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  • 101.
    Knaust, Eva
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Porwit-MacDonald, Anna
    Departments of Pathology, Karolinska Hospital, Stockholm, Sweden.
    Gruber, Astrid
    Division of Hematology, Karolinska Hospital, Stockholm, Sweden.
    Xu, Dawei
    Division of Hematology, Karolinska Hospital, Stockholm, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Heterogeneity of isolated mononuclear cells from patients with acute myeloid leukemia affects cellular accumulation and efflux of daunorubicin2000Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 85, nr 2, s. 124-132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Pharmacologic studies on blasts from patients with leukemia are generally performed on density gradient isolated blood or bone marrow cells. Thereby, cellular drug accumulation and efflux are determined as mean values of the entire cell population. The objective of the present study was to characterize the heterogeneity in the accumulation and efflux of daunorubicin in various subpopulations of mononuclear cells isolated from patients with acute myeloid leukemia (AML).

    DESIGN AND METHODS: Mononuclear cells from 33 patients with AML were isolated from peripheral blood by density gradient centrifugation on Lymphoprep (1. 077 g/mL). Cellular accumulation of fluorescent daunorubicin was determined by flow cytometry after incubation of the cells at +37C for 1 hour. Thereafter, the cells were washed and reincubated in drug-free medium. Kinetics of drug efflux were determined by frequent determination of cellular fluorescence during 30 min. Daunorubicin accumulation and efflux were compared in the total isolated mononuclear cell population and in the various blast cell populations gated on FSC/SSC according to the results of immunophenotyping.

    RESULTS: In 8 of these 33 (24%) patient samples, two distinct blast cell populations could be identified. In 7 out of 8 these cases the more immature blasts had a lower drug accumulation and in 6 out of the 8 cases also a higher efflux rate than the differentiating cell population. Cyclosporin A increased daunorubicin accumulation and reduced efflux in the immature blast population. In the differentiating cell population cyclosporin A increased both the accumulation and the efflux. In patients with a single blast cell population, the gated blast cells had a significantly lower drug accumulation but also a lower drug efflux rate than the total cell population.

    INTERPRETATION AND CONCLUSIONS: The results imply that drug transport studies on cells isolated from patients with AML give somewhat different results depending on the cell population studied. Some, but not all, of these differences in daunorubicin accumulation and efflux as well as in the effect of cyclo-sporin A can be explained by a heterogenous expression of the mdr1-gene. The observed heterogeneity may be of special relevance with regard to drug resistance. The presence of even a small resistant cell clone may jeopardize the effect of the chemotherapy due to expansion resulting in relapse of disease.

  • 102.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Alkass, Kanar
    Kingbäck, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Influence of blood loss on the pharmacokinetics of citalopram2006Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 161, nr 2-3, s. 163-168Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extended blood loss results in several compensatory physiological mechanisms, including transfer of extravascular fluid into the blood circulation. If drugs are present in the body, this fluid exchange may imply that blood drug concentrations found in a trauma victim may differ from the concentrations present at the time of the trauma. To address this issue, an animal model was used to investigate the influence of blood loss on pre-existing levels of the antidepressant drug citalopram and its demethylated metabolites. Rats were administered citalopram either acutely (40 mg/kg, orally) or chronically (20 mg/kg daily, subcutaneously) for 6 days using osmotic pumps. In the experimental rats, blood loss was accomplished by withdrawing 0.8 mL blood at 10 min intervals during 70 min. In the control rats, blood was withdrawn at 0 and 70 min only. Blood, brain and lung drug concentrations were analyzed with an enantioselective HPLC method. In the chronically treated rats, the ratios between final and initial citalopram concentrations were 1.08 ± 0.15 and 1.01 ± 0.09 in the experimental rats and controls, respectively, indicating no major effect of blood loss. In contrast, acute oral administration resulted in increased ratios in the exsanguinated rats as compared to controls (1.84 ± 0.50 versus 0.73 ± 0.07, p = 0.0495). In conclusion, the observation of increased blood drug levels in the acute oral rats indicates that absorption of fluid from the gastrointestinal tract may be important in the intravascular refill. Further, in the interpretation of post-mortem blood levels of drugs, these physiological mechanisms should be taken into account. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 103.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Apelqvist, G
    Klinisk farmakologi Lund.
    Wikell, C
    Klinisk farmakologi Lund.
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Open-field behavioural alterations in liver-impaired and sham-operated rats after acute exposure to the antidepressant venlafaxine2005Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 97, nr 3, s. 155-161Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 104.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri.
    Apelqvist, Gustav
    Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats2001Inngår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 132, nr 8, s. 1683-1690Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 105.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Apelqvist, Gustav
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Sustained citalopram treatment in experimental hepatic encephalopathy: Effects on entrainment to the light-dark cycle and melatonin2006Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 99, nr 1, s. 80-88Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 106.
    Kugelberg, Fredrik C.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Chiral and toxicological aspects of citalopram: an experimental study in rats2003Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Citalopram (CIT) is a selective serotonin reuptake inhibitor (SSRI), which is used for the treatment of different psychiatric disorders. The indications for prescription of OT are linked to high risks for intentional intoxications. CIT is one of the most commonly found drugs in Swedish forensic autopsy cases. CIT is a chiral compound, which exists as a racemic mixture (50:50) of the S-(+)-enantiomer (S-CIT) and the R-(-)-enantiomer (R-CIT). The main metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DCIT), are also chiral compounds. The SSRI effect of CIT is mediated by S-CIT. The routine toxicological screening is an achiral analysis, in which the total amount of the two enantiomers of CIT and metabolites are measured. An extended analysis of the disposition of the Sand R-enantiomers may provide additional information in interpreting forensic toxicological results. Hence, the blood and brain dispositions of the enantiomers of CIT, DCIT and DDCIT in vivo as well as postmortem were studied in an animal model, which also included studies of the behavioural activity.

    Rats underwent systemic CIT exposure of clinically relevant and high/toxic doses, which were administered acute, chronic or acute-on-chronic. Samples from serum/blood and two brain regions (cortex and mesencephalon-pons) were collected for analysis of the concentrations of the enantiomers of CIT and metabolites using a chiral high performance liquid chromatography (HPLC) method. The open-field locomotor and rearing activities were examined after the chronic CIT exposure.

    Following chronic CIT administration, R-CIT was present in an increased proportion compared with S-CIT when higher CIT concentration prevailed. Higher drug levels were observed in brain than in serum, and the drug levels between the two compartments correlated well. The rats treated with the high/toxic dose displayed lower behavioural activity during the first test hour as compared to controls and rats given clinically relevant doses. No major effects of CIT on the behavioural rhythm were observed. Shortly after the acute CIT administration, the ratio between S- and R-CIT was close to unity, whereas R-OT was found in higher amount than S-CIT at the end of the study period. The heart blood levels of CIT and metabolites increased postmortem in comparison with the levels observed antemortem after acute, chronic and acute-on-chronic administration. Irrespective of administered dose, the ratios between the S- and R-enantiomers of CIT and DCIT, as well as the CIT/DCIT ratios, were similar antemortem and postmortem.

    Chiral analysis provided additional information regarding the different administration procedures as compared to achiral analysis. The stereoselective in vivo disposition of the enantiomers of CIT and metabolites was found similar in blood and brain. An equal degree of postmortem redistribution was also seen regarding the enantiomers of CIT and metabolites. These findings may facilitate and improve the interpretation of forensic toxicological results in humans.

    Delarbeid
    1. In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats
    Åpne denne publikasjonen i ny fane eller vindu >>In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats
    Vise andre…
    2001 (engelsk)Inngår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 132, nr 8, s. 1683-1690Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-26749 (URN)10.1038/sj.bjp.0704015 (DOI)11344 (Lokal ID)11344 (Arkivnummer)11344 (OAI)
    Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats
    2002 (engelsk)Inngår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 90, nr 6, s. 303-310Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-27659 (URN)10.1034/j.1600-0773.2002.900603.x (DOI)12397 (Lokal ID)12397 (Arkivnummer)12397 (OAI)
    Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. Stereoselective single-dose kinetics of citalopram and its metabolites in rats
    Åpne denne publikasjonen i ny fane eller vindu >>Stereoselective single-dose kinetics of citalopram and its metabolites in rats
    2003 (engelsk)Inngår i: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 15, nr 7, s. 622-629Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-26746 (URN)10.1002/chir.10266 (DOI)11341 (Lokal ID)11341 (Arkivnummer)11341 (OAI)
    Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    4. Postmortem redistribution of the enantiomers of citalopram and its metabolites: an experimental study in rats
    Åpne denne publikasjonen i ny fane eller vindu >>Postmortem redistribution of the enantiomers of citalopram and its metabolites: an experimental study in rats
    Vise andre…
    2004 (engelsk)Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 28, nr 8, s. 631-637Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-24023 (URN)10.1093/jat/28.8.631 (DOI)3578 (Lokal ID)3578 (Arkivnummer)3578 (OAI)
    Tilgjengelig fra: 2009-10-07 Laget: 2009-10-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert
  • 107.
    Kugelberg, Fredrik C.
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    Apelqvist, Gustav
    Department of Clinical Pharmacology, Institute of Laboratory Medicine,Lund University, Lund, Sweden.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    Effects of chronic citalopram treatment on central and peripheral spontaneous open-field behaviours in rats2002Inngår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 90, nr 6, s. 303-310Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 108.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Ahlner, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Pharmacokinetics of citalopram enantiomers after chronic and acute administration of racemate in rats.2002Inngår i: Nord J Psychiatry,2002, 2002, s. 22-22Konferansepaper (Fagfellevurdert)
  • 109.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Disposition of the enantiomers of citalipram and its demethylated metabolites in rats.2003Inngår i: Ther Drug Monit,2003, 2003, s. 527-527Konferansepaper (Fagfellevurdert)
  • 110.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Stereoselective single-dose kinetics of citalopram and its metabolites in rats2003Inngår i: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 15, nr 7, s. 622-629Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 111.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Ther Drug Monit: Disposition of the enantiomers of citalopram and its demethlated metabolites in rats.2003Inngår i: Skriv in din egen text för ej reg. tidskrift etc.,2003, 2003, s. 527-527Konferansepaper (Fagfellevurdert)
  • 112.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Druid, Henrik
    Division of Forensic Medicine, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Postmortem redistribution of the enantiomers of citalopram and its metabolites: an experimental study in rats2004Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 28, nr 8, s. 631-637Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 113.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Holmgren, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Druid, Henrik
    Stockholm.
    Codeine and morphine blood concentrations increase during blood loss2003Inngår i: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 48, nr 3, s. 664-667Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During extensive blood loss, a plasma volume refill will take place by transfer of extravascular fluid into the circulation. Drugs present in this fluid may follow and cause a rise or a drop in blood drug concentration, depending on their levels and accessibility in the restoration fluid. This study explored the possible changes of codeine, and its metabolite morphine, in whole blood during a standardized exsanguination in the rat. Three doses containing 5 mg codeine were given orally. In eight rats, blood loss was accomplished by slowly withdrawing 0.8 mL blood at 10 min intervals during 70 min. In control rats, blood was withdrawn only at 0 and 70 min. At 70 min, the final/initial codeine and morphine concentration ratios were 0.70 +/- 0.38 and 0.88 +/- 0.47, respectively, in controls, but increased to 1.28 +/- 0.44 (p=0.014) and 1.41 +/- 0.34 (p=0.021), respectively, in exsanguinated rats. It is concluded that blood loss can affect blood drug concentrations.

  • 114.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Holmgren, Per
    Druid, Henrik
    Rättsmedicin, KI Stockholm.
    Codeine and morphine blood levels increase during blood loss.2002Inngår i: Annales de Toxicologie Analytique,2002, 2002, s. 229-229Konferansepaper (Fagfellevurdert)
  • 115.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Jones, A Wayne
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för klinisk kemi.
    Interpreting results of ethanol analysis in postmortem specimens: A review of the literature2007Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 165, nr 1, s. 10-29Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We searched the scientific literature for articles dealing with postmortem aspects of ethanol and problems associated with making a correct interpretation of the results. A person's blood-alcohol concentration (BAC) and state of inebriation at the time of death is not always easy to establish owing to various postmortem artifacts. The possibility of alcohol being produced in the body after death, e.g. via microbial contamination and fermentation is a recurring issue in routine casework. If ethanol remains unabsorbed in the stomach at the time of death, this raises the possibility of continued local diffusion into surrounding tissues and central blood after death. Skull trauma often renders a person unconscious for several hours before death, during which time the BAC continues to decrease owing to metabolism in the liver. Under these circumstances blood from an intracerebral or subdural clot is a useful specimen for determination of ethanol. Bodies recovered from water are particular problematic to deal with owing to possible dilution of body fluids, decomposition, and enhanced risk of microbial synthesis of ethanol. The relationship between blood and urine-ethanol concentrations has been extensively investigated in autopsy specimens and the urine/blood concentration ratio might give a clue about the stage of alcohol absorption and distribution at the time of death. Owing to extensive abdominal trauma in aviation disasters (e.g. rupture of the viscera), interpretation of BAC in autopsy specimens from the pilot and crew is highly contentious and great care is needed to reach valid conclusions. Vitreous humor is strongly recommended as a body fluid for determination of ethanol in postmortem toxicology to help establish whether the deceased had consumed ethanol before death. Less common autopsy specimens submitted for analysis include bile, bone marrow, brain, testicle, muscle tissue, liver, synovial and cerebrospinal fluids. Some investigators recommend measuring the water content of autopsy blood and if necessary correcting the concentration of ethanol to a mean value of 80% w/w, which corresponds to fresh whole blood. Alcoholics often die at home with zero or low BAC and nothing more remarkable at autopsy than a fatty liver. Increasing evidence suggests that such deaths might be caused by a pronounced ketoacidosis. Recent research has focused on developing various biochemical tests or markers of postmortem synthesis of ethanol. These include the urinary metabolites of serotonin and non-oxidative metabolites of ethanol, such as ethyl glucuronide, phosphatidylethanol and fatty acid ethyl esters. This literature review will hopefully be a good starting point for those who are contemplating a fresh investigation into some aspect of postmortem alcohol analysis and toxicology. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 116.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Kingbäck, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Druid, H
    Rättsmedicin KI.
    Early-phase postmortem redistribution of the enantiomers of citalopram and its demethylated metabolites in rats2005Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 29, nr 4, s. 223-228Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to investigate the early-phase postmortem redistribution of the enantiomers of citalopram (CIT) and its metabolites demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) in a rat model. Furthermore, we wanted to examine the role of the lungs as a reservoir of postmortem drug release and to investigate the influence of storage temperature (21°C vs. 4°C) on postmortem changes. Rats were administered a single CIT dose of 100 mg/kg (s.c.), and heart blood and lung samples were collected antemortem and 15 min postmortem for enantioselective high-performance liquid chromatographic analysis. About three times higher blood drug and metabolite levels were observed in the postmortem rats than in the antemortem rats (p < 0.0001). Refrigeration at 4°C did not prevent, but significantly reduced, the postmortem increase in heart blood CIT levels as compared to the concentrations in the rats stored at 21°C (p < 0.05). The lung drug concentrations were lower postmortem than antemortem (p < 0.05). The enantiomeric (S/R) concentration ratios of CIT and metabolites in blood and lungs were of similar magnitude before and after death. The parent-drug-to- metabolite ratios for CIT/DCIT were unchanged after death. In conclusion, this study shows that heart blood CIT and metabolite levels increase rapidly after death. Further, a fall in postmortem CIT concentrations in the lungs was observed, indicating that the lungs seemed to represent one major source of drug release during early-phase postmortem redistribution.

  • 117.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Kingbäck, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Druid, H
    Rättsmedicin KI.
    Postmortem redistribution of the enantiomers of citalopram and its metabolites in a rat model2005Inngår i: Joint SOFT/TIAFT/FBI meeting on Forensic Toxicology,2005, Niles, Illinois, USA: Preston publications , 2005, s. 494-Konferansepaper (Fagfellevurdert)
  • 118.
    Kugelberg, Fredrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Kingbäck, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Carlsson, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Druid, Henrik
    Postmortem redistribution of the enantiomers of citalopram and itsmetabolities in a rat model2004Inngår i: 2004 SOFT/TIAFT meeting,2004, 2004, s. 338-338Konferansepaper (Annet vitenskapelig)
  • 119.
    Kurland, L.
    et al.
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden, Department of Internal Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
    Melhus, H.akan
    Melhus, H.åkan, Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Karlsson, J.
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Kahan, T.
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Danderyd, Sweden.
    Malmqvist, K.
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Danderyd, Sweden.
    Öhman, P.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Nyström, Fredrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Hagg, A.
    Hägg, A., Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Lind, L.
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: Results from the Swedish Irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA) trial2002Inngår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 15, nr 5, s. 389-393Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. Methods: Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the ß1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. Results: After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 ± 19 SD mm Hg, n = 17) than both the TC (-14 ± 18 mm Hg, n = 18) and CC (0 ± 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. Conclusions: The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan. © 2002 American Journal of Hypertension, Ltd.

  • 120. Langhorne, P
    et al.
    Dey, P
    Woodman, M
    Kalra, L
    Wood-Dauphinee, S
    Patel, N
    Hamrin, Elisabeth
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Is stroke unit care portable? A systematic review of the clinical trials2005Inngår i: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 34, nr 4, s. 324-330Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: It is not known if mobile stroke teams can achieve the good results seen in trials of geographically discrete stroke wards (stroke units). Objective: To establish the effectiveness of mobile stroke teams. Design: Systematic review of controlled clinical trials that compared peripatetic systems of organised stroke care (stroke team care) with alternative hospital services. Methods: Systematic review and meta-analysis (using Cochrane Collaboration methodology and involving the primary trialists). Clinical outcomes included death, dependency, the need for institutional care and measures of the process of care such as the delivery of key investigations and treatments. Results: Six clinical trials (1,085 patients) were identified, five (781 patients) compared some form of stroke team care with conventional care in general medical wards and one (304 patients) compared team care with a comprehensive stroke unit. Compared with care in general wards, stroke team care improved some aspects of the process of care, but clinical outcomes were similar. Compared with a comprehensive stroke unit, stroke team patients were significantly less likely to survive (P< 0.001), return home (P< 0.001) or regain independence (P< 0.0001). Most aspects of the process of care were also poorer than in the stroke unit. Conclusions: Care from a mobile stroke team had no major impact on death, dependency or the need for institutional care. © The Author 2005. Published by Oxford University Press. All rights reserved.

  • 121.
    Lennestål, Roland
    et al.
    Umeå.
    Asplund, Cay
    Umeå.
    Nilsson, Mats
    Umeå.
    Lakso, Hans-Åke
    Umeå.
    Mjörndal, Tom
    Umeå.
    Hägg, Staffan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Serum levels of olanzapine in a non-fatal overdose2007Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 31, nr 2, s. 119-121Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Olanzapine is a widely used second generation antipsychotic drug. Case reports of intoxications have been published, but reports in the literature of non-fatal intoxications of olanzapine containing repeated measurements of serum levels are scarce. Therefore, this case of non-fatal olanzapine intoxication is presented, in which 19 blood samples were drawn during 2 weeks. The highest (initial) measured value was estimated at 800 μg/L. This patient ingested 550 mg of olanzapine resulting in clinical signs of intoxication, including seizures. Because the patient was found the day after the intoxication, the initial concentration had probably been higher. The pharmacokinetics of olanzapine has been described as linear and dose-proportional throughout the therapeutic dosing range. Large overdoses, however, have been described to show non-linear pharmacokinetics. In this study's series of serum concentrations, a two-phase elimination was seen, with an initial elimination half-life of about 24 h during the first 3 days, followed by a second phase with a half-life of about 2.5 days. The patient in this case recovered completely. Because the elimination time after intoxication can be considerably longer than expected, it is recommended that the patient's serum concentrations after intoxication be monitored.

  • 122.
    Lindberg, Malou
    et al.
    Linköpings universitet, Institutionen för hälsa och samhälle, Allmänmedicin. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ekström, Tommy
    Linköpings universitet, Institutionen för medicin och vård, Lungmedicin. Linköpings universitet, Hälsouniversitetet.
    Jonsson, Dick
    Linköpings universitet, Institutionen för hälsa och samhälle, Centrum för utvärdering av medicinsk teknologi. Linköpings universitet, Hälsouniversitetet.
    Möller, Margareta
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    Asthma nurse practice improves outcomes and reduces costs in primary health care2002Inngår i: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, E-ISSN 1471-6712, Vol. 16, nr 1, s. 73-78Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. The aim of this study was to elucidate the care of patients with asthma in primary health care from medical, patient self-management, health, quality of live, and health economic perspectives.

    Methods. Asthma nurse practice (ANP), an alternative asthma self-management strategy, was compared with traditional asthma care in primary health care in southern Sweden regarding medical history, lifestyle, self-management, symptoms caused by asthma, effects on sick leave, state of health, quality of life and health care costs. The first part of the investigation comprised a retrospective study of a randomly selected sample of patient records of asthmatics (n=152). The second part, lasting 3 months, was prospective and included consecutive patients visits (n=347).

    Results. The ANP approach showed better results in most of the evaluated outcomes such as asthma quality documentation and self-management and the number of asthma symptoms was significantly lower. From a health economic perspective the results were encouraging with respect to ANP.

    Conclusion. This alternative asthma strategy, ANP, improved asthma care in primary health care and resulted in economic advantages in the health care sector. However the result may only be generalized to other practices working with asthma nurses in the same way.

  • 123.
    Lindberg, Malou
    et al.
    Linköpings universitet, Institutionen för hälsa och samhälle, Allmänmedicin. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ekström, Tommy
    Linköpings universitet, Institutionen för medicin och vård, Lungmedicin. Linköpings universitet, Hälsouniversitetet.
    Möller, Margareta
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    Patient questionnaires in primary health care: Validation of items used in asthma care2000Inngår i: International Journal for Quality in Health Care, ISSN 1353-4505, E-ISSN 1464-3677, Vol. 12, nr 1, s. 19-24Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective.To evaluate each item in a patient questionnaire for the purpose of investigating whether the validity of each item is acceptable.

    Design.The questionnaire was completed by the patients at an ordinary follow-up visit for their asthma, and within 1 week a nurse interviewed them by telephone with the aim of analysing the validity of each item through the use of predetermined criteria.

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

    Study participants.Fifty-one patients were consecutively included from three different primary health care units.

    Results.Nine of 13 items had an acceptable validity. The four items that were not found to have acceptable validity were developed further.

    Conclusion.Evaluating each item in a questionnaire by means of interviews with the specific patient population is a useful method of assuring that the intention of the patient questionnaire has been met.

  • 124.
    Lindberg, Malou
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för hälsa och samhälle, Allmänmedicin.
    Ekström, Tommy
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Lungmedicin. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Lungmedicinska kliniken US.
    Möller, Margareta
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Astma care and factors affectin medication comliance; the patient's point of view2001Inngår i: International Journal for Quality in Health Care, ISSN 1353-4505, E-ISSN 1464-3677, Vol. 13, s. 375-383Artikkel i tidsskrift (Fagfellevurdert)
  • 125.
    Lindholm, Lisbet
    et al.
    Åbo Akademi Vasa.
    Rehnsfeldt, Arne
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för samhälls- och välfärdsstudier.
    Arman, Maria
    Åbo Akademi Vasa.
    Hamrin, Elisabeth
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Significant others' experience of suffering when living with women with breast cancer2002Inngår i: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, E-ISSN 1471-6712, Vol. 16, nr 3, s. 248-255Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This is an inquiry into how significant others experience being close to a woman suffering from breast cancer. In order to find this out, theme interviews were arranged with 17 women and 16 significant others from four different caring cultures in Sweden and Finland. A phenomenological case study methodology was adopted and in the analysis of the data a scientific teamwork model was employed, based on ideas developed at the Vancouver School of Doing Phenomenology. The findings show that the significant others experience deep often unrelieved suffering. They consider themselves prisoners of a situation of uncertainty and powerlessness when standing by the woman. They are torn between their own suffering and their desire to alleviate the woman's suffering. A vicious circle of mutual protection intensifies the suffering of the significant other, while actively sharing the suffering brings relief. The gravity of the situation creates an ethical urge in the significant other to assume responsibility for life in common with the woman.

  • 126.
    Lindqvist Appell, Malin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Pharmacogenetic studies of thiopurines - focus on thiopurine methyltransferase2005Inngår i: Gastrokuriren, ISSN 1651-0453, Vol. 10Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
  • 127.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacogenetic studies of thiopurines: focus on thiopurine methyltransferase2005Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Pharmacogenetics represents the study ofvariability in drug response due to genetic variations. The thiopurines (6-mercaptopurine, 6-thioguanine and azathioprine) are prodrugs which require metabolic transformation to exert effect. Thiopurines are used in inflammatory bowel disease, as maintenance treatment of childhood acute lymphoblastic leukaemia, and for immunosuppression after transplantation. The metabolism is complex and one important enzyme involved is thiopurine methyltransferase (TPMT). Inherited variation in TPMT activity is one factor responsible for individual differences in susceptibility to thiopurine-induced toxicity or in the therapeutic response to thiopurines. The enzyme activity is under controi of agenetic polymorphism. The frequency distribution of TPMT activity in Caucasians is trimodal, with 89% having high enzyme activity, 10% having intermediate activity and l of 300 having almost undetectable activity. The TPMT gene has been characterised and several single nucleotide polymorphisms (SNPs) identified causing decreased enzyme activity. The most common SNPs are TPMT*2, TPMT*3A and TPMT*3C.

    In the investigations for this thesis we have studied the pharmacogenetics of thiopurines with focus on TPMT. A real-time RT-PCR method was developed for quantification of TPMT gene expression, and a pyrosequencing method was developed for genotyping of TPMT SNPs. TPMT gene expression correlated to enzyme activity in individuals with high enzyme activity. The allele frequencies of TPMT*3A and TPMT*3C in samples from 800 Swedish individuals were in agreement with those in other Caucasian populations, although TPMT*3B was more common and TPMT*2 was rarer.

    We investigated the concordance between genotype and phenotype and found discordance between genotype and phenotype in two unrelated patients. In these patients, we detected two new sequence variants, TPMT*14 and TPMT*15, which lead to a non-functional TPMT enzyme. The TPMT genotype and phenotype were also determined in the parents of the two patients and the inheritance of these alleles was investigated.

    Sixty patients with inflammatory bowel disease following a standardised dose escalation schedule of azathioprine or 6-mercaptopurine were closely monitored over the course of 20 weeks. During treatment, the TPMT gene expression decreased. In contrast, TPMT enzyme activity did not change. TPMT heterozygous patients had a lower probability of remaining in the 20week study. Forty-five percent of the patients were withdrawn due to adverse events, but 67% of these tolerated a lower dose of thiopurines. The inosine triphosphate pyrophosphatase polymorphism (ITPA 94C>A) was not associated with occurrences of adverse events.

  • 128.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-magtarm.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Real-time RT-PCR methodology for quantification of thiopurine methyltransferase gene expression2003Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 59, nr 3, s. 207-211Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The aim of the present study was to develop a real-time reverse-transcription polymerase chain reaction (RT-PCR) methodology for the quantification of thiopurine methyltransferase (TPMT) gene expression in whole blood and compare it with the TPMT enzyme activity measured in red blood cells. Methods: TPMT gene expression was quantified relative to the housekeeping gene cyclophilin (huCYC) and expressed as a TPMT/huCYC ratio. TPMT activity in red blood cells was determined by measuring the formation rate of 6- 14C-methylmercaptopurine from 6-MP using S-adenosyl-L-( 14C-methyl)-methlonine as methyl donor. Thirty-nine individuals were included in the study. A cut-off value of 9 U/ml pRBC was used to distinguish intermediate TPMT enzyme activity from high TPMT enzyme activity. Results: Sequencing of the real-time RT-PCR amplicon proved that the method was specific for the TPMT cDNA, without co-amplification of the highly similar TPMT processed pseudogene. The intra-assay coefficients of variation (CVs), as determined by the threshold cycle, were 0.7% for TPMT and 0.5% for huCYC. The interassay CVs were 1.5% for TPMT and 4.0% for huCYC. The intra- and interassay CVs, as determined by the TPMT/huCYC ratio, were 8.6% and 25%, respectively. There was a statistically significant correlation between TPMT enzyme activity and mRNA level in blood cells from individuals with an enzyme activity above 9 U/ml pRBC (rs = 0.66, P = 0.0001). However, we did not find any statistically significant correlation in individuals with lower enzyme activity or when analysing the whole population. Conclusion: We present a specific and robust real-time RT-PCR method for quantifying TPMT gene expression. The method may be used for studies on TPMT gene regulation.

  • 129.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Haglund, Sofie
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Taipalensuu, Jan
    Division of Research and Development in Laboratory Medicine, Ryhov County Hospital, Jönköping.
    Hertervig, Erik
    dDepartment of Medicine, Lund University Hospital, Lund.
    Lyrenäs, Ebbe
    Department of Medicine, Blekinge County Hospital, Karlskrona.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Identification of two novel sequence variants affecting thiopurine methyltransferase enzyme activity2004Inngår i: Pharmacogenetics, ISSN 0960-314X, E-ISSN 1473-561X, Vol. 14, nr 4, s. 261-265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The polymorphic enzyme thiopurine methyltransferase (TPMT) is involved in the methylation of thiopurines. On comparing the phenotype with the genotype in Swedish patients with inflammatory bowel disease and healthy individuals, we found two discordant cases with low TPMT enzyme activity (0.3 and 0.4 U/ml packed red blood cells (pRBC). Genotyping by pyrosequencing revealed that they carried the nucleotide substitutions 460G>A and 719A>G, giving two possible genotypes (TPMT*1/*3A or TPMT*3B/ *3C). DNA sequencing of exon III to X was performed in the patients and their parents. We identified an A>G transition in the start codon (exon III, 1A>G, Met>Val, TPMT*14) in one of the patients and her father (6.3 U/ml pRBC). The mother in this family carried the 460G>A and 719A>G nucleotide substitutions (TPMT*3A, 5.0 U/ml pRBC). In the second family, sequencing revealed a G>A transition in the acceptor splice site in intron VII/exon VIII (IVS7 - 1G>A, TPMT*15) in the patient and his mother (6.9 U/ml pRBC). His father was genotyped as TPMT*1/*3A (6.0 U/ml pRBC). Hence, we report the identification of two novel sequence variants, present in highly conserved nucleotide positions of the human TPMT gene, resulting in a loss of enzyme activity.

  • 130.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Hindorf, U
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Ström, Magnus
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Hjortswang, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    No induction of thiopurine methyltransferase during thiopurine treatment in inflammatory bowel disease2006Inngår i: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 25, nr 9-11, s. 1033-1037Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naïve patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3, 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were followed every week during Weeks 1-8 from baseline and then every 4 weeks until 20 weeks. TPMT activity and thiopurine metabolites were determined in erythrocytes, TPMT and ITPA genotypes, and TPMT gene expression were determined in whole blood. One homozygous TPMT-deficient patient was excluded. Five non compliant patients were withdrawn during the first weeks. Twenty-seven patients completed the study per protocol, 27 patients were withdrawn because of adverse events. Sixty-seven percent of the withdrawn patients tolerated thiopurines at a lower dose at Week 20. There was no difference in baseline TPMT enzyme activity between individuals completing the study and those withdrawn for adverse events (p = 0.45). A significant decrease in TPMT gene expression (TPMT/huCYC ratio, p = 0.02) was found, however TPMT enzyme activity did not change. TPMT heterozygous individuals had a lower probability of remaining in the study on the predetermined dose (p = 0.039). The ITPA 94C > A polymorphism was not predictive of adverse events (p = 0.35). Copyright © Taylor & Francis Group, LLC.

  • 131.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Hindorf, Ulf
    Lund.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Thiopurines in inflammatory bowel disease - The role of pharmacogenetics and therapeutic drug monitoring2006Inngår i: Current Pharmacogenomics, ISSN 1570-1603, Vol. 4, nr 4, s. 285-300Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pharmacogenetics represents the study of variability in drug response due to genetic variations. Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterized by a chronic or relapsing inflammation of the digestive tract. The thiopurines 6-mercaptopurine (6-MP) and azathioprine (AZA), an imidazol derivative and pro-drug of 6-MP, are widely used in IBD, particularly in Crohn's disease. The metabolism of thiopurines is complex and individually variable. Thiopurine methyltransferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for a defective enzyme. The formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably due to the TPMT activity. Patients with decreased TPMT activity are at increased risk of developing severe side effects if treated with conventional thiopurine doses, due to the accumulation of toxic metabolites. Determination of the TPMT phenotype or genotype is often used to identify individuals with increased risk for adverse events. Twenty-one variant TPMT alleles have been described, of which three are more common than the others. An association between inosine triphosphate pyrophosphatase polymorphisms and adverse events during thiopurine treatment has also been proposed. In this review, the clinical value of TPMT status determination and pharmacological monitoring of thiopurine metabolites are discussed as well as the increased interest in the use of 6-thioguanine, a thiopurine with a less complex metabolism, as an alternative for patients who do not tolerate AZA or 6-MP. It can be concluded that TPMT determination before start of thiopurine therapy is of value to identify individuals with increased risk for adverse reactions due to genetic enzyme deficiency. However, large prospective studies are still needed to evaluate the true benefit of monitoring thiopurine metabolites during thiopurine treatment. © 2006 Bentham Science Publishers Ltd.

  • 132.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Hindorf, Ulf
    Lund.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Ström, Magnus
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Hjortswang, Henrik
    Linköpings universitet, Institutionen för molekylär och klinisk medicin.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    No induction of thiopurine methyltransferase (TPMT) during thiopurine treatment in IBD2005Inngår i: 10th Symposium European Society for the Study of Purine and Pyrimidine Metabolism in Man,2005, 2005Konferansepaper (Fagfellevurdert)
  • 133.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Hindorf, Ulf
    Lund.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Ström, Magnus
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Hjortswang, Henrik
    Linköpings universitet, Institutionen för molekylär och klinisk medicin.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    No induction of thiopurine methyltransferase (TPMT) during thiopurine treatment in IBD2005Inngår i: 13th United European Gastroenterology week,2005, Stuttgart: Georg Thieme Verlag KG , 2005, s. A173-Konferansepaper (Fagfellevurdert)
  • 134.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Pettersson, Birgitta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: gastromed.
    Albertioni, Freidoun
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Söderhäll, Stefan
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    The role of TPMT polymorphism for thiopurine metabolism and clinical effects.2001Inngår i: European society for the study of purine and pyrimidine metabolism in Man.,2001, 2001Konferansepaper (Fagfellevurdert)
  • 135.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Skoglund, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Karlgren, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Kidhall, Irene
    Danderyds sjukhus.
    Almer, Sven
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Gastroenterologi och hepatologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Explaining TPMT genotype/phenotype discrepancy by haplotyping of TPMT*3A and identification of a novel sequence variant, TPMT*232007Inngår i: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 17, nr 10, s. 891-895Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 136.
    Linner, Love
    et al.
    Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Endersz, Hanna
    Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Öhman, Daniel
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Schalling, Martin
    Neurogenetics Unit, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Svensson, Torgny
    Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex2001Inngår i: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 297, nr 2, s. 540-546Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Central dopaminergic neurons have been suggested to be involved in the pathophysiology of several psychiatric disorders, including depression, and appear to be modulated by noradrenergic activity both at the nerve terminal level and at the somatodendritic level. In recent years reboxetine, a selective noradrenaline reuptake inhibitor that differs from tricyclic anti-depressants by its low affinity for muscarinic, cholinergic and α1-adrenergic receptors, has been introduced clinically. In the present study the effect of reboxetine on the function of the mesolimbocortical dopamine system was investigated by means of single cell recording and microdialysis in rats following administration of reboxetine in doses that appear to yield clinically relevant plasma concentrations. Reboxetine (0.625-20 mg/kg intravenously) induced an increase in burst firing, but not in average firing frequency of dopamine (DA) cells in the ventral tegmental area (VTA). Moreover, reboxetine (0.15-13.5 mg/kg intraperitoneally) caused a significantly enhanced DA output in the medial prefrontal cortex, whereas no effect was observed in the nucleus accumbens. Local administration of reboxetine (333 μM, 60 min), by means of reversed microdialysis into these brain regions, caused a significant increase in DA output in both brain regions. However, local administration of reboxetine into the VTA (333 μM, 60 min) did not affect DA availability in these terminal areas. Our results imply that clinical treatment with reboxetine may result in facilitation of both prefrontal DA output and the excitability of VTA DA neurons, effects that may contribute to its antidepressant action, especially on drive and motivation.

  • 137.
    Lofti, Kourosh
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Månsson, Emma
    Stockholm.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Eriksson, Staffan
    Uppsala.
    Low level of mitochondrical deoxyguanosine kinase is the dominant factor in acquired resistance to 9- -D-arabinofuranosylguanine cytotoxicity2002Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 293, s. 1489-1496Artikkel i tidsskrift (Fagfellevurdert)
  • 138.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacology and resistance mechanisms of nucleoside analogues and topoisomerase II interactive agents: studies on human leukemia cells with a focus on cross-resistance2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The purpose of this thesis was to elucidate mechanisms of action and resistance of clinically relevant nucleoside analogues and topoisomerase interactive agents in human leukemia cell lines and leukernia cells isolated from peripheral blood of leukemia patients. Interactions and cross-resistance patterns of these different cytotoxic drug families were also studied since these drugs are usually administrated in combination in the clinic.

    Two novel nucleoside analogues, clofarabine (2-chloro-2'-arabino-fluoro 2'-deoxyadenosine, CAFdA) and nelarabine (9-ß-D-arabinofuranosylguanine, AraG) were studied regarding cellular activation and mechanisms of resistance. Compared to cladribine (2-chloro- 2'-deoxyadenosine, CdA), CAFdA was more effective due to better stability and more efficient phosphorylation by deoxycytidine kinase (dCK). The mechanism of resistance to CAFdA was decreased activity of dCK. The most important mechanism contributing to resistance to AraG seems to be the deficiency of the activating enzymes dCK and deoxyguanosine kinase (dGK), as measured by enzyme activity assays, Western blotting, and real-time polymerase chain reaction. Unexpected cross-resistance between topoisomerase interactive agents and nucleoside analogues was identified in CEM and MOLT-4 cell lines developed for resistance to etoposide (VP) and AraG, respectively, by means of a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide viability assay. Resistance to VP was due to a decrease in the activity and amount of topoisomerase TI. Major cause of resistance to the nucleoside analogues CdA and AraC was metabolic alterations producing increased activity of 5'-nucleotidase and higher level of endogenous deoxycytidine triphosphate. The AraG-resistant cells showed also classical multidrug resistance (MDR) phenomena. The accumulation and cytotoxicity of daunorubicin (Dnr) were studied in AraG-resistant cells and in response to the resistance modifiers, such as cyclosporin A. The level of mdr1 mRNA and its product, P-glycoprotein, was increased. The topoisomerase interactive agent, idarubicin (Ida), a semisynthetic derivative of Dnr, was more effective in inducing apoptosis as determined by the Annexin V -FITC method, and Ida-resistant cells did not show any classical MDR phenomena.

    Thus, these studies suggest that anticancer agents from the same class of cytostatics could have important differences in effectivity and mechanisms of resistance. These results confirm the possibility of coexpression of multiple mechanisms of resistance in human leukemic cells, which have been selected by exposure to a single-dmg. The generally assumed lack of crossresistance between nucleoside analogues and topoisomerase interactive agents is questionable.

    The rationale for combination therapy should be based on biological properties and cross-resistance analyses of the included drugs.

    Delarbeid
    1. Biochemical Pharmacology and Resistance to 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine, a Novel Analogue of Cladribine in Human Leukemic Cells
    Åpne denne publikasjonen i ny fane eller vindu >>Biochemical Pharmacology and Resistance to 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine, a Novel Analogue of Cladribine in Human Leukemic Cells
    Vise andre…
    1999 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 5, nr 9, s. 2438-2444Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The objective of the present study was to investigate the biochemical pharmacology of 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (CAFdA) — a fluorinated analogue of cladribine [2-chloro-2′-deoxyadenosine, Leustatin (CdA)] with improved acid and metabolic stability — in human leukemic cell lines and in mononuclear cells isolated from patients with chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). We have also made and characterized two cell lines that are not sensitive to the growth inhibitory and cytotoxic effects of CAFdA. Incubation of cells isolated from the blood of CLL and AML patients with various concentrations of CdA or of CAFdA accumulated CdA and CAFdA nucleotides in a dose-dependent manner. A significantly higher rate of phosphorylation to monophosphates was observed for CAFdA than for CdA in cells from CLL patients (n = 14; P = 0.04). The differences in the phosphorylation were even more pronounced for the respective triphosphates in both CLL (n = 14; P = 0.001) and AML (n = 4; P = 0.04) cells. Retention of CAFdA 5′-triphosphate (CAFdATP) was also longer than that for CdA 5′-triphosphate (CdATP) in cells from leukemic patients. The relative efficacy of CAFdA as a substrate for purified recombinant deoxycytidine kinase (dCK), the key enzyme in the activation of nucleoside analogues, was very high and exceeded that of CdA as well as the natural substrate, deoxycytidine, by a factor of 2 and 8, respectively. The Km for CAFdA with dCK was also lower than that for CdA, as measured in crude extracts from the human acute lymphoblastic leukemia cell line CCRF-CEM and the promyelocytic leukemia cell line HL60. Acquired resistance to CAFdA in HL60 and in CCRF-CEM cell lines was directly correlated to the decreased activity of the nucleoside phosphorylating enzyme, dCK. Resistant cells also showed a considerable degree of cross-resistance to analogues that were activated by dCK. These observations demonstrated that dCK phosphorylates CAFdA more efficiently than CdA. Furthermore, CAFdATP is apparently more stable than CdATP and the mechanisms of resistance to CAFdA are similar to those leading to CdA resistance. These results encourage studies on the clinical effect of CAFdA in lymphoproliferative diseases.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-27106 (URN)11753 (Lokal ID)11753 (Arkivnummer)11753 (OAI)
    Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide
    Åpne denne publikasjonen i ny fane eller vindu >>Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide
    Vise andre…
    2001 (engelsk)Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 113, nr 2, s. 339-346Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Cross-resistance between different classes of anti-neoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P < 0·001) and β protein (P < 0·026), formed substantially lower amounts of the topo II–DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P < 0·001) for the high Km and 134% (P < 0·331) for the low Km 5′-NT in resistant cells. The high Km 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′-triphosphate [40% decreased (P < 0·045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P < 0·001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

    Emneord
    etoposide, cladribine, CD95, deoxycytidine kinase, 5′-nucleotidase
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-26977 (URN)10.1046/j.1365-2141.2001.02751.x (DOI)11611 (Lokal ID)11611 (Arkivnummer)11611 (OAI)
    Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. On the mechanism of 9-ß-D-arabinofuroanosylguanine resistance in human leukemic cells
    Åpne denne publikasjonen i ny fane eller vindu >>On the mechanism of 9-ß-D-arabinofuroanosylguanine resistance in human leukemic cells
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The present study was undertaken to elucidate the mechanism of resistance to a relatively new nucleoside, 9-ß-D-arabinofuranosylguanine (Ara-G), which is highly toxic to T-cell malignancies. In order to do this we generated two stable resistant cell lines, MOLT-4/AraG500 (100-fold resistant) and MOLT-4/Ara-G900 (180-fold resistant). The presumed limiting step in the activation of Ara-G is catalyzed by both deoxycytidine kinase (dCK) and the mitochondrial deoxyguanosine kinase (dGK). Cross-resistance was noted to analogues such as cytosine arabinoside (Ara-C), cladribine, and fludarabine, but not to difluorodeoxycytidine. HPLC measurements of intracellular triphosphates of Ara-C and Ara-G showed that resistant cells generated significantly lower levels of metabolites. The activity of dGK (MOLT-4/AraG500, 79%, and MOLT-4/Ara-G900, 83%) and dCK (MOLT-4/Ara-G500, 54%, and MOLT- 4/Ara-G900, 73%), as well as protein and mRNA levels were significantly reduced in the resistant cell lines compared to the wild type. The resistant cells also showed decreased activity as well as decreased mRNA expression of the cytosolic 5'-nucleotidase (5'-NT), compared to the wild type. The reduced levels of enzyme activity in the resistant cells may be a consequence of reduced numbers of chromosomes carrying the genes for dGK, dCK and 5 'NT. Unexpectedly, the resistant cells showed higher activity of the mitochondrial enzyme thymidine kinase 2, probably resulting from down-regulation of dGK. No mutations were found in the dCK gene ofMOLT-4/Ara-G500 but in 2 of 13 clones ofMOLT-4/Ara-G900, we found two point mutations, one T to C and other A to G, which gave rise to changes in the amino acid sequence and affected the catalytic activity. The intracellular dNTP levels were determined and a nearly unchanged dCTP pool was observed in the resistant cells, while the other dNTP pools were significantly reduced compared to those in the wild type. These results show that altered activity of the deoxyribonucleoside kinases confer resistance to Ara-G in these cell lines.

    Emneord
    Leukemia, 9-ß-D-arabinofuroanosylguanine, deoxycytidine kinase, deoxyguanosine kinase, resistance and cytotoxicity
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-80283 (URN)
    Tilgjengelig fra: 2012-08-23 Laget: 2012-08-23 Sist oppdatert: 2012-08-23bibliografisk kontrollert
    4. Altered expression of multidrug resistance (mDR1) gene in cells selected for resistance to 9-ß-D-Arabinofuranosylguanine
    Åpne denne publikasjonen i ny fane eller vindu >>Altered expression of multidrug resistance (mDR1) gene in cells selected for resistance to 9-ß-D-Arabinofuranosylguanine
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    9-ß-D-Arabinofuranosylguanine (AraG) is an important and relatively new guanine nucleoside analogue that is highly toxic to T-cell maliguancies. Two resistant sublines with low activity of nucleoside phosphorylating enzymes, deoxycytidine kinase (dCK) (50-70% reduction) and deoxyguanosine kinase (dGK, 70-80% reduction), were generated from a MOLT-4 cell line with stepwise-increasing concentrations of AraG. As expected, the resistant sublines were highly cross-resistance to analogues that are activated by dCK and dGK such as cytosine arabinoside, cladribine, and fludarabine. Surprisingly, the resistant cells were siguificantly less sensitive to anthracyclines and podophyllotoxin derivatives resulting from decreased cellular drug accumulation restored by cyclosporin A, as determined by calcein uptake and flow cytometry studies. To clarify the mechanisms of this resistance, the gene expression of various multidrug resistance proteins, e.g. the multidrug resistance gene (mdr1), multidrng resistance-associated protein, lung resistance-associated protein and topoisomerase IIα or IIß were investigated. We found that the resistant cells overexpressed the mdr1 gene, as assessed by a real-time PCR, and contained higher levels of P-glycoprotein, as assessed by western blotting. The expression of other multidrug resistance proteins was not affected in the AraG-resistant sublines. These fmdings may be useful in the clinical trials of AraG singly and in combination with anthracyclines and related agents.

    Emneord
    leukaemia, 9-ß-D-arabinofuranosylguanine, multidrug resistance, cytotoxicity
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-80287 (URN)
    Tilgjengelig fra: 2012-08-23 Laget: 2012-08-23 Sist oppdatert: 2012-08-23bibliografisk kontrollert
    5. Comparison of idarubicin and daunorubicin regarding intracellular uptake, induction of apoptosis, and resistance
    Åpne denne publikasjonen i ny fane eller vindu >>Comparison of idarubicin and daunorubicin regarding intracellular uptake, induction of apoptosis, and resistance
    2002 (engelsk)Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 178, nr 2, s. 141-149Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Anthracycline antibiotics are widely used as anticancer agents. Idarubicin (4-demethoxydaunorubicin; Ida), a semisynthetic derivative of daunorubicin (Dnr) is more potent than the parent compound in vitro and in vivo. The equitoxic dose of Ida in patients is about one-fourth of that of Dnr. We compared these drugs regarding cytotoxicity, apoptosis induction, and resistance mechanisms in human leukaemic cell lines. Cytotoxicity was studied by means of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and drug-induced apoptosis by means of the Annexin V–fluorescein isothiocyanate method at similar intracellular concentrations (extracellular concentrations of 0.35 μM for Ida and 1 μM for Dnr). Ida was at least twice as potent as Dnr in MOLT-4, HL60, CEM, and K562 cell lines. It took 8 h for Ida to induce approximately 20% apoptosis, but at least 22 h for Dnr to reach 20% apoptosis at identical intracellular concentration. Ida induces a faster and higher apoptosis rate compared with Dnr. The human chronic myelogenous leukaemia cell line (K562) was selected for resistance to Dnr and Ida with and without verapamil (Ver). Continuous incubation with Dnr, but not with Ida, led to an increased mdr1 gene expression as assessed by real-time PCR. The development of mdr1 gene expression in Dnr-resistant cells could be reversed by the presence of Ver. Ver also reversed the cytotoxicity to Dnr, but not to Ida, in K562/Dnr cells. The results show that Ida is more effective than Dnr in inducing apoptosis and that there are differences in resistance mechanisms between the drugs.

    Emneord
    Idarubicin, Daunorubicin, Apoptosis, Intracellular accumulation, MOLT-4, Cytotoxicity
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-27006 (URN)10.1016/S0304-3835(01)00824-2 (DOI)11642 (Lokal ID)11642 (Arkivnummer)11642 (OAI)
    Tilgjengelig fra: 2009-10-08 Laget: 2009-10-08 Sist oppdatert: 2017-12-13bibliografisk kontrollert
  • 139.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hjortsberg, Linn
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Albertioni, Freidoun
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
    Altered expression of multidrug resistance (mDR1) gene in cells selected for resistance to 9-ß-D-ArabinofuranosylguanineManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    9-ß-D-Arabinofuranosylguanine (AraG) is an important and relatively new guanine nucleoside analogue that is highly toxic to T-cell maliguancies. Two resistant sublines with low activity of nucleoside phosphorylating enzymes, deoxycytidine kinase (dCK) (50-70% reduction) and deoxyguanosine kinase (dGK, 70-80% reduction), were generated from a MOLT-4 cell line with stepwise-increasing concentrations of AraG. As expected, the resistant sublines were highly cross-resistance to analogues that are activated by dCK and dGK such as cytosine arabinoside, cladribine, and fludarabine. Surprisingly, the resistant cells were siguificantly less sensitive to anthracyclines and podophyllotoxin derivatives resulting from decreased cellular drug accumulation restored by cyclosporin A, as determined by calcein uptake and flow cytometry studies. To clarify the mechanisms of this resistance, the gene expression of various multidrug resistance proteins, e.g. the multidrug resistance gene (mdr1), multidrng resistance-associated protein, lung resistance-associated protein and topoisomerase IIα or IIß were investigated. We found that the resistant cells overexpressed the mdr1 gene, as assessed by a real-time PCR, and contained higher levels of P-glycoprotein, as assessed by western blotting. The expression of other multidrug resistance proteins was not affected in the AraG-resistant sublines. These fmdings may be useful in the clinical trials of AraG singly and in combination with anthracyclines and related agents.

  • 140.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Karlsson, Karin
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Fyrberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Juliusson, Gunnar
    Lund University Hospital.
    Jonsson, Viggo
    Oslo University.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Eriksson, Staffan
    Swedish University of Agricultural Sciences, The Biomedical Center, Uppsala.
    Albertioni, Freidoun
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    The pattern of deoxycytidine- and deoxyguanosine kinase activity in relation to messenger RNA expression in blood cells from untreated patients with B-cell chronic lymphocytic leukemia2006Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 71, nr 6, s. 882-890Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 141.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Månsson, Emma
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital Stockholm, Sweden.
    Chandra, Joya
    Oncology Department, Mayo Clinic, Rochester, Minnesota, USA.
    Wang, Yuyinh
    Department of Oncology-Pathology, Karolinska Hospital Stockholm, Sweden.
    Xu, Dawei
    Department of Internal Medicine, Karolinska Hospital Stockholm, Sweden.
    Knaust, Eva
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Spasokoukotskaja, Tanja
    Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University of Medicine, Budapest, Hungary.
    Liliemark, Eva
    Department of Oncology-Pathology, Karolinska Hospital Stockholm, Sweden.
    Eriksson, Staffan
    Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Uppsala, Sweden.
    Albertioni, Freidoun
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital Stockholm, Sweden.
    Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide2001Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 113, nr 2, s. 339-346Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cross-resistance between different classes of anti-neoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P < 0·001) and β protein (P < 0·026), formed substantially lower amounts of the topo II–DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P < 0·001) for the high Km and 134% (P < 0·331) for the low Km 5′-NT in resistant cells. The high Km 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′-triphosphate [40% decreased (P < 0·045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P < 0·001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

  • 142.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Letter: Monitoring oral cyclosporine therapy2005Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 36, s. 367-367Artikkel i tidsskrift (Annet vitenskapelig)
  • 143.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Spasokoukotskaja, Tatjana
    Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University of Medicine, Budapest, Hungary.
    Pettersson, Birgitta
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Liliemark, Jan
    Department of Clinical Oncology, Karolinska Hospital, Stockholm, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Eriksson, Staffan
    Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Center, Uppsala, Sweden.
    Biochemical Pharmacology and Resistance to 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine, a Novel Analogue of Cladribine in Human Leukemic Cells1999Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 5, nr 9, s. 2438-2444Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The objective of the present study was to investigate the biochemical pharmacology of 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (CAFdA) — a fluorinated analogue of cladribine [2-chloro-2′-deoxyadenosine, Leustatin (CdA)] with improved acid and metabolic stability — in human leukemic cell lines and in mononuclear cells isolated from patients with chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). We have also made and characterized two cell lines that are not sensitive to the growth inhibitory and cytotoxic effects of CAFdA. Incubation of cells isolated from the blood of CLL and AML patients with various concentrations of CdA or of CAFdA accumulated CdA and CAFdA nucleotides in a dose-dependent manner. A significantly higher rate of phosphorylation to monophosphates was observed for CAFdA than for CdA in cells from CLL patients (n = 14; P = 0.04). The differences in the phosphorylation were even more pronounced for the respective triphosphates in both CLL (n = 14; P = 0.001) and AML (n = 4; P = 0.04) cells. Retention of CAFdA 5′-triphosphate (CAFdATP) was also longer than that for CdA 5′-triphosphate (CdATP) in cells from leukemic patients. The relative efficacy of CAFdA as a substrate for purified recombinant deoxycytidine kinase (dCK), the key enzyme in the activation of nucleoside analogues, was very high and exceeded that of CdA as well as the natural substrate, deoxycytidine, by a factor of 2 and 8, respectively. The Km for CAFdA with dCK was also lower than that for CdA, as measured in crude extracts from the human acute lymphoblastic leukemia cell line CCRF-CEM and the promyelocytic leukemia cell line HL60. Acquired resistance to CAFdA in HL60 and in CCRF-CEM cell lines was directly correlated to the decreased activity of the nucleoside phosphorylating enzyme, dCK. Resistant cells also showed a considerable degree of cross-resistance to analogues that were activated by dCK. These observations demonstrated that dCK phosphorylates CAFdA more efficiently than CdA. Furthermore, CAFdATP is apparently more stable than CdATP and the mechanisms of resistance to CAFdA are similar to those leading to CdA resistance. These results encourage studies on the clinical effect of CAFdA in lymphoproliferative diseases.

  • 144.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Zackrisson, Anna Lena
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Comparison of idarubicin and daunorubicin regarding intracellular uptake, induction of apoptosis, and resistance2002Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 178, nr 2, s. 141-149Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anthracycline antibiotics are widely used as anticancer agents. Idarubicin (4-demethoxydaunorubicin; Ida), a semisynthetic derivative of daunorubicin (Dnr) is more potent than the parent compound in vitro and in vivo. The equitoxic dose of Ida in patients is about one-fourth of that of Dnr. We compared these drugs regarding cytotoxicity, apoptosis induction, and resistance mechanisms in human leukaemic cell lines. Cytotoxicity was studied by means of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and drug-induced apoptosis by means of the Annexin V–fluorescein isothiocyanate method at similar intracellular concentrations (extracellular concentrations of 0.35 μM for Ida and 1 μM for Dnr). Ida was at least twice as potent as Dnr in MOLT-4, HL60, CEM, and K562 cell lines. It took 8 h for Ida to induce approximately 20% apoptosis, but at least 22 h for Dnr to reach 20% apoptosis at identical intracellular concentration. Ida induces a faster and higher apoptosis rate compared with Dnr. The human chronic myelogenous leukaemia cell line (K562) was selected for resistance to Dnr and Ida with and without verapamil (Ver). Continuous incubation with Dnr, but not with Ida, led to an increased mdr1 gene expression as assessed by real-time PCR. The development of mdr1 gene expression in Dnr-resistant cells could be reversed by the presence of Ver. Ver also reversed the cytotoxicity to Dnr, but not to Ida, in K562/Dnr cells. The results show that Ida is more effective than Dnr in inducing apoptosis and that there are differences in resistance mechanisms between the drugs.

  • 145.
    Lundgren, Anna
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Perifer intravenös infart i klinisk rutin: Utveckling av omvårdnadsrutiner för att minska risken för komplikationer1999Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The general aim was to study the way nurses plan, take care of and document a peripheral intravenous cannula (PIV) line related to complications, and to give a basis for quality assurance in surgery and internal medicine wards. The methods used were examination of patients' records, interview of patients and nurses, and observation of the cannula and its insertion area. An analysis of risk factors was also performed. The sample included 300 patients with 501 inserted peripheral cannulae, as well as nurses. The patients were followed from the day of insertion until the day the insertion area and the vein were free from symptoms.

    A significantly higher frequency of thrombophlebitis and severe long-term problems were found in patients treated by nurses without special training than among those with (p<0.001 ). The complication risks increased after long time in situ and were especially high when hypertonic drugs, solutions, or anticoagulants were given. Complications could exist up to six months. The care and handling decreased with time in situ and the cannulae were not always removed or documented. The intention was that a cannula should be inserted less than three days, but nurses were aware that the PIV remained in situ longer. Bad routines and neglected areas were said to be the reasons. Discomfort reported by the patients could be directly referred to technical mistakes or/and bad routines. When asked what governed the work with PI Vs the most decisive factors in the case of PIV were said to be knowledge 86%, experience 83%, and routine 32%. Educated nurses performed more satisfactory care and handling. No significant difference could be found between the nurses· years of experience and care and handling of PIV.

    A gap was shown between nursing research and nurses practice. The findings were not in accordance with, or based on, well-tried experience or scientific performance and diverges from "good knowledge" and '"good care". Reflection over current routines should be of value. One example of a good routine to reduce infections is daily change of the cannula. The conclusion is that the nurse has to be technically and theoretically acquainted with the subject.

    Nursing care demands special competence and relevant knowledge to enable nurses to assess and give satisfactory care in relation to patients" needs. Good nursing care should include prevention of pain and discomfort, be planned and implemented in a secure way, and also follow research and development in this area so that new knowledge and experience can be brought into the profession.

  • 146.
    Lundmark, Jöns
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Nordin, Conny
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    Reis, Margareta
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wålinder, Jan
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients2000Inngår i: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 101, nr 5, s. 354-359Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: This study was initiated in order to describe and evaluate the effects of a therapeutic drug monitoring (TDM) routine of selective serotonin reuptake inhibitors (SSRIs) on treatment strategies and drug costs in depressed elderly patients.

    Method: Blood samples were drawn from elderly depressed patients and analysed for steady-state trough serum concentrations of citalopram (n=48), paroxetine (n=48) or sertraline (n=39). A global efficacy evaluation was made at baseline and after 6–9 months. Antidepressant drug costs before and after TDM were estimated.

    Results: Eight samples were excluded due to technical problems or non-compliance. In 65 of the 127 (51.2%) remaining cases, the treatment strategy was changed according to the TDM outcome, in most a reduction of the prescribed dose. Bioanalytical TDM costs included the antidepressant drug costs after TDM were reduced by 10.2%.

    Conclusion: The results support the utility of TDM in the search for the individual minimum effective SSRI dose in the elderly.

  • 147.
    Lundmark, Jöns
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    Reis, Margareta
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Serum concentrations of fluoxetine in the clinical treatment setting2001Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 23, nr 2, s. 139-147Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This article discusses fluoxetine serum concentrations as displayed in a clinical setting. A racemic serum fluoxetine and norfluoxetine high-performance liquid chromatography method, including ultraviolet light detection, was used for routine therapeutic drug monitoring (TDM) purposes. In all, 508 samples were analyzed. For the scientific investigation, predefined inclusion and exclusion criteria were applied and 150 samples representative of trough values in steady-state conditions with essential clinical information provided on the assay request forms were evaluated. Fluoxetine plus norfluoxetine concentration-to-dose (C/D) ratio showed Gaussian distribution. Interindividual coefficients of variation of fluoxetine and norfluoxetine serum concentrations after different doses were found to be 40-63%. Intraindividual fluoxetine TDM variability was low. The Spearman rank correlation coefficient for fluoxetine and norfluoxetine C/D ratios in first and second samples was 0.68. Minor increases in norfluoxetine C/D and fluoxetine plus norfluoxetine C/D ratios were found in elderly patients compared with younger adult patients. A higher body-mass index was associated with minor decreases in fluoxetine and fluoxetine plus norfluoxetine C/D ratios. New fluoxetine pharmacokinetic data are added to the results from earlier phases of drug development. Moreover, the results of this study support the usefulness of a fluoxetine TDM procedure for individual dose optimization, detection of drug interactions, and assessments of patient compliance.

  • 148.
    Lundmark, Jöns
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Hälsouniversitetet.
    Reis, Margareta
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Finn
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Psykiatri. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Therapeutic drug monitoring of sertraline: Variability factors as displayed in a clinical setting2000Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 22, nr 4, s. 446-454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This report describes sertraline pharmacokinetics derived from routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method with ultraviolet detection was established for routine sertraline TDM, and 924 analyses were performed from April 1995 to May 1997. Extensive predefined inclusion/exclusion criteria were applied to increase the validity of scientifically evaluated data. Subsequently, 605 samples (65.5%) were excluded. The remaining 319 samples from 319 patients, representative of steady state through specimens and accompanied by essential clinical information provided on request forms, were scrutinized. A pronounced interindividual variability was observed. Smokers had significantly lower concentration-to-dose (C/D) mean ratios of serum sertraline (s-sert) and its main metabolite desmethylsertraline (s-dsert) than nonsmokers. Higher s-sert and s-dsert C/D mean ratios were found in elderly patients than in adults aged less than 65 years. In a subset of 20 patients in whom repeated TDM analyses were performed, observed intraindividual sertraline TDM outcome variability was low. The results highlight sertraline TDM as a tool for individual dose optimization and evaluation of patient drug compliance as well as drug-drug interactions.

  • 149.
    Lundström, Staffan
    et al.
    Department of Palliative Medicine, Stockholms Sjukhem, Stockholm, Sweden.
    Fürst, Carl Johan
    Department of Palliative Medicine, Stockholms Sjukhem, Stockholm, Sweden.
    Börjeson, Sussanne
    Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
    Steineck, Gunnar
    Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
    Åvall-Lundqvist, Elisabeth
    Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
    Hursti, Timo J.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Aspects of delayed chemotherapy-induced nausea: Dexamethasone and adrenal response patterns in patients and healthy volunteers2000Inngår i: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 8, nr 5, s. 431-434Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Delayed chemotherapy-induced nausea is still a clinical problem, and the underlying mechanisms are poorly understood. Previous studies have suggested that corticosteroids are involved, although the mechanisms by which corticosteroids exert their anti-emetic effect are largely unknown. We have previously found impaired control of delayed nausea after injection of dexamethasone. The possibility of differences in the recovery of the hypothalamic-pituitary-adrenal (HPA) axis after injection of dexamethasone was investigated in patients (n = 5) with gynaecological cancer being treated with platinum-based chemotherapy and in healthy female volunteers (n = 10). Urinary free cortisol was used to assess the levels of endogenous cortisol. Results showed that in both patients and controls injections of dexamethasone led to a significant decline in endogenous cortisol levels in 24 h and a subsequent significant recovery in the next 24 h. We conclude that the recovery of the HPA axis is rapid after a single dose of dexamethasone in patients and controls. The absence of an abnormal response pattern in patients makes it probable that the suppression and recovery of the HPA axis after injection of dexamethasone does not influence the corticosteroid-induced rebound effect on delayed platinum-induced nausea.

  • 150. Löfgren, C
    et al.
    Hjortsberg, L
    Blennow, M
    Lotfi, Kourosh
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Paul, C
    Eriksson, S
    Albertioni, F
    Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells2004Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 320, nr 3, s. 825-832Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (Nas) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside) -induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5′- nucleotidases (50-100%). The ratio 5′-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5′-nucleotidase/ deoxycytidine kinase ratio might be an important factor in predicting resistance to Nas. Implications of this finding for combining anthracyclines or vinca alkaloids with Nas toward leukemic cells are discussed.

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