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Bengtsson, Finn
Publications (10 of 86) Show all publications
Karlsson, L., Green, H., Zackrisson, A. L., Bengtsson, F., Jakobsen Falk, I., Carlsson, B., . . . Kugelberg, F. (2013). ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram. International journal of legal medicine (Print), 127(3), 579-586
Open this publication in new window or tab >>ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram
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2013 (English)In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, no 3, p. 579-586Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
Keywords
ABCB1, Citalopram, Forensic material, Genotype, Postmortem, Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-93390 (URN)10.1007/s00414-013-0849-0 (DOI)000318247100006 ()
Note

Funding Agencies|National Board of Forensic Medicine in Sweden||Swedish Research Council||

Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-12-06Bibliographically approved
Karlsson, L., Carlsson, B., Hiemke, C., Ahlner, J., Bengtsson, F., Schmitt, U. & Kugelberg, F. C. (2013). Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment. European Neuropsychopharmacology, 23(11), 1636-1644
Open this publication in new window or tab >>Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment
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2013 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 23, no 11, p. 1636-1644Article in journal (Refereed) Published
Abstract [en]

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

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

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

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Citalopram, enantiomers, escitalopram, mice knockout, P-glycoprotein
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76122 (URN)10.1016/j.euroneuro.2013.01.003 (DOI)000328014700033 ()
Available from: 2012-03-28 Created: 2012-03-28 Last updated: 2017-12-07Bibliographically approved
Kingbäck, M., Karlsson, L., Zackrisson, A.-L., Josefsson, M., Carlsson, B., Bengtsson, F., . . . Kugelberg, F. C. (2012). Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood. Forensic Science International, 214(1-3), 124-134
Open this publication in new window or tab >>Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood
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2012 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, no 1-3, p. 124-134Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
CYP2D6; Enantiomers; Forensic toxicology; Postmortem toxicology; Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72238 (URN)10.1016/j.forsciint.2011.07.034 (DOI)000298634900032 ()21840145 (PubMedID)
Note

Funding agencies|Forensic Science Center of Linkoping University||National Board of Forensic Medicine in Sweden||Swedish Research Council| 2009-4740 |

Available from: 2011-11-23 Created: 2011-11-23 Last updated: 2017-12-08Bibliographically approved
D Cherma, M., Ahlner, J., Bengtsson, F. & Gustafsson, P. (2011). Antidepressant Drugs in Children and Adolescents Analytical and Demographic Data in a Naturalistic, Clinical Study. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 31(1), 98-102
Open this publication in new window or tab >>Antidepressant Drugs in Children and Adolescents Analytical and Demographic Data in a Naturalistic, Clinical Study
2011 (English)In: JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, ISSN 0271-0749, Vol. 31, no 1, p. 98-102Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Williams andamp; Wilkins, 2011
Keywords
antidepressants, therapeutic drug monitoring, dosage, serum concentration, pediatrics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64763 (URN)10.1097/JCP.0b013e318205e66d (DOI)000285771000017 ()
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2011-02-04
Kingbäck, M., Carlsson, B., Ahlner, J., Bengtsson, F. & Kugelberg, F. (2011). Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats. Chirality, 23(2), 172-177
Open this publication in new window or tab >>Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats
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2011 (English)In: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 23, no 2, p. 172-177Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
John Wiley and Sons, Ltd, 2011
Keywords
citalopram, CYP2D6, Dark Agouti, enantiomer, pharmacokinetics, Sprague-Dawley
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65566 (URN)10.1002/chir.20901 (DOI)000285976800013 ()
Available from: 2011-02-11 Created: 2011-02-11 Last updated: 2017-12-11
Karlsson, L., Hiemke, C., Carlsson, B., Josefsson, M., Ahlner, J., Bengtsson, F., . . . Kugelberg, F. C. (2011). Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model. Psychopharmacology, 215(2), 367-377
Open this publication in new window or tab >>Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model
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2011 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 2, p. 367-377Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Springer, 2011
Keywords
abcb1ab . Blood–brain barrier . Knockout mice . P-glycoprotein . Pharmacodynamic . Pharmacokinetic .Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68038 (URN)10.1007/s00213-010-2148-5 (DOI)000289985700016 ()21191569 (PubMedID)
Note
The original publication is available at www.springerlink.com: Louise Karlsson, Christoph Hiemke, Björn Carlsson, Martin Josefsson, Johan Ahlner, Finn Bengtsson, Ulrich Schmitt and Fredrik C Kugelberg, Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model., 2011, Psychopharmacology, (215), 2, 367-377. http://dx.doi.org/10.1007/s00213-010-2148-5 Copyright: Springer Science Business Media http://www.springerlink.com/Available from: 2011-05-06 Created: 2011-05-06 Last updated: 2017-12-11
Karlsson, L., Schmitt, U., Josefsson, M., Carlsson, B., Ahlner, J., Bengtsson, F., . . . Hiemke, C. (2010). Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein. European Neuropsychopharmacology, 20(9), 632-640
Open this publication in new window or tab >>Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein
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2010 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, no 9, p. 632-640Article in journal (Refereed) Published
Abstract [en]

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

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58805 (URN)10.1016/j.euroneuro.2010.04.004 (DOI)20466523 (PubMedID)
Note
Original Publication: Louise Karlsson, Ulrich Schmitt, Martin Josefsson, Björn Carlsson, Johan Ahlner, Finn Bengtsson, Fredrik C Kugelberg and Christoph Hiemke, Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein, 2010, European Neuropsychopharmacology, (20), 9, 632-640. http://dx.doi.org/10.1016/j.euroneuro.2010.04.004 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12
Olsson, A., Bengtsson, F., Rosengren, A. & Tornvall, P. (2010). Kolesterolhypotesen står sig. Läkartidningen, 107(12), 831-836
Open this publication in new window or tab >>Kolesterolhypotesen står sig
2010 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 12, p. 831-836Article in journal (Refereed) Published
Abstract [sv]

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

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

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

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

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

Place, publisher, year, edition, pages
Lakartidningen, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-57020 (URN)
Available from: 2010-06-14 Created: 2010-06-09 Last updated: 2017-12-12
Olsson, A., Bengtsson, F., Rosengren, A. & Tornvall, P. (2010). Patienten framför allt!. Läkartidningen, 107(24), 1639
Open this publication in new window or tab >>Patienten framför allt!
2010 (English)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 24, p. 1639-Article in journal (Refereed) Published
Abstract [en]

[No abstract available]

Place, publisher, year, edition, pages
Lakartidningen, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59097 (URN)
Available from: 2010-09-21 Created: 2010-09-09 Last updated: 2017-12-12
Kingbäck, M., Josefsson, M., Karlsson, L., Ahlner, J., Bengtsson, F., Kugelberg, F. C. & Carlsson, B. (2010). Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction. Journal of Pharmaceutical and Biomedical Analysis, 53(3), 583-590
Open this publication in new window or tab >>Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction
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2010 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, no 3, p. 583-590Article in journal (Refereed) Published
Abstract [en]

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

Keywords
Venlafaxine; Enantiomers; LC–ESI-MS/MS; Metabolites; Human
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58798 (URN)10.1016/j.jpba.2010.03.043 (DOI)20435422 (PubMedID)
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12
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