liu.seSearch for publications in DiVA
Endre søk
Begrens søket
34567 251 - 300 of 331
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Treff pr side
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
Merk
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 251.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Drug therapy of cancer2011Inngår i: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, ISSN 0031-6970, Vol. 67, nr 5, s. 437-447Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success. However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic myelogenous leukemia by imatinib, inhibiting the bcrabl-activated tyrosine kinase and thereby interrupting the signal transduction pathways that lead to leukemic transformation with impressive survival benefit, has paved the way for this new optimism. Another success story is the introduction of trastuzumab in breast cancers overexpressing the HER-2 receptor. In contrast, there has been little progress in other malignancies such as metastatic malignant melanoma, although very recently, clinical trials with new targeted drugs have shown increased survival. All major pharmaceutical companies now have ambitious development programs in the cancer area. However, the high costs of the novel drugs cause economic distress in the health care system in many countries leading to an intense debate on the cost-effectiveness of these drugs in relation to other health care activities.

  • 252.
    Petersson, A.
    et al.
    Department of Forensic Medicine, Karolinska Institute, Sweden.
    Garle, M.
    Department of Pharmacology, Huddinge University Hospital, Doping Laboratory, Sweden.
    Holmgren, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Druid, H.
    Department of Forensic Medicine, Karolinska Institute, Sweden.
    Krantz, P.
    Department of Forensic Medicine, Lund University Hospital, Sweden.
    Thiblin, I.
    Department of Forensic Medicine, Uppsala University, Dag Hammarskjöds v 17, S-752 37 Uppsala, Sweden.
    Toxicological findings and manner of death in autopsied users of anabolic androgenic steroids2006Inngår i: Drug And Alcohol Dependence, ISSN 0376-8716, E-ISSN 1879-0046, Vol. 81, nr 3, s. 241-249Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    With the aim to characterize patterns in toxicological profile and manner of death in deceased users of anabolic androgenic steroids (AAS), a retrospective autopsy protocol study of 52 deceased users of AAS was undertaken. The AAS users were compared to 68 deceased users of amphetamine and/or heroin who were consecutively tested and found to be negative for AAS. Use of AAS was in the majority of cases (79%) associated with concomitant use of psychotropic substances. AAS-related deaths differed in several respects from deaths among users of heroin or amphetamine, most strikingly with regard to: (a) the median age at death, which was significantly lower for AAS users (24.5 years) than for users of heroin and/or amphetamine (34 and 40 years, respectively), (b) the manner of death, with AAS users dying significantly more often from homicide or suicide than users of other drugs, and (c) the body mass index (BMI), with AAS users exhibiting significantly higher BMI than users of other drugs. These results support the earlier reported association between use of AAS and use of other psychoactive substances. In addition, the data suggest that AAS users are more likely to become involved in incidents leading to violent death and have a higher risk of dying at a younger age than users of other drugs. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 253.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Aamo, T.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Druid, H.
    Reference concentrations of antidepressants. A compilation of postmortem and therapeutic levels2007Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 31, nr 5, s. 254-264Artikkel i tidsskrift (Fagfellevurdert)
  • 254.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Aamo, Trond
    St Olaf Hospital, Norway.
    Spigset, Olav
    St Olaf Hospital, Norway.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Serum Concentrations of Antidepressant Drugs in a Naturalistic Setting: Compilation Based on a Large Therapeutic Drug Monitoring Database2009Inngår i: THERAPEUTIC DRUG MONITORING, ISSN 0163-4356, Vol. 31, nr 1, s. 42-56Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A compilation of therapeutic drug monitoring data for 15 antidepressant drugs in a naturalistic routine clinical setting is presented. A substantial number of serum concentrations, at different daily doses, are outlined, and the intraindividual and overall serum concentration coefficient of variation for a respective substance is presented. Also, concentration comparisons between women and men, and patients older or younger than 65 years are made. The drugs included are amitriptyline (n = 394), citalopram (n = 5457), clomipramine (n = 400), escitalopram (n = 3066), fluoxetine (n = 793), fluvoxamine (n = 165), mianserin (n = 1063), mirtazapine (n = 1427), moclobemide (n = 200), nortriptyline (n = 206), paroxetine (n = 1677), reboxetine (n = 85), sertraline (n = 2998), trimipramine (n = 158), and venlafaxine (n = 1781). Of the 9 drugs exhibiting linear (first order) kinetics, all but reboxetine gave a significant negative dose-to-dose-normalized correlation with concentrations, that is an increased clearance with higher dose. When dose was correlated to the metabolite: parent substance ratio for drugs exhibiting linear kinetics, citalopram and mianserin gave a positive slope, contrary to a negative slope shown for sertraline and venlafaxine. The intraindividual variations of the serum concentrations were lower than the overall variations, and the intraindividual variation of the metabolite: parent substance ratio was lower than the intraindividual variation of respective parent substance (except clomipramine and mianserin). Women had significantly higher serum concentrations than men (significant for citalopram, escitalopram, mianserin, mirtazapine, and venlafaxine), and patients older than 65 years had higher serum concentrations than the younger ones for all drugs except amitriptyline, moclobemide, and trimipramine. By presenting a comprehensive compilation of therapeutic drug monitoring data for each drug, a reference toot is created, in addition to improved pharmacokinetic knowledge of antidepressant drugs.

  • 255.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Akerblad, A C
    Uppsala University.
    von Knorring, L
    Uppsala University.
    Ekselius, L
    Uppsala University.
    Hidden partial non-compliance with antidepressants and its effect on treatment response2009Inngår i: in EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol 19, 2009, Vol. 19, s. S415-S415Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 256.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Akerblad, Ann-Charlotte
    Uppsala University.
    Ekselius, Lisa
    Uppsala University.
    von Knorring, Lars
    Uppsala University.
    Letter: Partial Compliance as Determined From Plasma Levels of Sertraline and Its Metabolite in Depressed Patients in Primary Care2010Inngår i: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 30, nr 6, s. 746-748Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 257.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kallen, B
    Lund University.
    Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data2010Inngår i: PSYCHOLOGICAL MEDICINE, ISSN 0033-2917, Vol. 40, nr 10, s. 1723-1733Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Concerns have been expressed about possible adverse effects of the use of antidepressant medication during pregnancy, including risk for neonatal pathology and the presence of congenital malformations. Method. Data from the Swedish Medical Birth Register (MBR) from 1 July 1995 up to 2007 were used to identify women who reported the use of antidepressants in early pregnancy or were prescribed antidepressants during pregnancy by antenatal care : a total of 14 821 women with 15 017 infants. Maternal characteristics, maternal delivery diagnoses, infant neonatal diagnoses and the presence of congenital malformations were compared with all other women who gave birth, using the Mantel-Haenszel technique and with adjustments for certain characteristics. Results. There was an association between antidepressant treatment and pre-existing diabetes and chronic hypertension but also with many pregnancy complications. Rates of induced delivery and caesarean section were increased. The preterm birth rate was increased but not that of intrauterine growth retardation. Neonatal complications were common, notably after tricyclic antidepressant (TCA) use. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) was verified. The congenital malformation rate was increased after TCAs. An association between use of paroxetine and congenital heart defects was verified and a similar effect on hypospadias was seen. Conclusions. Women using antidepressants during pregnancy and their newborns have increased pathology. It is not clear how much of this is due to drug use or underlying pathology. Use of TCAs was found to carry a higher risk than other antidepressants and paroxetine seems to be associated with a specific teratogenic property.

  • 258.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kallen, B
    Lund University.
    IMPACT OF IN UTERO EXPOSURE TO ANTIDEPRESSANTS ON THE FETUS in JOURNAL OF PSYCHOPHARMACOLOGY, vol 25, issue 8, pp A9-A92011Inngår i: JOURNAL OF PSYCHOPHARMACOLOGY, SAGE Publications (UK and US) , 2011, Vol. 25, nr 8, s. A9-A9Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 259.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kallen, B.
    Maternal use of antipsychotics in early pregnancy and delivery outcome.2008Inngår i: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, nr 3, s. 279-288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effect of various antipsychotics during pregnancy has repeatedly been studied, but for most atypical antipsychotics, only little information is available. We identified from the Swedish Medical Birth Register 2908 women who had reported the use of any antipsychotic or lithium in early pregnancy and studied malformation rates with data also from the Register of Congenital Malformations and the Hospital Discharge Register. Comparisons were made with all births (n = 958,729) after adjustment for some confounders. Risks were expressed as odds ratios (ORs).Most women had used dixyrazine or prochlorperazine mainly because of nausea and vomiting in early pregnancy. Seventy-nine women had used lithium, and these outcomes are reported separately. Hence, the main analysis was restricted to 570 women (576 infants) using other antipsychotics. There was a statistically significant increase in the risk for a congenital malformation-after exclusion of some common and minor conditions, the OR was 1.52 (95% confidence interval, 1.05-2.19). Exclusion of infants exposed to anticonvulsants reduced the OR only slightly. Most of the increased risk was caused by cardiovascular defects, mainly atrium or ventricular septum defect. No certain drug specificity was found. Except for an increased risk for congenital malformations, a nearly doubling of the risk for gestational diabetes and a 40% increased risk for cesarean delivery was noted. Because there seems to be little drug specificity, it is possible that underlying pathology or unidentified confounding explains the excess risk.

  • 260.
    Reis, Margareta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    von Knorring, Lars
    Uppsala University.
    Akerblad, Ann-Charlotte
    Uppsala University.
    Ekselius, Lisa
    Uppsala University.
    Hidden Partial Non-Compliance with Antidepressants and its Effect on Treatment Response2009Inngår i: in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, vol 18, 2009, Vol. 18, s. S169-S170Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 261.
    Rickardson, Linda
    et al.
    Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University Hospital, Sweden.
    Wickström, Malin
    Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University Hospital, Sweden.
    Larsson, Rolf
    Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University Hospital, Sweden.
    Lövborg, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Image-based screening for the identification of novel proteasome inhibitors.2007Inngår i: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 12, nr 2, s. 203-10Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The proteasome is a new, interesting target in cancer drug therapy, and the proteasome inhibitor bortezomib has shown an effect in myeloma patients. It is of interest to efficiently discover and evaluate new proteasome inhibitors. The authors describe the development of an image-based screening assay for the identification of compounds with proteasome-inhibiting activity. The stably transfected human embryo kidney cell line HEK 293 ZsGreen Proteasome Sensor Cell Line expressing the ZsProSensor-1 fusion protein was used for screening and evaluation of proteasome inhibitors. Inhibition of the proteasome leads to accumulation of the green fluorescent protein ZsGreen, which is measured in the ArrayScan High Content Screening system, in which cell morphology is studied simultaneously. When screening the LOPAC(1280) substance library, several compounds with effect on the proteasome were found; among the hits were disulfiram and ammonium pyrrolidinedithiocarbamate (PDTC). Cytotoxic analysis of disulfiram and PDTC showed that the compounds induced cytotoxicity in the myeloma cell line RPMI 8226. The average Z' value for the assay was 0.66. The results indicate that the assay rapidly identifies new proteasome-inhibiting substances, and it will be further used as a tool for image-based screening of other chemically diverse compound libraries.

  • 262.
    Ring Eriksson, Linda
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Lövborg, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Bradley, Thomas
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Drug Related Morbidity among Patients with Complex Health Care Needs Visiting an Emergency Room - A Pilot Study in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, vol 20, issue , pp S330-S3312011Inngår i: PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, John Wiley and Sons , 2011, Vol. 20, s. S330-S331Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 263.
    Rodríguez-Antona, Cristina
    et al.
    Spanish National Cancer Centre.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Editorial: Microtubule-targeting drugs and personalization of cancer treatment.2011Inngår i: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 12, nr 4, s. 449-51Artikkel i tidsskrift (Fagfellevurdert)
  • 264.
    Rosenqvist, Ulrika
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Psykiatri. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Tornqvist, M
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    An interaction between sertraline and carbamazepine which resluted in sub-therapeutic concentrations of sertraline and N-desmethylsertraline in serum2003Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, nr 4, s. 166-Konferansepaper (Annet vitenskapelig)
  • 265.
    Russo, Andrea
    et al.
    San Raffaele University.
    Castiglione, Fabio
    San Raffaele University.
    Salonia, Andrea
    San Raffaele University.
    Benigni, Fabio
    San Raffaele University.
    Rigatti, Patrizio
    San Raffaele University.
    Montorsi, Francesco
    San Raffaele University.
    Andersson, Karl-Erik
    Wake Forest Institute for Regenerative Medicine.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Effects of the Gonadotropin-Releasing Hormone Antagonist Ganirelix on Normal Micturition and Prostaglandin E-2-Induced Detrusor Overactivity in Conscious Female Rats2011Inngår i: EUROPEAN UROLOGY, ISSN 0302-2838, Vol. 59, nr 5, s. 868-874Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Gonadotropin-releasing hormone (GnRH) antagonists have been reported to have beneficial effects on lower urinary tract symptoms in patients with benign prostatic hyperplasia. Objective: Our aim was to investigate the effects of ganirelix, a GnRH receptor antagonist, on bladder function and detrusor overactivity (DO) in female rats. Design, setting, and participants: Female Sprague-Dawley rats received 2 wk of daily systemic (0.1 mg/kg) or acute intravesical administration (IVES; 0.14 mg/l or 1.4 mg/l) ganirelix or vehicle (controls). Measurements: Assessments were obtained using cystometry in awake rats, organ bath studies, enzyme-linked immunosorbent assay, and western blot (WB). Results and limitations: Luteinising hormone levels were lower in rats treated systemically with ganirelix than in controls. No differences were observed in body or bladder weights. Micturition interval (MI), micturition volume (MV), residual volume, and bladder capacity (BC) were similar in both groups at baseline. No differences in urodynamic pressure parameters were observed between groups at baseline. Intravesical prostaglandin E-2 reduced MI, MV, and BC, and it increased basal pressure (BP), threshold pressure (TP), flow pressure (FP), and maximum pressure (MP) in all rats. MI, MV, and BC were reduced by 43% +/- 4%, 50% +/- 4%, and 43% +/- 4% (controls) versus 22% +/- 3%, 23% +/- 3%, and 21% +/- 3% (ganirelix-treated rats; p andlt; 0.001). TP and FP increased by 38% +/- 8% and 30% +/- 4% (controls) versus 16% +/- 7% and 16% +/- 5% (ganirelix; p andlt; 0.05). The maximal force of contractions for carbachol was larger in detrusor from ganirelix-treated rats (231% vs 177% of 60 mM K+-induced contractions). At 0.14 mg/l, but not 0.14 mg/l, IVES ganirelix increased MI, MV, and BC and decreased BP, TP, FP, and MP. In vitro, ganirelix had no effect on detrusor function. The gonadotropin-releasing hormone receptor was expressed (by WB) in the bladder mucosa. Conclusions: Systemic treatment with ganirelix counteracted experimental DO in female rats. Because bladder preparations from these rats exhibited larger contractions to carbachol and because intravesical ganirelix affected both micturition intervals and urodynamic pressure profiles, a peripheral site of action of ganirelix in the urinary bladder cannot be excluded.

  • 266.
    Russo, Andrea
    et al.
    San Raffaele University.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Montorsi, Francesco
    San Raffaele University.
    Silodosin From Bench to Bedside: Selectivity, Safety, and Sustained Efficacy2011Inngår i: European urology. Supplement, ISSN 1569-9056, E-ISSN 1878-1500, Vol. 10, nr 6, s. 445-450Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Silodosin is the alpha(1)-adrenoceptor (AR) antagonist with the highest selectivity for the alpha(1A)-AR subtype that is available for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). How do preclinical findings translate into clinical effect? less thanbrgreater than less thanbrgreater thanObjective: Analyse information on the preclinical selectivity profile of silodosin in relation to clinical efficacy and safety. less thanbrgreater than less thanbrgreater thanEvidence acquisition: A Medline search for published articles on silodosin in preclinical and clinical studies was conducted. Information was also acquired from documents published by the European Medicines Agency. less thanbrgreater than less thanbrgreater thanEvidence synthesis: Silodosin exhibits high selectivity for the alpha(1A) subtype of the adrenoceptor, and it also displays selectivity for the lower urinary tract and prostate versus vascular functions as assessed in studies of isolated tissues, animal models, and patients. Silodosin causes symptom relief within days and is superior to placebo and noninferior to tamsulosin in reducing symptoms in patients with BPH. The effects of silodosin were sustained for 40-52 wk in open-label extension studies of 1170 patients. The safety and tolerability of silodosin are excellent. Silodosin more frequently causes abnormal ejaculation than placebo or tamsulosin, although only a minority of the patients discontinues treatment due to this adverse event. less thanbrgreater than less thanbrgreater thanConclusions: Both preclinical and clinical studies support the contention that silodosin has high uroselectivity and a positive cardiovascular safety profile, likely related to its selectivity for the alpha(1A)-AR subtype. Silodosin has a rapid onset of action and a sustained efficacy on LUTS due to BPH. 

  • 267.
    Schmitt, U
    et al.
    Johannes Gutenberg University Mainz.
    Schoenfelder, Y
    Johannes Gutenberg University Mainz.
    Karlsson, L
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, F C
    National Board of Forensic Medicine.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Hiemke, C
    Johannes Gutenberg University Mainz.
    Forced swim-test-related antidepressant effects depend on P-glycoprotein expression in the Blood-Brain-Barrier2009Inngår i: in PHARMACOPSYCHIATRY, ISSN 0176-3679, vol 42, issue 5, 2009, Vol. 42, nr 5, s. 241-241Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 268.
    Seldén, Tor
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Roman, Markus
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Druid, Henrik
    National Board of Forensic Medicine, Department of Forensic Medicine, Linköping, Sweden.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    LC-MS-MS analysis of buprenorphine and norbuprenorphine in whole blood from suspected drug users2011Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 209, nr 1-3, s. 113-119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A liquid chromatography tandem mass spectrometry method is described for the analysis of buprenorphine and norbuprenorphine in whole blood. Linearity was achieved between 0.2-5 ng/g for buprenorphine and 0.5-5 ng/g for norbuprenorphine. Stability studies on spiked whole blood and an authentic sample showed no degradation of buprenorphine- and norbuprenorphine-glucuronide to their respective aglycones. Buprenorphine and norbuprenorphine showed some degradation when stored at 4 degrees C for three weeks, but was stable when stored at -20 degrees C for 4 weeks. The method was applied to forensic cases of driving under the influence of drugs (DUID) and petty drug offences (PDO) during 2007-2009. Out of 2459 cases analyzed, 322 were positive for both buprenorphine and norbuprenorphine (13%), 219 for buprenorphine only (9%), and 12 for norbuprenorphine only (0.5%). The mean and median concentrations (N = 322) were 1.7 and 1.0 ng/g, respectively, for buprenorphine and norbuprenorphine. The mean and median norbuprenorphine/buprenorphine ratios were 1.5 and 1.1, respectively. There was no significant difference in concentration ratios for DUID and PDO cases (p andgt; 0.05). We conclude that the described method for analysis of buprenorphine and norbuprenorphine in whole blood could be used to investigate use or misuse of buprenorphine but that many of the cases presented with very low concentrations of buprenorphine. We also conclude that analysis should be performed within two weeks unless samples are stored frozen prior to analysis.

  • 269.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Greén, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    A validated and rapid high-performance liquidchromatography method for the quantification ofconversion of radio-labelled sex steroids2010Inngår i: Hormone Molecular Biology and Clinical Investigation, ISSN 1868-1891, Vol. 3, nr 1, s. 375-381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 17b -hydroxysteroid dehydrogenase enzymes modify the availability of potent sex steroids and have thus attracted interest in the study of several steroid-dependent pathologies including breast, endometrial and prostate cancers. An increased awareness of the importance of steroidogenic enzymes has brought forth a demand for efficient assays to study the effects of individual enzymes on steroid levels. Methods used for assessing steroid conversion are often laborious and frequently involve hazardous sample preparation steps. We developed and validated an optimised simple method for sample preparation of sex steroids using protein precipitation by the addition of zinc sulphate/sodium hydroxide. The interconversion of radio-labelled oestrogens and androgens was quantified using high-performance liquid chromatography separation of oestrone, oestradiol, androstenedione and testosterone followed by online radiometric flow scintillation analysis. The method, which can be applied for assessing, e.g., the efficacy of inhibitors of steroidogenic enzymes, was successfully used for evaluating oestrogenic interconversion in breast cancer cell lines MCF7 and T-47D.

  • 270.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues2012Inngår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 44, nr 13, s. 949-956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    17βHSD enzymes catalyze the stereospecific oxidation/reduction at carbon 17β of androgens and estrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells was investigated by assessing interconversion products of estrone, estradiol, androstenedione, testosterone, and dehydroepiandrosterone. Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the finding that 17HSD14 oxidizes both estradiol and testosterone into less bioactive steroid metabolites estrone and androstenedione, respectively.

  • 271.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Boiso Moreno, Samuel
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Functional Characterization of ABCG2 Polymorphisms and Their Influence on Tyrosine Kinase Inhibitor Effects in Chronic Myeloid Leukemia Cells in BLOOD, vol 118, issue 21, pp 1491-14912011Inngår i: BLOOD, American Society of Hematology , 2011, Vol. 118, nr 21, s. 1491-1491Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 272.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almér, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    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.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Low expression of TPMT wild type alleles in a patient with absent TPMT activity2008Konferansepaper (Annet vitenskapelig)
  • 273.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almér, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    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.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Low Expression of TPMT wild type alleles in a patient with absent TPMT activity2008Konferansepaper (Annet vitenskapelig)
  • 274.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Karlgren, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    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.
    Kidhall, Irene
    Div of Gastroenterology and Hepatology, Danderyd Hospital.
    Almér, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Explaining TPMT Genotype/Phenotype Discrepancy by Identification of a Novel Sequence Variant, TPMT*232007Konferansepaper (Annet vitenskapelig)
  • 275.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Richter, J.
    Department of Hematology and Coagulation, Skåne University Hospital, Lund, Sweden.
    Olsson-Strömberg, U.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Bergquist, J.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Aluthgedara, W.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Ubhayasekera, K.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Svedberg, A.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Söderlund, S.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Sandstedt, Anna
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier. Linköpings universitet, Hälsouniversitetet.
    Johnsson, A.
    Department of Internal Medicine, Motala Hospital, Motala, Sweden.
    Aagesen, J.
    Department of Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Alsenhed, J.
    Department of Internal Medicine, Västervik Hospital, Västervik, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patientsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Introduction: The hepatic enzymes CYP3A4 and CYP3A5 metabolize the tyrosine kinase inhibitor imatinib into a large number of metabolites including the pharmacologically active N-desmethyl imatinib (CGP74588). Because the metabolic activity of CYP3A varies considerably between individuals and a previous pilot study suggested an inverse association between in vivo CYP3A metabolic activity and therapeutic outcome of imatinib, the primary aim of this study was to investigate the influence of CYP3A metabolic activity on the outcome of imatinib therapy in chronic myeloid leukemia patients.

    Methods: Fifty-five patients were included and CYP3A activity was estimated in vivo using quinine as a probe drug. Imatinib and CGP74588 trough concentrations in the plasma were determined at steady state in 34 patients. Cytogenetic and molecular responses after 12 months of first-line imatinib were retrospectively collected from patients’ medical records.

    Results: Patients with optimal response to imatinib (complete cytogenetic response (CCgR) or molecular response of BCR-ABL <1%) did not have different levels of CYP3A activity compared to non-optimal responders. Similar results were found when analyzing the molecular response and CCgR separately. Neither the imatinib trough concentration nor the CGP74588/imatinib ratio were significantly associated with CYP3A activity.

    Conclusion: CYP3A enzyme activity, as measured by quinine metabolic ratio, does not correlate with the plasma concentrations of imatinib or CGP74588 and is not predictive of imatinib therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the   ratelimiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes such as plasma protein binding or transport protein activity to look for the major contributor to patient variability in imatinib plasma concentration.

  • 276.
    Stamyr, Kristin
    et al.
    Karolinska Institute, Sweden .
    Thelander, Gunilla
    National Board for Forens Medicine, Sweden .
    Ernstgard, Lena
    Karolinska Institute, Sweden .
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Johanson, Gunnar
    Karolinska Institute, Sweden .
    Letter: Reply to "Hydrogen cyanide related deaths and detection in the blood" by Vihyat S. Bebarta2012Inngår i: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 24, nr 10, s. 688-688Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 277.
    Stamyr, Kristin
    et al.
    Karolinska Institute.
    Thelander, Gunilla
    National Board for Forensic Medicine.
    Ernstgard, Lena
    Karolinska Institute.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Johanson, Gunnar
    Karolinska Institute.
    Swedish forensic data 1992-2009 suggest hydrogen cyanide as an important cause of death in fire victims2012Inngår i: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 24, nr 3, s. 194-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Between 60 and 80% of all deaths related to fire are attributed to toxic fumes. Carbon monoxide (CO) is commonly thought to be the major cause. However, hydrogen cyanide (HCN) is also formed. Still, the exact contribution of HCN to fire-related fatalities is unknown. The aim of the study was to investigate the impact of HCN in relation to CO as a cause of death in fire victims. Data on carboxyhemoglobin (COHb) and blood cyanide from deceased fire victims in the period 1992-2009 were collected from two Swedish nationwide forensic databases (ToxBase and RattsBase). The databases contain data on COHb and/or cyanide from 2303 fire victims, whereof 816 on both COHb and cyanide. Nonparametric statistical tests were used. Seventeen percent of the victims had lethal or life-threatening blood cyanide levels (andgt;1 mu g/g) and 32% had lethal COHb levels (andgt;50% COHb). Over 31% had cyanide levels above 0.5 mu g/g, an indication of significant HCN exposure. The percentages may be underestimates, as cyanide is quickly eliminated in blood also after death. Our results support the notion that HCN contributes more to the cause of death among fire victims than previously thought.

  • 278.
    Steentoft, A
    et al.
    University of Copenhagen.
    Teige, B
    University of Oslo.
    Holmgren, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Vuori, E
    University of Helsinki.
    Kristinsson, J
    University of Iceland.
    Hansen, A. C.
    University of Aarhus.
    Ceder, Gun
    Linköpings universitet, Institutionen för medicin och hälsa, Sjukgymnastik. Linköpings universitet, Hälsouniversitetet.
    Wethe, G
    Norwegian Institute of Public Health.
    Rollmann, D
    University of Odense.
    Fatal poisoning in Nordic drug addicts in 20022006Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 160, nr 03-Feb, s. 148-156Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study from 2002 includes medicolegally examined fatal poisonings among drug addicts in the five Nordic countries: Denmark, Finland, Iceland, Norway and Sweden. A common definition "drug addict" is applied by the participating countries. The number of deaths, age, sex, place of death, main intoxicant and other drugs present in the blood are recorded in order to obtain national data, as well as comparable Nordic data and data comparable to earlier studies from 1997 and 1991. The Icelandic results are commented on separately due to the low number of cases The most fatal overdoses are seen in Norway, in both the death rate (number per 100,000 inhabitants = 8.44) and in absolute number (n = 232). The comparable figures for the other four countries are Denmark 5.43 (n = 175), Iceland 3.6 (n = 6), Finland 2.93 (n = 94) and Sweden 2.56 (n = 136). In earlier studies from 1991 and 1997, the highest death rate is seen in Denmark, with Norway as number two. Denmark is the only country where the death rate decreases from 1997 to 2002. A relatively large increase in deaths in the younger age groups(less than 30 years) is noted from 1997 to 2002, except in Denmark, where only a small increase in overdose deaths in very young people (15-19 years) is observed. Females account for 12-20% of the overdoses (three out of six deaths in Iceland). Relatively fewer deaths are recorded in the capital areas in 2002 than in 1997 and 199 1, suggesting more geographically widespread drug use in the Nordic countries Heroin/morphine is the single most frequently encountered main intoxicant, varying from 10% of the cases in Finland to 72% of the cases in Norway. Finland differs from the other countries in that a high percentage of the fatal overdoses in Finland are not caused by an illicit drug; buprenorphine, overdoses are seen, and relatively few deaths resulting from heroin are seen. Methadone is the main intoxicant in 41% of the Danish overdose cases, 15% of the Norwegian cases, 4% of the Swedish cases and none of the Finnish overdose cases, an observation probably linked to different national prescription rules for methadone The analytical screening reveals extended polydrug use. Frequently seen substances, in addition to the main intoxicant are amphetamine, tetrahydrocannabinol (THC), benzodiazepines and ethanol.

  • 279.
    Strandell, J
    et al.
    WHO Collaborating Centre Int Drug Monitoring.
    Noren, G N
    WHO Collaborating Centre Int Drug Monitoring.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Key Elements Contributing to Adverse Drug Interaction Safety Signals in DRUG SAFETY, vol 34, issue 10, pp 1004-10052011Inngår i: DRUG SAFETY, Adis , 2011, Vol. 34, nr 10, s. 1004-1005Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 280.
    Strandell, J.
    et al.
    Uppsala Monitoring Centre.
    Noren, G.N.
    Uppsala Monitoring Centre.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    REPORTED INFORMATION CONTRIBUTING TO ADVERSE DRUG INTERACTION SAFETY SIGNALS in BASIC and CLINICAL PHARMACOLOGY and TOXICOLOGY, vol 109, issue , pp 84-842011Inngår i: BASIC and CLINICAL PHARMACOLOGY and TOXICOLOGY, WILEY-BLACKWELL , 2011, Vol. 109, s. 84-84Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 281.
    Strandell, Johanna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Drug interaction surveillance using individual case safety reports2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and society in general. Post-marketing pharmacovigilance reporting databases with compiled individual case safety reports (ICSRs) have been shown to be particularly useful in the detection of novel drug - ADR combinations, though these reports have not been fully used to detect adverse drug interactions.

    Aim: To explore the potential to identify drug interactions using ICSRs and to develop a method to facilitate the detection of adverse drug interaction signals in the WHO Global ICSR Database, VigiBase.

    Methods: All six studies included in this thesis are based on ICSRs available in VigiBase. Two studies aimed to characterise drug interactions reported in VigiBase. In the first study we examined if contraindicated drug combinations (given in a reference source of drug interactions) were reported on the individual reports in the database, and in the second study we examined the scientific literature for interaction mechanisms for drug combinations most frequently co-reported as interacting in VigiBase. Two studies were case series analyses where the individual reports were manually reviewed. The two remaining studies aimed to develop a method to facilitate detection of novel adverse drug interactions in VigiBase. One examined what information (referred to as indicators) was reported on ICSRs in VigiBase before the interactions became listed in the literature. In the second methodological study, logistic regression was used to set the relative weights of the indicators to form triage algorithms. Three algorithms (one completely data driven, one semi-automated and one based on clinical knowledge) based on pharmacological and reported clinical information and the relative reporting rate of an ADR with a drug combination were developed. The algorithms were then evaluated against a set of 100 randomly selected case series with potential adverse drug interactions. The algorithm’s performances were then evaluated among DDAs with high coefficients.

    Results: Drug interactions classified as contraindicated are reported on the individual reports in VigiBase, although they are not necessarily recognised as interactions when reported. The majority (113/123) of drug combinations suspected for being responsible for an ADR were established drug interactions in the literature. Of the 113 drug interactions 46 (41%) were identified as purely pharmacodynamic; 28 (25%) as pharmacokinetic; 18 (16%) were a mix of both types and for 21 (19%) the mechanism have not yet been identified. Suspicions of a drug interaction explicitly noted by the reporter are much more common for known adverse drug interactions than for drugs not known to interact. The clinical evaluation of the triage algorithms showed that 20 were already known in the literature, 30 were classified as signals and 50 as not signals. The performance of the semi-automated and the clinical algorithm were comparable. In the end the clinical algorithm was chosen. At a relevant level, 38% were of the adverse drug interactions were already known in the literature and of the remaining 80% were classified as signals for this algorithm.

    Conclusions: This thesis demonstrated that drug interactions can be identified in large post-marketing pharmacovigilance reporting databases. As both pharmacokinetic and pharmacodynamic interactions were reported on ICSRs the surveillance system should aim to detect both. The proposed triage algorithm had a high performance in comparison to the disproportionality measure alone.

    Delarbeid
    1. Letter: Drug-drug interactions - a preventable patient safety issue?
    Åpne denne publikasjonen i ny fane eller vindu >>Letter: Drug-drug interactions - a preventable patient safety issue?
    2008 (engelsk)Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, nr 1, s. 144-146Artikkel i tidsskrift, Letter (Annet vitenskapelig) Published
    Abstract [en]

    n/a

    sted, utgiver, år, opplag, sider
    Wiley, 2008
    Emneord
    Adverse drug reactions, adverse drug interaction surveillance, drug interactions, individual case safety reports, postmarketing pharmacovigilance, signal detection
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-70845 (URN)10.1111/j.1365-2125.2007.02981.x (DOI)17635497 (PubMedID)
    Tilgjengelig fra: 2011-09-20 Laget: 2011-09-20 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    2. Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction
    Åpne denne publikasjonen i ny fane eller vindu >>Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction
    2009 (engelsk)Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 68, nr 3, s. 427-34Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    AIMS: In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis-azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction.

    METHODS: The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively.

    RESULTS: The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow-up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses.

    CONCLUSIONS: Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.

    sted, utgiver, år, opplag, sider
    Wiley-Blackwell, 2009
    Emneord
    Adverse drug reaction reporting systems, azithromycin, disproportionality measure, drug interaction, statins, WHO-ADR database
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-70846 (URN)10.1111/j.1365-2125.2009.03473.x (DOI)000269575200015 ()19740401 (PubMedID)
    Tilgjengelig fra: 2011-09-20 Laget: 2011-09-20 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    3. Pharmacodynamic and pharmacokinetic drug interactions reported to VigiBase, the WHO global individual case safety report database.
    Åpne denne publikasjonen i ny fane eller vindu >>Pharmacodynamic and pharmacokinetic drug interactions reported to VigiBase, the WHO global individual case safety report database.
    2011 (engelsk)Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, nr 6, s. 633-641Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and the community. Despite this, limited information is reported in the literature on the drug interaction categories responsible for causing ADRs. In the study reported here, we investigated the drug combinations most frequently co-reported as interacting in the WHO Global Individual Case Safety Report (ICSR) database, VigiBase, and categorised these according to the drug interaction mechanism. METHODS: Reports in which drug combinations were co-reported as interacting in at least 20 reports in VigiBase during the past 20 years were included in the study. Each drug combination was reviewed in the literature to identify the mechanism of interaction and subsequently classified as pharmacodynamic and/or pharmacokinetic reaction. Report characteristics were also analysed. RESULTS: A total of 3766 case reports of drug interactions from 47 countries were identified. Of the 123 different drug combinations reported, 113 were described in the literature to interact. The mechanism of the drug interaction was categorised as pharmacodynamic (46 combinations; 41%), pharmacokinetic (28; 25%), a combination of both types (18; 16%) and unidentified (21; 19%). Pharmacodynamic drug interactions primarily concerned pharmacological additive effects, whereas enzyme inhibition was the most frequent pharmacokinetic interaction. The combinations reviewed primarily implicated drugs such as warfarin, heparin, carbamazepine and digoxin. CONCLUSIONS: Drug interactions reported in globally collected ADR reports cover both pharmacodynamic, specifically additive pharmacological effects, and pharmacokinetic mechanisms primarily accredited to the inhibition of hepatic cytochrome P450 enzymes. These ADR reports often concern serious threats to patients' safety and are particularly related to the use of high risk drugs such as warfarin and heparin.

    sted, utgiver, år, opplag, sider
    Springer-Verlag New York, 2011
    Emneord
    Pharmacovigilance, VigiBase, Enzyme, inhibition, Additive effects
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-66507 (URN)10.1007/s00228-010-0979-y (DOI)000291607500010 ()21253716 (PubMedID)
    Tilgjengelig fra: 2011-03-18 Laget: 2011-03-18 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    4. Reporting Patterns Indicative of Adverse Drug Interactions: A Systematic Evaluation in VigiBase.
    Åpne denne publikasjonen i ny fane eller vindu >>Reporting Patterns Indicative of Adverse Drug Interactions: A Systematic Evaluation in VigiBase.
    Vise andre…
    2011 (engelsk)Inngår i: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, nr 3, s. 253-66Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Adverse drug interaction surveillance in collections of Individual Case Safety Reports (ICSRs) remains underdeveloped. Most efforts to date have focused on disproportionality analysis, but the empirical support for its value is based on isolated examples. Additionally, too little attention has been given to the potential value of the detailed content of ICSRs for improved adverse drug interaction surveillance. Objective: The aim of the study was to identify reporting patterns indicative of suspected adverse drug interactions before the drug interactions are generally established. Methods: A reference set of known adverse drug interactions and drug pairs not known to interact was constructed from information added to Stockley's Drug Interactions Alerts between the first quarter of 2007 and the third quarter of 2009. The reference set was used to systematically study differences in reporting patterns between adverse drug interactions before they are generally established and adverse drug reactions (ADRs) to drug pairs that are not known to interact, in the WHO Global ICSR Database, VigiBase. The scope of the study included pharmacological properties such as common cytochrome P450 metabolism, explicit suspicions of drug interactions as noted by the reporter, clinical details such as dose and treatment overlap, and the lower limit of the 95% credibility interval of a three-way measure of disproportionality, Omega(025) (Ω(025)), based on the total number of reports on two drugs and one ADR together. Analyses were carried out including and excluding concomitant medicines. Results: Five reporting patterns were highlighted as particularly strong indicators of adverse drug interactions before they are known: suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair; and, finally, an excess total number of reports on the ADR together with the two drugs, as measured by Ω(025). Overall, the inclusion of concomitant medicines led to a larger number of true adverse drug interactions being highlighted, but at a substantial decrease in the strength of most indicators. Notably, the inclusion of concomitant medicines completely eliminated the value of Ω(025) as an indicator of adverse drug interactions, in this systematic evaluation. Conclusions: Reported suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair and by the Ω(025) each provide unique information to highlight adverse drug interactions before they become known in the literature. To our knowledge, this is the first systematic analysis demonstrating the value of disproportionality analysis for adverse drug interactions using a comprehensive reference set, and the first study to consider a broader basis including clinical information for systematic drug interaction surveillance.

    sted, utgiver, år, opplag, sider
    Adis International, 2011
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-66510 (URN)10.2165/11586990-000000000-00000 (DOI)000288349500008 ()21332249 (PubMedID)
    Tilgjengelig fra: 2011-03-18 Laget: 2011-03-18 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    5. Key Elements in Adverse Drug Interaction Safety Signals
    Åpne denne publikasjonen i ny fane eller vindu >>Key Elements in Adverse Drug Interaction Safety Signals
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Effective surveillance of adverse drug interactions (a problematic drug combination resulting in an adverse drug reaction (ADR)) in large collections of individual case safety reports (ICSRs) requires a combination of expert clinical assessments and efficient algorithms. To date, most methods proposed for adverse drug interaction surveillance focus on disproportionality analysis, although a recent study proposed that the reported clinical and pharmacological information is also useful for systematic screening of adverse drug interactions.

    Objective: The purpose of this study is to identify and describe key elements in adverse drug interaction safety signals.

    Methods: Altogether 137 case reports from three previously published safety signals of suspected adverse drug interaction were re-evaluated using an operational algorithm for causality analysis of drug interactions; the Drug Interaction Probability Scale (DIPS). Reports in the WHO Global ICSR Database, VigiBase, and their corresponding original files were analysed, examining whether the DIPS elements were registered. The retrieved case information was specified as being listed in the structured fields, free text and, in total. In addition, information not covered by DIPS, such as explicit notifications of a suspected drug interaction by the reporter or the pharmacovigilance centre was also registered.

    Results: As expected from the data used in this analysis, the most frequently fulfilled DIPS elements were: objective evidence (such as ADR) of a drug interaction (137 cases; 100%). Other frequent elements were (ranked order) plausible time to onset (53 cases; 38%), and resolution of the ADR after terminating the drug inducing the interaction (10 cases; 7%). Ten cases (7%) fulfilled both a plausible time to onset and resolution of the ADR after stopping the drug. Positive rechallenge was only reported in 3 cases (2%). For 32 cases additional information was reported in free text in the original files that were not available in VigiBase. A suspected drug interaction was noted by the reporter in 47 original cases (35%) and more than 80% of these were assessed as a possible or probable drug interaction according to the DIPS classification. Among cases without notes of suspected interactions were 58 original reports (64%) assessed as possible (56 cases) or probable (2 cases).

    Conclusions: A plausible time to onset pattern and resolution of the ADR after withdrawal of the drug inducing the interaction frequently strengthened the suspected causality of a drug interaction. Particularly strong cases were those containing both these key elements. Since this information is often available in structured format, it could potentially be used to automatically highlight strong cases in firstpass screening. Finally, this analysis also demonstrated the importance of free text where particularly relevant clinically details such as timeliness, severity, resolution of the reaction after withdrawal of the drug inducing the interaction, possible alternative causes, and dosage changes are available.

    Emneord
    Adverse drug interactions, signals, systematic surveillance system, plausible time to onset
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-70847 (URN)
    Tilgjengelig fra: 2011-09-20 Laget: 2011-09-20 Sist oppdatert: 2011-09-20bibliografisk kontrollert
    6. Triage algorithms for early discovery of adverse drug interactions
    Åpne denne publikasjonen i ny fane eller vindu >>Triage algorithms for early discovery of adverse drug interactions
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Most methodological research for broad surveillance of drug interactions in large collections of suspected ADR reports has focused on measures of disproportionality. However, recent results indicate that reported clinical information and pharmacological characteristics may be at least as valuable to detect adverse drug interactions early.

    Objective: To develop triage algorithms for adverse drug interaction surveillance, and to evaluate the algorithms prospectively relative to expert clinical assessment.

    Methods: A previously developed reference set based on Stockley’s Drug Interactions was used to train the algorithms. Logistic regression was used to set the relative weights of the different indicators (information potentially suggestive adverse drug interactions such as pharmacological properties including cytochrome P450 (CYP) activity; explicit suspicions of drug interactions as noted by the reporter in different forms; clinical details such as dose and treatment overlap; and a measure of disproportionality based on the total number of reports on two drugs and one ADR together) of each algorithm. Three triage algorithms were designed. All are logistic regression models producing an estimated probability that a given case series constitutes an adverse drug interaction signal. Two of them are data driven: one which used a very broad set of indicators (full data-driven) and one which used a more narrow set (lean data-driven). The third was manually derived (lean clinical) as a simplified version of the full data-driven algorithm. An independent evaluation set was constructed that consisted of 100 randomly selected case series in the WHO Global Individual Case Safety Report (ICSR) Database, VigiBase, from January 1990 to February 2011. Each algorithm’s ranking of case series was evaluated against an evaluation set. In a complementary analysis the algorithm were compared to a pure disproportionality analysis.

    Results: The two lean algorithms were comparable in performance. However both outperformed the full data-driven algorithm on the independent evaluation set. The areas under the curve (AUC) for the receiver operating characteristics (ROC) curves were as follows: 71% (lean clinical) and 69% (lean data-driven). For a false positive rate (FPR) of up to 0.04 the lean algorithms classifies about 14,000 case series as potential interaction signals. Thresholds corresponding to greater FPRs are unlikely to be feasible in practice. The algorithms clearly outperform disproportionality analysis alone.

    Conclusions: The value of incorporating clinical and pharmacological information in first-pass screening for adverse drug interactions is clear. Two triage algorithms have been proposed that each effectively identify adverse drug interaction signals and clearly outperforming pure disproportionality analysis in this respect.

    Emneord
    Individual Case Safety Reports, Adverse Drug Interactions, VigiBase, Triage algorithms
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-70848 (URN)
    Tilgjengelig fra: 2011-09-20 Laget: 2011-09-20 Sist oppdatert: 2011-09-20bibliografisk kontrollert
  • 282.
    Strandell, Johanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bate, Andrew
    The Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Lindquist, Marie
    The Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Edwards, I Ralph
    The Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Letter: Drug-drug interactions - a preventable patient safety issue?2008Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, nr 1, s. 144-146Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 283.
    Strandell, Johanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Caster, Ola
    Uppsala Monitoring Centre, Uppsala Sweden. Department of Computer and Systems Sciences, Stockholm University, Stockholm, Sweden.
    Bate, Andrew
    Uppsala Monitoring Centre, Uppsala Sweden. School if Information Systems, Brunel University, London, UK.
    Norén, Niklas
    Uppsala Monitoring Centre, Uppsala Sweden. Department of Mathematics, Stockholm University, Stockholm, Sweden.
    Edwards, I Ralph
    Uppsala Monitoring Centre, Uppsala, Sweden.
    Reporting Patterns Indicative of Adverse Drug Interactions: A Systematic Evaluation in VigiBase.2011Inngår i: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 34, nr 3, s. 253-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Adverse drug interaction surveillance in collections of Individual Case Safety Reports (ICSRs) remains underdeveloped. Most efforts to date have focused on disproportionality analysis, but the empirical support for its value is based on isolated examples. Additionally, too little attention has been given to the potential value of the detailed content of ICSRs for improved adverse drug interaction surveillance. Objective: The aim of the study was to identify reporting patterns indicative of suspected adverse drug interactions before the drug interactions are generally established. Methods: A reference set of known adverse drug interactions and drug pairs not known to interact was constructed from information added to Stockley's Drug Interactions Alerts between the first quarter of 2007 and the third quarter of 2009. The reference set was used to systematically study differences in reporting patterns between adverse drug interactions before they are generally established and adverse drug reactions (ADRs) to drug pairs that are not known to interact, in the WHO Global ICSR Database, VigiBase. The scope of the study included pharmacological properties such as common cytochrome P450 metabolism, explicit suspicions of drug interactions as noted by the reporter, clinical details such as dose and treatment overlap, and the lower limit of the 95% credibility interval of a three-way measure of disproportionality, Omega(025) (Ω(025)), based on the total number of reports on two drugs and one ADR together. Analyses were carried out including and excluding concomitant medicines. Results: Five reporting patterns were highlighted as particularly strong indicators of adverse drug interactions before they are known: suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair; and, finally, an excess total number of reports on the ADR together with the two drugs, as measured by Ω(025). Overall, the inclusion of concomitant medicines led to a larger number of true adverse drug interactions being highlighted, but at a substantial decrease in the strength of most indicators. Notably, the inclusion of concomitant medicines completely eliminated the value of Ω(025) as an indicator of adverse drug interactions, in this systematic evaluation. Conclusions: Reported suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair and by the Ω(025) each provide unique information to highlight adverse drug interactions before they become known in the literature. To our knowledge, this is the first systematic analysis demonstrating the value of disproportionality analysis for adverse drug interactions using a comprehensive reference set, and the first study to consider a broader basis including clinical information for systematic drug interaction surveillance.

  • 284.
    Strandell, Johanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Caster, Ola
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Hopstadius, Johan
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Edwards, Ralph I.
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Noren, Niklas G.
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    The Development and Evaluation of Triage Algorithms for Early Discovery of Adverse Drug Interactions2013Inngår i: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 36, nr 5, s. 371-388Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Around 20 % of all adverse drug reactions (ADRs) are due to drug interactions. Some of these will only be detected in the postmarketing setting. Effective screening in large collections of individual case safety reports (ICSRs) requires automated triages to identify signals of adverse drug interactions. Research so far has focused on statistical measures, but clinical information and pharmacological characteristics are essential in the clinical assessment and may be of great value in first-pass filtering of potential adverse drug interaction signals. less thanbrgreater than less thanbrgreater thanObjective The aim of this study was to develop triages for adverse drug interaction surveillance, and to evaluate these prospectively relative to clinical assessment. less thanbrgreater than less thanbrgreater thanMethods A broad set of variables were considered for inclusion in the triages, including cytochrome P450 (CYP) activity, explicit suspicions of drug interactions as noted by the reporter, dose and treatment overlap, and a measure of interaction disproportionality. Their unique contributions in predicting signals of adverse drug interactions were determined through logistic regression. This was based on the reporting in the WHO global ICSR database, VigiBase (TM), for a set of known adverse drug interactions and corresponding negative controls. Three triages were developed, each producing an estimated probability that a given drug-drug-ADR triplet constitutes an adverse drug interaction signal. The triages were evaluated against two separate benchmarks derived from expert clinical assessment: adverse drug interactions known in the literature and prospective adverse drug interaction signals. For reference, the triages were compared with disproportionality analysis alone using the same benchmarks. less thanbrgreater than less thanbrgreater thanResults The following were identified as valuable predictors of adverse drug interaction signals: plausible CYP metabolism; notes of suspected interaction by the reporter; and reports of unexpected therapeutic response, altered therapeutic effect with dose information and altered therapeutic effect when only two drugs had been used. The new triages identified reporting patterns corresponding to both prospective signals of adverse drug interactions and already established ones. They perform better than disproportionality analysis alone relative to both benchmarks. less thanbrgreater than less thanbrgreater thanConclusions A range of predictors for adverse drug interaction signals have been identified. They substantially improve signal detection capacity compared with disproportionality analysis alone. The value of incorporating clinical and pharmacological information in first-pass screening is clear.

  • 285.
    Strandell, Johanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Caster, Ola
    Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Hopstadius, Johan
    Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Edwards, Ralph
    Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Norén, Niklas
    Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Triage algorithms for early discovery of adverse drug interactionsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Most methodological research for broad surveillance of drug interactions in large collections of suspected ADR reports has focused on measures of disproportionality. However, recent results indicate that reported clinical information and pharmacological characteristics may be at least as valuable to detect adverse drug interactions early.

    Objective: To develop triage algorithms for adverse drug interaction surveillance, and to evaluate the algorithms prospectively relative to expert clinical assessment.

    Methods: A previously developed reference set based on Stockley’s Drug Interactions was used to train the algorithms. Logistic regression was used to set the relative weights of the different indicators (information potentially suggestive adverse drug interactions such as pharmacological properties including cytochrome P450 (CYP) activity; explicit suspicions of drug interactions as noted by the reporter in different forms; clinical details such as dose and treatment overlap; and a measure of disproportionality based on the total number of reports on two drugs and one ADR together) of each algorithm. Three triage algorithms were designed. All are logistic regression models producing an estimated probability that a given case series constitutes an adverse drug interaction signal. Two of them are data driven: one which used a very broad set of indicators (full data-driven) and one which used a more narrow set (lean data-driven). The third was manually derived (lean clinical) as a simplified version of the full data-driven algorithm. An independent evaluation set was constructed that consisted of 100 randomly selected case series in the WHO Global Individual Case Safety Report (ICSR) Database, VigiBase, from January 1990 to February 2011. Each algorithm’s ranking of case series was evaluated against an evaluation set. In a complementary analysis the algorithm were compared to a pure disproportionality analysis.

    Results: The two lean algorithms were comparable in performance. However both outperformed the full data-driven algorithm on the independent evaluation set. The areas under the curve (AUC) for the receiver operating characteristics (ROC) curves were as follows: 71% (lean clinical) and 69% (lean data-driven). For a false positive rate (FPR) of up to 0.04 the lean algorithms classifies about 14,000 case series as potential interaction signals. Thresholds corresponding to greater FPRs are unlikely to be feasible in practice. The algorithms clearly outperform disproportionality analysis alone.

    Conclusions: The value of incorporating clinical and pharmacological information in first-pass screening for adverse drug interactions is clear. Two triage algorithms have been proposed that each effectively identify adverse drug interaction signals and clearly outperforming pure disproportionality analysis in this respect.

  • 286.
    Strandell, Johanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Noren, Niklas G
    WHO Collaborating Centre Int Drug Monitoring, Sweden .
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Key Elements in Adverse Drug Interaction Safety Signals An Assessment of Individual Case Safety Reports2013Inngår i: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 36, nr 1, s. 63-70Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background A large proportion of potential drug interactions are known from pre-authorization studies, but adverse drug reactions (ADRs) due to interactions (adverse drug interactions) are often first detected through astute observation in clinical practice. Individual case safety reports (ICSRs) are collected from broad patient populations and allow for the identification of groups of similar reports. Systematic screening for adverse drug interactions in ICSRs will require an understanding of which information on these reports can be suggestive of adverse drug interactions. less thanbrgreater than less thanbrgreater thanObjective The aim of the study was to identify what reported information may support the identification of drug interaction safety signals in collections of ICSRs. less thanbrgreater than less thanbrgreater thanMethods Three previously published safety signals of suspected adverse drug interactions were re-evaluated. To this end, 137 reports related to these signals were retrieved from the WHO Global ICSR Database, VigiBase (TM), and corresponding original reports were obtained from national pharmacovigilance centres. Criteria from an operational score for causality analysis of drug interactions of clinical cases, the Drug Interaction Probability Scale (DIPS), were applied to each of these reports with the aim of identifying what supportive information tends to be available in ICSRs. For three DIPS elements (plausible time course, resolution of the ADR after terminating the drug inducing the interaction without changes in affected drug therapy (positive dechallenge) and alternative causes of the reaction) we also compared the amount of information in VigiBase (TM) and in original reports, and in free text and structured data. less thanbrgreater than less thanbrgreater thanResults Commonly fulfilled DIPS elements on reports supporting an adverse drug interaction signal were plausible time course (50 reports; 36 %) and positive dechallenge (8 reports; 6 %). Alternative causes for the observed adverse reaction were observed in 72 (53 %) reports. We found limited differences between VigiBase (TM) and original reports for the structured data, although a substantial amount of additional information was available in free text in original reports. less thanbrgreater than less thanbrgreater thanConclusions Information on plausible time courses and resolution of the adverse reaction upon withdrawal of the drug suspected to have induced the interaction may be a useful element in identifying suspected adverse drug interactions from ICSRs. Of these, plausible time course is by far the most commonly reported element in the three signals studied here. Our analysis also demonstrated the importance of sharing and analysing information available in free text where relevant clinical details are often available, such as those mentioned above, along with severity and dosage changes.

  • 287.
    Strandell, Johanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Norén, Niklas G.
    Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Key Elements in Adverse Drug Interaction Safety SignalsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Effective surveillance of adverse drug interactions (a problematic drug combination resulting in an adverse drug reaction (ADR)) in large collections of individual case safety reports (ICSRs) requires a combination of expert clinical assessments and efficient algorithms. To date, most methods proposed for adverse drug interaction surveillance focus on disproportionality analysis, although a recent study proposed that the reported clinical and pharmacological information is also useful for systematic screening of adverse drug interactions.

    Objective: The purpose of this study is to identify and describe key elements in adverse drug interaction safety signals.

    Methods: Altogether 137 case reports from three previously published safety signals of suspected adverse drug interaction were re-evaluated using an operational algorithm for causality analysis of drug interactions; the Drug Interaction Probability Scale (DIPS). Reports in the WHO Global ICSR Database, VigiBase, and their corresponding original files were analysed, examining whether the DIPS elements were registered. The retrieved case information was specified as being listed in the structured fields, free text and, in total. In addition, information not covered by DIPS, such as explicit notifications of a suspected drug interaction by the reporter or the pharmacovigilance centre was also registered.

    Results: As expected from the data used in this analysis, the most frequently fulfilled DIPS elements were: objective evidence (such as ADR) of a drug interaction (137 cases; 100%). Other frequent elements were (ranked order) plausible time to onset (53 cases; 38%), and resolution of the ADR after terminating the drug inducing the interaction (10 cases; 7%). Ten cases (7%) fulfilled both a plausible time to onset and resolution of the ADR after stopping the drug. Positive rechallenge was only reported in 3 cases (2%). For 32 cases additional information was reported in free text in the original files that were not available in VigiBase. A suspected drug interaction was noted by the reporter in 47 original cases (35%) and more than 80% of these were assessed as a possible or probable drug interaction according to the DIPS classification. Among cases without notes of suspected interactions were 58 original reports (64%) assessed as possible (56 cases) or probable (2 cases).

    Conclusions: A plausible time to onset pattern and resolution of the ADR after withdrawal of the drug inducing the interaction frequently strengthened the suspected causality of a drug interaction. Particularly strong cases were those containing both these key elements. Since this information is often available in structured format, it could potentially be used to automatically highlight strong cases in firstpass screening. Finally, this analysis also demonstrated the importance of free text where particularly relevant clinically details such as timeliness, severity, resolution of the reaction after withdrawal of the drug inducing the interaction, possible alternative causes, and dosage changes are available.

  • 288.
    Strandell, Johanna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wahlin, Stina
    Department of Pharmaceutical Biosciences, Bioactivation and Toxicity, Uppsala University, Uppsala, Sweden.
    Pharmacodynamic and pharmacokinetic drug interactions reported to VigiBase, the WHO global individual case safety report database.2011Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, nr 6, s. 633-641Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and the community. Despite this, limited information is reported in the literature on the drug interaction categories responsible for causing ADRs. In the study reported here, we investigated the drug combinations most frequently co-reported as interacting in the WHO Global Individual Case Safety Report (ICSR) database, VigiBase, and categorised these according to the drug interaction mechanism. METHODS: Reports in which drug combinations were co-reported as interacting in at least 20 reports in VigiBase during the past 20 years were included in the study. Each drug combination was reviewed in the literature to identify the mechanism of interaction and subsequently classified as pharmacodynamic and/or pharmacokinetic reaction. Report characteristics were also analysed. RESULTS: A total of 3766 case reports of drug interactions from 47 countries were identified. Of the 123 different drug combinations reported, 113 were described in the literature to interact. The mechanism of the drug interaction was categorised as pharmacodynamic (46 combinations; 41%), pharmacokinetic (28; 25%), a combination of both types (18; 16%) and unidentified (21; 19%). Pharmacodynamic drug interactions primarily concerned pharmacological additive effects, whereas enzyme inhibition was the most frequent pharmacokinetic interaction. The combinations reviewed primarily implicated drugs such as warfarin, heparin, carbamazepine and digoxin. CONCLUSIONS: Drug interactions reported in globally collected ADR reports cover both pharmacodynamic, specifically additive pharmacological effects, and pharmacokinetic mechanisms primarily accredited to the inhibition of hepatic cytochrome P450 enzymes. These ADR reports often concern serious threats to patients' safety and are particularly related to the use of high risk drugs such as warfarin and heparin.

  • 289.
    Streng, T.
    et al.
    Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland, Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden.
    Axelsson, H.E.
    Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, D.A.
    Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
    Jordt, S.-E.
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States.
    Bevan, S.
    Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
    Andersson, K.-E.
    Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, NC, United States.
    Hogestatt, E.D.
    Högestätt, E.D., Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden.
    Zygmunt, P.M.
    Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden.
    Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder2008Inngår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 53, nr 2, s. 391-400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: To investigate the distribution of the transient receptor potential (TRP) A1 ion channel in the rat urinary bladder, and to study the effects of hydrogen sulfide (H2S) and known TRPA1 activators on micturition in conscious rats and on heterologously expressed ion channels. Methods: The expression of TRPA1 in urinary bladder was studied with fluorescence immunohistochemistry and real-time PCR in female Sprague-Dawley rats. Cystometric investigations were performed in conscious animals subjected to intravesical administration of sodium hydrogen sulfide (NaHS, donor of H2S), allyl isothiocyanate (AI), and cinnamaldehyde (CA). Fluorometric calcium imaging was used to study the effect of NaHS on human and mouse TRPA1 expressed in CHO cells. Results: TRPA1 immunoreactivity was found on unmyelinated nerve fibres within the urothelium, suburothelial space, and muscle layer as well as around blood vessels throughout the bladder. All TRPA1 immunoreactive nerves fibres also expressed TRPV1 immunoreactivity and vice versa. TRPA1 was also detected in urothelial cells at both transcriptional and protein levels. AI increased micturition frequency and reduced voiding volume. CA and NaHS produced similar changes in urodynamic parameters after disruption of the urothelial barrier with protamine sulfate. NaHS also induced calcium responses in TRPA1-expressing CHO cells, but not in untransfected cells. Conclusions: The expression of TRPA1 on C-fibre bladder afferents and urothelial cells together with the finding that intravesical TRPA1 activators initiate detrusor overactivity indicate that TRPA1 may have a role in sensory transduction in this organ. The study also highlights H2S as a TRPA1 activator potentially involved in inflammatory bladder disease. © 2007.

  • 290.
    Svensson, S.
    et al.
    Department of Clinical Pharmacology, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
    Kjellgren, K.I.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Saljo, R.
    Säljö, R., Department of Education, Göteborg University, Box 300, SE-405 30 Gothenburg, Sweden.
    Reasons for adherence with antihypertensive medication2000Inngår i: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 76, nr 2-3, s. 157-163Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Hypertension is often insufficiently controlled in clinical practice, a prominent reason for this being poor patient adherence with therapy. Little is known about the underlying reasons for poor adherence. We set out to investigate hypertensive patients' self-reported reasons for adhering to or ignoring medical advice regarding antihypertensive medication. Methods: Qualitative analysis of semi-structured interviews with 33 hypertensive patients in a general-practice centre and a specialist hypertension unit in Southern Sweden. Blood-pressure measurements and laboratory measurements of antihypertensive medication were performed. Results: Nineteen out of 33 patients were classified as adherent. Adherence was a function of faith in the physician, fear of complications of hypertension, and a desire to control blood pressure. Non-adherence was an active decision, partly based on misunderstandings of the condition and general disapproval of medication, but mostly taken in order to facilitate daily life or minimize adverse effects. Adherent patients gave less evidence of involvement in care than non-adherent patients. There was no obvious relation between reported adherence, laboratory markers of adherence and blood-pressure levels. Conclusions: The interview is a powerful tool for ascertaining patients' concepts and behaviour. To optimize treatment of hypertension, it is important to form a therapeutic alliance in which patients' doubts and difficulties with therapy can be detected and addressed. For this, effective patient-physician communication is of vital importance. Copyright (C) 2000 Elsevier Science Ireland Ltd.

  • 291.
    Söderbäck, Erik
    et al.
    Biotage AB, Uppsala, Sweden.
    Zackrisson, Anna-Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindblom, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Alderborn, Anders
    Biotage AB, Uppsala, Sweden.
    Determination of CYP2D6 gene copy number by pyrosequencing2005Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 51, nr 3, s. 522-531Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Identification of CYP2D6 alleles *5 (deletion of the whole CYP2D6 gene) and *2xN (gene duplication) is very important because they are associated with decreased or increased metabolism of many drugs. The most commonly used method for analysis of these alleles is, however, considered to be laborious and unreliable.

    METHODS: We developed a method to determine the copy number of the CYP2D6*5 and CYP2D6*2xN alleles by use of Pyrosequencing technology. A single set of PCR and sequencing primers was used to coamplify and sequence a region in the CYP2D6 gene and the equivalent region in the CYP2D8P pseudogene, and relative quantification between these fragments was performed. The CYP2D8P-specific Pyrosequencing peak heights were used as references for the CYP2D6-specific peak heights.

    RESULTS: Analysis of 200 pregenotyped samples showed that this approach reliably resolved 0-4 genome copies of the CYP2D6 gene. In 15 of these samples, the peak pattern from one analyzed position was unexpected but could be solved by conclusive results from a second position. The method was verified on 270 other samples, of which 267 gave results that corresponded to the expected genotype. One of the samples could not be interpreted. The reproducibility of the method was high.

    CONCLUSIONS: CYP2D6 gene copy determination by Pyrosequencing is a reliable and rapid alternative to other methods. The use of an internal CYP2D8P control as well as generation of a sequence context ensures a robust method and hence facilitates method validation.

  • 292.
    Söderfeldt, Birgitta
    et al.
    Karolinska institutet.
    Ragnehed, Mattias
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiofysik. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Linköpings universitet, Hälsouniversitetet.
    Håkansson, Irene
    Östergötlands Läns Landsting, Sinnescentrum. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Lundberg, Peter
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiofysik. Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Hälsouniversitetet.
    Nilsson, M
    Ahlner, Johan
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Engström, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Hälsouniversitetet.
    Influence of Diazepam on Clinically Designed fMRI2006Konferansepaper (Annet vitenskapelig)
  • 293.
    Terman, Alexei
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet. Laboratory of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Kurz, Tino
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Bertil
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och cytologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Brunk, Ulf
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    The involvement of lysosomes in myocardial aging and disease2008Inngår i: Current Cardiology Reviews, ISSN 1573-403X, Vol. 4, nr 2, s. 107-115Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The myocardium is mainly composed of long-lived postmitotic cells with, if there is any at all, a very low rate of replacement through the division and differentiation of stem cells. As a consequence, cardiac myocytes gradually undergo pronounced age-related alterations which, furthermore, occur at a rate that inversely correlates with the longevity of species. Basically, these alterations represent the accumulation of structures that have been damaged by oxidation and that are useless and often harmful. These structures (so-called 'waste' materials), include defective mitochondria, aberrant cytosolic proteins, often in aggregated form, and lipofuscin, which is an intralysosomal undegradable polymeric substance. The accumulation of 'waste' reflects the insufficient capacity for autophagy of the lysosomal compartment, as well, as the less than perfect functioning of proteasomes, calpains and other cellular digestive systems. Senescent mitochondria are usually enlarged, show reduced potential over their inner membrane, are deficient in ATP production, and often produce increased amounts of reactive oxygen species. The turnover of damaged cellular structures is hindered by an increased lipofuscin loading of the lysosomal compartment. This particularly restricts the autophagic turnover of enlarged, defective mitochondria, by diverting the flow of lysosomal hydrolases from autophagic vacuoles to lipofuscin-loaded lysosomes where the enzymes are lost, since lipofuscin is not degradable by lysosomal hydrolases. As a consequence, aged lipofuscin-rich cardiac myocytes become overloaded with damaged mitochondria, leading to increased oxidative stress, apoptotic cell death, and the gradual development of heart failure. Defective lysosomal function also underlies myocardial degeneration in various lysosomal storage diseases, while other forms of cardiomyopathies develop due to mitochondrial DNA mutations, resulting in an accumulation of abnormal mitochondria that are not properly eliminated by autophagy. The degradation of iron-saturated ferritin in lysosomes mediates myocardial injury in hemochromatosis, an acquired or hereditary disease associated with iron overload. Lysosomes then become sensitized to oxidative stress by the overload of low mass, redox-active iron that accumulates when iron-saturated ferritin is degraded following autophagy. Lysosomal destabilization is of importance in the induction and/or execution of programmed cell death (either classical apoptotic or autophagic), which is a common manifestation of myocardial aging and a variety of cardiac pathologies. © 2008 Bentham Science Publishers Ltd.

  • 294.
    Thelander, Gunilla
    et al.
    National Board for Forensic Medicine.
    Kristina Jonsson, Anna
    Nordic School of Public Health, Gothenburg.
    Personne, Mark
    Poisons Information Centre, Stockholm.
    Sjolin Forsberg, Gunilla
    Med Prod Agcy.
    Magnusson Lundqvist, Kristina
    Med Prod Agcy.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Caffeine fatalities - Do sales restrictions prevent intentional intoxications?2010Inngår i: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 48, nr 4, s. 354-358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. Caffeine is widely available in beverages and in different over-the-counter products, including tablets containing 100 mg caffeine. Because intentional fatal intoxications with caffeine occur, the maximum quantity of caffeine tablets that can be bought over the counter in a single purchase was restricted from 250 to 30 in Sweden in the year 2004. The objective of this article was to study the effect of this decision on the number of fatal caffeine intoxications. Method. In Sweden 95% of all cases undergoing forensic autopsy are screened for a number of drugs including caffeine. All cases during January 1993-September 2009 with a caffeine concentration above 80 mu g/g blood were recorded. Results. During the study period toxicological investigations were performed in 83,580 forensic autopsies. Caffeine contributed to the fatal outcome in 20 cases (0.02%). Thirteen (65%) of these fatalities occurred before the introduction of the sales restriction. However, no fatal intoxications where caffeine contributed to the cause of death was recorded between May 2007 and September 2009. Conclusion. Overdoses of tablets containing caffeine can be fatal, suicides as well as accidents occur. Restricting the maximum quantity of caffeine tablets available over the counter seemed to be effective in preventing suicides because of caffeine although some time elapsed until the effect was noted. Further monitoring is required to ensure that the observed lower caffeine mortality is a sustained effect.

  • 295.
    Tjäderborn, Micaela
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Anna
    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, Rättskemi. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Tramadol Dependence: A Survey of Spontaneously Reported Cases in Sweden2008Konferansepaper (Fagfellevurdert)
  • 296.
    Tjäderborn, Micaela
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Anna
    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, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Tramadolberoende: En studie av spontanrapporterade fall i Sverige 1995-20062008Konferansepaper (Fagfellevurdert)
  • 297.
    Tjäderborn, Micaela
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Anna K
    Nordic School of Public Health, Gothenburg, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Rättskemi. Linköpings universitet, Hälsouniversitetet.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Tramadol dependence: a survey of spontaneously reported cases in Sweden.2009Inngår i: Pharmacoepidemiology and drug safety, ISSN 1099-1557Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Tramadol is a weak opioid analgesic, which is generally considered to be safe. However, conflicting data exist on the dependence potential of tramadol. OBJECTIVE: The aim of this study was to investigate occurrence of tramadol dependence and associated risk factors using spontaneously reported adverse drug reactions. METHODS: The Swedish database for spontaneously reported adverse drug reactions, Swedish Drug Information System (SweDIS), was searched for reports on tramadol dependence from 1 January 1995 until 31 December 2006. Selection was conducted based on the DSM-IV definition of dependence. Available information was scrutinised and registered and then presented descriptively. RESULTS: A total of 104 reports of tramadol dependence were identified, of which 60 (58%) concerned women. The median age (range) was 45 (15-84) years. Information on a history of substance abuse was present in 31 patients (30%) and 41 patients (39%) had a documented past or current use of a drug of abuse. Prescribed doses of tramadol ranged between 50-800 mg/day, and ingested doses between 50-4000 mg/day. Time of onset ranged from some weeks up to 4 years. In 72 (69%) cases the reaction was classified as serious, mainly due to hospitalisations for detoxification or discontinuation of tramadol. CONCLUSIONS: There is an occurrence of tramadol dependence in association with analgesic treatment within the recommended dose range. In susceptible patients a severe and serious dependence syndrome may develop. A history of abuse or use of a drug of abuse seems to be an important risk factor. Copyright (c) 2009 John Wiley & Sons, Ltd.

  • 298.
    Trinks, Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Severinsson, Emelie A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gréen, Anna
    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.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    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.
    The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells2011Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 410, nr 3, s. 422-427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

  • 299.
    Uckert, Stefan
    et al.
    Hannover Medical School, Germany.
    Kedia, George T.
    Hannover Medical School, Germany.
    Satzger, Imke
    Hannover Medical School, Germany.
    Geismar, Ulrike
    Hannover Medical School, Germany.
    Sohn, Michael
    St. Markus Academic Hospital, Frankfurt am Main, Germany).
    Kuczyk, Markus A.
    Hannover Medical School, Germany.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Waldkirch, Eginhard S.
    Hannover Medical School, Germany.
    C-kit-positive multipolar cells in human penile erectile tissue: expression of connexin 43 and relation to trabecular smooth muscle cells2010Inngår i: Georgian medical news, ISSN 1512-0112, nr 180, s. 13-19Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to evaluate the hypothesis that interstitial cells might play a role in controlling and synchronizing via gap junctions the electrical activity of smooth muscle cells. The expression and distribution of interstitial cells in human penile erectile tissue was evaluated to determine whether or not cavernous interstitial cells express the gap junction protein connexin 43. Specimens of human corpus cavernosum were excised from full preparations of human penises. Cryostat sections (10 microm to 15 microm) of formaldehyde-fixated tissue segments were incubated using a double-labelling technique with antibodies directed against smooth muscle alpha-actin, c-kit, and connexin 43. Then, sections were exposed to secondary antibodies. Visualization was commenced by means of laser fluorescence microscopy. Double-staining techniques revealed immunosignals specific for c-kit (transmembrane receptor protein) and connexin 43 (gap junction protein) in multipolar cells located adjacent to smooth muscle cells. The number of c-kit-positive cells was significantly lower within the smooth musculature than within bundles of connective tissue surrounding smooth muscle cells of corpus cavernosum or cavernous arteries. Our findings demonstrate the distribution of c-kit- and connexin 43-positive interstitial cells in the connective tissue and smooth musculature of the corpus cavernosum. Additional studies are needed in order to evaluate further the ultrastructure of human penile erectile tissue and enable the identification of gap junctions mediating direct cell-to-cell communication.

  • 300.
    Ueckert, S.
    et al.
    Hannover Medical Sch, Germany .
    Simon, A.
    Hannover Medical Sch, Germany .
    Merseburger, A. S.
    Hannover Medical Sch, Germany .
    Bannowsky, A.
    Osnabruck Municipal Hospital GmbH, Germany .
    Kuczyk, M. A.
    Hannover Medical Sch, Germany .
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    EXPRESSION AND DISTRIBUTION OF THE TRANSIENT RECEPTOR POTENTIAL CATIONIC CHANNEL A1 (TRPA1) IN THE HUMAN SEMINAL VESICLES in JOURNAL OF SEXUAL MEDICINE, vol 9, issue , pp 270-2702012Inngår i: JOURNAL OF SEXUAL MEDICINE, Wiley-Blackwell , 2012, Vol. 9, s. 270-270Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

34567 251 - 300 of 331
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf