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  • 301.
    Ueckert, Stefan
    et al.
    Hannover Medical School.
    Oelke, Matthias
    University of Amsterdam.
    Albrecht, Knut
    Hannover Medical School.
    Stief, Christian
    Ludwig-Maximilians-University.
    Jonas, Udo
    Hannover Medical School.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Immunohistochemical description of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human labia minora2007Inngår i: JOURNAL OF SEXUAL MEDICINE, ISSN 1743-6095, Vol. 4, nr 3, s. 602-608Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Up until now, only minimal research has been carried out on those female genital organs known to contribute to the normal cycle of sexual arousal and orgasm. Some findings indicated that there might be a significance of cyclic nucleotide-mediated pathways in the control of the normal function of female genital tissues.

    AIM: To elucidate, by means of immunohistochemistry, the distribution of the phosphodiesterase (PDE) isoenzymes 1, 3, 4, 5, 10, and 11 in the human labia minora.

    MAIN OUTCOME MEASURES: The amount of immunohistochemical staining specific for cyclic adenosine monophosphate (cAMP)- and/or cyclic guanosine monophosphate (cGMP)-degrading PDE isoenzymes was detected.

    METHODS: Human labial tissue was obtained from four female cadavers (age at death: 18-42 years). Vibratome sections prepared from formaldehyde-fixated tissue specimens were incubated with primary antibodies directed against the respective PDE isoenzymes. Sections were then incubated with fluorochrome (fluorescein isothiocyanate, Texas Red)-labeled secondary antibodies. Visualization was commenced by means of a laser fluorescence microscope.

    RESULTS: Immunostaining indicating the expression of PDE4 and PDE5 was abundantly observed in the smooth musculature of vessels interspersing the tissue. Immunoreactions specific for PDE3 were recognized in epithelial and subepithelial layers, sebaceous glands, and interstitial or neuroendocrine-like single cells located in the epithelium. Signals related to PDE10 and PDE11 were limited to the epithelium or glandular-like structures, respectively.CONCLUSIONS: Our results, for the first time, demonstrate the presence of cAMP- and cGMP-PDE isoenzymes in the human labia minora and give a hint to a significance of PDE4 and PDE5 in the control of labial vascular tissue function.

  • 302.
    Ueckert, Stefan
    et al.
    Hannover Medical Sch, Germany .
    Waldkirch, Eginhard S.
    Hannover Medical Sch, Germany .
    Merseburger, Axel S.
    Hannover Medical Sch, Germany .
    Kuczyk, Markus A.
    Hannover Medical Sch, Germany .
    Oelke, Matthias
    Hannover Medical Sch, Germany .
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi. Hospital San Raffaele, Italy .
    Phosphodiesterase type 5 (PDE5) is co-localized with key proteins of the nitric oxide/cyclic GMP signaling in the human prostate2013Inngår i: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 31, nr 3, s. 609-614Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Experimental studies have provided the basis for the evaluation of inhibitors of the phosphodiesterase type 5 (PDE5) in the treatment of lower urinary tract symptomatology (LUTS) secondary to benign prostatic hyperplasia (BPH). It has been speculated that the clinical efficacy of PDE5 inhibitors in patients with LUTS/BPH can be explained by their effects on the urinary bladder rather than on the prostate. Hence, the significance of the nitric oxide (NO)/cyclic GMP signaling in the control of the human prostate requires further clarification. less thanbrgreater than less thanbrgreater thanThe present study aimed to investigate by means of immunohistochemistry in the human prostate the expression and distribution of key mediators of the NO pathway, namely cyclic GMP, the neuronal nitric oxide synthase (nNOS), and cyclic GMP-binding protein kinases type I (cGKI alpha, cGKI), in relation to PDE5, protein kinase A (cAK), and the vasoactive intestinal polypeptide (VIP). less thanbrgreater than less thanbrgreater thanIn the smooth muscle portion of the transition zone, immunosignals specific for the PDE5 were found co-localized with cyclic GMP, cGKI alpha, and cGKI, as well as with the cyclic cAMP-binding protein kinase A. Smooth muscle bundles were seen innervated by slender varicose nerves characterized by the expression of nNOS. Some of these nerves also presented staining related to the neuropeptide VIP. less thanbrgreater than less thanbrgreater thanThe findings give hints that the cyclic GMP- and cyclic AMP-dependent signal transduction may synergistically work together in regulating muscle tension in the transition zone. This might be of significance for the identification of new pharmacological avenues to treat patients with symptomatic BPH.

  • 303.
    Ulff, E.
    et al.
    Ryhov Hospital, Jönköping, Sweden.
    Maroti, M.
    Ryhov Hospital, Jönköping, Sweden.
    Kettis-Lindblad, A.
    Uppsala University, Sweden.
    Kjellgren, Karin
    Sahlgrenska Academy, Göteborg University, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ring, L.
    Uppsala University, Sweden.
    Serup, Jörgen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Hudkliniken i Östergötland.
    Single application of a fluorescent test cream by healthy volunteers: assessment of treated and neglected body sites2007Inngår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 156, nr 5, s. 974-978Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Management of dermatological self-treatment is demanding. Imperfect application of creams and ointments and poor adherence to topical treatment are common, resulting in unsatisfactory treatment outcome. Objectives: To assess the technique and precision of test subjects' self-application of a test cream. Treated and neglected skin sites were measured after intended widespread single application of a fluorescent test cream. Methods: Twenty healthy volunteers (10 women, 10 men) were included. They were asked to treat their whole skin surface with the fluorescent test cream, except the head and neck and skin covered by underwear. Treated and untreated sites were subsequently measured under Wood's ultraviolet radiation. Results: Thirty-one per cent of the skin surface that was a target for application did not show any fluorescence and thus was assumed to have been untreated. Typical neglected sites included the central back, the upper breast, the axilla with surrounding skin, the legs and the feet, particularly the sole. The posterior aspect of both trunk and extremities, not easily inspected, was more often neglected. In the treated sites the fluorescence was typically uneven. Conclusions: Qualified and motivated persons with no obvious physical limitations practised imperfect self-application of a test cream mimicking a therapeutic cream product. As much as 31% of the skin surface was neglected. Sites especially prone to nonapplication were identified. This might imply that dermatological patients on long-term self-treatment may practise local application very poorly, a problem of major therapeutic and economic importance. A fluorescent test cream can be used for research, and as an educational tool in the training of dermatological patients on how to apply local treatment.

  • 304.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Development of new methodology for therapeutic drug monitoring of thiopurine treatment2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The three thiopurine drugs azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat several diseases, including inflammatory bowel disease (IBD). They are pro-drugs and are believed to act through the formation of thioguanine nucleotides (TGNs). Other important metabolites are the methylthioinosine nucleotides (meTINs). These metabolites are active in the white blood cells (WBCs).Most patients respond well to the thiopurine drugs but up to a third have to modify or discontinue their treatment due to adverse events or a lack of therapeutic effects. This could be caused by inter-patient variability in the metabolism of the drugs. Therapeutic drug monitoring (TDM) of thiopurine nucleotides in red blood cells (RBCs) is used to guide treatment. Current routine assays measure the nucleotides after hydrolysation to nucleic bases and are therefore unable to distinguish between mono-, di-, and triphosphates. Recently it was shown that these assays failed to predict the clinical outcome in about 40% of the patients. It has been suggested that measuring thioguanosine triphosphate (TGTP) (believed to be the most active of the TGNs) separately might increase the clinical value.An assay suitable for measuring thioguanosine mono- (TGMP) and diphosphate (TGDP) and TGTP, as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) separately in RBCs in clinical samples has been developed. In clinical studies of 82 IBD patients, we found no correlation between the thiopurine dose and metabolite levels in RBCs, thus illustrating the importance of metabolite measurements in the TDM of thiopurines.The TGN peak measured by the routine assay during TDM of patients treated with thiopurines consisted of TGTP and TGDP with a small contribution from TGMP. The meTIN also consisted of mono-, di- and triphosphates, but in different proportions, indicating differences in the formation. The inter-individual differences in nucleotide distribution were very small and a strong correlation between the different nucleotides and their respective sums was observed. As a consequence, measuring the mono-, di- and triphosphates separately was not beneficial in predicting remission, which was confirmed by the results from the clinical study.Further research into the metabolism and mode of action of thiopurine drugs is needed to understand the inter-patient variability in response and metabolite formation. An assay suitable for such studies, measuring TGNs and meTINs in cultured cells, has also been developed.

    Delarbeid
    1. Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?
    Åpne denne publikasjonen i ny fane eller vindu >>Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?
    2009 (engelsk)Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, nr 3, s. 345-50Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-18985 (URN)10.1097/FTD.0b013e3181a1ea58 (DOI)19363461 (PubMedID)
    Tilgjengelig fra: 2009-06-07 Laget: 2009-06-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical use
    Åpne denne publikasjonen i ny fane eller vindu >>Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical use
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBC:s were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials in thiopurine therapy and proven valid by analysis of authentic patient samples.

    The method measured thioguanosine mono- (TGMP), di- (TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine).

    LOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8x10^8 RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 5 °C for 8 hours after sampling.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-84843 (URN)
    Tilgjengelig fra: 2012-10-24 Laget: 2012-10-24 Sist oppdatert: 2012-10-24bibliografisk kontrollert
    3. Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separately
    Åpne denne publikasjonen i ny fane eller vindu >>Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separately
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The thiopurines are widely used in the treatment of inflammatory bowel diseases but are limited by poor dose-effect relationship and large interindividual variability in clinical effects. Many attempts have been made to predict response by therapeutic drug monitoring of phosphorylated and methylated metabolites grouped together as thioguanine nucleotides and methylthioinosine monophosphate. We have developed a method to determine the individual metabolites, thioguanosine mono-, di-, and triphosphates, as well as methylthioinosine mono-, di-, and triphosphates, separately in red blood cells.

    This aim of this study was to assess the ability of our novel method to predict clinical outcome compared to the routine method in 82 patients with inflammatory bowel diseases.

    TPMT wild-type patients with TGN levels below the cut-off level were more likely to have an active disease when TGN was measured by both the routine method (p < 0.05), the novel method (p<0.05), and when TGTP was measured separately (p < 0.01). TGN levels and TGTP were, however, not correlated to disease activity in TPMT defective patients. Patients with meTIN levels above 1500 pmol were more likely to have an active disease (39%, 18/46 vs. 17%, 5/30; p = 0.02). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R2 > 0.88) and the TGTP ratio (TGTP/(TGDP+TGTP)) was not different in patients with active disease or in clinical remission.

    Thiopurine metabolites should still be measured by the routine method, since the novel and technically more challenging method, including determination of TGTP and TGTP ratio, does not offer a clinical advantage compared to the routine method.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-84844 (URN)
    Tilgjengelig fra: 2012-10-24 Laget: 2012-10-24 Sist oppdatert: 2012-10-24bibliografisk kontrollert
    4. The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease
    Åpne denne publikasjonen i ny fane eller vindu >>The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease
    Vise andre…
    2011 (engelsk)Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 33, nr 2, s. 200-208Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated.

    METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities.

    RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001).

    CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.

    sted, utgiver, år, opplag, sider
    Lippincott Williams & Wilkins, 2011
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-66431 (URN)10.1097/FTD.0b013e31820b42bb (DOI)000288498100010 ()21311411 (PubMedID)
    Tilgjengelig fra: 2011-03-15 Laget: 2011-03-15 Sist oppdatert: 2017-12-11bibliografisk kontrollert
  • 305.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use2013Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 75, s. 145-152Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBCs were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials. Ten patient samples were analysed to demonstrate clinical application and to establish pilot ranges for all analytes. less thanbrgreater than less thanbrgreater thanThe method measured thioguanosine mono-(TGMP), di-(TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine). less thanbrgreater than less thanbrgreater thanLOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8 x 10(8) RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 4 degrees C for 8 h after sampling.

  • 306.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical useManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBC:s were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials in thiopurine therapy and proven valid by analysis of authentic patient samples.

    The method measured thioguanosine mono- (TGMP), di- (TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine).

    LOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8x10^8 RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 5 °C for 8 hours after sampling.

  • 307.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, David
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hindorf, Ulf
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separatelyManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The thiopurines are widely used in the treatment of inflammatory bowel diseases but are limited by poor dose-effect relationship and large interindividual variability in clinical effects. Many attempts have been made to predict response by therapeutic drug monitoring of phosphorylated and methylated metabolites grouped together as thioguanine nucleotides and methylthioinosine monophosphate. We have developed a method to determine the individual metabolites, thioguanosine mono-, di-, and triphosphates, as well as methylthioinosine mono-, di-, and triphosphates, separately in red blood cells.

    This aim of this study was to assess the ability of our novel method to predict clinical outcome compared to the routine method in 82 patients with inflammatory bowel diseases.

    TPMT wild-type patients with TGN levels below the cut-off level were more likely to have an active disease when TGN was measured by both the routine method (p < 0.05), the novel method (p<0.05), and when TGTP was measured separately (p < 0.01). TGN levels and TGTP were, however, not correlated to disease activity in TPMT defective patients. Patients with meTIN levels above 1500 pmol were more likely to have an active disease (39%, 18/46 vs. 17%, 5/30; p = 0.02). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R2 > 0.88) and the TGTP ratio (TGTP/(TGDP+TGTP)) was not different in patients with active disease or in clinical remission.

    Thiopurine metabolites should still be measured by the routine method, since the novel and technically more challenging method, including determination of TGTP and TGTP ratio, does not offer a clinical advantage compared to the routine method.

  • 308.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven H C
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?2009Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, nr 3, s. 345-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.

  • 309.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    How Should Thiopurine Treatment be Monitored? Methodological Aspects2010Inngår i: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 29, nr 04-Jun, s. 278-283Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Monitoring of thiopurine metabolites is important due to a complex metabolism with large interindividual variation, but the suitability of currently used methods has been questioned. The drawbacks include poor reproducibility, the inability to differentiate between the different analytes, as well as the use of a nontarget matrix. Further research should be directed toward measuring thiopurine metabolites in mononuclear cells, measuring the different nucleotides specifically, as well as measuring the incorporation of thioguanine into DNA. The studies should not be limited to thioguanosine nucleotides but include methylthioinosine nucleotides as well.

  • 310.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Coulthard, S
    Newcastle University, Northern Institute for Cancer Research.
    Josefsson, Martin
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linkoping.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rapid Method to Measure Thioguanine Incorporation Into DNA2011Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, nr Supplement 1, s. S650-S650Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: The thiopurine drugs, 6-mercaptopurine, azathioprine, and thioguanine, are used in the treatment of acute lymphoblastic leukaemia (ALL). During treatment the thioguanine nucleotides formed are incorporated into the DNA, causing apoptosis due to the cells inability to repair the resulting damage. This mechanism is believed to be important for the effects of thiopurine drugs. We have developed a novel method for the determination of thioguanine incorporation into DNA which is both faster and cheaper than earlier methods.

    Monitoring the effects of thiopurine treatment by measuring thiopurine metabolites in erythrocytes has proven to be elusive due to the lack of good correlation between measured concentrations and thiopurine effects. If the incorporation is the main mechanism of thiopurine action, a reliable method capable of measuring the incorporation in an ordinary blood sample, such as the method we have developed, should provide a significantly better correlation with treatment effect.

    Material and Methods: Briefly, DNA extracted from buffy coat is degraded using nuclease P1 and alkaline phosphatase to produce free nucleosides which are purified by filtration. Thioguanosine and thymidine are separated and detected using an LC-MS/MS system and the ratio between the bases provides a measurement of the extent of thioguanine incorporation in DNA. The method has been successfully applied to cell culture samples as well as samples from patients treated orally with thiopurines.

    Results: In 8 inflammatory bowel disease patients treated with azathioprine the measured incorporation ranged from 2.2 to 8.4 thioguanine bases for every 10 000 thymidine bases (median 5.2). This is in agreement with earlier reports on incorporation in childhood leukemia patients.

    Conclusions: With the presented method it is possible to determine the incorporation of thioguanine into DNA during thiopurine treatment in a cost effective manner, but further research is needed to determine if there is a place for this type of methods in the monitoring of thiopurine treatment.

    An ongoing study aims to compare the incorporation to treatment effects as well as conventional measurements of erythrocyte metabolite levels. By this study we hope to determine if incorporation is a more reliable measurement to predict treatment effect and if the erythrocyte metabolite levels correlate with the incorporation.

  • 311.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, SE-581 33 Linköping, Sweden.
    Retention of opioids and their glucuronides on a combined zwitterion and hydrophilic interaction stationary phase2008Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1187, nr 01-Feb, s. 46-52Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A stationary phase combining zwitterionic ion chromatography and hydrophilic interaction chromatography (ZIC-HILIC) from SeQuant was evaluated for the chromatography of some opiates and their polar metabolites. The effects of mobile phase constitution on retention and resolution were extensively evaluated. Different aspects of mobile phase constitution such as ion strength and type of buffer, type and amount of organic modifier and pH were examined. The selectivity and retention of the opiates compared to their glucuronides could be substantially altered with small changes of the mobile phase, especially when the type of buffer, i.e., formate, or acetate and organic modifier, i.e., acetonitrile or methanol were changed. The retention on the ZIC-HILIC was dominated by hydrophilic interaction chromatography (HILIC) but considerable effects on the selectivity was observed, possibly caused by an ion exchange mechanism due to interactions with the charges on the stationary phase.

  • 312.
    Villa, L
    et al.
    Ist Science San Raffaele, Italy .
    Buono, R
    Ist Science San Raffaele, Italy .
    Fossati, N
    Ist Science San Raffaele, Italy .
    Rigatti, P
    University of Vita Salute San Raffaele, Italy .
    Montorsi, F
    Ist Science San Raffaele, Italy .
    Benigni, F
    Ist Science San Raffaele, Italy .
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi. Hospital San Raffaele, Italy .
    Effects by silodosin on the partially obstructed rat ureter in vivo and on human and rat isolated ureters2013Inngår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 169, nr 1, s. 230-238Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose 1-adrenoceptor (-AR) antagonists may facilitate ureter stone passage in humans. We aimed to study effects by the 1A-AR selective antagonist silodosin (compared to tamsulosin and prazosin) on ureter pressures in a rat model of ureter obstruction, and on contractions of human and rat isolated ureters. Experimental Approach After ethical approval, ureters of male rats were cannulated beneath the kidney pelvis for in vivo ureteral intraluminal recording of autonomous peristaltic pressure waves. A partial ureter obstruction was applied to the distal ureter. Mean arterial blood pressure (MAP) was recorded. Approximate clinical and triple clinical doses of the 1-AR antagonists were given intravenously. Effects by the 1-AR antagonists on isolated human and rat ureters were studied in organ baths. Key Results Intravenous silodosin (0.10.3mgkg1) or prazosin (0.030.1mgkg1) reduced obstruction-induced increases in intraluminal ureter pressures by 2137% or 1840% respectively. Corresponding effects by tamsulosin (0.01 or 0.03mgkg1) were 920%. Silodosin, prazosin and tamsulosin reduced MAP by 1012%, 2526% (P andlt; 0.05), or 1825% (P andlt; 0.05) respectively. When effects by the 1A-AR antagonists on obstruction-induced ureter pressures were expressed as a function of MAP, silodosin had six- to eightfold and 2.5- to eightfold better efficacy than tamsulosin or prazosin respectively. Silodosin effectively reduced contractions of both human and rat isolated ureters. Conclusions and Implications Silodosin inhibits contractions of the rat and human isolated ureters and has excellent functional selectivity in vivo to relieve pressure-load of the rat obstructed ureter. Silodosin as pharmacological ureter stone expulsive therapy should be clinically further explored.

  • 313.
    von, Knorring L.
    et al.
    von Knorring, L., Department of Neuroscience, Psychiatry, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Akerblad, A.-C.
    Åkerblad, A.-C., Department of Neuroscience, Psychiatry, Uppsala University Hospital, 75185 Uppsala, Sweden, Medical Department, Pfizer AB, Täby, Sweden.
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Carlsson, A.
    Carlsson, Å., Medical Department, Pfizer AB, Täby, Sweden.
    Ekselius, L.
    Department of Neuroscience, Psychiatry, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Cost of depression: effect of adherence and treatment response2006Inngår i: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 21, nr 6, s. 349-354Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: The purpose of the present study has been to assess the societal cost of major depression and the distribution into different cost components. The impact of adherence and treatment response was also explored. Method: Data were collected from a randomized controlled trial of patients with major depressive disorder who were treated in a naturalistic primary care setting. Resource use and quality of life were followed during the two-year trial. Results: The mean total cost per patient during two years was KSEK 363 (EUR 38 953). Indirect costs were the most important component (87%), whereas the cost of drugs was minor (4.5%). No significant differences in costs or quality of life between treatment arms or between adherent and non-adherent patients were demonstrated. However, treatment responders had 39% lower total costs per patient and experienced a larger increase in quality of life compared to non-responders. Conclusions: Major depression has high costs for society, primarily due to indirect costs. Treatment responders have considerably lower costs per patient and higher quality of life than non-responders. This indicates that measures to increase response rates are also important from an economic perspective. © 2006 Elsevier SAS. All rights reserved.

  • 314.
    Waldkirch, Eginhard S.
    et al.
    Hannover Medical School.
    Uckert, Stefan
    Hannover Medical School.
    Langnaese, Kristina
    Otto-von-Guericke-University.
    Richter, Karin
    Otto-von-Guericke-University.
    Jonas, Udo
    Hannover Medical School.
    Wolf, Gerald
    Otto-von-Guericke-University.
    Andersson, Karl-Erik
    Lund University Hospital.
    Stief, Christian G.
    Ludwig-Maximilians-University.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Immunohistochemical distribution of cyclic GMP-dependent protein kinase-1 in human prostate tissue2007Inngår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 52, nr 2, s. 495-501Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Phosphodiesterase 5 (PDE5) inhibitors improve smooth muscle relaxation and therefore are considered for pharmacotherapy of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Cyclic guanosine monophosphate (cGMP)-dependent protein kinase-1 (cGKI) has been identified as one of the downstream targets for cGMP. The aim of the present study was to evaluate, by means of immunohistochemistry and Western blot analysis, the expression and localization of cGKI isoforms in relation to smooth muscle alpha-actin and cGMP in the human prostate.

    METHODS: Cryostat sections of tissue segments excised from the transition zone of human prostates from 11 patients (aged 54-68 yr) were incubated with primary antibodies directed against smooth muscle alpha-actin, cGMP, cGKI, cGKIalpha, and cGKIbeta. Visualization of double-labelled immunofluorescent staining was achieved by laser microscopy. Western blot analysis was performed to confirm the expression of cGKI isoforms.

    RESULTS: Immunoreactivities specific for cGKI, cGKIalpha, and cGKIbeta were observed in the smooth musculature of the transition zone. Double-staining revealed the colocalization of smooth muscle alpha-actin, cGMP, and cGKI isoforms in smooth muscle cells of the fibromuscular stroma. The expression of cGKI isoforms was confirmed by Western blot analysis.

    CONCLUSIONS: Our results confirm the presence of cGKI isoforms alpha and beta in the transition zone of human prostate tissue. In addition, the colocalization of alpha-actin, cGMP, and cGKI isoforms provides further evidence for a significant role of the nitric oxide/cGMP pathway in the regulation of smooth muscle contractility in human prostate tissue and therefore could provide additional targets for pharmacotherapy of BPH and LUTS.

  • 315.
    Waldkirch, Eginhard
    et al.
    Hannover Medical School.
    Ucker, Stefan
    Hannover Medical School.
    Schultheiss, Dirk
    von Baldersche Stiftung, Giessen.
    Geismar, Ulrike
    Private Practice of Dermatology, Hannover.
    Bruns, Carola
    Hannover Medical School.
    Scheller, Friedemann
    Hannover Medical School.
    Jonas, Udo
    Hannover Medical School.
    Becker, Armin J.
    Ludwig-Maximilians-University, Academic Hospital Grosshadern, Munich.
    Stief, Christian G.
    Ludwig-Maximilians-University, Academic Hospital Grosshadern, Munich.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue2008Inngår i: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 101, nr 1, s. 71-75Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: To evaluate non-genomic effects of testosterone and dihydrotestosterone (DHT) on isolated human cavernosal arteries (HCA) and corpus cavernosum (HCC) using organ-bath studies and radio-immunoassays (RIA), as non-genomic effects of androgens are reported for vascular smooth musculature and there is evidence that the relaxant response involves a modulation of cyclic nucleotide tissue levels.

    MATERIALS AND METHODS: The relaxation induced by the cumulative addition of testosterone and DHT (0.01-10 microm) was studied using circular segments of HCA and strip preparations of HCC. To evaluate the effects of testosterone and DHT on tissue levels of cAMP and cGMP, specimens were exposed to increasing concentrations of the hormones. Forskolin and sodium nitroprusside (SNP) served as reference compounds.

    RESULTS: Testosterone and DHT dose-dependently reversed the noradrenaline-induced tension of vascular segments and HCC strips. At the maximum concentration, testosterone and DHT reduced the mean (sd) tension to 79.8 (4.43)% and 83.9 (10.94)%, respectively. SNP and forskolin significantly stimulated the production of cGMP and cAMP. No effects of testosterone and DHT on cGMP and cAMP levels were detected.

    CONCLUSION: Rapid androgen-induced relaxation of HCA and HCC occurs via non-genomic mechanisms. In penile erectile tissue, non-genomic relaxant effects of testosterone and DHT are not mediated via modulation of cyclic nucleotide tissue levels. Additional studies are required to establish if non-genomic relaxant effects are important in ensuring a basal level of perfusion to maintain overall penile function.

  • 316.
    Waldkirch, Eginhard
    et al.
    Hannover Medical School, Germany.
    Uckert, Stefan
    Hannover Medical School, Germany.
    Sigl, Katja
    MorphoSys AG, Martinsried, Germany.
    Langnaese, Kristina
    Otto-von-Guericke-University, Magdeburg, Germany.
    Richter, Karin
    Otto-von-Guericke-University, Magdeburg, Germany.
    Stief, Christian G.
    Ludwig-Maximilians-University, Munich, Germany.
    Kuczyk, Markus A.
    Hannover Medical School, Germany.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Expression of cAMP-dependent protein kinase isoforms in the human prostate: functional significance and relation to PDE42010Inngår i: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 76, nr 2, s. 515.e8-515.e14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: To investigate the expression of isoforms of the cyclic AMP (cAMP)-dependent protein kinase (cAK) in the transition zone of the human prostate and the functional significance of the enzyme in the control of prostate smooth muscle.

    METHODS: Using Western blot analysis and immunohistochemistry, the expression and distribution in the prostate of cAKIalpha, cAKIbeta, cAKIIalpha, and cAKIIbeta in relation to alpha-actin and the phosphodiesterase PDE4 (types A and B) were investigated. The effects of the cAK inhibitor Rp-8-CPT-cAMPS on the reversion of the adrenergic tension of isolated prostate tissue induced by forskolin, rolipram, sodium nitroprusside (SNP), and tadalafil were examined by means of the organ bath technique.

    RESULTS: Immunosignals specific for cAKIalpha, cAKIIalpha, and cAKIIbeta were observed in the smooth musculature and glandular structures of the prostate. Double stainings revealed the colocalization of alpha-actin and PDE4 with the cAK isoforms. The expression of the cAK isoforms was confirmed by Western blot analysis. The relaxation of the tension induced by norepinephrine brought about by forskolin, rolipram, SNP, and tadalafil was significantly attenuated by Rp-8-CPT-cAMPS.

    CONCLUSIONS: The colocalization of smooth muscle alpha-actin and PDE4 with cAK, as well as the results from the organ bath experiments, provide further evidence for a pivotal role of the cAMP-dependent signaling in the regulation of prostate smooth muscle contractility. Compounds interacting with the cAMP/cAK pathway might represent a new therapeutic avenue to treat symptoms of benign prostatic hyperplasia and lower urinary tract symptomatology.

  • 317.
    Walther, Sten
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Fysiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärtcentrum, Thorax-kärlkliniken.
    Erlandsson, M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Olsson-Liljequist, B.
    Smittskyddsinstitutet, Solna, Sweden.
    Hanberger, Håkan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Infektionskliniken i Östergötland.
    The Icustrama Study Group (2002),
    Burman, L.G.
    Smittskyddsinstitutet, Solna, Sweden.
    Cars, O.
    Smittskyddsinstitutet, Solna, Sweden.
    Gill, Hans
    Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska högskolan.
    Hoffman, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Isaksson, Barbro
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk mikrobiologi.
    Kahlmeter, G.
    Department of Clinical Microbiology, Växjö lasarett.
    Lindgren, S.
    Nilsson, Lennart
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Antibiotic prescription practices, consumption and bacterial resistance in a cross section of Swedish intensive care units2002Inngår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, Vol. 46, nr 9, s. 1075-1081Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The purpose of this work was to study usage of antibiotics, its possible determinants, and patterns of bacterial resistance in Swedish intensive care units (ICUs).

    Methods: Prospectively collected data on species and antibiotic resistance of clinical isolates and antibiotic consumption specific to each ICU in 1999 were analyzed together with answers to a questionnaire. Antibiotic usage was measured as defined daily doses per 1000 occupied bed days (DDD1000).

    Results: Data were obtained for 38 ICUs providing services to a population of approximately 6 million. The median antibiotic consumption was 1257 DDD1000 (range 584–2415) and correlated with the length of stay but not with the illness severity score or the ICU category. Antibiotic consumption was higher in the ICUs lacking bedside devices for hand disinfection (2193 vs. 1214 DDD1000, p=0.05). In the ICUs with a specialist in infectious diseases responsible for antibiotic treatment the consumption pattern was different only for use of glycopeptides (58% lower usage than in other ICUs: 26 vs. 11 DDD1000,P=0.02). Only 21% of the ICUs had a written guideline on the use of antibiotics, 57% received information on antibiotic usage at least every 3 months and 22% received aggregated resistance data annually. Clinically significant antimicrobial resistance was found among Enterbacter spp. to cephalosporins and among Enterococcus spp. to ampicillin.

    Conclusions: Availability of hand disinfection equipment at each bed and a specialist in infectious diseases responsible for antibiotic treatment were factors that correlated with lower antibiotic consumption in Swedish ICUs, whereas patient-related factors were not associated with antibiotic usage.

  • 318.
    Wennerstrand, Patricia
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Dametto, Paolo
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Hennig, Janosch
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Klingstedt, Therése
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Structural Characteristics Determine the Cause of the Low Enzyme Activity of Two Thiopurine S-Methyltransferase Allelic Variants: A Biophysical Characterization of TPMT*2 and TPMT*52012Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 51, nr 30, s. 5912-5920Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The enzyme thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs used to treat acute lymphoblastic leukemia and inflammatory bowel disease. Thus far, at least 29 variants of the TPMT gene have been described, many of which encode proteins that have low enzyme activity and in some cases become more prone to aggregation and degradation. Here, the two naturally occurring variants, TPMT*2 (Ala80 → Pro) and TPMT*5 (Leu49 → Ser), were cloned and expressed in Escherichia coli. Far-UV circular dichroism spectroscopy showed that TPMT*2 was substantially destabilized whereas TPMT*5 showed much greater stability comparable to that of wild-type TPMT (TPMTwt). The extrinsic fluorescent molecule anilinonaphthalene sulfonate (ANS) was used to probe the tertiary structure during thermal denaturation. In contrast to TPMTwt, neither of the variants bound ANS to a large extent. To explore the morphology of the TPMT aggregates, we performed luminescent conjugated oligothiophene staining and showed fibril formation for TPMT*2 and TPMT*5. The differences in the flexibility of TPMTwt, TPMT*2, and TPMT*5 were evaluated in a limited proteolysis experiment to pinpoint stable regions. Even though there is only one amino acid difference between the analyzed TPMT variants, a clear disparity in the cleavage patterns was observed. TPMT*2 displays a protected region in the C-terminus, which differs from TPMTwt, whereas the protected regions in TPMT*5 are located mainly in the N-terminus close to the active site. In conclusion, this in vitro study, conducted to probe structural changes during unfolding of TPMT*2 and TPMT*5, demonstrates that the various causes of the low enzyme activity in vivo could be explained on a molecular level.

  • 319.
    Wennerstrand, Patricia
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Dametto, P
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Hennig, Janosch
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Different mechanisms behind low enzyme activity in vivo of two different variants of Thiopurine S-methyltransferase, TPMT2010Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, nr Suppl. 1, s. 257-258Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    In treatment of acute lymphoblastic leukemia and inflammatorybowel disease (IBD) thiopurines such as azathioprine and 6-mercaptopurineare used. All of these drugs are prodrugs and are, inthe cell, converted to 6-thioguanines (6-TGNs) and incorporatedinto DNA or inhibiting purine synthesis. A key enzyme for thisregulation is the cytosolic enzyme thiopurine S-methyltransferase(TPMT). This enzyme degrades azathioprine and 6-mercaptopurineto methylmercapto-purine and thereby reduces the bioavailabilityof the 6-TGNs incorporated into DNA. TPMT is apolymorphic enzyme with at least 29 different allelic variantsknown today and is one of the more classical examples of pharmacogeneticswhere the TPMT enzyme activity of the allelic variantsis directly correlated to the clinical dosages of the thiopurines, with a 10–15 fold dosage reduction for an allelic variantwith low TPMT enzyme activity. Even though TPMT is awell studied protein. Many studies have been performed in yeast‘‘suspensions’’ and not on pure protein solutions. It has beenspeculated and in a few cases shown that the reason for the lowactivity for most of the allelic variants is mainly due to the lowstability and/or tendency to aggregate. The mutations in thisstudy TPMT *2 (A80P) and TPMT * 5 (L49S) are both situatedat a distance far from the active site, however the enzyme activitiesare severely affected at 37°C. Preliminary results, using a repertoireof techniques such as CD, fluorescence and limitedproteolysis experiments suggest two different mechanisms for thelow enzyme activity at a temperature corresponding to in vivo conditions.

  • 320.
    Wennerstrand, Patricia
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Söderhäll, Stefan
    Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Zimdahl, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia2013Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, nr 9, s. 1641-1649Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose

    Important drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) are 6-mercaptopurine (6-MP) and methotrexate (MTX). Thiopurine methyltransferase (TPMT) is a polymorphic enzyme causing variability in 6-MP response and toxicity. The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients.

    Methods

    Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX (HD-MTX) infusions and at 66 h post-infusion. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line.

    Results

    Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis. TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions (−9.2 %; p = 0.013). MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity (remaining activity 16 %).

    Conclusions

    Our results show that TPMT genotyping should be performed in children with ALL, since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined. MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding.

  • 321.
    Werkstrom, Viktoria
    et al.
    Lund University Hospital.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lee, Tack
    Inha University Hospital.
    Andersson, Karl-Erik
    Wake Forest University.
    Vardenafil-induced relaxation and cyclic nucleotide levels in normal and obstructed rat urinary bladder2009Inngår i: BJU INTERNATIONAL, ISSN 1464-4096, Vol. 104, nr 11, s. 1740-1745Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE To study the effects of the phosphodiesterase-5 inhibitor, vardenafil, on contraction and cyclic nucleotide levels in isolated detrusor preparations with and without mucosa, from control rats and rats with partial urethral obstruction (PUO) and intact mucosa. MATERIALS AND METHODS Female Sprague-Dawley rats were divided into groups subjected to PUO for 14 days (six), and sham-operated control rats (12). Detrusor preparations were mounted in organ baths and effects of increasing concentrations of vardenafil (1 nm to 100 mu m) assessed on carbachol-activated (1 mu m) preparations, and on contractions induced by transmural activation of nerves (electrical field stimulation, EFS). Levels of cGMP and cAMP were determined using radioimmunoassays. RESULTS Vardenafil caused concentration-dependent relaxations of carbachol-contracted detrusor, the mean (sd) of which at 100 mu m was 91 (4)% in control and 100% in PUO rats. The -log 50% inhibitory concentration (IC50) was 4.41 (0.08) and 4.73 (0.05) (P andlt; 0.01), respectively. Removing the mucosa increased the relaxant effect of vardenafil at 1-10 mu m (P andlt; 0.05) although -log IC50 values were unaffected compared to the control. The cGMP levels ( pmol/mg protein) in control preparations increased from 2.5 (0.6) to 5.0 (0.8), and from 1.4 (0.2) to 7.2 (1.3) in obstructed bladders. In mucosa-denuded preparations the cGMP content increased from 0.6 (0.1) to 1.6 (0.4) in response to vardenafil. In control rats, the levels of cAMP increased from 12.8 (2.5) to 18.9 (0.9) (P andlt; 0.05) after vardenafil. In mucosa-denuded preparations the cAMP levels after vardenafil increased from 16.5 (2.11) to 37.8 (3.4) (P andlt; 0.01). In PUO bladders, the tissue content of cAMP increased from 12.6 (2.4) to 20.6 (3.4) (P andlt; 0.01). Vardenafil concentration-dependently inhibited nerve-induced contractions in all groups studied. At 100 mu m 19 (3)% of the control contraction remained, vs 8 (1)% for preparations from obstructed rats, and 11 (4)% in mucosa-denuded preparations. CONCLUSION In normal rats, vardenafil relaxed carbachol- and inhibited EFS-induced contractions of detrusor preparations with and without urothelium, and in PUO rats with urothelium. Relaxations were accompanied by increases in both cAMP and cGMP content. It is proposed that vardenafil-induced relaxation of rat detrusor, also in obstructed and mucosa-denuded preparations, is mediated via cAMP.

  • 322.
    Wester, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Incidence of Suspected Drug-Related Deaths in a Swedish Population2007Inngår i: Pharmacoepidemiology and drug safety, Wiley , 2007, s. 196-Konferansepaper (Fagfellevurdert)
  • 323.
    Wester, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Anna K.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Spigset, Olav
    Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
    Druid, Henrik
    Department of Forensic Medicine, Karolinska Institute, Stockholm, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Incidence of fatal adverse drug reactions: A population based study2008Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 65, nr 4, s. 573-579Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    What is already known about this subject

    • Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.

    • The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.

    • In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

    What this study adds

    • Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.

    • Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.

    • Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

     

    Aims: To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

     

    Methods: Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.

     

    Results: Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

     

    Conclusions: The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

  • 324.
    Wickstrom, M.
    et al.
    Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University Hospital, Entrance 61, 75185 Uppsala, Sweden.
    Johnsen, J.I.
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Ponthan, F.
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Segerstrom, L.
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Sveinbjornsson, B.
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Lindskog, M.
    Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Lovborg, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Viktorsson, K.
    Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
    Lewensohn, R.
    Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
    Kogner, P.
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Larsson, R.
    Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Gullbo, J.
    Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo2007Inngår i: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 6, nr 9, s. 2409-2417Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SHSY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group. Copyright © 2007 American Association for Cancer Research.

  • 325.
    Wikström, M
    et al.
    National Board of Forensic Medicine.
    Holmgren, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    A2 (N-benzylpiperazine) a new drug of abuse in Sweden2004Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 28, nr 1, s. 67-70Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    N-Benzylpiperazine was tested in the beginning of the 1970s as a possible antidepressant drug. However, in both animal and human studies, it was shown to possess amphetamine-like properties, and any further studies were stopped. In a forensic autopsy case in 1999, we found a substance so far unknown to us in the chromatogram of our method used for amphetamines. We could swiftly identify this compound as N-benzylpiperazine because of information given to us by a newly formed network comprising, among others, customs and the police. Since then, we have found N-benzylpiperazine in several cases, among them 11 cases from a number of prisons.

  • 326.
    Zackrisson, Anna-Lena
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacogenetics from a Forensic Perspective: CYP2D6 and CYP2C19 genotype distributions in autopsy cases2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In Sweden about 550 individuals die every year due to drug intoxication. A challenge for the forensic toxicologist is to determine whether or not the analytical results can explain intoxication as a cause of death. The most common drugs found among intoxication cases are psychiatric drugs and analgesics. Many of these drugs are metabolised by CYP-enzymes such as CYP2D6 and CYP2C19. Genetic variations, polymorphisms, in the genes coding for these enzymes can lead to an inactive enzyme resulting in poor metabolism, which can lead to adverse drug reactions, even with fatal outcome. The CYP2D6 gene can be multiplied, which can lead to an ultra-rapid metabolism if the alleles are active. Another polymorphism, in the CYP2C19 gene, can also lead to an ultra-rapid metabolism. This increased metabolism can result in insufficient drug plasma concentration and, with that, failed treatment. Alternately, if the drug is a pro-drug and has to be activated by these enzymes, it can lead to a high amount of active metabolites. There is a large inter-individual variation of these polymorphisms and also a large variation between different populations. Additional information about an individual’s pharmacogenetics may possibly facilitate the interpretation of the postmortem result and contribute to solve the “toxicological puzzle”.

    The general aim of this thesis was to study if genetic variation in the drug metabolising enzymes, CYP2D6 and CYP2C19 can contribute to fatal intoxication. Reliable and rapid SNP and CNV assays suitable for forensic samples using PCR and pyrosequencing were developed for CYP2D6 and genotype frequencies in a Swedish population were shown to be in concordance with earlier published data. SNP assays were established for polymorphisms in the CYP2C19 gene.

    Genotype distributions in fatal intoxication cases were compared with Swedish blood donors and significant difference between the materials were established. The allele CYP2D6*4 was found to be less frequent among the intoxication cases, as compared with the blood donors. No differences in CYP2C19 genotype frequencies were found between the materials. These findings are the opposite of our hypothesis that we expected to find an increased number of individuals carrying genetic variations, leading to poor metabolism among fatal intoxication cases. However, we are convinced that information concerning an individual’s genotype can be of importance in specific intoxication cases. Further studies are required to illuminate this question. Two further autopsy materials were studied; suicide cases (intoxications excluded) and natural death cases. A significant increased number of individuals carrying more than two active CYP2D6 alleles among the suicide cases were found compared to natural death cases. Furthermore, we found some significant differences between the materials when the individuals in each material were grouped according to how many active CYP2D6 alleles they carry in combination with the CYP2C19 genotype, which was divided into six subgroups. We do not currently have any explanation for the differences between the materials.

    Delarbeid
    1. Identification of CYP2D6 alleles by single nucleotide polymorphism analysis using pyrosequencing
    Åpne denne publikasjonen i ny fane eller vindu >>Identification of CYP2D6 alleles by single nucleotide polymorphism analysis using pyrosequencing
    2003 (engelsk)Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 59, nr 7, s. 521-526Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: To develop a single nucleotide polymorphism (SNP) analysis for identification of cytochrome P450 (CYP)2D6 alleles by pyrosequencing.

    METHODS: Swedish blood donors ( n=282) were typed for a partial CYP2D6 genotype comprising the alleles *1 (wild type), *2 (2850C>T), *3 (2549A>del), *4 (1846G>A) and *6 (1707T>del) using polymerase chain reaction (PCR) and pyrosequencing analysis. CYP2D6*5 (CYP2D6 deleted) was identified using an established long multiplex PCR method. Pyrosequencing is a sequencing-by-synthesis method in which a cascade of enzymatic reactions yields detectable light, which is proportional to the incorporated nucleotides. One feature of typing SNPs by pyrosequencing is that each allelic variant will give a unique sequence. These variants can be readily distinguished by pattern recognition software.

    RESULTS: Of 281 individuals analysed, 24 (8.5%) were found to be poor metabolisers with two non-functional alleles. This is in the range of 7-10%, previously reported for Caucasians. A total of 126 individuals (45%) had one functional and one non-functional allele and 131 individuals (47%) had two functional alleles.

    CONCLUSION: Pyrosequencing was found to be a fast and efficient tool for genotyping. The method is robust, reliable, rapid and has high throughput.

    Emneord
    CYP2D6 - Pyrosequencing - Pharmacogenetics
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17932 (URN)10.1007/s00228-003-0654-7 (DOI)13680033 (PubMedID)
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Fatal intoxication cases: cytochrome P450 2D6 and 2C19 genotype distributions
    Åpne denne publikasjonen i ny fane eller vindu >>Fatal intoxication cases: cytochrome P450 2D6 and 2C19 genotype distributions
    Vise andre…
    2004 (engelsk)Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 60, nr 8, s. 547-552Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: Many commonly used pharmaceuticals, such as antidepressants and neuroleptics as well as some illegal drugs, are metabolised by the cytochrome P450 enzyme debrisoquine 4-hydroxylase (CYP2D6). Of Caucasians, 7-10% lack this enzyme, which can, upon administration of drugs in normal therapeutic doses, lead to adverse reactions and unexpected intoxication, leading in turn even to a fatal outcome in some cases.

    METHODS: Individuals (n=242) who had died due to intoxication by pharmaceuticals were genotyped for CYP2D6 and CYP2C19 and compared with a reference group of 281 blood donors. A single nucleotide polymorphism (SNP) method was used to identify five CYP2D6 alleles: *1 (wt), *2, *3, *4 and *6. The allele *5, a complete gene deletion, was identified by a multiplex amplification of long DNA fragments. Four CYP2C19 alleles *1 (wt), *2, *3 and *4 were also identified by SNP analysis.

    RESULTS: The prevalence of the CYP2D6 poor metaboliser (PM) genotypes in individuals with fatal intoxication was lower (4.7%) than expected from the frequencies of these genotypes in the blood donors (8.5%). A significantly lower frequency P<0.005 (0.03 with correction according to Bonferroni) was found for the CYP2D6*4 allele among the fatal intoxication cases. The CYP2C19 genotype analyses showed the same results for the fatal intoxication cases and for the blood donors.

    CONCLUSIONS: The findings in this study confirm our earlier observations of a lower frequency of CYP2D6 PM genotypes in cases of fatal intoxication. To our knowledge, it has not been shown previously that intoxication victims might have a lower frequency of PMs than the general population.

    Emneord
    CYP2D6, CYP2C19, Post-mortem
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17933 (URN)10.1007/s00228-004-0800-x (DOI)15349706 (PubMedID)
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2018-09-01bibliografisk kontrollert
    3. Determination of CYP2D6 gene copy number by pyrosequencing
    Åpne denne publikasjonen i ny fane eller vindu >>Determination of CYP2D6 gene copy number by pyrosequencing
    2005 (engelsk)Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 51, nr 3, s. 522-531Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

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

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

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

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

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17934 (URN)10.1373/clinchem.2004.043182 (DOI)15650034 (PubMedID)
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    4. High Frequency of Occurrence of CYP2D6 Gene Duplication/Multiduplication Indicating Ultrarapid Metabolism Among Suicide Cases: High frequency of CYP2D6 ultra-rapid metabolizers among suicide cases
    Åpne denne publikasjonen i ny fane eller vindu >>High Frequency of Occurrence of CYP2D6 Gene Duplication/Multiduplication Indicating Ultrarapid Metabolism Among Suicide Cases: High frequency of CYP2D6 ultra-rapid metabolizers among suicide cases
    2009 (engelsk)Inngår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535Artikkel i tidsskrift (Annet vitenskapelig) Published
    Abstract [en]

    In Sweden about 550 individuals die every year due to intoxication with drugs. Many of these drugs are metabolized by CYP-enzymes, such as CYP2D6 and CYP2C19. Lack of these enzymes, resulting in a poor metabolism, can lead to adverse reactions, even leading to a fatal outcome. On the other hand, socalled ultra-rapid metabolism can lead to insufficient drug plasma concentration and with that failed treatment or it can lead to a high amount of active/toxic metabolites. The aim of this project was to study the genetic distributions of CYP2D6 and CYP2C19 in fatal intoxication cases (242), suicide cases (intoxications excluded) (262) and natural death cases (212). PCR followed by pyrosequencing was used for all the analyses. Surprisingly, we found an increased number of individuals carrying more than two active CYP2D6 alleles, corresponding to the phenotype of an ultra-rapid metabolizer, among the suicide cases as compared to the natural death cases (p=0.007).

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17935 (URN)10.1038/clpt.2009.216 (DOI)
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2017-12-13bibliografisk kontrollert
  • 327.
    Zackrisson, Anna-Lena
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Holmgren, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gladh, Ann-Britt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindblom, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fatal intoxication cases: cytochrome P450 2D6 and 2C19 genotype distributions2004Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 60, nr 8, s. 547-552Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Many commonly used pharmaceuticals, such as antidepressants and neuroleptics as well as some illegal drugs, are metabolised by the cytochrome P450 enzyme debrisoquine 4-hydroxylase (CYP2D6). Of Caucasians, 7-10% lack this enzyme, which can, upon administration of drugs in normal therapeutic doses, lead to adverse reactions and unexpected intoxication, leading in turn even to a fatal outcome in some cases.

    METHODS: Individuals (n=242) who had died due to intoxication by pharmaceuticals were genotyped for CYP2D6 and CYP2C19 and compared with a reference group of 281 blood donors. A single nucleotide polymorphism (SNP) method was used to identify five CYP2D6 alleles: *1 (wt), *2, *3, *4 and *6. The allele *5, a complete gene deletion, was identified by a multiplex amplification of long DNA fragments. Four CYP2C19 alleles *1 (wt), *2, *3 and *4 were also identified by SNP analysis.

    RESULTS: The prevalence of the CYP2D6 poor metaboliser (PM) genotypes in individuals with fatal intoxication was lower (4.7%) than expected from the frequencies of these genotypes in the blood donors (8.5%). A significantly lower frequency P<0.005 (0.03 with correction according to Bonferroni) was found for the CYP2D6*4 allele among the fatal intoxication cases. The CYP2C19 genotype analyses showed the same results for the fatal intoxication cases and for the blood donors.

    CONCLUSIONS: The findings in this study confirm our earlier observations of a lower frequency of CYP2D6 PM genotypes in cases of fatal intoxication. To our knowledge, it has not been shown previously that intoxication victims might have a lower frequency of PMs than the general population.

  • 328.
    Zackrisson, Anna-Lena
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindblom, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Identification of CYP2D6 alleles by single nucleotide polymorphism analysis using pyrosequencing2003Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 59, nr 7, s. 521-526Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To develop a single nucleotide polymorphism (SNP) analysis for identification of cytochrome P450 (CYP)2D6 alleles by pyrosequencing.

    METHODS: Swedish blood donors ( n=282) were typed for a partial CYP2D6 genotype comprising the alleles *1 (wild type), *2 (2850C>T), *3 (2549A>del), *4 (1846G>A) and *6 (1707T>del) using polymerase chain reaction (PCR) and pyrosequencing analysis. CYP2D6*5 (CYP2D6 deleted) was identified using an established long multiplex PCR method. Pyrosequencing is a sequencing-by-synthesis method in which a cascade of enzymatic reactions yields detectable light, which is proportional to the incorporated nucleotides. One feature of typing SNPs by pyrosequencing is that each allelic variant will give a unique sequence. These variants can be readily distinguished by pattern recognition software.

    RESULTS: Of 281 individuals analysed, 24 (8.5%) were found to be poor metabolisers with two non-functional alleles. This is in the range of 7-10%, previously reported for Caucasians. A total of 126 individuals (45%) had one functional and one non-functional allele and 131 individuals (47%) had two functional alleles.

    CONCLUSION: Pyrosequencing was found to be a fast and efficient tool for genotyping. The method is robust, reliable, rapid and has high throughput.

  • 329. Zaitoun, AA
    et al.
    Apelqvist, G
    Al-Mardini, H
    Gray, T
    Bengtsson, Finn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Record, CO
    Quantitative studies of liver atrophy after portacaval shunt in the rat2006Inngår i: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 131, nr 2, s. 225-232Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. It is well known that portacaval shunting ultimately leads to a decrease in liver volume and hepatic function, but the mechanism is uncertain. The aim of the present study was to evaluate the effect of portacaval shunting (PCS) upon the morphological changes that occur in the liver in rats after port caval. anastomosis. Materials and methods. Sixty-six male rats underwent either PCS (n = 35) or sham operations (n = 31). Hormone levels were determined in blood samples taken just before removal and weighing of the livers. Hematoxylin and eosin-stained sections were used for quantitative morphometric analysis. Apoptosis, mitosis, and cellular organelles also were assessed quantitatively. Results. There was a significant reduction in the liver mass together with testosterone levels in PCS rats in comparison with sham rats. The distance between presinusoidal and postsinusoidal vessels was reduced from 500 mu m in the sham rats to 299 mu m in the PCS rats (P = 0.000001). Within the same group, there was a significant reduction in the area of hepatocyte nuclei in zone 3 in comparison with zone 1. Electron microscopy revealed a highly significant (P = 0.0007) reduction in the membrane-bound cytoplasmic organelles of zone 3 hepatocytes in PCS rats in comparison with the sham rats. Apoptosis was increased in zone 3 in PCS rats (P = 0.00001), whereas in zone 1 of the same group, there was an associated increased in mitosis (P = 0.000001). Overall, the degree of apoptosis was in excess of mitosis, resulting in a general loss of liver mass. Conclusion. Morphometric analysis at cellular and subcellular levels confirms the morphological findings of liver atrophy in PCS rats. The mechanism of atrophy is a complex one. Portacaval shunting leads to hepatic atrophy that, in turn, results in microcirculatory and hormonal changes that further contribute to liver cell loss in this animal model. (C) 2006 Elsevier Inc. All rights reserved.

  • 330.
    Zhenchuk, Anna
    et al.
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
    Lotfi, Koroush
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Juliusson, Gunnar
    Lund Strategic Center for Stem Cell Biology and Therapy, Department of Hematology, Lund University Hospital, Lund, Sweden.
    Albertioni, Freidoun
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
    Commentary: Mechanisms of anti-cancer action and pharmacology of clofarabine: in BIOCHEMICAL PHARMACOLOGY, ISSN 0006-2952, vol 78, issue 11, pp 1351-13592009Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 78, nr 11, s. 1351-1359Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Clofarabine, a next-generation deoxyadenosine analogue, was developed on the basis of experience with cladribine and fludarabine in order to achieve higher efficacy and avoid extramedullary toxicity. During the past decade this is the only drug granted approval for treatment of pediatric acute leukemia. Recent clinical studies have established the efficacy of clofarabine in treating malignancies with a poor prognosis, such as adult, elderly, and relapsed pediatric leukemia. The mechanisms of its anti-cancer activity involve a combination of direct inhibition of DNA synthesis and ribonucleotide reductase and induction of apoptosis. Due to this broad cytotoxicity, this drug is effective against various subtypes of leukemia and is currently being tested as an oral formulation and for combination therapy of both leukemias and solid tumors. In this review we summarize current knowledge pertaining to the molecular mechanisms of action and pharmacological properties of clofarabine, as well as clinical experiences with this drug with the purpose of facilitating the evaluation of its efficacy and the development of future therapies.

  • 331.
    Åström-Lilja, Cecilia
    et al.
    Lund.
    Mercke Odeberg, Johanna
    Lund.
    Ekman, Elisbet
    Lund.
    Hägg, Staffan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Drug-induced torsades de pointes: A review of the Swedish pharmacovigilance database2008Inngår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 17, nr 6, s. 587-592Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To describe spontaneously reported cases of torsades de pointes (TdP) in Sweden and to investigate if this adverse drug reaction (ADR) was labelled in the summary of product characteristics (SPC) for the drugs implicated. Methods: Reported cases of TdP 1991-2006 were identified and evaluated with regard to drug use and other possible risk factor. Results: Among a total of 61 788 ADRs, 88 cases of TdP were identified. In these cases, 27 different suspected drugs were implicated. Cardiac drugs were involved in most reports (74%, 65/88), with sotalol being the most frequently suspected drug (57%, 58/88). In addition to drug treatment two or more established risk factors were present in 85% of the cases (75/88). Heart disease (90%, 79/88) was the most common risk factor followed by age over 65 years (72%, 63/88) and female gender (70%, 62/88). TdP or QT prolongation were labelled in the SPC for 33% (9/ 27) of the drugs implicated in the 88 cases. However, supporting evidence for an association was found elsewhere in 56% (15/27) for the different drugs implicated in the reports. Although citalopram was the third most common suspected drug in the reports (10%, 9/88), TdP was not listed in the SPC. Conclusion: TdP is a rarely reported ADR. Several risk factors are often present. In two thirds of the drugs implicated in the reports neither TdP nor QT prolongation was labelled in the SPC. Further investigations are needed regarding the association between citalopram and TdP. Copyright © 2008 John Wiley & Sons, Ltd.

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