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  • 1.
    Aagaard, Lise
    et al.
    University of So Denmark, Denmark FKL Research Centre Qual Medical Use, Denmark Danish Pharmacovigilance Research Project DANPREP, Denmark .
    Strandell, Johanna
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Melskens, Lars
    University of Copenhagen, Denmark .
    Petersen, Paw S. G.
    University of Copenhagen, Denmark .
    Holme Hansen, Ebba
    FKL Research Centre Qual Medical Use, Denmark Danish Pharmacovigilance Research Project DANPREP, Denmark University of Copenhagen, Denmark .
    Global Patterns of Adverse Drug Reactions Over a Decade Analyses of Spontaneous Reports to VigiBase (TM)2012In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 35, no 12, p. 1171-1182Article in journal (Refereed)
    Abstract [en]

    Background: Although systems to collect information about suspected adverse drug reactions (ADRs) were established in many countries and by the WHO in the 1960s, few studies have examined reported ADRs related to national income. Objective: The aim of the study was to characterize ADRs reported to the WHO-ADR database, VigiBase (TM), and to relate data to national income. Methods: We analysed ADR reports submitted to VigiBase (TM) from 2000 to 2009 with respect to reporting rate, age and sex of patient, type, seriousness and medications. Reports were also analysed with respect to national income level, classified in accordance with the World Bank definition: low, lower-middle, upper-middle and high. Results: We analysed 1 359 067 ADR reports including 3 013 074 ADRs. Overall, 16% of reports were serious and 60% were reported for females. High-income countries had the highest ADR reporting rates (range 3-613 reports/million inhabitants/year) and low-income countries the lowest (range 0-21). Distribution of ADRs across income groups with respect to age group, seriousness and sex was non-significant. Overall, the majority of ADRs were reported for nervous system medications, followed by cardiovascular medicines. Low-income countries reported relatively more ADRs for antiinfectives for systemic use than high-income countries, and high-income countries reported more ADRs for antineoplastic and immunomodulating agents than lower-income groups. Conclusion: This study showed that high-income countries had the highest ADR reporting rates and low-income countries the lowest, with large variations across countries in each group. Significant differences in ADR reporting rates were only found for ADRs of the type skin and subcutaneous tissue disorders and for the therapeutic groups antiinfectives for systemic use and antineoplastic and immunomodulation agents. To strengthen ADR reporting rates, especially in low-income countries, more research is needed about the impact of organizational structures and economic resources of national pharmacovigilance centres and ADR reporting practices on the large variations in ADR reporting rates within income groups.

  • 2.
    Ahlner, Johan
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Aamo, T. O.
    Trondheims University.
    THERAPEUTIC DRUG MONITORING AND CLINICAL TOXICOLOGY2009In: in BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, vol 105, 2009, Vol. 105, p. 16-16Conference paper (Refereed)
    Abstract [en]

    n/a

  • 3.
    Ahlner, Johan
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindblom, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Forensic Genetics. Linköping University, Faculty of Health Sciences.
    Bertilsson, Leif
    Karolinska Institute.
    Editorial Material: CYP2D6, serotonin and suicide2010In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 11, no 7, p. 903-905Article in journal (Other academic)
    Abstract [en]

    n/a

  • 4.
    Albrecht, Knut
    et al.
    Hannover Medical School, Deparment of Legal Medicine, Hannover, Germany.
    Ückert, Stefan
    Hanover Medical School, Department of Urology, Hannover, Germany.
    Oelke, Matthias
    University of Amsterdam, Academic Medical Center (AMC), Department of Urology, Amsterdam, The Netherlands.
    Andersson, Karl-Erik
    Lund University Hospital, Department of Clinical and Experimental Pharmacology, Lund, Sweden.
    Jonas, Udo
    University of Amsterdam, Academic Medical Center (AMC), Department of Urology, Amsterdam, The Netherlands.
    Tröger, Hans-Dieter
    Hannover Medical School, Deparment of Legal Medicine, Hannover, Germany.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology.
    Immunohistochemical distribution of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human vagina:: A potential forensic value?2007In: Journal of forensic and legal medicine, ISSN 1752-928X, Vol. 14, no 5, p. 270-274Article in journal (Refereed)
    Abstract [en]

    Objectives

    Phosphodiesterase (PDE) isoenzymes are key proteins involved in the maintenance of the normal function of various tissues of the human body including those of the male and female urogenital tract. More recently, PDEs and their main substrates, cyclic GMP and cyclic AMP, have also been assumed to play a crucial role in the control of the human vagina. In order to elucidate the potential significance of phosphodiesterases as marker proteins in female genital organs, it was the aim of the present study to evaluate by means of immunohistochemistry the distribution of cGMP- and cAMP-PDE isoenzymes in specimens of the human vagina.

    Methods

    Conventional immunohistochemical techniques (double antibody technique, laser fluorescence microscopy) were applied to sections of the human vaginal wall in order to evaluate the presence of the PDE isoenzymes 1, 2, 3, 4, 5 and 10.

    Results

    Immunoreactivities (IR) specific for PDE1 (cAMP/cGMP-PDE, Ca2+/Calmodulin-dependent), PDE2 (cAMP-PDE, cGMP-dependent) and PDE5 (cGMP-PDE) were exclusively registered in the smooth musculature of vaginal arterial vessels, whereas no signals were detected in non-vascular tissue. IR indicating the expression of the cAMP-degrading PDE4 was mainly observed in the vaginal epithelium. Vaginal epithelial cells also presented immunosignals specific for PDE3 (cAMP-PDE, inhibited by cGMP) and PDE10 (dual substrate PDE), nevertheless, these stainings were less abundant than those related to the PDE4. IR for PDE10 was also registered in inflammatory cells located in the subepithelial region of the vaginal wall.

    Conclusion

    Our study revealed the presence of IR specific for PDE1, PDE2, PDE4, PDE5 and PDE10 in sections of the human vagina and demonstrated that these enzymes are not evenly distributed in the tissue. Especially, the prominent expression of the cyclic AMP-PDE4A in the vaginal epithelium may give hint to a potential significance of this isoenzyme as a forensic marker protein. The findings give a rationale to investigate further as to whether the immunohistochemical detection of PDE4 may represent a new forensic tool in order to identify human vaginal epithelial cells.

  • 5.
    Andersson, Eva
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Technical Audiology. Linköping University, Faculty of Health Sciences.
    Arlinger, Stig
    Linköping University, Department of Clinical and Experimental Medicine, Technical Audiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Lennart
    Sahlgrenska University Hospital, Sweden.
    Hamrin, Elisabeth
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Audiometric screening of a population with intellectual disability2013In: International Journal of Audiology, ISSN 1499-2027, E-ISSN 1708-8186, Vol. 52, no 1, p. 50-56Article in journal (Refereed)
    Abstract [en]

    Objective: Evaluation of pure-tone audiometry (PTA) in hearing screening of a population with mild to profound intellectual disability (ID).

    Design: PTA was performed at six frequencies at the screening level 20 dB HL. Referral criteria were threshold levels ≥ 25 dB HL at two or more frequencies for one ear or both.

    Study sample: 1478 participants aged 7–91 years were included.

    Results: 1470 (99.5%) people cooperated in screening of which 1325 (90%) could be tested on both ears at all six frequencies. A majority, 987 (66.8%), performed ordinary PTA, 234 (15.8%) conditioned play audiometry, and 249 (16.9%) behavioural observation audiometry. Six hundred and sixty-nine (45%) passed and 809 (55%) failed according to referral criteria. Of those failing, 441 (54.5%) accepted referral to clinical evaluation.

    Conclusions: PTA with slight modifications is applicable for screening of a population with mild to profound intellectual disability. The most challenging and time-consuming activity is to introduce the test procedure in a way that reduces anxiety and establishes trust.

  • 6.
    Andersson, Karl-Erik
    et al.
    Wake Forest University.
    Gratzke, Christian
    University of Munich.
    Hedlund, Petter
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder2010In: BJU INTERNATIONAL, ISSN 1464-4096, Vol. 106, no 8, p. 1114-1127Article, review/survey (Refereed)
    Abstract [en]

    center dot The transient receptor potential (TRP) channel superfamily has been shown to be involved in nociception and mechanosensory transduction in various organ systems, and studies of the LUT have indicated that several TRP channels, including TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1, are expressed in the bladder, and may act as sensors of stretch and/or chemical irritation. center dot However, the roles of these individual channels for normal LUT function and in LUTS/DO/OAB, have not been established. center dot TRPV1 is the channel best investigated. It is widely distributed in LUT structures, but despite extensive information on morphology and function in animal models, the role of this channel in normal human bladder function is still controversial. Conversely, its role in the pathophysiology and treatment of particularly neurogenic DO is well established. center dot TRPV1 is co-expressed with TRPA1, and TRPA1 is known to be present on capsaicin-sensitive primary sensory neurones. Activation of this channel can induce DO in animal models. center dot TRPV4 is a Ca2+-permeable stretch-activated cation channel, involved in stretch-induced ATP release, and TRPV4-deficient mice exhibit abnormal frequencies of voiding and non-voiding contractions in cystometric experiments. center dot TRPM8 is a cool receptor expressed in the urothelium and suburothelial sensory fibres. It has been implicated in the bladder-cooling reflex and in idiopathic DO. center dot The occurrence of other members of the TRP superfamily in the LUT has been reported, but information on their effects on LUT functions is scarce. There seem to be several links between activation of different members of the TRP superfamily and LUTS/DO/OAB, and further exploration of the involvement of these channels in LUT function, normally and in dysfunction, may be rewarding.

  • 7.
    Andersson, Karl-Erik
    et al.
    Wake Forest University, Winston Salem, North Carolina.
    Uckert, Stefan
    Hannover Medical School.
    Stief, Christian
    Ludwig-Maximilian University, Munich.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS2007In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 26, no 6, p. 928-933Article in journal (Refereed)
    Abstract [en]

    Lower urinary tract (LUT) smooth muscle can be relaxed by drugs that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both of these substances are degraded by phosphodiesterases (PDEs), which play a central role in the regulation of smooth muscle tone. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. Targeting specific PDE isoenzymes should thus allow organ selectivity. PDE 4 and 5 appear to predominate in the prostate, PDE 1 and 4 are thought to influence detrusor smooth muscle function, and PDE 5 may be functionally important in the urethra and vasculature. Studies on the use of PDE inhibitors to treat various LUT symptoms (LUTS), have yielded favorable results. Thus, positive effects of the PDE 5 inhibitors sildenafil and tadalafil on symptoms and quality of life in men with LUTS, erectile dysfunction, and BPH have also been demonstrated. These effects may be due to effects on cGMP signaling and/or modification of afferent input from bladder, urethral, and prostate tissue. This review gives an update on the distribution of PDEs in structures relevant for LUT function, and discusses how inhibition of these enzymes can contribute to beneficial effects on LUTS. Information for the review was obtained from searches of the PubMed database, and from the authors' files.

  • 8.
    Baslund, B
    et al.
    Department of Rheumatology, Rigshospitalet and the University of Copenhagen.
    Gregers, Jannie
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Nielsen, C H
    Institute for Inflammation Research, Rigshospitalet, The University Hospital of Copenhagen, Denmark..
    Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells2008In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 47, no 4, p. 451-453Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.

    METHODS: Mononuclear cells were isolated from peripheral blood of healthy persons. Real-time PCR was used to detect the RFC80 variants. FITC-labelled MTX was added to cells stimulated with Candida albicans or tetanus toxoid, and the uptake of MTX was measured by flow cytometry. A FITC-conjugated monoclonal antibody against RFC was used to detect the cellular RFC expression.

    RESULTS: Antigen-stimulated CD4+ T cells and B cells from individuals with the GG variant (n = 9) exhibited lower uptake of MTX than individuals expressing the AA variant (n = 8), or the GA variant (n = 8). No difference could be demonstrated between the three groups with respect to the expression of RFC by CD4+ T cells and B cells, and CD4+ T cells from individuals homozygous for the G allele exhibited lower uptake of MTX per receptor than CD4+ T cells from individuals homozygous for the A allele.

    CONCLUSION: MTX is taken up more efficiently via the A allele than via the G allele. This difference between the variant forms of RFC suggests that genotyping could be relevant for determining the relevant dosage of MTX in the treatment of neoplastic and autoimmune disease.

  • 9.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Frödin, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Dermatology and Venerology in Östergötland.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study2012In: International Wound Journal, ISSN 1742-4801, E-ISSN 1742-481X, Vol. 9, no 4, p. 419-427Article in journal (Refereed)
    Abstract [en]

    Chronic painful wounds, a major health problem, have a detrimental impact on the quality of life due to associated pain. Some clinical reports have suggested that local administration of morphine could be beneficial. The aim of this study was to evaluate the analgesic effect of topically applied morphine on chronic painful leg ulcers. Twenty-one patients were randomly assigned to receive either morphine or placebo in a randomised, placebo-controlled, crossover pilot study. Each patient was treated four times in total. Pain was measured by the visual analogue score (VAS) before application of gel, directly after and after 2, 6, 12 and 24 hours. Although an overall, clinically relevant, reduction of pain was observed upon treatment with morphine, the difference was not statistically significant. Morphine reduced pain scores more than placebo on treatment occasions 1 and 2. The difference was statistically significant only 2 hours after dressing on the first treatment occasion. Thus, our study did not demonstrate a consistent and globally significant difference in nociception in patients treated with morphine. However, the relatively small number of patients included in our study and other methodological limitations makes it difficult for us to draw general conclusions regarding efficacy of topically applied morphine as an effective treatment for some painful ulcers. Further studies are warranted to evaluate the value of topically applied morphine in the treatment of patients with chronic painful leg ulcers.

  • 10.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Haage, Pernilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik C.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamicsManuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.

    Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.

    Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the  variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.

    Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.

  • 11.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Norling, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Walz, Thomas M
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Inhibitory effect of opiates on LPS mediated release of TNF and IL-82013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 5, p. 1022-1033Article in journal (Refereed)
    Abstract [en]

    Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

  • 12.
    Bauer, Ricarda M.
    et al.
    University of Munich, Germany.
    Strittmatter, Frank
    University of Munich, Germany.
    Gratzke, Christian
    University of Munich, Germany.
    Göttinger, Johanna
    University of Munich, Germany.
    Schlenker, Boris
    University of Munich, Germany.
    Reich, Oliver
    University of Munich, Germany.
    Stief, Christian G.
    University of Munich, Germany.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Karl-Erik
    Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, N.C., USA.
    Hennenberg, Martin
    University of Munich, Germany.
    Coupling of α1-adrenoceptors to ERK1/2 in the human prostate2011In: Urologia internationalis, ISSN 0042-1138, E-ISSN 1423-0399, Vol. 86, no 4, p. 427-433Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: α1-Adrenoceptors are considered critical for the regulation of prostatic smooth muscle tone. However, previous studies suggested further α1-adrenoceptor functions besides contraction. Here, we investigated whether α1-adrenoceptors in the human prostate may activate extracellular signal-regulated kinases (ERK1/2).

    METHODS: Prostate tissues from patients undergoing radical prostatectomy were stimulated in vitro. Activation of ERK1/2 was assessed by Western blot analysis. Expression of ERK1/2 was studied by immunohistochemistry. The effect of ERK1/2 inhibition by U0126 on phenylephrine-induced contraction was studied in organ-bath experiments.

    RESULTS: Stimulation of human prostate tissue with noradrenaline (30 μM) or phenylephrine (10 μM) resulted in ERK activation. This was reflected by increased levels of phosphorylated ERK1/2. Expression of ERK1/2 in the prostate was observed in smooth muscle cells. Incubation of prostate tissue with U0126 (30 μM) resulted in ERK1/2 inhibition. Dose-dependent phenylephrine-induced contraction of prostate tissue was not modulated by U0126.

    CONCLUSIONS: α1-Adrenoceptors in the human prostate are coupled to ERK1/2. This may partially explain previous observations suggesting a role of α1-adrenoceptors in the regulation of prostate growth.

  • 13.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    260 therapeutic drug monitorings (TDM) in relation to compliance and co-medication in psychiatric treatment2002In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 17, p. 3S-3SConference paper (Other academic)
  • 14.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Brain tryptophan/serotonin perturbations in metabolic encephalopathy and the hazards involved in the use of psychoactive drugs1999In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 467, p. 139-154Article in journal (Refereed)
    Abstract [en]

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

  • 15.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    From receptor pharmacology to clinical prescription: Antidepressants2000In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 15, p. 288S-288SConference paper (Other academic)
  • 16.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Therapeutic drug monitoring of psychotropic drugs - TDM "Nouveau"2004In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 26, no 2, p. 145-151Article in journal (Refereed)
    Abstract [en]

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

  • 17.
    Benigni, Fabio
    et al.
    San Raffaele University.
    Hedlund, Petter
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Editorial Material: Reply from Authors re: Apostolos Apostolidis. Taming the Cannabinoids: New Potential in the Pharmacologic Control of Lower Urinary Tract Dysfunction. Eur Urol 2012;61:107-1092012In: European Neurology, ISSN 0014-3022, E-ISSN 1421-9913, Vol. 61, no 1, p. 109-111Article in journal (Other academic)
    Abstract [en]

    n/a

  • 18.
    Bergmann, T K
    et al.
    University of South Denmark.
    Brasch-Andersen, C
    University of South Denmark.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Mirza, M
    Odense University Hospital.
    Pedersen, R S
    University of South Denmark.
    Nielsen, F
    University of South Denmark.
    Skougaard, K
    Herlev Hospital.
    Wihl, J
    Lund Hospital.
    Keldsen, N
    Herning Hospital.
    Damkier, P
    Odense University Hospital.
    Friberg, L E
    Uppsala University.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Vach, W
    University of South Denmark.
    Karlsson, M O
    Uppsala University.
    Brosen, K
    University of South Denmark.
    Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer2011In: PHARMACOGENOMICS JOURNAL, ISSN 1470-269X, Vol. 11, no 2, p. 113-120Article in journal (Refereed)
    Abstract [en]

    The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h(-1) (range 176-726 l h(-1)). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P = 0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P = 0.04) and ABCC1 g.7356253C andgt; G (P = 0.04).

  • 19.
    Bergmann, T K
    et al.
    University So Denmark, Institute Language and Commun, Odense, Denmark .
    Green, Henrik
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Karlsson, M O
    Uppsala University, Div Pharmacokinet and Drug Therapy, Uppsala, Sweden .
    Friberg, L
    Uppsala University, Div Pharmacokinet and Drug Therapy, Uppsala, Sweden .
    Nielsen, F
    Odense University Hospital, Department Oncol, DK-5000 Odense, Denmark .
    Brasch-Andersen, C
    n/a.
    Brosen, K
    n/a.
    Impact of sequence variants in CYP2C8 on paclitaxel clearance in ovarian cancer patients in EJC SUPPLEMENTS, vol 7, issue 2, pp 92-922009In: EJC SUPPLEMENTS, 2009, Vol. 7, no 2, p. 92-92Conference paper (Refereed)
    Abstract [en]

    n/a

  • 20.
    Bergmann, Troels K
    et al.
    University of Queensland.
    Brasch-Andersen, Charlotte
    University of So Denmark.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Mirza, Mansoor R
    Odense University Hospital.
    Skougaard, Kristin
    Herlev Hospital.
    Wihl, Jessica
    Lund Hospital.
    Keldsen, Nina
    Herning Hospital.
    Damkier, Per
    Odense University Hospital.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Vach, Werner
    Institute Medical Biometry and Medical Informat, Freiburg.
    Brosen, Kim
    University of So Denmark.
    Impact of ABCB1 Variants on Neutrophil Depression: A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer2012In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 110, no 2, p. 199-204Article in journal (Refereed)
    Abstract [en]

    The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T /A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.

  • 21.
    Bergmann, Troels K.
    et al.
    University of South Denmark.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Brasch-Andersen, Charlotte
    University of South Denmark.
    Mirza, Mansoor R.
    Odense University Hospital.
    Herrstedt, Jorn
    Odense University Hospital.
    Holund, Berit
    Odense University Hospital.
    du Bois, Andreas
    Dr Horst Schmidt Clinic.
    Damkier, Per
    Odense University Hospital.
    Vach, Werner
    University Medical Centre Freiburg.
    Brosen, Kim
    University of South Denmark.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer2011In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, no 7, p. 693-700Article in journal (Refereed)
    Abstract [en]

    Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival. The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis. Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival. CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.

  • 22.
    Bergmann, Troels K
    et al.
    University of Queensland, Australia .
    Vach, Werner
    University of Medical Centre, Germany .
    Feddersen, Soren
    Odense University Hospital, Denmark .
    Eckhoff, Lise
    Odense University Hospital, Denmark .
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Herrstedt, Jorn
    Odense University Hospital, Denmark .
    Brosen, Kim
    University of Southern Denmark, Denmark .
    Letter: GWAS-based association between RWDD3 and TECTA variants and paclitaxel induced neuropathy could not be confirmed in Scandinavian ovarian cancer patients2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 4, p. 871-U231Article in journal (Other academic)
    Abstract [en]

    n/a

  • 23.
    Berndt, Carsten
    et al.
    Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute for Clinical Cytobiology and Cytopathology, Philipps-Universität, 35037 Marburg, Germany..
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bannenberg, Sarah
    Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Jacob, Ralf
    Institute for Clinical Cytobiology and Cytopathology, Philipps-Universität, 35037 Marburg, Germany..
    Holmgren, Arne
    Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Brunk, Ulf T
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ascorbate and endocytosed Motexafin gadolinium induce lysosomal rupture.2011In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 307, no 2, p. 119-23Article in journal (Refereed)
    Abstract [en]

    Motexafin gadolinium (MGd) sensitizes malignant cells to ionizing radiation, although the underlying mechanisms for uptake and sensitization are both unclear. Here we show that MGd is endocytosed by the clathrin-dependent pathway with ensuing lysosomal membrane permeabilization, most likely via formation of reactive oxygen species involving redox-active metabolites, such as ascorbate. We propose that subsequent apoptosis is a synergistic effect of irradiation and high MGd concentrations in malignant cells due to their pronounced endocytic activity. The results provide novel insights into the mode of action of this promising anti-cancer drug, which is currently under clinical trials.

  • 24.
    Boiso, Samuel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Karlsson, Louise
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Tillmar, Andreas
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden .
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    ABCB1 gene polymorphisms are associated with suicide in forensic autopsies2013In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, no 9, p. 463-469Article in journal (Refereed)
    Abstract [en]

    Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

  • 25.
    Börjeson, Sussanne
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Nursing Science. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Hursti, T.J.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Tishelman, C.
    Department of Nursing, Karolinska Institute, Stockholm Hospital, Stockholm, Sweden.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Steineck, G.
    Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden.
    Treatment of nausea and emesis during cancer chemotherapy: Discrepancies between antiemetic effect and well-being2002In: Journal of Pain and Symptom Management, ISSN 0885-3924, E-ISSN 1873-6513, Vol. 24, no 3, p. 345-358Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to describe the relationship between antiemetic effect and well-being in patients receiving four different antiemetic treatment strategies, representing developments in the field during the past 15 years. A total of 162 women with ovarian cancer receiving cisplatin-based chemotherapy and participating in two comparative antiemetic trials were enrolled and studied for up to four cycles. In study I, a combined antiemetic strategy including a nursing intervention program (increased access to support and increased information) and antiemetics based on high-dose metoclopramide and dexamethasone was compared with the standard antiemetic treatment during the 1980s. In study II, ondansetron plus dexamethasone/placebo was evaluated. The assessment methods used were similar for all patients. Questionnaires were used to assess frequency, intensity, and duration of nausea, emesis, anxiety, pain, and well-being at baseline, and for acute (24 hours after chemotherapy) and delayed (up to 2 weeks after chemotherapy) symptoms. The mean intensity of acute nausea during the first cycle was higher in the groups in study I, as compared to the groups in study II. The group receiving a nursing intervention reported better well-being than the other groups. Duration of nausea was an important predictor of well-being, even when nausea intensity was controlled. Apart from nausea intensity, nausea duration and nursing interventions may be important determinants for well-being during chemotherapy. © U.S. Cancer Pain Relief Committee, 2002.

  • 26.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    From achiral to chiral analysis of citalopram2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Within the field of depression the “monoamine hypothesis” has been the leading theory to explain the biological basis of depression. This theory proposes that the biological basis of depression is due to a deficiency in one or more of three key neurotransmitter systems, namely noradrenaline, dopamine and serotonin which are thought to mediate the therapeutic actions of virtually every known antidepressant agent.

    Citalopram is a selective serotonin-reuptake inhibitor (SSRI) used for the treatment of depression and anxiety disorders. Citalopram is a racemic compound, in other words composed of a 50:50 mixture of two enantiomers (S-(+)-citalopram and R-(-)-citalopram) and with one of the enantiomers (S-(+)-citalopram) accounting for the inhibitory effect. At the time of introduction of citalopram the physician needed a therapeutic drug monitoring service to identify patients with interactions, compliance problems and for handling questions concerning polymorphic enzymes and drug metabolism. An achiral analytical separation method based on solid-phase extraction followed by high-performance liquid chromatography (HPLC) was developed for routine therapeutic drug monitoring (TDM) of citalopram and its two main demethylated metabolites.

    As the data available on citalopram were from achiral concentration determinations and to be able to further investigate citalopram enantiomers effects and distribution, a chiral method for separation of the enantiomers of citalopram and its demethylated metabolites was established. The advances within chiral separation techniques have made measurement of the concentrations of the individual enantiomers in biological fluids possible.

    The process behind enantioselective separation is however not fully understood and the mechanism behind the separation can be further scrutinized by the use of multivariate methods. A study of the optimization and characterization of the separation of the enantiomers of citalopram, desmethylcitalopram and didesmethylcitalopram on an acetylated ß-cyclodextrin column, by use of two different chemometric programs - response surface modelling and sequential optimization was performed. Sequential optimization can be a quicker mean of optimizing a chromatographic separation; response surface modelling, in addition to enabling optimization of the chromatographic process, also serves as a tool for learning more about the separation mechanism.

    Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent, despite the increasing use of citalopram in these age groups.

    A study was initiated to investigate adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites. The ratios between the S- and R-enantiomers of citalopram and didesmethylcitalopram were in agreement with studies involving older patients. The concentrations of the S-(+)- and R-(-) enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the polymorphic CYP2C19 enzyme.

    Even though the SSRIs are considered less toxic compared with older monoamine-active drugs like the tricyclic/tetracyclic antidepressants, the risk of developing serious side effects such as ECG abnormalities and convulsions has been seen for citalopram, when larger doses have been ingested. Furthermore, fatal overdoses have been reported where citalopram alone was the cause of death. Data on the toxicity of each of the enantiomers in humans have not been reported and no data on blood levels of the enantiomers in cases of intoxication have been presented.

    An investigation was initiated on forensic autopsy cases where citalopram had been found at the routine screening and these cases were further analysed with enantioselective analysis to determine the blood concentrations of the enantiomers of citalopram and metabolites. Furthermore the genotyping regarding the polymorphic enzymes CYP2D6 and CYP2C19 were performed.

    In 53 autopsy cases, we found increasing S/R ratios with increasing concentrations of citalopram. We found also that high citalopram S/R ratio were associated with high parent drug to metabolite ratio and may be an indicator of recent intake. Only 3.8 % were found to be poor metabolizers regarding CYP2D6 and for CYP2C19 no poor metabolizer was found.

    Enantioselective analysis of citalopram and its metabolites can provide valuable information about the time that has elapsed between intake and death. Genotyping can be of help in specific cases but the possibility of pharmacokinetic interactions is apparently a far greater problem than genetic enzyme deficiency.

    List of papers
    1. Solid-phase extraction with end-capped C2 columns for the routine measurement of racemic citalopram and metabolites in plasma by high-performance liquid chromatography
    Open this publication in new window or tab >>Solid-phase extraction with end-capped C2 columns for the routine measurement of racemic citalopram and metabolites in plasma by high-performance liquid chromatography
    1997 (English)In: Journal of Chromatography B: Biomedical Sciences and Applications, ISSN 1570-0232, Vol. 702, no 1-2, p. 234-239Article in journal (Refereed) Published
    Abstract [en]

    An assay based on solid-phase extraction followed by high-performance liquid chromatography (HPLC) was developed for the measurement of citalopram and its main metabolites desmethylcitalopram and didesmethylcitalopram. The best extraction procedure was performed with end-capped C2 column utilising secondary silanol interactions to obtain clean extract. The HPLC analysis was done on a phenyl column with a mobile phase without any amine additives. Fluorescence detection gave a limit of detection of 0.8 nmol/l plasma for the compounds analysed.

    Keywords
    Citalopram, Desmethylcitalopram, Didesmethylcitalopram
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13689 (URN)10.1016/S0378-4347(97)00366-6 (DOI)
    Available from: 2003-06-20 Created: 2003-06-20 Last updated: 2009-08-17
    2. Optimization and Characterization of the Chiral Separation of Citalopram and its Demethylated Metabolites by Response Surface Methodology
    Open this publication in new window or tab >>Optimization and Characterization of the Chiral Separation of Citalopram and its Demethylated Metabolites by Response Surface Methodology
    2001 (English)In: Chromatographia, ISSN 0009-5893, Vol. 53, no 5/6, p. 266-272Article in journal (Refereed) Published
    Abstract [en]

    Response-surface modelling and sequential optimization have been used for optimization and characterization of the separation of the enantiomers of citalopram, desmethylcitalopram, and didesmethylcitalopram on an acetylated ▀-cyclodextrin column. In the model chosen the separation conditions mobile phase methanol content, buffer concentration, column temperature, and pH were varied to investigate their influence on the chromatography. It was found that what is good for selectivity within an enantiomer pair is bad for selectivity between enantiomer pairs. Because within-pair and between-pair selectivity does not reach its optimum at the same conditions, a middle course approach has to be followed. Use of an experimental design for this investigation enabled understanding of the mechanisms of within- and between-pair separation for citalopram, desmethylcitalopram, and didesmethylcitalopram. Sequential optimization can be a quicker means of optimizing a chromatographic separation, response-surface modelling, in addition to enabling optimization of the chromatographic process, also serves as a tool for learning more about the separation mechanism.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13690 (URN)
    Available from: 2003-06-20 Created: 2003-06-20 Last updated: 2009-08-17
    3. Enantioselective Analysis of Citalopram and Metabolites in Adolescents
    Open this publication in new window or tab >>Enantioselective Analysis of Citalopram and Metabolites in Adolescents
    Show others...
    2001 (English)In: Therapeutic drug monitoring, ISSN 0163-4356, Vol. 23, no 6, p. 658-664Article in journal (Refereed) Published
    Abstract [en]

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

    Keywords
    Citalopram; Enantiomer; Genotypes; Adolescent
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13691 (URN)10.1097/00007691-200112000-00011 (DOI)
    Available from: 2003-06-20 Created: 2003-06-20 Last updated: 2013-10-28
    4. Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19
    Open this publication in new window or tab >>Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19
    Show others...
    2004 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 28, no 2, p. 94-104Article in journal (Refereed) Published
    Abstract [en]

    Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S- and R- enantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral high-performance liquid chromatography (HPLC) method. The mean (± standard deviation) S/R ratio for citalopram was 0.67 ± 0.25 and for desmethylcitalopram, 0.68 ± 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13692 (URN)10.1093/jat/28.2.94 (DOI)
    Available from: 2003-06-20 Created: 2003-06-20 Last updated: 2017-12-13
  • 27.
    Carlsson, Björn
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Holmgren, A.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Forensic Science and Toxicology .
    Ahlner, Johan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Enantioselective analysis of citalopram and escitalopram in postmortem blood together with genotyping for CYP2D6 and CYP2C192009In: Journal of Analytical Toxicology, ISSN 0146-4760, Vol. 33, no 2, p. 65-76Article in journal (Refereed)
    Abstract [en]

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

  • 28.
    Carlsson, Björn
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Norlander, Björn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Optimization and Characterization of the Chiral Separation of Citalopram and its Demethylated Metabolites by Response Surface Methodology2001In: Chromatographia, ISSN 0009-5893, Vol. 53, no 5/6, p. 266-272Article in journal (Refereed)
    Abstract [en]

    Response-surface modelling and sequential optimization have been used for optimization and characterization of the separation of the enantiomers of citalopram, desmethylcitalopram, and didesmethylcitalopram on an acetylated ▀-cyclodextrin column. In the model chosen the separation conditions mobile phase methanol content, buffer concentration, column temperature, and pH were varied to investigate their influence on the chromatography. It was found that what is good for selectivity within an enantiomer pair is bad for selectivity between enantiomer pairs. Because within-pair and between-pair selectivity does not reach its optimum at the same conditions, a middle course approach has to be followed. Use of an experimental design for this investigation enabled understanding of the mechanisms of within- and between-pair separation for citalopram, desmethylcitalopram, and didesmethylcitalopram. Sequential optimization can be a quicker means of optimizing a chromatographic separation, response-surface modelling, in addition to enabling optimization of the chromatographic process, also serves as a tool for learning more about the separation mechanism.

  • 29.
    Carlsson, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Norlander, Björn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Solid-phase extraction with end-capped C2 columns for the routine measurement of racemic citalopram and metabolites in plasma by high-performance liquid chromatography1997In: Journal of Chromatography B: Biomedical Sciences and Applications, ISSN 1570-0232, Vol. 702, no 1-2, p. 234-239Article in journal (Refereed)
    Abstract [en]

    An assay based on solid-phase extraction followed by high-performance liquid chromatography (HPLC) was developed for the measurement of citalopram and its main metabolites desmethylcitalopram and didesmethylcitalopram. The best extraction procedure was performed with end-capped C2 column utilising secondary silanol interactions to obtain clean extract. The HPLC analysis was done on a phenyl column with a mobile phase without any amine additives. Fluorescence detection gave a limit of detection of 0.8 nmol/l plasma for the compounds analysed.

  • 30.
    Carlsson, Björn
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Olsson, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Wålinder, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundmark, Jöns
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Scordo, M. G.
    Dahl, M-L.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Enantioselective Analysis of Citalopram and Metabolites in Adolescents2001In: Therapeutic drug monitoring, ISSN 0163-4356, Vol. 23, no 6, p. 658-664Article in journal (Refereed)
    Abstract [en]

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

  • 31.
    Carlsson, Marianne
    et al.
    Uppsala universitet Uppsala.
    Arman, Maria
    Karolinska institutet Stockholm.
    Backman, Maria
    Röda Korsets Högskola Stockholm.
    Flatters, Ursula
    Vidarkliniken Järna.
    Hatschek, Thomas
    Karolinska inst Stockholm.
    Hamrin, Elisabeth
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    A five-year follow-up of quality of life in women with breast cancer in anthroposophic and conventional care2006In: Evidence-based Complementary and Alternative Medicine, ISSN 1741-427X, Vol. 3, no 4, p. 523-531Article in journal (Refereed)
    Abstract [en]

    Complementary and alternative medicine is used by many cancer patients in most parts of the world, and its use is increasing. The aim of the present study was to examine, over 5 years, the perceived quality of life/life satisfaction in two samples of women with breast cancer who were treated with anthroposophic care or conventional medical treatment only. Data from admission, after 1 year and after 5 years are used for the comparisons. On admission to the study the women in anthroposophic care perceived their quality of life to be lower than that of the women in the conventional treatment group, especially for emotional, cognitive and social functioning and overall quality of life. Sixty women who actively chose treatment with anthroposophic medicine and 60 individually matched women treated with conventional medicine participated. Quality of life was measured by the EORTC QLQ-C30 and the Life Satisfaction Questionnaire. Twenty-six women within anthroposophic care and 31 women within conventional medicine survived the 5 years. Effect size (ES) estimation favored the anthroposophic group in seven of the subscales mostly measuring emotional functioning. The ES for four of the subscales favored the conventional treatment group, mostly concerning physical functioning. After 5 years there were improvements in overall quality of life and in emotional and social functioning compared to admission for the women in anthroposophic care. The improvements took place between admission and 1 year, but not further on. Only minor improvements were found in the matching group. © 2006 The Author (s).

  • 32.
    Carlsson, Marianne
    et al.
    Department of Public Health and Caring Sciences, Section of Caring Sciences, Uppsala University, Sweden.
    Arman, Maria
    Department of Caring Sciences, Åbo Akademi University, Vasa, Finland and Blekinge Institute of Technology, Karlskrona, Sweden.
    Backman, Marie
    The Swedish Red Cross University College of Nursing, Stockholm, SwedenRed Cross Univ. Coll. Nursing, Stockholm, Sweden.
    Flatters, Ursula
    The Vidar Clinic, Järna, Sweden.
    Hatschek, Thomas
    The Department of Oncology (Radiumhemmet), Karolinska Hospital and Institute, Stockholm, Sweden.
    Hamrin, Elisabeth
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Evaluation of Quality of Life/Life Satisfaction in Women with Breast Cancer in Complementary and Conventional Care2004In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, no 1, p. 27-34Article in journal (Refereed)
    Abstract [en]

    The aim was to study the perceived quality of life/life satisfaction in a sample of women with breast cancer who were treated in a hospital with alternative/complementary care and the same variables in individually matched patients who received only conventional medical treatment. A non-randomized controlled trial design with repeated measurements was used. Sixty women with breast cancer treated with anthroposophic medicine (ABCW) and 60 with conventional medicine (CBCW) were included and 36 matched pairs took part on all occasions. The quality of life was measured by the EORTC QLQ-C30 and the Life Satisfaction Questionnaire (LSQ). The comparisons were calculated as effect sizes (ES). The women in the ABCW group reported small or moderate effects, expressed as ES, on their quality of life/life satisfaction compared to their matched "twins" in the CBCW group at the 1-year follow-up in 15 out of 21 scales/factors. It was concluded that the women who had chosen anthroposophic care increased their perceived quality of life/life satisfaction according to the methodology of the study.

  • 33.
    Carlsson, Per
    et al.
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Hoffmann, Mikael
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Levin, Lars-Åke
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Sandman, Lars
    Högskolan i Borås.
    Wiss, Johanna
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Prioritering och finansiering av läkemedel för behandling av patienter med sällsynta sjukdomar: Reviderad version2012Report (Other academic)
    Abstract [en]

    An addendum to the terms of reference for the inquiry on certain issues regarding pricing, accessibility, and market conditions in the pharmaceutical and pharmacy sector (Dir. 2011:82) calls for an analysis of the need for special solutions in decisions on subsidising orphan drugs. An orphan drug is a drug that fulfils certain conditions and is thereby covered by special stimulus measures prior to approval by agencies that evaluate medical products. Orphan drugs also have the possibility, but not the right, to hold sole rights in the marketplace for 10 years.

    The report includes an analysis of the ethics platform and the Pharmaceutical Benefits Act, which serve as the Dental and Pharmaceutical Benefits Agency’s base for making decisions on subsidies. One conclusion drawn is that the current ethics platform, along with the modification of the cost-effectiveness principle that appears in the Pharmaceutical Benefits Act, offers the option to determine that society is prepared to pay more per health benefit for drugs targeted at very rare and severe diseases/conditions.

    The human dignity principle indicates that irrelevant group affiliation or group characteristics should not affect equality in a patient group’s opportunities and outcomes regarding health. Whether a patient group is small or large is an irrelevant group characteristic, and the size of the group or the rarity of the condition should not affect the group’s opportunities for treatment, or the possibility to achieve an equitable health outcome compared to other larger groups or groups with more common diseases. However, the consequence of higher costs for intervention that can result from rarity could be grounds for special treatment.

    The needs and solidarity principle indicates that all citizens should be given equal opportunities to achieve good health and that we should achieve health outcomes that are as equitable as possible for citizens. If we allow the development costs for orphan drugs to influence the possibility to access these drugs, then the citizens are not given equal opportunities to achieve good health. Hence, we draw the conclusion that people with rare and severe conditions should be given opportunities to achieve good health that are equal to those given to people with common and serious conditions.

    The cost-effectiveness principle. When lower cost effectiveness is primarily due to high costs connected with the size of the patient group, i.e. the market size for a drug, and not poor effects from the intervention, there is just cause, on the grounds of equity, to try to influence the cost aspects of the drug and in some cases accept a lower level of cost effectiveness. The cost can be influenced, for example, by pricing based on special agreements with the company marketing the drug.

    There is value in knowing that we live in a compassionate society that cares for and attempts to help people that find themselves in life-threatening or other difficult situations. This value stems partly from the assertion that knowledge creates greater security and trust in the community (based on self interest since we are all at risk of contracting a severe condition) and partly from a more altruistic motivation stemming from the assertion that we are affected positively by knowing that we live in a compassionate society. This is a factor that should also be considered in cost-effectiveness analyses. The size of this value is uncertain.

    Orphan drugs are a relatively heterogeneous group, and there are other drugs with corresponding characteristics that have not applied for status as orphan drugs. From a standpoint of priority setting, it is more relevant to focus instead on drugs that are used for rare and severe diseases. Drugs for very rare and severe conditions, particularly when no other treatment is available, should therefore be processed in a special manner regardless of whether or not they are classified as an orphan drug. To assure equitable access, transparent decisions, and appropriate care it is preferable to use a model involving national decision- making for such drugs. Three alternative principles for decisions and financing can be discussed: 1) the state as the principal authority, 2) collaboration between the state and the county councils, and 3) collaboration among the county councils.

  • 34.
    Castiglione, Fabio
    et al.
    San Raffaele University, Italy .
    Bergamini, Alice
    San Raffaele University, Italy .
    Bettiga, Arianna
    San Raffaele University, Italy .
    Bivalacqua, Trinity J.
    Johns Hopkins University, MD, USA .
    Benigni, Fabio
    San Raffaele University, Italy .
    Strittmatter, Frank
    Munich University, Germany.
    Gandaglia, Giorgio
    San Raffaele University, Italy .
    Rigatti, Patrizio
    San Raffaele University, Italy .
    Montorsi, Francesco
    San Raffaele University, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Perioperative Betamethasone Treatment Reduces Signs of Bladder Dysfunction in a Rat Model for Neurapraxia in Female Urogenital Surgery2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 62, no 6, p. 1076-1085Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Information on autonomic neurapraxia in female urogenital surgery is scarce, and a model to study it is not available.

    OBJECTIVE:

    To develop a model to study the impact of autonomic neurapraxia on bladder function in female rats, as well as to assess the effects of corticosteroid therapy on the recovery of bladder function in this model.

    DESIGN, SETTING, AND PARTICIPANTS:

    Female Sprague-Dawley rats were subjected to bilateral pelvic nerve crush (PNC) and perioperatively treated with betamethasone or vehicle. Bladder function and morphology of bladder tissue were evaluated and compared with sham-operated rats.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

    Western blot, immunohistochemistry, organ bath experiments, and cystometry.

    RESULTS AND LIMITATIONS:

    Sham-operated rats exhibited regular micturitions without nonvoiding contractions (NVCs). Crush of all nerve branches of the pelvic plexus or PNC resulted in overflow incontinence and/or NVCs. Betamethasone treatment improved recovery of regular micturitions (87.5% compared with 27% for vehicle; p<0.05), reduced lowest bladder pressure (8 ± 2 cm H(2)O compared with 21 ± 5 cm H(2)O for vehicle; p<0.05), and reduced the amplitude of NVCs but had no effect on NVC frequency in PNC rats. Compared with vehicle, betamethasone-treated PNC rats had less CD68 (a macrophage marker) in the pelvic plexus and bladder tissue. Isolated bladder from betamethasone-treated PNC rats exhibited better nerve-induced contractions, contained more cholinergic and sensory nerves, and expressed lower amounts of collagen III than bladder tissue from vehicle-treated rats.

    CONCLUSIONS:

    PNC causes autonomic neurapraxia and functional and morphologic changes of isolated bladder tissue that can be recorded as bladder dysfunction during awake cystometry in female rats. Perioperative systemic betamethasone treatment reduced macrophage contents of the pelvic plexus and bladder, partially counteracted changes in the bladder tissue, and had protective effects on micturition function.

  • 35.
    Castiglione, Fabio
    et al.
    Hospital San Raffaele, Italy .
    Bergamini, Alice
    Hospital San Raffaele, Italy .
    Russo, Andrea
    Hospital San Raffaele, Italy .
    La Croce, Giovanni
    Hospital San Raffaele, Italy .
    Castagna, Giulia
    Hospital San Raffaele, Italy .
    Colciago, Giorgia
    Hospital San Raffaele, Italy .
    Salonia, Andrea
    Hospital San Raffaele, Italy .
    Rigatti, Patrizio
    Hospital San Raffaele, Italy .
    Montorsi, Francesco
    Hospital San Raffaele, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Hospital San Raffaele, Italy .
    Inhibition of Phosphodiesterase 4 Enhances Clitoral and Vaginal Blood Flow Responses to Dorsal Clitoral Nerve Stimulation or PGE1 in Anesthetized Female Rats2013In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 10, no 4, p. 939-950Article in journal (Refereed)
    Abstract [en]

    Introduction. Cyclic adenosine 35 monophosphate (cAMP) is produced by adenylate cyclase after activation by, e.g., vasoactive intestinal polypeptide or prostaglandin E1 (PGE1). The cAMP-degrading phosphodiesterase 4 (PDE4) is expressed in the vagina and clitoris, but no information is available on the functional role for PDE4-related signals in the female neurovascular genital response. Aim. The aim of this study is to study the effect of inhibition of PDE4 with rolipram on nerve- and PGE1-induced vaginal and clitoral blood flow responses of rat. Methods. Measure of clitoral and vaginal blood flow and blood pressure in anesthetized rats during activation of the dorsal clitoral nerve (DCN) before and after intraperitoneal administration of rolipram or sildenafil (phosphodiesterase type 5 inhibitors [PDE5]) and nitro-L-arginine (L-NNA) (nitric oxide synthase inhibitor). Effect by topical administration of PGE1 on genital blood flow was also evaluated. Main Outcome Measure. Blood flow was recorded as tissue perfusion units (TPU) by a Laser Doppler Flowmeter. Mean arterial blood pressure (MAP) was recorded (cmH2O) in the carotid artery. Blood flow responses are expressed as TPU/MAP. Unpaired t-test and an analysis of variance were used. Results. Compared with control stimulations, rolipram (0.3mg/kg) caused a twofold increase in peak blood flow (Pandlt;0.05) and fourfold increase of the rate of clitoral blood flow during activation of the DCN (Pandlt;0.05). Simultaneously, a twofold increase in peak blood flow and threefold increase in rate of blood flow were noted in the vagina (Pandlt;0.05). Similar effects were noted for sildenafil (0.2mg/kg) (Pandlt;0.05). Inhibitory effects by L-NNA (60mg/kg) on blood flow responses to DCN activation were significantly lower for rats treated with rolipram than with sildenafil (Pandlt;0.05). PGE1-induced (10g) blood flow responses were significantly higher (Pandlt;0.05) in rats treated with rolipram than with sildenafil. Conclusions. These findings suggest that the cAMP/PDE4 system may be of similar functional importance as the nitric oxide/cyclic guanosine monophosphate/PDE5 pathway for neurovascular genital responses of the female rat. Castiglione F, Bergamini A, Russo A, La Croce G, Castagna G, Colciago G, Salonia A, Rigatti P, Montorsi F, and Hedlund P. Inhibition of phosphodiesterase 4 enhances clitoral and vaginal blood flow responses to dorsal clitoral nerve stimulation or PGE1 in anesthetized female rats. J Sex Med 2013; 10: 939-950.

  • 36.
    Castiglione, Fabio
    et al.
    University of Vita Salute San Raffaele, Milan, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Van der Aa, Frank
    Katholieke University of Leuven, Belgium .
    Bivalacqua, Trinity J.
    Johns Hopkins Medical Institute, Baltimore, MD, USA.
    Rigatti, Patrizio
    University of Vita Salute San Raffaele, Milan, Italy .
    Van Poppel, Hein
    Katholieke University of Leuven, Belgium .
    Montorsi, Francesco
    University of Vita Salute San Raffaele, Milan, Italy .
    De Ridder, Dirk
    Katholieke University of Leuven, Belgium .
    Albersen, Maarten
    University of Vita Salute San Raffaele, Milan, Italy .
    Intratunical Injection of Human Adipose Tissue-derived Stem Cells Prevents Fibrosis and Is Associated with Improved Erectile Function in a Rat Model of Peyronies Disease2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 63, no 3, p. 551-560Article in journal (Refereed)
    Abstract [en]

    Background: Peyronies disease (PD) is a connective tissue disorder of the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the disease in its active phase. less thanbrgreater than less thanbrgreater thanObjective: To test the effects of a local injection of adipose tissue-derived stem cells (ADSCs) in the active phase of a rat model of PD on the subsequent development of fibrosis and elastosis of the TA and underlying erectile tissue. less thanbrgreater than less thanbrgreater thanDesign, setting, and participants: A total of 27 male 12-wk-old Sprague-Dawley rats were divided in three equal groups and underwent injection of vehicle (sham), 50-mu g transforming growth factor (TGF)-beta 1 in a 50-mu l vehicle in either a PD or a PD plus ADSC group in the dorsal aspect of the TA. less thanbrgreater than less thanbrgreater thanIntervention: The sham and PD groups were treated 1 d after TGF-beta 1 injection with intralesional treatment of vehicle, and the PD plus ADSC group received 1 million human-labeled ADSCs in the 50-mu l vehicle. Five weeks after treatment, six rats per group underwent erectile function measurement. Following euthanasia, penises were harvested for histology and Western blot. less thanbrgreater than less thanbrgreater thanOutcome measurements and statistical analysis: The ratio of intracavernous pressure to mean arterial pressure (ICP/MAP) upon cavernous nerve stimulation, elastin, and collagen III protein expression and histomorphometric analysis of the penis. Statistical analysis was performed by analysis of variance followed by the Tukey-Kramer test for post hoc comparisons or the Mann-Whitney test when applicable. less thanbrgreater than less thanbrgreater thanResults and limitations: Erectile function significantly improved after ADSC treatment (ICP/MAP 0.37 in PD vs 0.59 in PD plus ADSC at 5-V stimulation; p = 0.03). PD animals developed areas of fibrosis and elastosis with a significant upregulation of collagen III and elastin protein expression. These fibrotic changes were prevented by ADSC treatment. less thanbrgreater than less thanbrgreater thanConclusions: This study is the first to test stem cell therapy in an animal model of PD. Injection of ADSCs into the TA during the active phase of PD prevents the formation of fibrosis and elastosis in the TA and corpus cavernosum.

  • 37.
    Castiglione, Fabio
    et al.
    University of Vita Salute San Raffaele, Milan, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Van der Aa, Frank
    Katholieke University of Leuven, Belgium .
    Bivalacqua, Trinity J.
    Johns Hopkins Medical Institute, MD USA .
    Rigatti, Patrizio
    University of Vita Salute San Raffaele, Italy .
    Van Poppel, Hein
    Katholieke University of Leuven, Belgium .
    Montorsi, Francesco
    University of Vita Salute San Raffaele, Milan, Italy .
    De Ridder, Dirk
    Katholieke University of Leuven, Belgium .
    Albersen, Maarten
    University of Vita Salute San Raffaele, Milan, Italy .
    Reply from Authors re: Ching-Shwun Lin, Tom F. Lue. Adipose-derived Stem Cells for the Treatment of Peyronie's Disease? Eur Urol 2013;63:561–2: Xenogeneic Adipose Stem Cell Treatment in a Rat Model of Peyronie's Disease2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 63, no 3, p. 563-564Article in journal (Other academic)
  • 38.
    Cherma Yeste, Maria Dolores
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Löfgren, Ulla-Britt
    Östergötlands Läns Landsting.
    Almkvist, Göran
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Primary Health Care Centres.
    Hallert, Claes
    Linköping University, Department of Social and Welfare Studies, Health, Activity, Care. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Prescription of antidepressant drugs in elderly nursing home patients.: A Follow-up investigation with focus on enantioselective citalopram analysis2007Conference paper (Other academic)
  • 39.
    Chermá Yeste, Maria Dolores
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Therapeutic Drug Monitoring in Psychiatry: Some aspects of utility in clinical practice and research2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described.

    Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study.

    The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype.

    The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug.

    Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.

    List of papers
    1. Therapeutic Drug Monitoring of Escitalopram in an outpatient setting
    Open this publication in new window or tab >>Therapeutic Drug Monitoring of Escitalopram in an outpatient setting
    2007 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 29, no 6, p. 758-766Article in journal (Refereed) Published
    Abstract [en]

    The main objectives of this study were to outline the inter- and intraindividual and overall pharmacokinetic variability of S-citalopram, S-desmethylcitalopram, and S-didesmethylcitalopram in serum by means of therapeutic drug monitoring, and to investigate potential correlations between the serum concentration and simultaneously collected clinical data. The study was conducted on outpatients in Sweden in 2002 to 2005. Included in the pharmacokinetic evaluation were 155 patients (68% women and 32% men) aged 17 to 95 years (average, 51 years). One serum sample per patient, taken as a trough value in steady state, was assessed. For the inter- and intraindividual variation calculation, 16 patients were included with two eligible samples each. The median daily dose was 20 mg/day (range, 5-40 mg). Extensive overall serum concentration variability was seen for all dose levels. The interindividual coefficient of variation for dose-normalized concentrations was 71% for S-citalopram, 36% for S-desmethylcitalopram, and 50% for S- didesmethylcitalopram. The intraindividual variations over time for the same parameters were approximately 30%, except for the ratio S-desmethylcitalopram/S- citalopram, which was 23%. The median S-desmethylcitalopram level was approximately 60% of the parent substance and the S-didesmethylcitalopram level approximately 9%. Higher age was correlated with higher serum concentrations, but no gender-related concentration differences were found. A majority (76%) of the patients took one or more drugs in addition to escitalopram, but concomitant medication did not seem to interact with escitalopram. However, women taking oral contraceptives showed a lower metabolic ratio compared with age-matched women. As a result of the wide range of the ratio in this population, these findings are not considered of clinical relevance.

    Keywords
    Escitalopram, Serum concentration, SSRI, Therapeutic drug monitoring
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-41188 (URN)10.1097/FTD.0b013e31815b3f62 (DOI)55316 (Local ID)55316 (Archive number)55316 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    2. Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
    Open this publication in new window or tab >>Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
    Show others...
    2008 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, no 6, p. 682-688Article in journal (Refereed) Published
    Abstract [en]

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

    Keywords
    Antipsychotic agents, ziprasidone, therapeutic drug monitoring, serum concentration, naturalistic setting
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16195 (URN)10.1097/FTD.0b013e31818ac8ba (DOI)
    Available from: 2009-01-09 Created: 2009-01-09 Last updated: 2017-12-14Bibliographically approved
    3. Assessment of the prescription of antidepressant drugs in elderly nursing home patients
    Open this publication in new window or tab >>Assessment of the prescription of antidepressant drugs in elderly nursing home patients
    Show others...
    2008 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, no 4, p. 424-431Article in journal (Refereed) Published
    Abstract [en]

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

    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-20985 (URN)10.1097/JCP.0b013e31817d79eb (DOI)
    Available from: 2009-09-27 Created: 2009-09-27 Last updated: 2018-01-13Bibliographically approved
    4. Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
    Open this publication in new window or tab >>Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Objective: The aims of this study were to evaluate the pharmacokinetics (PKs) of antidepressant agents, in terms of steady-state and trough values, in a heterogeneous cohort of patients and to describe the utilisation of antidepressant drugs (ATDs) in Child and Adolescent Psychiatry in the south- east of Sweden.

    Method: Patients from Child and Adolescent Psychiatry centres in the counties of Östergötland, Jönköping and Kalmar (Sweden) to be prescribed an antidepressant drug, were studied between 2002 and 2004. The blood concentration of ATDs and, in some cases, also CYP2D6 were determined and relevant clinical information provided.

    Results: Two hundred and eleven children: 64 % girls and 36 % boys, between the ages of 8 and 20 were evaluated. The concentrations of drugs in the patient evaluated (PE) population were as expected from the dose administered in 63 % of this population, higher than expected in 26 % and lower than expected in 11 %.

    Dose-concentration relationships for sertraline (rs=0.48, p<0.001) and metabolite desmethylsertraline (rs=0.5, p<0.001) were seen. No relationship was found between dose and ratio desmethylsertraline-to-sertraline. CYP2D6*4 was the most common poor metabolizer (PM) allele. The primary indication for the antidepressant treatment was depression in 69 % of subjects. Suspected adverse drug reactions were spontaneously reported in 31 %. Monotherapy was indicated in 49 % of request forms. The most common drug combinations with the antidepressant drug were oral anticontraceptives and anxiolytics/sedatives/hypnotic drugs.

    Conclusion: the most prescribed antidepressant drug in children and adolescents in the present study was sertraline. The pharmacokinetic outcomes of serum concentration of sertraline, as well as daily doses administered were similar to the referenced data for adults. Antidepressant drug monotherapy was most common. No serious adverse side effects were spontaneously reported. TDM may provide support to the prescribing physicians to individual dose optimising and to assess drug compliance, above all when the antidepressant drugs are not well studied in pediatric patients before approval for general prescription. Further clinical trials, as well as naturalistic studies are necessary to ensure that children are not exposed to unnecessary risk and to determine the most appropriate dose in children of different ages.

    Keywords
    antidepressants, therapeutic drug monitoring, dosage, serum concentration, pediatrics
    National Category
    Pharmacology and Toxicology Psychiatry
    Identifiers
    urn:nbn:se:liu:diva-52106 (URN)
    Available from: 2009-12-04 Created: 2009-12-04 Last updated: 2018-01-12Bibliographically approved
  • 40.
    Chermá Yeste, Maria Dolores
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Gustafsson, Per A.
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry . Linköping University, Faculty of Health Sciences.
    Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical studyManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: The aims of this study were to evaluate the pharmacokinetics (PKs) of antidepressant agents, in terms of steady-state and trough values, in a heterogeneous cohort of patients and to describe the utilisation of antidepressant drugs (ATDs) in Child and Adolescent Psychiatry in the south- east of Sweden.

    Method: Patients from Child and Adolescent Psychiatry centres in the counties of Östergötland, Jönköping and Kalmar (Sweden) to be prescribed an antidepressant drug, were studied between 2002 and 2004. The blood concentration of ATDs and, in some cases, also CYP2D6 were determined and relevant clinical information provided.

    Results: Two hundred and eleven children: 64 % girls and 36 % boys, between the ages of 8 and 20 were evaluated. The concentrations of drugs in the patient evaluated (PE) population were as expected from the dose administered in 63 % of this population, higher than expected in 26 % and lower than expected in 11 %.

    Dose-concentration relationships for sertraline (rs=0.48, p<0.001) and metabolite desmethylsertraline (rs=0.5, p<0.001) were seen. No relationship was found between dose and ratio desmethylsertraline-to-sertraline. CYP2D6*4 was the most common poor metabolizer (PM) allele. The primary indication for the antidepressant treatment was depression in 69 % of subjects. Suspected adverse drug reactions were spontaneously reported in 31 %. Monotherapy was indicated in 49 % of request forms. The most common drug combinations with the antidepressant drug were oral anticontraceptives and anxiolytics/sedatives/hypnotic drugs.

    Conclusion: the most prescribed antidepressant drug in children and adolescents in the present study was sertraline. The pharmacokinetic outcomes of serum concentration of sertraline, as well as daily doses administered were similar to the referenced data for adults. Antidepressant drug monotherapy was most common. No serious adverse side effects were spontaneously reported. TDM may provide support to the prescribing physicians to individual dose optimising and to assess drug compliance, above all when the antidepressant drugs are not well studied in pediatric patients before approval for general prescription. Further clinical trials, as well as naturalistic studies are necessary to ensure that children are not exposed to unnecessary risk and to determine the most appropriate dose in children of different ages.

  • 41.
    Chermá Yeste, Maria Dolores
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Löfgren, Ulla-Britt
    n/a.
    Almkvist, Göran
    n/a.
    Hallert, Claes
    Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland. Linköping University, Department of Social and Welfare Studies, Health, Activity, Care. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Assessment of the prescription of antidepressant drugs in elderly nursing home patients2008In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, no 4, p. 424-431Article in journal (Refereed)
    Abstract [en]

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

  • 42.
    Christensen, Mette M H
    et al.
    University of So Denmark.
    Brasch-Andersen, Charlotte
    Odense University Hospital.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Nielsen, Flemming
    University of So Denmark.
    Damkier, Per
    Odense University Hospital.
    Beck-Nielsen, Henning
    Odense University Hospital.
    Brosen, Kim
    University of So Denmark.
    The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c2011In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 21, no 12, p. 837-850Article in journal (Refereed)
    Abstract [en]

    Objective The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac). less thanbrgreater than less thanbrgreater thanMethod The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment. less thanbrgreater than less thanbrgreater thanResults The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54-4133 ng/ml, rho = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months. less thanbrgreater than less thanbrgreater thanConclusion In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous 80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.

  • 43.
    Coulthard, Sally A
    et al.
    Newcastle University.
    Redfern, Christopher P F
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hall, Andrew G
    Newcastle University.
    Taylor, Gordon A
    Newcastle University.
    Hogarth, Linda A
    Newcastle University.
    Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers2011In: MOLECULAR CANCER THERAPEUTICS, ISSN 1535-7163, Vol. 10, no 3, p. 495-504Article in journal (Refereed)
    Abstract [en]

    The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dG(s)) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP(-)) transfected to express MTAP constitutively (A549-MTAP(+)). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP(-) conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dG(s) incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP.

  • 44.
    Coulthard, Sally
    et al.
    Newcastle University, UK.
    Redfern, Christopher
    Newcastle University, UK.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hall, Andrew
    Newcastle University, UK.
    Taylor, Gordon
    Newcastle University, UK.
    Hogarth, Linda
    Newcastle University, UK.
    Increased sensitivity to thiopurines in methylthioadenosine phosphorylase-deleted cancers in PURINERGIC SIGNALLING, vol 6, issue , pp 33-332010In: PURINERGIC SIGNALLING, Springer Science Business Media , 2010, Vol. 6, p. 33-33Conference paper (Refereed)
    Abstract [en]

    The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used in the treatment of leukaemia. Incorporation of deoxythioguanosine nucleotides (dGs) into the DNA of thiopurine-treated cells causes cell death but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Since the growth of MTAP-deleted tumour cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukaemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP-ve) transfected to express MTAP constitutively (A549-MTAP+ve). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intra-cellularly to MeTIMP, was markedly higher in both cell lines under MTAP-ve conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dGs incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP.

  • 45.
    D Cherma, Maria
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Gustafsson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry.
    Antidepressant Drugs in Children and Adolescents Analytical and Demographic Data in a Naturalistic, Clinical Study2011In: JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, ISSN 0271-0749, Vol. 31, no 1, p. 98-102Article in journal (Refereed)
    Abstract [en]

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

  • 46.
    Dizdar (Dizdar Segrell), Nil
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences.
    Kullman, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Norlander, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Olsson, Jan-Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Human pharmacokinetics of L-3,4-dihydroxyphenylalanine studied with microdialysis1999In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 45, no 10, p. 1813-1820Article in journal (Refereed)
    Abstract [en]

    Background: Intravenous and subcutaneous microdialysis was performedto compare the free concentrations and pharmacokinetics of L-3,4-dihyroxyphenylalanine(L-dopa) in blood and tissue in healthy subjects and in patientswith Parkinson disease.

    Methods: Nine healthy volunteers and 10 patients with Parkinson disease, stage 1.5–2 according to the Hoehn-Yahr rating scale, took part of the study. In the patient group subcutaneous microdialysis and ordinary blood sampling were performed, whereas in the control group intravenous microdialysis was also performed. Microdialysis samples were collected in fractions of 15 min. The first two fractions were collected for analysis of basal concentrations. A blood sample was also taken. The patients were then given one tablet of Madopar® (100 mg of L-dopa and 25 mg of benserazide),and the microdialysis was continued for another 210 min. Bloodsamples were obtained at 30-min intervals.

    Results: The serum samples gave a significantly higher meanarea under the curve (AUC; 491 ± 139 µmol ·min/L) than that for intravenous dialysates (235 ± 55.3µmol · min/L), suggesting a protein binding of50%. The L-dopa concentrations from the subcutaneous dialysatesmatched those from the intravenous dialysates, indicating rapiddistribution of L-dopa to the tissues.

    Conclusions: Parkinsonian patients in early stages of the disease have a pharmacokinetic pattern of free L-dopa similar to that of healthy subjects. Comparison of AUCs from microdialysis with ordinary serum analysis revealed data indicating significant protein binding. Microdialysis is a suitable and easily applied tool in pharmacokinetic studies.

  • 47.
    Dizeyi, Nishtman
    et al.
    Malmö University Hospital, Lund University, Malmö.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bjartell, Anders
    Malmö University Hospital, Lund University, Malmö.
    Tinzl, Martina
    Malmö University Hospital, Lund University, Malmö.
    Austild-Taskén, Kristin
    Oslo Urological University Clinic, Aker University Hospital, University of Oslo, Norway.
    Abrahamsson, Per-Anders
    Malmö University Hospital, Lund University, Malmö.
    Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines2011In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 29, no 4, p. 436-445Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study was conducted to examine the effects of 5-HT on extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt pathways in prostate cancer (PC) cells.

    METHODS: PC cell lines PC-3, Du145, and LNCaP stimulated with 5-HT in the presence of MEK or PI3K inhibitors and 5-HT receptor subtype 1A antagonist were analyzed by Western blotting and immunofluorescence. The proliferation assay BrdU and Boyden chamber were used to determine proliferation and migration, respectively.

    RESULTS: 5-HT dose-dependently induced rapid activation of Erk1/2 in PC-3 and Du145 cells, whereas in LNCaP cells, Erk1/2 phosphorylation was slow and sustained for up to 18 h. Similarly, 5-HT induced phosphorylation of Akt within 1 hour of stimulation, however, Akt phosphorylation was more pronounced in Du145 cells compared with PC-3 or LNCaP cells. The action of 5-HT was inhibited to varying degrees by inhibitors of MAPK and PI3K as well as by a 5-HT receptor subtype 1A antagonist. In addition to proliferation, 5-HT induced migration of PC-3 and Du145 cells, which were alleviated by the aforementioned inhibitors. The effects of 5-HT on LNCaP cells appeared to be related to neuroendocrine-phenotype acquisition and chromogranin A and neuron specific enolase expression.

    CONCLUSIONS: This study addresses the role of 5-HT in Erk1/2 and Akt activation in PC cells. The data presented here identify 5-HT receptors as a novel target in castration-resistant PC. Furthermore, our observations are in line with previous studies, which point towards neuroendocrine factors facilitating progression and migration of prostatic cancer cells in an androgen-deficient environment. Nonetheless, additional studies are warranted to corroborate the role of 5-HTR antagonists as a potential target for anticancer therapy.

  • 48.
    Djerf, Emelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Abdiu, Avni
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Plastic Surgery, Hand surgery UHL.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, no 3, p. 563-568Article in journal (Refereed)
    Abstract [en]

    The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses less than= 5 mu M canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.

  • 49.
    Dolores Cherma Yeste, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting2008In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, no 6, p. 682-688Article in journal (Refereed)
    Abstract [en]

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

  • 50.
    Drake, M.
    et al.
    Urological Institute, Southmead Hospital, Bristol, UK.
    Gillespie, J.
    University of Newcastle, Newcastle-upon-Tyne, UK.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Harvey, I.
    University of Newcastle, Newcastle-upon-Tyne, UK.
    Lagou, M.
    University of Newcastle, Newcastle-upon-Tyne, UK.
    Andersson, K-E
    Lund University Hospital.
    Muscarinic stimulation of the rat isolated whole bladder: pathophysiological models of detrusor overactivity2006In: Autonomic & Autacoid Pharmacology, ISSN 1474-8665, E-ISSN 1474-8673, Vol. 26, no 3, p. 261-266Article in journal (Refereed)
    Abstract [en]

    1 Hypotheses as to the pathophysiological basis of bladder detrusor muscle overactivity (DO) have identified both central nervous and peripheral mechanisms as likely contributory factors. In this paper, we describe peripheral autonomous bladder activity in two animal models of DO and discuss how the differences observed between the two models support the likelihood that clinical DO has a multifactorial basis. 2 A total of 12 adult female Sprague-Dawley rats underwent obstruction or sham operation for 1 or 4 weeks. Six adult female spontaneously hypertensive rats (SHR) were compared with normal Wistar controls. Bladders were microsurgically removed and mounted in whole organ tissue baths. Recordings of intravesical pressure in response to the muscarinic receptor agonist arecaidine were performed under standardized conditions. 3 In the partially obstructed rat bladder, the amplitude of pressure fluctuations elicited by the muscarinic agonist arecaidine was significantly increased compared with sham-operated animals. The tonic component of the response was no different for the two groups. No difference from controls was apparent in the SHR. 4 We conclude that alterations in autonomous bladder activity in the obstructed rat model suggest that peripheral functional changes contribute to the pathophysiological abnormality. In contrast, the fundamental abnormality in the SHR appears to be at a more central level. The observations support the supposition that lesions at widely separate sites can give rise to apparently similar abnormalities of lower urinary tract function.

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