolites Using a Mechanism-Based Model2011Inngår i: DRUG METABOLISM AND DISPOSITION, ISSN 0090-9556, Vol. 39, nr 2, s. 247-255Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6 alpha-hydroxypaclitaxel and p-3-hydroxypaclitaxel, and its secondary metabolite, 6 alpha-p-3-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6 alpha-hydroxypaclitaxel and p-3-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6 alpha-p-3-dihydroxypaclitaxel. Clearance of 6 alpha-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p andlt; 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6 alpha-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

  • 239.
    Nilsson, Gunnel
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Stability of zopiclone in whole blood: Studies from a forensic perspective2010Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Bio‐analytical results are influenced by in vivo factors like genetic, pharmacological and physiological conditions and in vitro factors like specimen composition, sample additives and storage conditions. The knowledge of stability of a drug and its major metabolites in biological matrices is very important in forensic cases for the interpretation of analytical results. Many drugs are unstable and undergo degradation during storage.

    Zopiclone is a short‐acting hypnotic drug, introduced as a treatment for insomnia in the 1980s. However, this drug is also subject to abuse and can be found in samples from drug‐impaired drivers, recreational drug users and forensic autopsy cases. Zopiclone is analyzed in biological materials using different analytical methods. It is unstable in certain solvents and depending on storage conditions unstable in biological fluids. The aim of this thesis was to investigate the stability of zopiclone in human whole blood and to compare stability between authentic and spiked samples. Interpretation of zopiclone concentrations in whole blood is important in forensic toxicology. The following investigations were performed to study the stability of zopiclone in both spiked and authentic human blood.

    First, different stability tests were performed. Spiked blood samples were stored at –20°C, 5°C and 20°C and the degradation of zopiclone was investigated in long‐ and short‐term stability. Authentic and spiked blood samples were stored at 5°C and differences in zopiclone stability were studied. Processed sample stability and effect of freeze/thaw cycles were also evaluated.

    Second, influence of pre‐analytical conditions on the interpretation of zopiclone concentrations in whole blood was investigated. Nine volunteers participated in the study. Whole blood was obtained before and after oral administration of 2 x 5 mg Imovane®. Aliquots of authentic and spiked blood were stored under different conditions and zopiclone stability was evaluated. In this study, the influence from physiological factors such as drug interactions, matrix composition and plasma protein levels were minimized.

    Analyses of zopiclone were performed by gas chromatography with nitrogen phosphorous detection and zopiclone concentrations were measured at selected time intervals. Degradation product of zopiclone was identified using liquid chromatography‐tandem mass spectrometry.

    The first study showed that zopiclone degrades in human blood depending on time and temperature and may not be detected after long‐term storage. The degradation product 2‐amino‐5‐chloropyridine was identified following zopiclone degradation. The best storage condition was at –20°C even for short storage times, because freeze‐thaw had no influence on the results. In butyl acetate extracts, zopiclone was stable for at least two days when kept in the autosampler. However, in blood samples stored at 20°C a rapid decrease in concentration, was noticed. This rapid degradation at ambient temperature can cause an underestimation of the true concentration and consequently flaw the interpretation.

    The second study showed no stability differences between authentic and spiked blood but confirmed the poor stability in whole blood at ambient temperature. The results showed that zopiclone was stable for less than 1 day at 20°C, less than 2 weeks at 5°C, but stable for 3 months at –20°C. This study, demonstrates the importance of controlling pre‐analytical conditions from sampling to analysis to avoid misinterpretation of toxicological results.

    Delarbeid
    1. Stability tests of zopiclone in whole blood
    Åpne denne publikasjonen i ny fane eller vindu >>Stability tests of zopiclone in whole blood
    2010 (engelsk)Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 200, nr 01-Mar, s. 130-135Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

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

    sted, utgiver, år, opplag, sider
    Elsevier Science B.V., Amsterdam., 2010
    Emneord
    Degradation; Forensic toxicology; Stability; Storage; Zopiclone
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-58328 (URN)10.1016/j.forsciint.2010.04.001 (DOI)000279024800017 ()
    Tilgjengelig fra: 2010-08-13 Laget: 2010-08-11 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    2. Influence of pre-analytical conditions on the interpretation of zopiclone concentrations in whole blood
    Åpne denne publikasjonen i ny fane eller vindu >>Influence of pre-analytical conditions on the interpretation of zopiclone concentrations in whole blood
    2011 (engelsk)Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 207, nr 1-3, s. 35-39Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

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

    sted, utgiver, år, opplag, sider
    Elsevier, 2011
    Emneord
    Degradation; Forensic toxicology; Stability; Storage; Zopiclone
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-59046 (URN)10.1016/j.forsciint.2010.08.016 (DOI)000288851300028 ()20851542 (PubMedID)
    Tilgjengelig fra: 2010-09-07 Laget: 2010-09-07 Sist oppdatert: 2018-01-12bibliografisk kontrollert
  • 240.
    Nilsson, Gunnel
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Influence of pre-analytical conditions on the interpretation of zopiclone concentrations in whole blood2011Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 207, nr 1-3, s. 35-39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 241.
    Nilsson, Gunnel
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Stability tests of zopiclone in whole blood2010Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 200, nr 01-Mar, s. 130-135Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 242.
    Nordgren, Helena K
    et al.
    Karolinska Institutet.
    Holmgren, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Liljeberg, Paula
    Karolinska Institutet.
    Eriksson, Nadja
    Karolinska Institutet.
    Beck, Olof
    Karolinska Institutet.
    Application of direct urine LC-MS-MS analysis for screening of novel substances in drug abusers2005Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 29, nr 4, s. 234-239Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A newly developed liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was used to study 3000 human urine samples from 3 different populations for 23 analytes covering phenylethylamines, benzylpiperazine, and non-benzodiazepine hypnotics. Direct injection of urine and LC-MS-MS with rapid chromatography and atmospheric pressure chemical ionization was used in the screening step. The cutoff levels were chosen to be at the limit of detection for most analytes to identify as many positive samples as possible. Typically one ion transition was monitored from the pseudo-molecular ions in the multiple reaction monitoring mode. Of the 797 positive screening findings, 518 (65%) were confirmed by a second LC-MS-MS analysis including solid-phase extraction. Confirmed analytical findings included 22 cases positive for N-benzylpiperazine, 88 for 3,4-methylenedioxy-N-methylamphetamine and metabolites, 4 for 1-phenyl-2-butylamine, 24 for zolpidem and metabolites, 118 for zopiclone and metabolites, and 1 for zaleplon. In conclusion, LC-MS-MS was found to be a robust alternative for drugs of abuse screening, offering high sensitivity compared with immunochemical screening methodology.

  • 243.
    Nordigården, Amanda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Zetterblad, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Trinks, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Druid, Pia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ronnstrand, Lars
    Lund University.
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice2011Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, nr 2, s. 198-208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

  • 244.
    Olsson, Anders
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Rosengren, A.
    Avdelningen för akut och kardiovaskulär medicin, Sahlgrenska akademin, Göteborg, Sweden.
    Tornvall, P.
    Svenska cardiologföreningen, hjärtkliniken, Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Kolesterolhypotesen står sig2010Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, nr 12, s. 831-836Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    Då kolesterolhypotesen nyligen ifrågasatts har en uppdatering gjorts av kolesterolets roll i aterogenesen hos människa.

    Genetiska, epidemiologiska, cellbiologiska, molekylärbiologiska och kliniska skäl som anförs visar entydigt på en viktig roll för low-density lipoprotein (LDL) i aterosklerosutvecklingen.

    Behandlingsstudier med olika typer av LDL-sänkande behandling styrker ytterligare att kolesterol har stor betydelseför uppkomsten av atero­skleros.

    Fortfarande kvarstår en stor risk för hjärt–kärlsjukdom i Sverige. Nya hypoteser kring orsaken till ateroskleros är därför välkomna.

    Nya tankar kan vara att optimal LDL-nivå ännu inte uppnåtts och/eller att andra lipoproteiner, såsom high-density lipoprotein (HDL) eller triglycerider också måste tas med som viktiga aterogena faktorer.

  • 245.
    Olsson, Anders
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Rosengren, A.
    Sahlgrenska akademin, Göteborg.
    Tornvall, P.
    Karolinska universitetssjukhuset.
    Patienten framför allt!2010Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, nr 24, s. 1639-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    [No abstract available]

  • 246.
    Paul, Christer
    et al.
    Karolinska University Hospital.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jakobsen Falk, Ingrid
    n/a.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Paul, Esbjorn
    Karolinska University Hospital.
    Hermansson, Monika
    Uppsala University.
    Rosenquist, Richard
    Uppsala University.
    Jonsson-Videsater, Kerstin
    n/a.
    Nahi, Hareth
    n/a.
    Implications On Drug Resistance and Survival of ABCB1 Single Nucleotide Polymorphisms in Normal Karyotype De Novo AML in BLOOD, vol 114, issue 22, pp 1038-10392009Inngår i: BLOOD, American Society of Hematology , 2009, Vol. 114, nr 22, s. 1038-1039Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 247.
    Paul, E.
    et al.
    Karolinska Institute.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Jakobsen Falk, I.
    n/a.
    Rosenquist, R.
    Uppsala Univ.
    Paul, C.
    Karolinska Institute.
    Nahi, H.
    Karolinska Institute.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    ABCB1 SINGLE NUCLEOTIDE POLYMORPHISMS IN DE NOVO AML WITH NORMAL KARYOTYPE - IMPLICATIONS ON DRUG RESISTANCE AND SURVIVAL2009Inngår i: in HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, vol 94, 2009, Vol. 94, s. 0576-Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 248.
    Persson, Ingrid A L
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Persson, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf G G
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective.2011Inngår i: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 57, nr 1, s. 44-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Evidence suggests that cocoa from the bean of Theobroma cacao L. has beneficial effects on cardiovascular disease. The aim of this study was to investigate if cocoa extract and dark chocolate influence angiotensin-converting enzyme (ACE) and nitric oxide (NO) in human endothelial cells (in vitro) and in healthy volunteers (in vivo). ACE activity was analyzed with a commercial radioenzymatic assay and measured in human endothelial cells from umbilical veins (HUVEC) after 10 minutes of incubation with cocoa extract. NO was measured after 24 hours of incubation. ACE activity and NO were measured at baseline and after 30, 60, and 180 minutes in 16 healthy volunteers after a single intake of 75 g of dark chocolate containing 72% cocoa. Significant inhibition of ACE activity (P < 0.01) and significant increase of NO (P < 0.001) were seen in HUVEC. In the study subjects, a significant inhibition of ACE activity (mean 18%) 3 hours after intake of dark chocolate was seen, but no significant change in NO was seen. According to ACE genotype, significant inhibition of ACE activity was seen after 3 hours in individuals with genotype insertion/insertion and deletion/deletion (mean 21% and 28%, respectively). Data suggest that intake of dark chocolate containing high amount of cocoa inhibits ACE activity in vitro and in vivo.

  • 249.
    Persson, Ingrid A-L
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Persson, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Andersson, Rolf G G
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Effects of green tea, black tea and Rooibos tea on angiotensin-converting enzyme and nitric oxide in healthy volunteers2010Inngår i: Public Health Nutrition, ISSN 1368-9800, E-ISSN 1475-2727, Vol. 13, nr 5, s. 730-737Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Tea has been reported to reduce cardiovascular mortality, but the underlying mechanisms are largely unknown. The aim of the current project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos tea (South Africa) on angiotensin-converting enzyme (ACE) and nitric oxide (NO). DESIGN: Seventeen healthy volunteers received a single oral dose of 400 ml green tea, black tea or Rooibos tea in a randomized, three-phase, crossover study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 min) in all phases. ACE activity was analysed by means of a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition, ACE genotype was determined using a PCR method. RESULTS: Oral intake of a single dose of Rooibos tea significantly inhibited ACE activity after 30 min (P < 0.01) and after 60 min (P < 0.05). A significant inhibition of ACE activity was seen with green tea for the ACE II genotype 30 min after intake of the tea (P < 0.05) and for the ACE ID genotype 60 min after intake (P < 0.05). A significant inhibition of ACE activity was also seen with Rooibos tea for the ACE II genotype 60 min after intake (P < 0.05). No significant effect on NO concentration was seen. CONCLUSIONS: These results suggest that green tea and Rooibos tea may have cardiovascular effects through inhibition of ACE activity.

  • 250.
    Persson, Ingrid
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Persson, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Effects of green tea, black tea and rooibos on angiotensin-converting enzyme activity in healthy volunteers2009Inngår i: in Planta Medica(ISSN 0032-0943), 2009, Vol. 75, nr 9, s. 1030-1030Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Tea has been reported to reduce cardiovascular mortality, but the mechanisms behind are largely unknown. The aim of this project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos on angiotensin-converting enzyme and nitric oxide. Seventeen healthy volunteers received a single oral dose of either 400 ml green tea, black tea or Rooibos tea in a randomized three-phase cross over study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 minutes) in all phases. ACE activity was analysed with a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition ACE genotype was determined using a PCR method. Oral intake of a single dose of Rooibos significantly inhibited ACE activity, p<0.01 after 30 min and p<0.05 after 60 min. A significant inhibition of ACE activity was seen with green tea for the ACE genotype II (p<0.05), 30 minutes after intake of the tea and for the ACE genotype ID (p<0.05), 60 minutes after intake. A significant inhibition of ACE activity was also seen with Rooibos for the ACE genotype II (p<0.05), 60 minutes after intake. No significant effect on NO concentration was seen.

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