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  • 1. Apelqvist, G
    et al.
    Wikell, C
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Hjorth, S
    Bergqvist, P B F
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Dynamic and kinetic effects of chronic citalopram treatment in experimental hepatic encephalopathy2000In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 23, no 6, p. 304-317Article in journal (Refereed)
    Abstract [en]

    Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that arises in liver-impaired subjects. Patients with HE display various neuropsychiatric symptoms including affective disturbances and may therefore likely receive treatment with novel thymoleptics like citalopram (CIT). The simultaneous pharmacokinetic and pharmacodynamic outcome of the commonly used serotonin-selective thymoleptic drugs in liver-impaired subjects with pending chronic HE is far from understood today. We therefore investigated the effects of chronic, body-weight-adjusted (10 mg ╖ kg-1 ╖ day-1), treatment with CIT in rats with and without portacaval shunts (PCS). Open-field activity was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) output were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were determined in serum, brain parenchyma, and extracellular fluid. The rats with PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham treatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the S/R ratios between PCS rats and control rats could be detected. The CIT treatment resulted in neocortical output differences between PCS rats and control rats mainly within the 5-HT and DA systems but not within the NA system. For the 5-HT system, this change was further evidenced by outspoken elevation in 5-HT output after KCl-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT treatment resulted in an increased or "normalized" behavioral activity in the PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in control rats. The results further support the contention of an altered 5-HT neurotransmission prevailing in the chronic HE condition. However, the tentatively beneficial behavioral response also seen following chronic CIT treatment to PCS rats in this study has to be viewed in relation to both the pharmacokinetic and pharmacodynamic changes observed.

  • 2. Apelqvist, G
    et al.
    Wikell, C.
    Hindfeldt, B
    Bergqvist, PBF
    Andersson, G.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges.1999In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 143, p. 408-416Article in journal (Refereed)
  • 3.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    260 therapeutic drug monitorings (TDM) in relation to compliance and co-medication in psychiatric treatment2002In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 17, p. 3S-3SConference paper (Other academic)
  • 4.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Arrogant maktspråk från landstingsledningen2005In: Östgöta Correspondenten, ISSN 1104-0394, Vol. 11 marsArticle in journal (Other (popular science, discussion, etc.))
  • 5.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Brain tryptophan/serotonin perturbations in metabolic encephalopathy and the hazards involved in the use of psychoactive drugs1999In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 467, p. 139-154Article in journal (Refereed)
    Abstract [en]

    Several combined pathogenetic factors such as hyperammonemia, different brain tryptophan metabolic disturbancies and serotonin physiological/pharmacological alterations not yet defined in all details, will often give rise to the clinical neuropsychiatric condition known as hepatic encephalopathy (HE). Indeed, to this the probable exposure to novel potent CNS-monoamine acting drugs today may put such patients at certain risk for other pharmacodynamic (PD) responses than usually are expected from these "safe" drugs. Moreover, with a compromised liver function in HE, also pharmacokinetic (PK) features for the drugs are likely changed in these patients. Thus, the ultimate clinical outcome by this probable but unknown PD/PK-deviation for such psychoactive drugs when given to HE-patients needs further clarifrcation. Accordingly, delineation of both PD- and PK-effects in experimental HE should shed light on this issue of relevance for monoamine-active drug safety as well as on some further details in the complex tryptophan/monoamine-related pathophysiology that comes into play in HE.

  • 6.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Fler arbetsgivare i vården2005In: Östgöta Correspondenten, ISSN 1104-0394, Vol. 24 augustiArticle in journal (Other (popular science, discussion, etc.))
  • 7.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    From receptor pharmacology to clinical prescription: Antidepressants2000In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 15, p. 288S-288SConference paper (Other academic)
  • 8.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Hur är det ställt med demokratin?2005In: Östgöta Correspondenten, ISSN 1104-0394, Vol. 23 marsArticle in journal (Other (popular science, discussion, etc.))
  • 9.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Klinisk farmakokinetik vid antidepressiv läkemedelsbehandling. Inom ramen för projektgruppen för depressionsbehandling.2004Report (Other academic)
  • 10.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    "Neurologi. Diagnostisk handledning" av Bengt Hindfelt2001In: Neurologi : diagnostisk handledning / [ed] Hindfelt, Bengt, Linköping: Linköpings universitet , 2001, 1, p. -104Chapter in book (Other academic)
    Abstract [sv]

    Lägg i varukorgSpara som favorit Den här artikeln kan inte längre levereras innan jul. Fri frakt vid beställning på minst 99 kr för privatpersoner i Sverige - Läs mer

    Alltid återbäringBetala i din egen takt Ämnesområdet neurologi är omfattande. Det inkluderar skador och sjukdomar i det centrala (storhjärna, lillhjärna, hjärnstam och ryggmärg) och perifera nervsystemet (somatiska och autonoma) samt neuromuskulära transmissionsstörningar och muskelsjukdomar. Flera neurologiska sjukdomstillstånd kan rubriceras som folksjukdomar, t.ex. slaganfall (stroke), epilepsi, degenerativa hjärnsjukdomar såsom Alzheimers och Parkinsons sjukdom etc. Många patienter söker för neurologiska symtom utan att för den skull lida av organisk neurologisk sjukdom. Hit hör flertalet patienter med olika former av huvudvärk (t.ex. spänningshuvudvärk, migrän etc.), kortvariga medvetslöshetsattacker, yrsel etc. Sammantaget har det visat sig att var fjärde patient som söker i öppenvård söker för neurologiska symtom. Således är neurologiska symtom vanligt förekommande i klinisk praxis men inte liktydigt med neurologisk sjukdom eller skada. Denna bok är ett försök att hjälpa Dig i Din ”bedside-diagnostik” av vanliga neurologiska symtom. Grunden är en ingående anamnes i kombination med en noggrann somatisk och neurologisk undersökning. Utifrån vanligt förekommande symtom i klinisk praxis exemplifieras neurologisk differentialdiagnostik och utredning. Terapin har inte inkluderats. Innehåll, uppläggning (till stor del i algoritmisk form) etc. ersätter därför på inget sätt en god lärobok i neurologi som referenskälla. Avsikten med boken är att den skall vara till hjälp i den kliniska vardagen och till stöd i problembaserad undervisning för främst läkarstuderande. För att underlätta för läsaren att bredda sitt kunnande har de enskilda kapitlen försetts med kommentarer. Aktuella referenser har adderats för eventuella fördjupningsstudier.

  • 11.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Postmarketing surveillance studier av antidepressiva via läkemedelsanalyser. I.2001In: Aktuell neuropsykiatrisk forskning / [ed] Finn Bengtsson and H. Lundbeck AB., Linköping: Linköpings universitet , 2001, p. 66-74Chapter in book (Other academic)
  • 12.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Therapeutic drug monitoring of psychotropic drugs - TDM "Nouveau"2004In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 26, no 2, p. 145-151Article in journal (Refereed)
    Abstract [en]

    TDM applied in psychiatry dates back several decades. The reason for this is that, after the advent of modem clinical psychopharmacology around the middle of the past century, an insight came to common knowledge about the existence of (1) a large inter-individual pharmacokinetic (PK) variability for virtually all psychoactive drugs and (2) a worse clinical efficacy not only in inadequate drug concentrations but also in excessively high concentrations. From this concept, the definition of a therapeutic concentration "window" was evidenced for a substantial number of, primarily, antidepressant drugs. However, with the further extensive development of the clinically available pharmacopoeia of psychoactive drugs from the later 1980s until today, the concept of less toxic compounds than before has commonly been launched in the marketing strategies for these newer drugs. This concept also led to the idea that TDM was no longer necessary for the newer types of psychoactive drugs, a position backed up by difficulties in unraveling concentration-effect relationships generally for these drugs in clinical trials. The present survey summarizes the background history for TDM in psychiatry and makes a critical appraisal of why a "lack" of definition of concentration-effect relationships for newer psychoactive drugs is now common. This survey also provides the reader with a novel concept challenging ambient TDM strategies (referred to as TDM "traditionelle") in psychiatry by forwarding a theoretical model called TDM "nouveau." In this model both inter- and intraindividual (over time) PK variation is suggested to be used for dose optimization by TDM in a naturalistic clinical setting. The previous concept of a simple, common concentration "window" existing for all such drugs is questioned by promotion of the use of available PK data merely as "guiding principles" rather than as "reference values" when interpreting the TDM outcome in individual cases.

  • 13.
    Bengtsson, Finn
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Insights in stereopharmacology in modern antidepressant treatment2005In: Association of European Psychiatrists AEP Congress,2005, 2005Conference paper (Other academic)
  • 14.
    Bengtsson, Finn
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Kugelberg, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Fate of psychotropic drugs at the blood-brain-barrier and the brain: pharmacokinetic, pharmacodynamic and clinical consequences2005In: Association of European Psychiatrists AEP Congress,2005, 2005Conference paper (Other academic)
  • 15. Bergkvist, P.
    et al.
    Carpenedo, R
    Apelqvist, G
    Moroni, F
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Plasma and brain levels of oxindole in experimental chronic hepatic encephalopathy: effects of systemic ammonium acetate and L-tryptophan.1999In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 85, p. 138-143Article in journal (Refereed)
  • 16.
    Carlsson, Björn
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Cherma Yeste, Maria Dolores
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Achiral determination of venlafaxine and metabolites, in human plasma, by high-performance liquid chromatography and on-line automated sample preparation using restricted access material.2002In: 18th European Workshop on Drug Metabolism, Valencia, Spain,2002, 2002Conference paper (Refereed)
  • 17.
    Carlsson, Björn
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Holmgren, A.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Forensic Science and Toxicology .
    Ahlner, Johan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Enantioselective analysis of citalopram and escitalopram in postmortem blood together with genotyping for CYP2D6 and CYP2C192009In: Journal of Analytical Toxicology, ISSN 0146-4760, Vol. 33, no 2, p. 65-76Article in journal (Refereed)
    Abstract [en]

    Citalopram is marketed as a racemate (50:50) mixture of the S(+)-enantiomer and R(-)-enantiomer and the active S(+)-enantiomer (escitalopram) that possess inhibitory effects. Citalopram was introduced in Sweden in 1992 and is the most frequently used antidepressant to date in Sweden. In 2002, escitalopram was introduced onto the Swedish market for treatment of depression and anxiety disorders. The main objective of this study was to investigate S(+)-citalopram [i.e., the racemic drug (citalopram) or the enantiomer (escitalopram)] present in forensic autopsy cases positive for the presence of citalopram in routine screening using a non-enantioselective bioanalytical method. Fifty out of the 270 samples found positive by gas chromatography-nitrogen-phosphorus detection were further analyzed using enantioselective high-performance liquid chromatography. The 50 cases were genotyped for CYP2D6 and CYP2C19, as these isoenzymes are implicated in the metabolism of citalopram and escitalopram. In samples positive for racemic citalopram using the screening method for forensic autopsy cases, up to 20% would have been misinterpreted in the absence of an enantioselective method. An enantioselective method is thus necessary for correct interpretation of autopsy cases, after the enantiomer has been introduced onto the market. The percentage of poor metabolizers was 6% for CYP2D6 and 8% for CYP2C19.

  • 18.
    Carlsson, Björn
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Holmgren, Anita
    RMV.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Citalopram and escitalopram in postmortem blood: Confirmation of screening results from autopsy cases with enantioselective analysis.2007In: Nordisk kollokvium Rättstoxikologi.,2007, 2007Conference paper (Other academic)
  • 19.
    Carlsson, Björn
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Olsson, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Wålinder, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundmark, Jöns
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Scordo, M. G.
    Dahl, M-L.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Enantioselective Analysis of Citalopram and Metabolites in Adolescents2001In: Therapeutic drug monitoring, ISSN 0163-4356, Vol. 23, no 6, p. 658-664Article in journal (Refereed)
    Abstract [en]

    Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.

  • 20.
    Cherma Yeste, Maria Dolores
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Achiral determination of venlafaxine and metabolities in human plasma by high-performance liquid chromatography and on-line automated sample preparation using restricted access material. Outcome from an naturalistic setting2004In: 8th International Congress of Therapeutic Drug Monitoring and Clinical Toxikology,2004, 2004Conference paper (Other academic)
  • 21.
    Cherma Yeste, Maria Dolores
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Löfgren, Ulla-Britt
    Östergötlands Läns Landsting.
    Almkvist, Göran
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Primary Health Care Centres.
    Hallert, Claes
    Linköping University, Department of Social and Welfare Studies, Health, Activity, Care. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Prescription of antidepressant drugs in elderly nursing home patients.: A Follow-up investigation with focus on enantioselective citalopram analysis2007Conference paper (Other academic)
  • 22.
    Chermá Yeste, Maria Dolores
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Löfgren, Ulla-Britt
    n/a.
    Almkvist, Göran
    n/a.
    Hallert, Claes
    Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland. Linköping University, Department of Social and Welfare Studies, Health, Activity, Care. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Assessment of the prescription of antidepressant drugs in elderly nursing home patients2008In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, no 4, p. 424-431Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate the use of antidepressant drugs among elderly people in nursing homes. Elderly residents who where found to have been prescribed at least one antidepressant drug according to the specific medication dispensing system were identified in 8 nursing homes in the county of Östergötland, Sweden. Data were collected from the medical record forms at the nursing home. Blood samples were drawn for the assessment of drug concentration, blood chemistry parameters and cytochrome P450 expression. At least one antidepressant drug was prescribed to 38% of elderly people in the nursing home studied. A total of 71 patients were evaluated, 80% women and 20% men. The median age was 84 years (range, 71-100 years). Indications for antidepressant drug treatment were found on 96% of medical record forms (depression, 60%); however, information relating to when treatment was initiated could not be found on 34% of medical record forms and a clear time schedule for how long this drug treatment was planned to continue could not be found either. A possible adverse effect of antidepressant drug treatment was retrieved in at least 77% of patients. Polypharmacotherapy was common; median number of drugs per patient was 11. Concentrations of drugs were higher than expected in 73%. Most patients were medicated with citalopram (n = 44). A clear interindividual variability of concentrations at each dose level was found for citalopram and for the metabolites desmethylcitalopram and didesmethylcitalopram. A significant correlation was found between the estimation of creatinine clearance and concentration-dose ratio of citalopram. Poor metabolizers, who had been prescribed an antidepressant drug that are substrate for the cytochrome P450 isoenzyme examined, have higher concentrations of prescribed antidepressant drug than do non-poor metabolizers in relation to dose. An increase in quality contribution to follow-up at antidepressant medications is needed. A more frequent clinical use of therapeutic drug monitoring and pharmacogenetic tests in addition to therapeutic drug monitoring may be one important tool in this process.

  • 23.
    D Cherma, Maria
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Gustafsson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry.
    Antidepressant Drugs in Children and Adolescents Analytical and Demographic Data in a Naturalistic, Clinical Study2011In: JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, ISSN 0271-0749, Vol. 31, no 1, p. 98-102Article in journal (Refereed)
    Abstract [en]

    Pharmacokinetics of antidepressant drugs (ATDs), in terms of steady-state and trough values, in patients from Child and Adolescent Psychiatry centers in the midsouth-eastern part of Sweden, were evaluated, and the use of ATDs in this population were described. Patients to be prescribed an ATD were studied between 2002 and 2004. Two hundred eleven children, 64% girls and 36% boys (ages 8-20 years) were evaluated. The primary indication for the antidepressant treatment was depression in 69% of subjects. The median body mass index was 20.2 kg/m(2) (range, 12.4-38.6 kg/m(2)). Suspected adverse drug reactions were spontaneously reported in 31% (no serious). Monotherapy was indicated in 49% of request forms. The most common drug combination with the ATD was oral contraceptives. The concentrations of drugs in the patient evaluated population to referenced data for adults from the dose administered were as expected in 63%, higher than expected in 26% and lower than expected in 11%. The most prescribed ATD was sertraline (SERT). Dose-concentration relationships for SERT and metabolite desmethylsertraline (DSERT) were seen, r(s) = 0.48 and r(s) = 0.5, respectively. No relationship was found between dose and ratio DSERT/SERT. The median daily dose was 50 mg (range, 12.5-150 mg), SERT concentration 16 ng/mL (range, 3-88 ng/mL), and DSERT 33 ng/mL (range, 0-253 ng/mL). CYP2D6*4 was the most common poor metabolizer allele. Therapeutic drug monitoring may provide support to prescribing physicians to individual dose optimizing and to assess drug compliance, above all when ATDs are not well studied in pediatric patients before approval for general prescription.

  • 24.
    Dolores Cherma Yeste, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting2008In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, no 6, p. 682-688Article in journal (Refereed)
    Abstract [en]

    There is limited information on the pharmacokinetics of ziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linkoping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20-320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L-1 mg(-1) d(-1)) for ZIP and SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively, with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for close-normalized scruin concentrations of ZIP, SMDZ, and SMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIP concentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.

  • 25. Ekselius, Lisa
    et al.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    von Knorring, Lars
    Non-compliance with pharmacotherapy of depression is associated with a sensation seeking personality.2000In: International Clinical Psychopharmacology, ISSN 0268-1315, E-ISSN 1473-5857, Vol. 15, p. 273-278Article in journal (Refereed)
  • 26. Humble, M
    et al.
    Bejerot, S
    Bergqvist, PB
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Reactivity of serotonin in whole blood: relationship with drug response in obsessive-compulsive disorder?2001In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 49, p. 360-368Article in journal (Refereed)
  • 27. Isaksson, Björn
    et al.
    Thorell, Lars-Håkan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Rosén, I
    Jeppsson, I
    Hepatic encephalopathy verified by psychometric testing and EEG in cirrhotic patients: Effects of mesocaval interposition shunt or sclerotherapy2005In: HPB, ISSN 1365-182X, Vol. 7, no 1, p. 65-72Article in journal (Refereed)
    Abstract [en]

    Background. The aim of this randomised prospective study was to evaluate hepatic encephalopathy after mesocaval interposition shunt operation and after repeated endoscopic sclerotherapy. Methods. Forty-five patients with bleeding oesophageal varices due to liver cirrhosis were randomised to the two treatment groups, 24 to the shunt group and 21 to the sclerotherapy group. The patients were evaluated preoperatively regarding blood tests, hepatic encephalopathy as measured by electroencephalogram with spectral analysis and by a battery of psychometric tests. The direction of portal flow in the shunt group was investigated by shunt phlebography and ultrasonography with Doppler. During follow-up the same investigations were performed twice at median 6.7 and 14.7 months after operation. Results. No statistically significant difference was found during follow-up regarding blood tests and electroencephalography with spectral analysis. Although the preoperative psychometric tests showed that the shunt group performed significantly better than the sclerotherapy group, the first follow-up showed that the shunt group performed statistically worse than the sclerotherapy group in seven of the tests: Synonyms (measuring verbal ability), Block Design Test (measuring visuo-spatial ability), Memory for Design Test, Error Score (measuring memory function), Revised Visual Retention Test, correct answers and the same test error answers (measuring visuo-spatial memory, ability and immediate memory), Digit Symbol Test (measuring perceptual ability) and Trial Making Test B (measuring cognitive motor abilities). Conclusions. Patients treated by mesocaval interposition shunt showed a progressive general reduction in psychometric performance compared with patients treated with repeated sclerotherapy, in whom a general intellectual improvement was observed. This finding corresponds to the reverse direction of the preoperative portal flow to a hepatofugal pattern at first follow-up and at 12 months among two-thirds of the patients. © 2005 Taylor & Francis Group Ltd.

  • 28.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Kugelberg, Fredrik C.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment2013In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 11, p. 1636-1644Article in journal (Refereed)
    Abstract [en]

    Background: According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the Senantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp.

    Methods: P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. Results: In brain, 3-fold higher concentrations of S- and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls.

    Conclusions: The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

  • 29.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, I
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram2013In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, no 3, p. 579-586Article in journal (Refereed)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood–brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.

  • 30.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik C.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    ABCB1 gene polymorphisms in forensic autopsy cases positive for citalopram and venlafaxineManuscript (preprint) (Other academic)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter expressed on e.g. the endothelial cells of the blood-brain barrier which regulates the efflux of many drugs. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates. It has previously been shown that the antidepressant drugs citalopram and venlafaxine are actively transported out of the brain by P-gp using a mouse model. In the present study we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases positive for these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The present study included 228 forensic autopsy cases positive for venlafaxine and citalopram with different causes of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined by Pyrosequencing. The SNPs C1236T, G2677T and C3435T in venlafaxine positive cases were significantly different between the intoxication cases and non-intoxications. The latter novel finding should, however, be confirmed in future studies with larger number of cases.

  • 31.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Kugelberg, Fredrik C
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 2, p. 367-377Article in journal (Refereed)
    Abstract [en]

    Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

  • 32.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kingbäck, Maria
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Josefsson, M
    Rättsmedicinalverket, Rättskemi.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Schmidt, U
    Tyskland.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hiemke, Ch
    Tyskland.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Penetration of the enantiomers of venlafaxine and its metabolites into the brain in mice lacking P-glycoprotein (mdr1ab)2008Conference paper (Other academic)
  • 33.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Kugelberg, Fredrik C
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
    Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein2010In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, no 9, p. 632-640Article in journal (Refereed)
    Abstract [en]

    According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (-/-) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2-3, 2-6 and 3-12 times higher in abcb1ab (-/-) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S- and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S- and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.

  • 34.
    Kingbäck, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats2011In: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 23, no 2, p. 172-177Article in journal (Refereed)
    Abstract [en]

    The female Sprague-Dawley (SD) and Dark Agouti (DA) rats are considered the animal counterparts of the human extensive and poor metabolizer cytochrome P450 (CYP) 2D6 phenotypes, respectively. The aim of this work was to study possible rat strain differences in the steady-state pharmacokinetics of the (+)-(S)- and (-)-(R)-enantiomers of citalopram and its demethylated metabolites. A chronic drug treatment regimen (15 mg/kg daily) was implemented for 13 days in separate groups of SD (n 5 9) and DA (n 5 9) rats by using osmotic pumps. The concentrations of citalopram and two major metabolites in serum and two brain regions were analyzed by an enantioselective high-performance liquid chromatography assay. Higher serum and brain levels of citalopram and demethylcitalopram, but lower levels of didemethylcitalopram, were observed in DA rats when compared with SD rats. The enantiomeric (S/R) concentrations ratios of citalopram were lower in the DA rats when compared with the SD rats (0.53 +/- 0.05 vs. 0.80 +/- 0.03, P andlt; 0.001), indicating a possibly decreased capacity in the metabolism of the (-)-(R)-enantiomer in the DA rats. This study shows that CYP2D deficiency results in steady-state pharmacokinetic differences of the enantiomers of citalopram and its metabolites.

  • 35.
    Kingbäck, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Josefsson, M
    Linköping University, Department of Medical and Health Sciences, Pharmacology.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Stereoselective analysis of venlafaxine and its three major metabolites by liquid chromatography with electrospray tandem mass spectrometry2008Conference paper (Other academic)
  • 36.
    Kingbäck, Maria
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Karlsson, Louise
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Kugelberg, Fredrik C
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction2010In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, no 3, p. 583-590Article in journal (Refereed)
    Abstract [en]

    A stereoselective method is described for simultaneous determination of the S- and R-enantiomers of venlafaxine and its three demethylated metabolites in human plasma and whole blood samples. This validated method involved LC/MS/MS with positive electrospray ionization and solid phase extraction. Chromatographic separation was performed on a 250 mm x 2.1mm Chirobiotic V column with a total run time of 35 min. In plasma, calibration curves were in the range of 1-1000 nM for the S- and R-enantiomers of venlafaxine and O-desmethylvenlafaxine, and 0.5-500 nM for N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. In whole blood the corresponding concentrations were 10-4000 and 5-2000 nM, respectively. The intra-day precision was <6.3% and the inter-day precision was <9.9% for plasma and <15% and <19% for whole blood. LLOQ ranged between 0.25 and 0.5 nM. No ion suppression/enhancement or other matrix effects were observed. The method was successfully applied for determination of venlafaxine and its metabolites in plasma from patients and whole blood samples from forensic autopsy cases.

  • 37.
    Kingbäck, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Karlsson, Louise
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology,National Board of Forensic Medicine.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Pharmacokinetic Differences in the Disposition of the Enantiomers of Venlafaxine and Its Metabolites in Sprague-Dawley and Dark Agouti RatsManuscript (preprint) (Other academic)
    Abstract [en]

    Venlafaxine is a frequently prescribed racemic antidepressant drug worldwide, consisting of two enantiomers that exhibit similar but not identical biological activity profiles. Venlafaxine is extensively metabolised by the cytochrome P450 (CYP) system. CYP2D6 is involved in the formation of O-desmethylvenlafaxine (Odm-venlafaxine) and CYP3A4 in the formation of Ndesmethylvenlafaxine (Ndm-venlafaxine). The female Dark Agouti and Sprague-Dawley rats are considered the animal counterparts of the human CYP2D6 poor and extensive metaboliser phenotypes, respectively. Since CYP2D6 seems to play a major role in the metabolism of venlafaxine, the aim of this work was to study possible differences in the pharmacokinetics of the enantiomers of venlafaxine and its metabolites in these two different rat strains. Following single administration of racemic venlafaxine (15 mg/kg) serum and brain samples were collected and the concentrations of the enantiomers of venlafaxine and its three major metabolites were determined using an enantioselective LC/MS/MS method. Higher serum and brain concentrations of venlafaxine were observed in Dark Agouti rats as compared to Sprague-Dawley rats (p=0.0002). In relation to the Odm-venlafaxine concentration, the Ndmvenlafaxine concentrations were much higher in Dark Agouti rats than in Sprague-Dawley rats (p<0.0001). The enantiomeric (S/R) venlafaxine ratios were almost two times higher in Dark Agouti rats than in Sprague-Dawley rats, which was observed in both serum and brain (p<0.0001). The present results give hints for possible differences in the pharmacokinetics of venlafaxine in human extensive and poor metaboliser CYP2D6 phenotype subjects.

  • 38.
    Kingbäck, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Karlsson, Louise
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna-Lena
    National Board of Forensic Medicine, Linköping, Sweden.
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Linköping, Sweden.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik C
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, no 1-3, p. 124-134Article in journal (Refereed)
    Abstract [en]

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

  • 39.
    Kugelberg, Fredrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Apelqvist, G
    Klinisk farmakologi Lund.
    Wikell, C
    Klinisk farmakologi Lund.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Open-field behavioural alterations in liver-impaired and sham-operated rats after acute exposure to the antidepressant venlafaxine2005In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 97, no 3, p. 155-161Article in journal (Refereed)
    Abstract [en]

    Patients with chronic liver impairment often display symptoms of affective psychiatric nature where the choice for antidepressant treatment is rational. Since caution is recommended when these drugs are used in such patients, a dose reduction is usually performed. We have previously reported that a dose reduction to liver-impaired portacaval shunted rats has resulted in similar brain concentrations of venlafaxine as compared to sham-operated control rats that received a two times higher dose. The main aim of the present study was therefore to investigate if this "normalisation" in pharma-cokinetics of the portacaval-shunted rats also was true for the pharmacodynamic response in terms of drug effect on spontaneous open-field behaviour. Thus, portacaval-shunted rats received a single reduced dose (5 mg/kg) of venlafaxine or saline, whereas sham-operated rats received either 10 mg/kg or saline. Thereafter, central and peripheral arena locomotor and rearing activities were recorded during 60 min. The venlafaxine-treated portacaval-shunted and sham rats displayed reduced and unchanged overall behavioural activities compared with corresponding controls, respectively. However, the ratios between centrally and peripherally performed behavioural activities were higher in the venlafaxine-treated sham rats, indicating an increase in central arena activity as compared to the sham-saline and portacaval-shunted rats. The present study indicates that, despite a 50% dose reduction, caution still is necessary when antidepressants are used in liver insufficient subjects. This study also shows the importance of detailed open-field behavioural studies in which both central and peripheral activities are recorded for measurement of open-field behavioural drug effects. © Basic & Clinical Pharmacology & Toxicology 2005.

  • 40.
    Kugelberg, Fredrik
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Department of Neuroscience and Locomotion, Psychiatry.
    Apelqvist, Gustav
    Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
    Carlsson, Björn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats2001In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 132, no 8, p. 1683-1690Article in journal (Refereed)
    Abstract [en]
    • The thymoleptic drug citalopram (CIT) belongs to the selective serotonin reuptake inhibitors (SSRIs) and is today extensively used in psychiatry. Further clarification of the enantiomer-selective distribution of racemic CIT in both clinical and toxic doses is highly warranted.

    • By a steady-state in vivo paradigm, rats underwent chronic systemic exposure for 10 days by using osmotic pumps and the total as well as the individual distributions of the S- and R-enantiomers of CIT, and its metabolites in serum and two different brain regions, were analysed.

    • In serum, the S/R ratios in the groups treated with 10, 20, or 100 mg kg−1 day−1 were 0.94, 0.83, and 0.34, respectively. The ratios were almost the same in the brain regions.

    • In the group treated with 100 mg kg−1 day−1, the serum and brain total CIT levels were found to be 20 times and 6 – 8 times higher than in the rats treated with 10 or 20 mg kg−1 day−1, respectively. In all groups, the CIT levels were higher in brain tissue as compared to serum.

    • In a spontaneous open-field behavioural test, a correlation between clinical and toxic drug concentrations was observed.

    • In conclusion, the R-enantiomer was present in an increased proportion compared with the S-enantiomer when higher steady-state CIT concentration was prevailing. This is of particular interest, since the S-enantiomer is responsible for the inhibition of serotonin reuptake in vitro. The present data may be of importance, as full understanding on where different racemic or enantiomeric drug effects of CIT and its main metabolites are unravelled.

  • 41.
    Kugelberg, Fredrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Apelqvist, Gustav
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Sustained citalopram treatment in experimental hepatic encephalopathy: Effects on entrainment to the light-dark cycle and melatonin2006In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 99, no 1, p. 80-88Article in journal (Refereed)
    Abstract [en]

    Patients with chronic hepatic encephalopathy often display altered diurnal rhythm as well as other affective disturbances which motivate treatment with antidepressants. We investigated the effects of sustained treatment with citalopram (10 mg/kg daily, 10 days) on 24-hr behavioural open-field activities in portacaval-shunted (PCS) rats and sham-operated control rats. In addition, the daytime and nighttime serum melatonin levels, as well as the serum concentrations of the enantiomers of citalopram and its metabolites, were analyzed. Untreated PCS rats showed reduced locomotor and rearing activities during nighttime. Citalopram treatment resulted in elevated behavioural activity in the PCS rats during night, indicative of an improved entrainment to the light-dark cycle, whereas no behavioural effect could be observed in sham rats. Higher melatonin levels in both PCS and sham rats were observed during nighttime compared with daytime, but the untreated PCS rats also showed higher daytime melatonin level than the corresponding sham group. Citalopram treatment seemed not to have any major effect on the melatonin levels. Higher serum levels of both citalopram and metabolites were observed in PCS rats as compared to sham rats. An altered ratio between the S- and R-enantiomers could also be observed in the PCS rats. In conclusion, the present data support the contention of a disturbed diurnal rhythm, and that the melatonin activity may be altered, in chronic hepatic encephalopathy. The citalopram treatment resulted in similar behavioural performances and daytime serum melatonin levels in PCS rats and controls, although pharmacokinetic differences were present between the groups. © Basic & Clinical Pharmacology & Toxicology 2006, All rights reserved.

  • 42.
    Kugelberg, Fredrik C.
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Apelqvist, Gustav
    Department of Clinical Pharmacology, Institute of Laboratory Medicine,Lund University, Lund, Sweden.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats2002In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 90, no 6, p. 303-310Article in journal (Refereed)
    Abstract [en]

    The spontaneous open-field behavioural effects of 10 days of chronic treatment with two clinical doses (10 and 20 mg/kg daily) and one high/toxic dose (100 mg/kg daily) of the selective serotonin reuptake inhibitor citalopram (delivered subcutaneously by implanted osmotic pumps) were examined in rats. Central and peripheral arena locomotor and rearing activities were recorded simultaneously, and the data were assessed during the first hour as well as during the following 24 hr (the latter for effects on the diurnal rhythm). Rats treated with 100 mg/kg daily exhibited lower peripheral locomotor and rearing activities than the other groups during the first test hour. The ratio between central and peripheral activity increased in a dose-dependent non-proportional manner during the first test hour, indicating a general increase in the central arena activity exerted by the rats when treated with citalopram. No major differences were observed between any of the four groups in overall behavioural activities over the 24-hr period. This study indicated that the open-field locomotor and rearing behaviours in normal rats were affected by increasing doses of racemic citalopram, particularly during the first hour of adaptation.

  • 43.
    Kugelberg, Fredrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Ahlner, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Pharmacokinetics of citalopram enantiomers after chronic and acute administration of racemate in rats.2002In: Nord J Psychiatry,2002, 2002, p. 22-22Conference paper (Refereed)
  • 44.
    Kugelberg, Fredrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Disposition of the enantiomers of citalipram and its demethylated metabolites in rats.2003In: Ther Drug Monit,2003, 2003, p. 527-527Conference paper (Refereed)
  • 45.
    Kugelberg, Fredrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Disposition of the enantiomers of citalopram and its demethylated metabolites in rats2003In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, no 4, p. 163-Conference paper (Other academic)
  • 46.
    Kugelberg, Fredrik
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Stereoselective single-dose kinetics of citalopram and its metabolites in rats2003In: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 15, no 7, p. 622-629Article in journal (Refereed)
    Abstract [en]

    The single-dose kinetics of the enantiomers of citalopram (CIT) and its metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), were investigated after administration of 10, 20, or 100 mg/kg (s.c.) rac-CIT to rats. Samples from serum and two brain regions were collected 1, 3, 10, or 20 h postdose for HPLC analysis. In the 100 mg/kg rats, the enantiomeric (S/R) serum concentration ratios of CIT decreased during the study period (0.93 at 1 h vs. 0.59 at 20 h; P < 0.001). In the 10 and 20 mg/kg rats, the decrease in serum S/R CIT ratios was not so evident as in the 100 mg/kg rats. In all three groups the S/R CIT ratio was almost the same in the brain as in serum, although both CIT enantiomer levels in the brain were found to be 5–10 times higher than the levels in serum. The serum and brain metabolite levels were low in the 10 and 20 mg/kg rats, whereas the levels increased during the study period in the 100 mg/kg rats. In conclusion, the CIT enantiomers were shown for the first time to be stereoselectively metabolized after single-dose administration to rats, as previously shown in steady-state dosing studies in humans and rats. Chirality 15:622–629, 2003. © 2003 Wiley-Liss, Inc.

  • 47.
    Kugelberg, Fredrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Carlsson, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ther Drug Monit: Disposition of the enantiomers of citalopram and its demethlated metabolites in rats.2003In: Skriv in din egen text för ej reg. tidskrift etc.,2003, 2003, p. 527-527Conference paper (Refereed)
  • 48.
    Kugelberg, Fredrik
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Druid, Henrik
    Division of Forensic Medicine, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Carlsson, Björn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Postmortem redistribution of the enantiomers of citalopram and its metabolites: an experimental study in rats2004In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 28, no 8, p. 631-637Article in journal (Refereed)
    Abstract [en]

    A rat model was used to study if postmortem redistribution of the S- and R-enantiomers of citalopram (CIT) and its metabolites demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) occurs after three different subcutaneous dosing procedures with racemic CIT. Two groups underwent chronic administration (20 mg/kg daily) using osmotic pumps. After 10 days, 1 of these groups received an acute-on-chronic drug challenge with a single injection of 100 mg/kg. The third group received the single 100 mg/kg dose only. Heart blood and brain samples were collected antemortem and 1, 3, or 24 h postmortem for enantioselective HPLC analysis. Increased postmortem blood drug and metabolite concentrations compared with corresponding antemortem concentrations were observed in all groups (p < 0.05 to p < 0.001). At 24 h after death, the ratios between postmortem and antemortem blood concentrations were around 3–4 for CIT as well as for the metabolites. In the brain, no major differences between antemortem and postmortem drug and metabolite concentrations were observed. The enantiomeric (S/R) concentrations ratios of CIT and metabolites in blood and brain were of similar magnitude before and after death. No differences between antemortem and postmortem parent drug-to-metabolite (P/M) ratios for CIT/DCIT in blood were observed. Finally, this animal model demonstrates that the S- and R-enantiomers of CIT and its metabolites were redistributed to the same extent postmortem.

  • 49.
    Landen, Mikael
    et al.
    Karolinska Institute.
    Erlandsson, Helena
    University of Gothenburg.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Andersch, Bjorn
    University of Gothenburg.
    Eriksson, Elias
    University of Gothenburg.
    Short Onset of Action of a Serotonin Reuptake Inhibitor When Used to Reduce Premenstrual Irritability2009In: NEUROPSYCHOPHARMACOLOGY, ISSN 0893-133X, Vol. 34, no 3, p. 585-592Article in journal (Refereed)
    Abstract [en]

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

  • 50.
    Lind, Anna-Britta
    et al.
    Uppsala University.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Jonzier-Perey, Michele
    University of Lausanne.
    Powell, Golay K.
    University of Lausanne.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Baumann, P.
    University of Lausanne.
    Dahl, M.-L.
    Uppsala University.
    Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour2009In: Clinical Pharmacokinetics, ISSN 0312-5963, Vol. 48, no 1, p. 63-70Article in journal (Refereed)
    Abstract [en]

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

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