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  • 1.
    Abrate, Alberto
    et al.
    IRCCS Osped San Raffaele, Italy.
    Buono, Roberta
    IRCCS Osped San Raffaele, Italy.
    Canu, Tamara
    IRCCS Osped San Raffaele, Italy.
    Esposito, Antonio
    IRCCS Osped San Raffaele, Italy.
    Del Maschio, Alessandro
    IRCCS Osped San Raffaele, Italy.
    Luciano, Roberta
    IRCCS Osped San Raffaele, Italy; IRCCS Osped San Raffaele, Italy.
    Bettiga, Arianna
    IRCCS Osped San Raffaele, Italy.
    Colciago, Giorgia
    IRCCS Osped San Raffaele, Italy.
    Guazzoni, Giorgio
    IRCCS Osped San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Hedlund, Petter
    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. IRCCS Osped San Raffaele, Italy.
    Altaner, Cestmir
    Slovak Academic Science, Slovakia; St Elisabeth Cancer Institute, Slovakia.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy.
    Cavarretta, Ilaria T. R.
    IRCCS Osped San Raffaele, Italy.
    Mesenchymal stem cells expressing therapeutic genes induce autochthonous prostate tumour regression2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 14, p. 2478-2488Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSC) as vehicles of therapeutic genes represent a unique tool to activate drugs within a neoplastic mass due to their property to home and engraft into tumours. In particular, MSC expressing the cytosine deaminase:: uracil phosphoribosyltransferase (CD-MSC) have been previously demonstrated to inhibit growth of subcutaneous prostate cancer xenografts thanks to their ability to convert the non-toxic 5-fluorocytosine into the antineoplastic 5-fluorouracil. Since both the immune system and the tumour microenvironment play a crucial role in directing cancer progression, in order to advance towards clinical applications, we tested the therapeutic potential of this approach on animal models that develop autochthonous prostate cancer and preserve an intact immune system. As cell vectors, we employed adipose-tissue and bone-marrow MSC. CD-MSC toxicity on murine prostate cancer cells and tumour tropism were verified in vitro and ex-vivo before starting the preclinical studies. Magnetic Resonance Imaging was utilised to follow orthotopic tumour progression. We demonstrated that intravenous injections of CD-MSC cells, followed by intraperitoneal administration of 5-fluorocytosine, caused tumour regression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which develops aggressive and spontaneous prostate cancer. These results add new insights to the therapeutic potential of specifically engineered MSC in prostate cancer disease.

  • 2.
    Aizawa, Naoki
    et al.
    University of Tokyo, Japan.
    Hedlund, Petter
    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.
    Fuellhase, Claudius
    University of Munich, Germany.
    Ito, Hiroki
    University of Tokyo, Japan.
    Homma, Yukio
    University of Tokyo, Japan.
    Igawa, Yasuhiko
    University of Tokyo, Japan .
    Inhibition of Peripheral FAAH Depresses Activities of Bladder Mechanosensitive Nerve Fibers of the Rat2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 192, no 3, p. 956-963Article in journal (Refereed)
    Abstract [en]

    Purpose: FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats. Materials and Methods: Female Sprague Dawley (R) rats were anesthetized. Single unit afferent activity of A delta or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP in the L6 dorsal root ganglion were compared by immunofluorescence. Results: A total of 102 single afferent fibers (48 A delta and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean +/- SEM of 78% +/- 9% and of A delta-fibers to a mean of 67% +/- 7% while increasing bladder compliance to a mean of 116% +/- 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity of each fiber type but SR144528 affected only A delta-fiber activity. CGRP positive L6 dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining. Conclusions: To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Ad and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.

  • 3.
    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

  • 4.
    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.

  • 5.
    Buono, Roberta
    et al.
    IRCCS Osped San Raffaele, Italy.
    Briganti, Alberto
    IRCCS Osped San Raffaele, Italy.
    Freschi, Massimo
    IRCCS Osped San Raffaele, Italy.
    Villa, Luca
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    La Croce, Giovanni
    IRCCS Osped San Raffaele, Italy; Lund University, Sweden.
    Moschini, Marco
    IRCCS Osped San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Castiglione, Fabio
    University of Vita Salute San Raffaele, Italy; Lund University, Sweden.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    Hedlund, Petter
    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.
    Silodosin and tadalafil have synergistic inhibitory effects on nerve-mediated contractions of human and rat isolated prostates2014In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 744, p. 42-51Article in journal (Refereed)
    Abstract [en]

    Lower urinary tract symptoms (CUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction. Alpha-1-adrenoceptor antagonists are effective drugs for treating symptomatic BPH. Clinical data show improvements in LUIS by phosphodiesterase 5 inhibitors. This study aimed to evaluate effects of siloclosin, a highly selective alpha(1A)-adrenoceptor antagonist, alone or in combination with the phosphocliesterase 5 inhibitor tadalafil on contractions of isolated human and rat prostates. In organbath studies, effects of increasing concentrations of siloclosin (1 nM-1 mu M) and tadalafil (100 nM-100 mu M) on contractions by electrical field stimulation or phenylephrine of human and rat prostate strip preparations were investigated. The combination silodosin and tadalafil reduced electrically-induced contractions of human prostate preparations better than single drugs alone. At any frequencies (1-32 Hz), inhibitory effects of combined therapy (P-values vs single drug) in human tissue were 26-42% (1 nM silodosin+100 nM tadalafil; P less than 0.05), 40-58% (10 nM silodosin+1 mu M tadalafil; P less than 0.001-0.05), 56-67% (100 nM silodosin+10 mu M tadalafil; P less than 0.01-0.05), and 33-55% (1 mu M silodosin+100 mu M tadalafil P less than 0.01-0.05), Similar findings were obtained in rat prostate preparations. In human and rat prostate tissue, the drug combination exerted similar inhibitory effect on phenylephrine contractions as silodosin alone. Silodosin plus tadalafil had greater potency than each drug alone to inhibit prostate contractions to electrical field stimulation but not to phenylephrine. This study supports the clinical application of a combination of an (alpha(1A)-adrenoceptor antagonist and a phosphodiesterase 5 inhibitor for symptomatic BPH and suggests that the drug combination requires endogenous nerve-activity for optimal effect.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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.

  • 9.
    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)
  • 10.
    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)
  • 11.
    Ekman, Elisabet
    et al.
    Regional Pharmacovigilance Unit, Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
    Hägg, Staffan
    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.
    Sundström, Anders
    Centre for Pharmacoepidemiology, Karolinska Institute, Stockholm, Sweden.
    Werkström, Viktoria
    Regional Pharmacovigilance Unit, Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
    Antihypertensive drugs and erectile dysfunction as seen in spontaneous reports, with focus on angiotensin II type 1 receptor blockers2010In: Drug, Healthcare and Patient Safety, ISSN 1179-1365, Vol. 2, p. 21-25Article in journal (Refereed)
    Abstract [en]

    Aim: To describe spontaneously reported cases of erectile dysfunction (ED) in association with angiotensin II type I blockers (ARB) and other antihypertensive drugs.

    Subjects and methods: All spontaneously reported cases of ED submitted to the Swedish Medical Products Agency (MPA) between 1990 and 2006, where at least one antihypertensive drug was the suspected agent, were scrutinized. Patient demographics, drug treatment and adverse reactions were recorded. Using the Bayesian Confidence Propagation Neural Network (BCPNN) method, the information component (IC) was calculated.

    Results: Among a total of 225 reports of ED, 59 involved antihypertensive drugs including ARB (9 cases) as suspected agents. A positive IC value was found indicating that ED was reported more often in association with antihypertensive drugs classes, except for angiotensin-converting enzyme inhibitors, compared with all other drugs in the database. Positive dechallenge was reported in 43 cases (72%).

    Discussion: All classes of major antihypertensive drugs including ARB were implicated as suspected agents in cases of ED. Few risk factors were identified. The relatively high reporting of ED in association with ARB is in contrast with previous studies, suggesting that ARB have neither a positive nor any effect on ED. This discrepancy suggests that further studies are warrnted on this potential adverse reaction to ARB.

  • 12.
    Falk, Magnus
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Bradley, Thomas
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Edström, Morgan
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Johansson-Fredin, Solveig
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Primary Health Care in Central County.
    Tärning, Eva
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Carlsson, Per
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Från evidens till praktik: utvärdering av ett nytt arbetssätt för att använda evidens i vårdens förbättringsarbete2014Report (Other academic)
    Abstract [sv]

    Att hälso- och sjukvården ska bedrivas utifrån vetenskap och beprövad erfarenhet är allmänt vedertaget. Ett snabbt ökande kunskapsflöde innebär dock höga krav på såväl behandlande enheter som på den enskilda läkaren, som i sitt vardagsarbete ska fatta medicinska beslut utifrån bästa möjliga kunskap. Att på ett strukturerat och effektivt sätt underlätta spridningen av, och tillgången till, evidensbaserad kunskap utgör en stor utmaning för hela samhället, inklusive forskarsamhället. För vården är det en utmaning att använda kunskapen.

    Syftet med projektet var att utveckla, pröva och utvärdera en lokalt anpassad modell för implementering av evidensbaserad kunskap i klinisk verksamhet, baserad på ett arbetssätt som tidigare prövats i Kanada (Alberta Ambassador Programme), och som modifierades för att passa de lokala förutsättningarna i Östergötland, där projektet genomfördes. Som kliniskt beslutsproblem att studera valdes förskrivning av läkemedlet pregabalin, som används vid epilepsi, generaliserat ångestsyndrom (GAD) och neuropatisk smärta. Valet grundades på att läkemedlet är dyrt i förhållande till alternativen, på en  ökande förskrivning med stor variationinom länet, samt på rapporter om  förskrivning utanför rekommenderadesjukdomstillstånd. Sammantaget pekade detta på osäkerhet i hur läkemedlet skulle användas och därmed utrymme för förbättring.

    Projektet genomfördes i fyra steg: 1) Framtagning av ett övergripande evidensdokument för pregabalin, 2) Expertgruppsmöten (uppdelade på psykiatri/smärta) där det utifrån evidensdokumentet arbetades fram ett sammanfattande evidensunderlag/expertrekommendation, 3) Dialogmöten på ett antal sjukhuskliniker/vårdcentraler, samt 4) Uppföljning och utvärdering. En webbenkät skickades till deltagarna direkt efter genomförda dialogmöten, samt efter tio veckor. Resultatet visade att deltagarna till övervägande del var nöjda med innehållet i och formerna för dialogen. En majoritet bedömde innehållet som värdefullt för kliniska ställningstaganden, och att det vid tioveckorsuppföljningen fått spridning på den egna enheten. Statistik över receptförskrivningen av pregabalin tio månader före och efter interventionen, visade för länets tre psykiatriska kliniker (vilka före interventionen skilt sig drastiskt åt i fråga om förskrivning per 1000 patienter) en tydlig utjämning i förskrivning mellan klinikerna. För övriga sjukhuskliniker och vårdcentraler gick det däremot inte att se någon tydlig förändring i detta avseende.

    Sammanfattningsvis bedöms den prövade modellen för implementering av evidensbaserad kunskap ha fungerat väl utifrån det praktiska genomförandet och baserat på deltagarnas omdömen, och bör därav kunna prövas även inom andra områden.

  • 13.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Lyth, Johan
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Lotfi, Kourosh
    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.
    A prospective evaluation of patients' health-related quality of life during auto-SCT: a 3-year follow-up2011In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 46, no 10, p. 1345-1352Article in journal (Refereed)
    Abstract [en]

    Few studies have evaluated long-term health-related quality of life (HRQL) in patients during auto-SCT. This prospective study examined HRQL in 96 eligible patients before, during and up to 3 years after auto-SCT. The aim of the study was to make a comprehensive assessment of the frequency and severity of different symptoms in patients undergoing auto-SCT. The European Organization for Treatment and Research of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) was administered 13 times. The second week during treatment was the period when patients had the lowest HRQL regarding both total quality of life and function and symptom scales. The patients recovered quickly and just two months after transplantation the baseline values were restored. Three years after transplantation most of the items in the questionnaire had stabilized, except role function and dyspnea, which had improved. There were significant differences between multiple myeloma (MM) and lymphoma patients’ physical function, quality of life, fatigue and pain during week 2. At the 3-year follow-up, lymphoma patients indicated a better HRQL than MM patients. The quick recovery of patients after transplantation suggests that treatment is well tolerated; however, the supportive care could be improved at week 2, especially for the lymphoma patients.

  • 14.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    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.
    Fomichov, Victoria
    Östergötlands Läns Landsting, Centre for Health and Developmental Care, Regional Cancer Centre.
    Juliusson, Gunnar
    Department of Hematology and Coagulation, Skåne County Council, Stem Cell Center, Lund University, Lund, Sweden.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Early and Long-Term Follow-Up of Health-Related Quality of Life Following Allogeneic Hematopoietic Stem-Cell Transplantation2013Manuscript (preprint) (Other academic)
    Abstract [en]

    Health-related quality of life (HRQL) of 94 consecutive patients undergoing allogeneic stem cell transplantation (SCT) with myeloablative conditioning (MAC, n = 18) or reduced intensity conditioning (RIC, n = 76) was evaluated using the EORTC QLQ C-30 questionnaire at baseline and 12 times up to 3 years after SCT. Functional status and the global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first three weeks, particularly appetite loss, nausea and vomiting, diarrhea, and fatigue. It took at least one year for HRQL to return to the baseline level. The only function that improved significantly three years after SCT was role function. MAC patients experienced worse HRQL at baseline than RIC patients, and subsequently more pain, sleep disturbance, and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease (GvHD) experienced reduced HRQL. These results provide a good overview of patients’ symptoms and HRQL during and after SCT and indicate when they require increased support. The results also demonstrate the importance of close follow-ups during the first year after SCT in order to improve the preventive interventions, particularly regarding appetite loss and chronic GvHD.

  • 15.
    Fuellhase, Claudius
    et al.
    University of Munich, Germany .
    Russo, Andrea
    San Raffaele University, Italy .
    Castiglione, Fabio
    San Raffaele University, Italy .
    Benigni, Fabio
    San Raffaele University, Italy .
    Campeau, Lysanne
    Wake Forest University, NC USA .
    Montorsi, Francesco
    San Raffaele University, Italy .
    Gratzke, Christian
    University of Munich, Germany .
    Bettiga, Arianna
    San Raffaele University, Italy .
    Stief, Christian
    University of Munich, Germany .
    Andersson, Karl-Erik
    Wake Forest University, NC USA .
    Hedlund, Petter
    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.
    Spinal Cord FAAH in Normal Micturition Control and Bladder Overactivity in Awake Rats2013In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 189, no 6, p. 2364-2370Article in journal (Refereed)
    Abstract [en]

    Purpose: We assessed whether spinal inhibition of the cannabinoid degrading enzyme FAAH would have urodynamic effects in normal rats and rats with bladder overactivity induced by partial urethral obstruction or prostaglandin E2. We also determined the expression of FAAH, and the cannabinoid receptors CB1 and CB2 in the sacral spinal cord. Materials and Methods: We used 44 rats for functional (cystometry) and Western blot experiments. The FAAH inhibitor oleoyl ethyl amide (3 to 300 nmol) was administered intrathecally (subarachnoidally) or intravenously. The expression of FAAH and CB1/CB2 receptors was determined by Western blot. Results: Oleoyl ethyl amide given intrathecally affected micturition in normal rats and rats with bladder overactivity but effects were more pronounced in the latter. In normal rats oleoyl ethyl amide only decreased micturition frequency, while it decreased frequency and bladder pressures in rats with bladder overactivity. Intravenous oleoyl ethyl amide (3 to 300 nmol) had no urodynamic effect. FAAH and CB1/CB2 receptors were expressed in the rat sacral spinal cord. The expression of CB1/CB2 receptors but not FAAH was higher in obstructed than in normal rats. Conclusions: FAAH inhibition in the sacral spinal cord by oleoyl ethyl amide resulted in urodynamic effects in normal rats and rats with bladder overactivity. The spinal endocannabinoid system may be involved in normal micturition control and it appears altered when there is bladder overactivity.

  • 16.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Albertioni, Freidoun
    Cancer Center Karolinska Department of Oncology and Pathology, Karolinska University Hospital, SE-171 76 Stockholm.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    The role of deoxyguanosine kinase for nucleoside analog activation in leukemic and solid tumor cell linesManuscript (preprint) (Other academic)
    Abstract [en]

    Screening malignant melanoma cell lines against nucleoside analogs revealed as high sensitivity to fludarabine, clofarabine, and gemcitabine as to leukemic cells, and especially in those cells expressing high levels of the mitochondrial enzyme deoxuguanosine kinase (dGK). This enzyme, together with the cytosolic deoxycytidine kinase (dCK), and the mitochondrial thymidine kinase 2 (TK2) contributes to the activation of natural deoxyribonucleosides and nucleoside analogs to phosphorylated compounds. dCK is the most prominent enzyme in hematopoietic cells, while dGK may be high in cells harbouring many mitochondria, such as neurons and melanocytes. We found that dGK mRNA and protein expression was considerably higher in melanoma cells than in a leukemic cell line, while the difference at the activity level was less profound.

    Downregulation of dGK in the melanoma cell line RaH5 using siRNA led to a compensatory increase in TK2 activity, which led to significantly increased sensitivity of the cells to gemcitabine. In contrast, downregulation of dGK in the human leukemic CEM cell line decreased TK2 activity, and rendered the cells more resistant to the drugs. The compensatory regulation of deoxynucleoside kinases with over-lapping substrate specificity differed in leukemic and melanoma cell lines probably because they preferably rely on different deoxynucleoside kinases for nucleoside and nucleoside analog activation. dGK and TK2 that are both located in the mitochondria, seems to be able to compensate for each other to a higher extent in the dGK-dependent melanoma cells compared to CEM cells that possess high dCK activity. Solid tumors, such as melanoma, expressing high levels of dGK should be considered for nucleoside analog therapy preferably in combination with their standard treatment.

  • 17.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    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.
    Kågedal, Bertil
    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.
    Lotfi, Kourosh
    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.
    Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells2011In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, no 3, p. 583-591Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To characterize resistance mechanisms to the nucleoside analog 9-β-D-arabinofuranosylguanine (AraG) in the T-cell acute lymphoblastic leukemia cell line MOLT-4 and its AraG-resistant variant.

    METHODS: A gene expression microarray analysis was performed, as well as gene expression and enzyme activity measurements of key enzymes in the activation of AraG. Cytotoxicity of AraG and cross-resistance to other compounds were evaluated using a standard cytotoxicity assay.

    RESULTS: Gene expression microarray analysis revealed that fetal hemoglobin genes and the multidrug resistance ABCB1 gene, encoding the drug efflux pump P-gp, were the most highly upregulated genes in the resistant cells, while genes traditionally associated with nucleoside analog resistance were not. Fetal hemoglobin and ABCB1 induction can be due to global DNA hypomethylation. This phenomenon was studied using AraG during a period of 4 weeks in MOLT-4 cells and the lung adenocarcinoma cell line A549, leading to up-regulation of hemoglobin gamma and ABCB1 as well as DNA hypomethylation. Inhibiting P-gp in the AraG-resistant MOLT-4 cells led to decreased proliferation, reduced hemoglobin expression, and highly induced ABCB1 expression.

    CONCLUSIONS: We show that AraG can cause hypomethylation of DNA and induce the expression of the fetal hemoglobin gamma gene and the ABCB1 gene. We speculate that the induction of ABCB1/P-gp may occur in order to help with excretion of hemoglobin degradation products that would otherwise be toxic to the cells, and we present data supporting our theory that P-gp may be linked to the induction of hemoglobin.

  • 18.
    Fyrberg, Anna
    et al.
    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.
    Wolk, M
    Israel Minist Health Central Labs, Israel .
    Lotfi, Kourosh
    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.
    A potential role of fetal hemoglobin in the development of multidrug resistance2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 427, no 3, p. 456-460Article in journal (Refereed)
    Abstract [en]

    Our previous data from a human leukemic cell line made resistant to the nucleoside analog (NA) 9-beta-D-arabinofuranosylguanine (AraG) revealed a massive upregulation of fetal hemoglobin (HbF) genes and the ABCB1 gene coding for the multidrug resistance P-glycoprotein (P-gp). The expression of these genes is regulated through the same mechanisms, with activation of the p38-MAPK pathway and inhibition of methylation making transcription factors more accessible to activate these genes. We could show that AraG, as well as other NAs, and P-gp substrates could induce global DNA demethylation and induction of Hb gamma and P-gp both at the mRNA and protein expression level. We speculate that the expression of HbF prior to drug exposure or in drug-resistant cell lines is a strategy of the cancer to gain more oxygen, and thereby survival benefits. We also believe that P-gp may be induced in order to excrete Hb degradation products from the cells that would otherwise be toxic. By using Hb gamma siRNA and pharmacological inhibitors of HbF production we here present a possible relationship between HbF induction and multi-drug resistance in a human leukemia cell line model.

  • 19.
    Gandaglia, G.
    et al.
    San Raffaele Scientific Institute, Milan, Italy.
    Strittmatter, F.
    Lund University, Sweden.
    La Croce, G.
    San Raffaele Scientific Institute, Milan, Italy.
    Benigni, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Bettiga, A.
    San Raffaele Scientific Institute, Milan, Italy.
    Castiglione, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Moschini, M.
    San Raffaele Scientific Institute, Milan, Italy.
    Mistretta, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Gratzke, C.
    Munich University, Germany.
    Montorsi, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Stief, C.
    Munich University, Germany.
    Hedlund, Petter
    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.
    The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats2014In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 33, no 8, p. 1251-1258Article in journal (Refereed)
    Abstract [en]

    AIMS:

    To study micturition and bladder overactivity in female rats after chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor oleoyl ethyl amide (OEtA).

    METHODS:

    Sprague-Dawley rats received daily subcutaneous injections of OEtA (0.3 mg/kg), or vehicle for 2 weeks. Cystometries, organ bath studies, Western blot, and immunofluorescence were then used. Expressions of FAAH, cannabinoid 1 and 2 receptors (CB1 and CB2), mitogen-activated protein kinase (MAPK), vesicular acetyl choline-transporter protein (VAChT), and calcitonin gene-related peptide (CGRP) were evaluated.

    RESULTS:

    At baseline, OEtA-treated rats had higher values (P < 0.05) of micturition intervals (MI) and volumes (MV), bladder capacity (BC), threshold pressure, and flow pressure than vehicle controls. Intravesical PGE2 reduced MI, MV, and BC, and increased basal pressure and the area under the curve in all rats. However, these urodynamic parameters were altered less by intravesical PGE2 in OEtA-treated rats (P < 0.05 vs. vehicle controls). Compared to vehicle controls, detrusor from OEtA-treated rats had larger contractions to carbachol at 10-0.1 µM, but no difference in Emax was recorded. FAAH, CB1, CB2, VAChT, or CGRP was similarly expressed in bladders from all rats. In separate experiments, intravesical OEtA increased mucosal expression of phosphorylated MAPK.

    CONCLUSIONS:

    Chronic FAAH inhibition altered sensory urodynamic parameters and reduced bladder overactivity. Even if it cannot be excluded that OEtA may act on central nervous sensory pathways to contribute to these effects, the presence of FAAH and CB receptors in the bladder and activation of intracellular signals for CB receptors by intravesical OEtA suggest a local role for FAAH in micturition control. Neurourol. Urodynam

  • 20.
    Gratzke, Christian
    et al.
    University Lund Hospital, Department Clin Chemistry and Pharmacol, S-22185 Lund, Sweden Ludwig Maximilians University Hospital, Department Urol, Munich, Germany Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Christ, George J
    Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Stief, Christian G
    Ludwig Maximilians University Hospital, Department Urol, Munich, Germany .
    Andersson, Karl-Erik
    Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    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.
    Localization and Function of Cannabinoid Receptors in the Corpus Cavernosum: Basis for Modulation of Nitric Oxide Synthase Nerve Activity2010In: EUROPEAN UROLOGY, ISSN 0302-2838, Vol. 57, no 2, p. 342-348Article in journal (Refereed)
    Abstract [en]

    Background: Anandamide, a proposed endogenous cannabinoid (CB) agonist, has been shown to enhance neurogenic responses in vitro of the rat corpus cavernosal tissue (CC). However, no information is available on the distribution of CB-receptors or effects by anandamide in CC from primates or humans. Objective: To characterize the distribution of CB-receptor isoforms in the human and primate CC and to investigate the effects of anandamide on isolated CC preparations. Design, setting, and participants: CC tissue was excised from the crura penis of six rhesus monkeys and five patients. Expression and distribution of CB1 and CB2 receptors were characterized with Western blot analyses and immunohistochemical investigations. The effects of anandamide on isolated CC preparations were analyzed during pharmacologic and nerve-mediated activation of primate tissue in aerated organ baths. Measurements: The expression and localization of CB1 and CB2 receptors in the primate CC and effects of anandamide on nerve-mediated relaxations and pharmacologically evoked contractions. Results and limitations: Western blot experiments revealed CB1 and CB2 receptors at expected band weights. Within and between strands of CC smooth muscle, CB1 and CB2 immunoreactivity (IR) was found in nerve fibers that also expressed IR for nitric oxide synthase (NOS) or transient receptor potential V1 (TRPV1). Neither CB1-IR nor CB2-IR nerves were colocalized with calcitoningene-related peptide (CGRP)-containing or tyrosine hydroxylase-containing nerves. No differences were observed between primate and human CC sections. Anandamide (10(-9) to 10(-4) M) had no contractile effects on CC smooth muscle, no relaxant effects on precontracted preparations, and no effect on phenylephrine-induced contractions. However, anandamide (10 mu M) inhibited electrically evoked smooth-muscle relaxations (34-48%; p andlt;= 0.05). Conclusions: CB1 and CB2 receptors are located on NOS-containing nerves in primate and human CC tissue. In contrast to findings in rats, anandamide antagonized nerve-mediated relaxations of the primate CC, suggesting important species differences for CB-mediated functions. The results also suggest a peripheral mechanism for cannabis-related sexual dysfunction.

  • 21.
    Green, Henrik
    et al.
    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.
    Lotfi, Kourosh
    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.
    Paul, E
    Karolinska University Hospital.
    Hermansson, M
    Uppsala University.
    Rosenquist, R
    Uppsala University.
    Paul, C
    Karolinska University Hospital.
    Nahi, H
    Karolinska University Hospital.
    Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype2012In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 12, no 2, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Overexpression of the multi-drug transporter P-glycoprotein, encoded by the ABCB1 gene, is a clinically relevant problem in acute myeloid leukemia (AML). Polymorphisms in ABCB1 might contribute to cancer risk and therapeutic response. We therefore investigated the influence of polymorphisms G1199A, C1236T, G2677T/A and C3435T on cancer susceptibility, in vitro cytotoxicity and overall survival in 100 de novo AML patients with normal karyotype. Patients with 1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes (P = 0.03 and P = 0.02, respectively). Both these genotypes were significant factors for survival in multivariate analysis, along with age, NPM1 and FLT3 mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 2677T/T patients were significantly more susceptible to mitoxantrone (P 0.02), and tended to be more susceptible to etoposide and daunorubicin (P = 0.07-0.09), but not to cytarabine. No significant difference in allele frequencies was found between patients and healthy volunteers (n = 400).

  • 22.
    Gyllensten, H
    et al.
    Nordic School Public Heatlh.
    Hakkarainen, K M
    Nordic School Public Heatlh.
    Jönsson, A K
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting.
    Andersson Sundell, K
    Nordic School Public Heatlh.
    Hägg, Staffan
    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.
    Rehnberg, C
    Karolinska Institute.
    Carlsten, A
    Nordic School Public Heatlh.
    DRUG-RELATED MORBIDITY - MODELING THE COST-OF-ILLNESS IN SWEDEN USING PHARMACISTS OPINION in VALUE IN HEALTH, vol 14, issue 7, pp A344-A3442011In: VALUE IN HEALTH, Wiley-Blackwell / Elsevier , 2011, Vol. 14, no 7, p. A344-A344Conference paper (Refereed)
    Abstract [en]

    n/a

  • 23.
    Gyllensten, Hanna
    et al.
    Nordic School Public Health NHV, Sweden University of Gothenburg, Sweden .
    Hakkarainen, Katja M.
    Nordic School Public Health NHV, Sweden University of Gothenburg, Sweden .
    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.
    Carlsten, Anders
    Nordic School Public Health NHV, Sweden Medical Prod Agency, Sweden .
    Petzold, Max
    University of Gothenburg, Sweden .
    Rehnberg, Clas
    Karolinska Institute, Sweden .
    Jönsson, Anna K
    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.
    Economic Impact of Adverse Drug Events - A Retrospective Population-Based Cohort Study of 4970 Adults2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. 0092061-Article in journal (Refereed)
    Abstract [en]

    Background: The aim was to estimate the direct costs caused by ADEs, including costs for dispensed drugs, primary care, other outpatient care, and inpatient care, and to relate the direct costs caused by ADEs to the societal COI (direct and indirect costs), for patients with ADEs and for the entire study population. Methods: We conducted a population-based observational retrospective cohort study of ADEs identified from medical records. From a random sample of 5025 adults in a Swedish county council, 4970 were included in the analyses. During a three-month study period in 2008, direct and indirect costs were estimated from resource use identified in the medical records and from register data on costs for resource use. Results: Among 596 patients with ADEs, the average direct costs per patient caused by ADEs were USD 444.9 [95% CI: 264.4 to 625.3], corresponding to USD 21 million per 100 000 adult inhabitants per year. Inpatient care accounted for 53.9% of all direct costs caused by ADEs. For patients with ADEs, the average societal cost of illness was USD 6235.0 [5442.8 to 7027.2], of which direct costs were USD 2830.1 [2260.7 to 3399.4] (45%), and indirect costs USD 3404.9 [2899.3 to 3910.4] (55%). The societal cost of illness was higher for patients with ADEs compared to other patients. ADEs caused 9.5% of all direct healthcare costs in the study population. Conclusions: Healthcare costs for patients with ADEs are substantial across different settings; in primary care, other outpatient care and inpatient care. Hence the economic impact of ADEs will be underestimated in studies focusing on inpatient ADEs alone. Moreover, the high proportion of indirect costs in the societal COI for patients with ADEs suggests that the observed costs caused by ADEs would be even higher if including indirect costs. Additional studies are needed to identify interventions to prevent and manage ADEs.

  • 24.
    Gyllensten, Hanna
    et al.
    Nordic School Public Health NHV, Sweden .
    Hakkarainen, Katja M.
    Nordic School Public Health NHV, Sweden .
    Jonsson, Anna K.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson Sundell, Karolina
    Nordic School Public Health NHV, Sweden .
    Hägg, Staffan
    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.
    Rehnberg, Clas
    Karolinska Institute, Sweden .
    Carlsten, Anders
    Nordic School Public Health NHV, Sweden Medical Prod Agency, Sweden .
    Modelling drug-related morbidity in Sweden using an expert panel of pharmacists2012In: INTERNATIONAL JOURNAL OF CLINICAL PHARMACY, ISSN 2210-7703, Vol. 34, no 4, p. 538-546Article in journal (Refereed)
    Abstract [en]

    Background Drug-related morbidity (DRM) is common and to some extent preventable, and associated with considerable costs in patients attending hospital. In outpatients and in the general public corresponding data are limited, but pharmacists expert opinion has suggested high rates of DRM also in US ambulatory care. It is unknown if the results are applicable in Sweden today. Objective To estimate the proportions of patients with DRM and preventable DRM and the cost-of-illness (COI) of DRM in Sweden based on pharmacists expert opinion. Setting Swedish healthcare. Method The study applied a conceptual model of DRM based on a decision tree. An expert panel of pharmacists determined the probabilities of therapeutic outcomes of medication therapy. The COI analysis included direct costs from the healthcare perspective. Sensitivity analyses were performed for variations in probabilities and pathway costs. Main outcome measure DRM included new medical problems (adverse drug reactions, drug dependence and intoxications) and therapeutic failures (insufficient effects of medicines and morbidity due to untreated indication). Results The expert panel estimated that 61 +/- A 14 % (mean +/- A SD) of all patients attending healthcare suffered from DRM, of which 29 +/- A 8 % suffered from new medical problems, 18 +/- A 6 % from therapeutic failures, and 15 +/- A 7 % from a combination of both. The DRM was considered preventable in 45 +/- A 15 % of the patients with DRM. The estimated COI was EUR 997 per patient attending healthcare, corresponding to an annual cost of EUR 6,600 million to the Swedish healthcare system. The COI ranged from EUR 490 to EUR 1,314 when varying the participants probabilities of DRM and clinical outcomes from the first to the third quartile. Of the pathway costs, the COI was most sensitive to variation in the cost of prolonged hospital stay (COI range EUR 953-1,306). Conclusion According to pharmacists expert opinion, a large proportion of patients in Sweden experience DRM and preventable DRM, and the estimated COI of DRM is extensive. Since observational studies have not addressed the burden of DRM to the general public, this study adds the pharmacists perception on DRM. Other healthcare professionals perceptions on DRM need to be investigated in future studies.

  • 25.
    Gyllensten, Hanna
    et al.
    Nordic School of Public Health NHV, Gothenburg, Sweden.
    Jönsson, Anna K
    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.
    Rehnberg, Clas
    Karolinska Institutet, Stockholm.
    Carlsten, Anders
    Nordic School of Public Health NHV, Gothenburg, Sweden,/Medical Products Agency, Uppsala, Sweden.
    How are the Costs of Drug-Related Morbidity Measured?: A Systematic Literature Review2012In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 35, no 3, p. 207-219Article, review/survey (Refereed)
    Abstract [en]

    Background: Drug-related morbidity has been associated with increased healthcare costs and has been suggested as one of the leading causes of death. Previous reviews have identified heterogeneity in research methods in studies measuring the cost of drug-related morbidity. To date, no attempt has been made to analyse different methods and cost sources used when estimating the costs of drug-related morbidity. Objective: The aim of this review was to evaluate and compare methods and data sources in cost estimates of drug-related morbidity. Methods: A literature search was conducted in three electronic databases (CINAHL, EMBASE and MEDLINE) to identify peer-reviewed articles written in English and published between January 1990 and November 2011. Articles were included if estimating the direct or indirect costs of drug-related morbidity based on clinical data from general patient groups. The general patient groups were defined as patients visiting, being admitted to, treated at or discharged from a general hospital, excluding studies from nursing homes or specialized hospitals. Study information was collected using a standardized data collection sheet. Studies were categorized according to the type of costs included in the cost analysis. Thereafter, the cost analyses of included studies were reviewed regarding viewpoint, costing methods and adjustments for timing of costs. Results: In total, 9569 articles were identified, of which 25 publications were included in this review, and four additional articles were identified from reference or citation lists of publications already included. Eighteen studies measured either the total or attributable costs of drug-related morbidity, while seven studies estimated the increased costs using matched controls or regression analyses. Six studies measured costs from a payer perspective, while the other 23 measured costs to the hospital. One study included costs resulting after discharge, and discounted future costs, while the remaining 28 studies measured costs during the initial admission only and involved no adjustment for timing of costs. Conclusions: The data sources and costs measured in the included studies varied considerably in terms of perspectives and use of data sources. Even though there is a trend towards more studies estimating costs from the payer perspective, the identified studies still focused on costs resulting from patients attending hospital, therefore underestimating the cost of drug-related morbidity. There is thus a need for more research on the costs of drug-related morbidity to providers other than hospitals, and costs occurring outside of hospitals and after the initial care episode. Such studies require clear descriptions of how the costs of drug-related morbidity are measured, and should adhere to published guidelines for observational studies and economic evaluation studies.

  • 26.
    Gyllensten, Hanna
    et al.
    Nordic School of Public Health NHV, Gothenburg, Sweden .
    Rehnberg, Clas
    Karolinska Institutet, Stockholm, Sweden .
    Jönsson, Anna K
    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.
    Petzold, Max
    Sahlgrenska Academy, University of Gothenburg, Sweden .
    Carlsten, Anders
    Nordic School of Public Health NHV, Gothenburg, Sweden .
    Andersson Sundell, Karolina
    Nordic School of Public Health NHV, Gothenburg, Sweden .
    Cost of illness of patient-reported adverse drug events: a population-based cross-sectional survey.2013In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 3, no 6Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To estimate the cost of illness (COI) of individuals with self-reported adverse drug events (ADEs) from a societal perspective and to compare these estimates with the COI for individuals without ADE. Furthermore, to estimate the direct costs resulting from two ADE categories, adverse drug reactions (ADRs) and subtherapeutic effects of medication therapy (STE).

    DESIGN: Cross-sectional study.

    SETTING: The adult Swedish general population.

    PARTICIPANTS: The survey was distributed to a random sample of 14 000 Swedish residents aged 18 years and older, of which 7099 responded, 1377 reported at least one ADE and 943 reported an ADR or STE.

    MAIN OUTCOME MEASURES: Societal COI, including direct and indirect costs, for individuals with at least one self-reported ADE, and the direct costs for prescription drugs and healthcare use resulting from self-reported ADRs and STEs were estimated during 30 days using a bottom-up approach.

    RESULTS: The economic burden for individuals with ADEs were (95% CI) 442.7 to 599.8 international dollars (Int$), of which direct costs were Int$ 279.6 to 420.0 (67.1%) and indirect costs were Int$ 143.0 to 199.8 (32.9%). The average COI was higher among those reporting ADEs compared with other respondents (COI: Int$ 442.7 to 599.8 versus Int$ 185.8 to 231.2). The COI of respondents reporting at least one ADR or STE was Int$ 468.9 to 652.9. Direct costs resulting from ADRs or STEs were Int$ 15.0 to 48.4. The reported resource use occurred both in hospitals and outside in primary care.

    CONCLUSIONS: Self-reported ADRs and STEs cause resource use both in hospitals and in primary care. Moreover, ADEs seem to be associated with high overall COI from a societal perspective when comparing respondents with and without ADEs. There is a need to further examine this relationship and to study the indirect costs resulting from ADEs.

  • 27.
    Hakkarainen, K M
    et al.
    Nordic School of Public Health NHV, Gothenburg, Sweden and University of Gothenburg, Sweden.
    Gyllensten, H
    Nordic School of Public Health NHV, Gothenburg, Sweden and University of Gothenburg, Sweden.
    Jönsson, Anna K
    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.
    Andersson Sundell, K
    University of Gothenburg, Sweden.
    Petzold, M
    University of Gothenburg, Sweden.
    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. Futurum Academy for Health and Care, Jönköping County, Jönköping County Council, Sweden.
    Prevalence, nature and potential preventability of adverse drug events - A population-based medical record study of 4970 adults2014In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 78, no 1, p. 170-183Article in journal (Refereed)
    Abstract [en]

    AIMS: To estimate the 3-month prevalence of adverse drug events (ADEs), categories of ADEs, and preventable ADEs, and the preventability of ADEs among adults in Sweden. Further, to identify drug classes and organ systems associated with ADEs and estimate their seriousness.

    METHODS: A random sample of 5025 adults in Swedish county council in 2008 was drawn from the Total Population Register. All their medical records in 29 inpatient care departments in three hospitals, 110 specialised outpatient clinics, and 51 primary care units were reviewed retrospectively in a stepwise manner, and complemented with register data on dispensed drugs. ADEs, including adverse drug reactions (ADRs), sub-therapeutic effects of drug therapy (STEs), drug dependence and abuse, drug intoxications from overdose, and morbidities due to drug-related untreated indication, were detected during a 3-month study period, and assessed for preventability.

    RESULTS: Among included 4970 individuals, the prevalence of ADEs was 12.0% (95% confidence interval 11.1-12.9%), and preventable ADEs 5.6% (5.0-6.2%). ADRs (6.9%; 6.2-7.6%) and STEs (6.4%; 5.8-7.1%) were more prevalent than the other ADEs. Of the ADEs, 38.8% (35.8-41.9%) was preventable, varying by ADE category and seriousness. ADEs were frequently associated with nervous system and cardiovascular drugs, but the associated drugs and affected organs varied by ADE category.

    CONCLUSIONS: The considerable burden of ADEs and preventable ADEs from commonly used drugs across care settings warrants large-scale efforts to redesign safer, higher quality healthcare systems. The heterogeneous nature of the ADE categories should be considered in research and clinical practice for preventing, detecting and mitigating ADEs.

  • 28.
    Hakkarainen, Katja M
    et al.
    Nordic School of Public Health NHV, Gothenburg, Sweden.
    Alström, Daniel
    Nordic School of Public Health NHV, Gothenburg, Sweden.
    Hägg, Staffan
    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.
    Carlsten, Anders
    Medical Products Agency, Uppsala, Sweden.
    Gyllensten, Hanna
    Nordic School of Public Health NHV, Gothenburg, Sweden.
    Modelling drug-related morbidity in Sweden using an expert panel of physicians2012In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 9, p. 1309-1319Article in journal (Refereed)
    Abstract [en]

    PURPOSE: In modelling studies using pharmacists' opinions, drug-related morbidity (DRM) and preventable DRM have been more common than in observational studies, and the resulting costs are extensive. Modelling studies' estimates may vary depending on informants' profession. The purpose of this modelling study was to estimate the proportion of patients with DRM and preventable DRM and the cost of illness (COI) of DRM in Sweden based on physicians' expert opinions. METHOD: A conceptual model of DRM was modified from previous studies. Using a modified Delphi technique, a panel of physicians (n = 19) estimated the probabilities of DRM, preventable DRM, and clinical outcomes of DRM separately for outpatients and inpatients. DRM included new medical problems (adverse drug reactions, drug dependence, and intoxications by overdose) and therapeutic failure (insufficient effects of medicines, and morbidity due to untreated indication). A COI analysis included the direct costs of DRM. RESULTS: Physicians estimated that 51 ± 22% [mean ± standard deviation (SD)] of outpatients experience DRM and 12 ± 8% preventable DRM. Of inpatients, 54 ± 17% was estimated to experience DRM and 16 ± 7% preventable DRM. Of outpatients with DRM, 24 ± 11% was estimated to experience preventable DRM, whereas this proportion for inpatients was 31 ± 15%. The estimated COI was 376 euros per outpatient and 838 euros per inpatient. CONCLUSIONS: Swedish physicians estimated that every other outpatient and inpatient experiences DRM, which is often preventable and costly. As physicians' estimates on the proportion of patients with DRM were higher than in observational studies in restricted subpopulations, DRM may be more common in the general population than observational studies suggest.

  • 29.
    Hakkarainen, Katja M
    et al.
    Nordic School of Public Health.
    Hedna, Khadidja
    Mediterranean University.
    Petzold, Max
    Nordic School of Public Health.
    Hägg, Staffan
    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.
    Frequency of Preventable Adverse Drug Reactions in Outpatients and Inpatients and Their Preventability A Meta-Analysis in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, vol 20, issue , pp S353-S3532011In: PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, John Wiley and Sons , 2011, Vol. 20, p. S353-S353Conference paper (Refereed)
    Abstract [en]

    n/a

  • 30.
    Hakkarainen, Katja M
    et al.
    Nordic School of Public Health (NHV), Gothenburg, Sweden.
    Hedna, Khadidja
    Université de la Méditerrané, Marseille, France.
    Petzold, Max
    Nordic School of Public Health (NHV), Gothenburg, Sweden, /Centre for Applied Biostatistics, University of Gothenburg, Gothenburg, Sweden .
    Hägg, Staffan
    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.
    Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions - a meta-analysis2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. 1-9, article id e33236Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Numerous observational studies suggest that preventable adverse drug reactions are a significant burden in healthcare, but no meta-analysis using a standardised definition for adverse drug reactions exists. The aim of the study was to estimate the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions in adult outpatients and inpatients.

    METHODS: Studies were identified through searching Cochrane, CINAHL, EMBASE, IPA, Medline, PsycINFO and Web of Science in September 2010, and by hand searching the reference lists of identified papers. Original peer-reviewed research articles in English that defined adverse drug reactions according to WHO's or similar definition and assessed preventability were included. Disease or treatment specific studies were excluded. Meta-analysis on the percentage of patients with preventable adverse drug reactions and the preventability of adverse drug reactions was conducted.

    RESULTS: Data were analysed from 16 original studies on outpatients with 48797 emergency visits or hospital admissions and from 8 studies involving 24128 inpatients. No studies in primary care were identified. Among adult outpatients, 2.0% (95% confidence interval (CI): 1.2-3.2%) had preventable adverse drug reactions and 52% (95% CI: 42-62%) of adverse drug reactions were preventable. Among inpatients, 1.6% (95% CI: 0.1-51%) had preventable adverse drug reactions and 45% (95% CI: 33-58%) of adverse drug reactions were preventable.

    CONCLUSIONS: This meta-analysis corroborates that preventable adverse drug reactions are a significant burden to healthcare among adult outpatients. Among both outpatients and inpatients, approximately half of adverse drug reactions are preventable, demonstrating that further evidence on prevention strategies is required. The percentage of patients with preventable adverse drug reactions among inpatients and in primary care is largely unknown and should be investigated in future research.

  • 31.
    Hakkarainen, Katja Marja
    et al.
    Nordic School of Public Health (NHV), Gothenburg, Sweden.
    Andersson Sundell, Karolina
    Nordic School of Public Health (NHV), Gothenburg, Sweden.
    Petzold, Max
    Nordic School of Public Health (NHV), Gothenburg, Sweden.
    Hägg, Staffan
    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.
    Methods for assessing the preventability of adverse drug events: A systematic review2012In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 35, no 2, p. 105-126Article in journal (Refereed)
    Abstract [en]

    Background: Preventable adverse drug events (ADEs) are common in both outpatient and inpatient settings. However, the proportion of preventable ADEs varies considerably in different studies, even when conducted in the same setting, and methods for assessing the preventability of ADEs are diverse. Objective: The aim of this article is to identify and systematically evaluate methods for assessing the preventability of ADEs. Data sources: Seven databases (Cochrane, CINAHL, EMBASE, IPA, MEDLINE, PsycINFO and Web of Science) were searched in September 2010 utilizing the databases' index terms and other common terminology on preventable ADEs. No limits for the years of publication were set. Reference lists of included original articles and relevant review articles were also screened. Study selection: After applying predetermined inclusion and exclusion criteria on 4161 unique citations, 142 (3.4%) original research articles were included in the review. One additional article was included from reference lists. Outcome measures of included studies had to include the frequency of ADEs and the assessment of their preventability. Studies were excluded if they focused on individuals with one specific type of treatment, medical condition, medical procedure or ADE. Data extraction: Measurement instruments for determining the preventability of ADEs in each article were extracted and unique instruments were compared. The process of assessing the preventability of ADEs was described based on reported actions taken to standardize and conduct the assessment, and on information about the reliability and validity of the assessment. Data synthesis: Eighteen unique instruments for determining the preventability of ADEs were identified. They fell under the following four groups: (i) instruments using a definition of preventability only (n = 3); (ii) instruments with a definition of preventability and an assessment scale for determining preventability (n = 5); (iii) instruments with specific criteria for each preventability category (n = 3); and (iv) instruments with an algorithm for determining preventability (n = 7). Of actions to standardize the assessment process, performing a pilot study was reported in 21 (15%), and use of a standardized protocol was reported in 18 (13%), of the included 143 articles. Preventability was assessed by physicians in 86 (60%) articles and by pharmacists in 41 (29%) articles. In 29 (20%) articles, persons conducting the assessment were described as trained for or experienced in preventability assessment. In 94 (66%) articles, more than one person assessed the preventability of each case. Among these 94 articles, assessment was done independently in 73 (51%) articles. Procedures for managing conflicting assessments were diverse. The reliability of the preventability assessment was tested in 39 (27%) articles, and 16 (11%) articles referred to a previous reliability assessment. Reliability ranged from poor to excellent (kappa 0.19-0.98; overall agreement 26-97%). Four (3%) articles mentioned assessing validity, but no sensitivity or specificity analyses or negative or positive predictive values were presented. Conclusions: Instruments for assessing the preventability of ADEs vary from implicit instruments to explicit algorithms. There is limited evidence for the validity of the identified instruments, and instrument reliability varied significantly. The process of assessing the preventability of ADEs is also commonly imprecisely described, which hinders the interpretation and comparison of studies. For measuring the preventability of ADEs more accurately and precisely in future, we believe that existing instruments should be further studied and developed, or that one or more new instruments should be developed, and the validity and reliability of the existing and new instruments be established.

  • 32.
    Hakkarainen, Katja Marja
    et al.
    Nordic School of Public Health NHV, Gothenburg.
    Andersson Sundell, Karolina
    Nordic School of Public Health NHV, Gothenburg. Department of Public Health and Community Medicine, University of Gothenburg.
    Petzold, Max
    Nordic School of Public Health NHV, Gothenburg. Centre fo Applied Biostatistics, Sahlgrenska Academy, University of Gothenburg.
    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.
    Prevalence and perceived preventability of self-reported adverse drug events - a population-based survey of 7099 adults2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e73166-Article in journal (Refereed)
    Abstract [en]

    Purpose

    Adverse drug events (ADEs) are common and often preventable among inpatients, but self-reported ADEs have not been investigated in a representative sample of the general public. The objectives of this study were to estimate the 1-month prevalence of self-reported ADEs among the adult general public, and the perceived preventability of 2 ADE categories: adverse drug reactions (ADRs) and sub-therapeutic effects (STEs).

    Methods

    In this cross-sectional study, a postal survey was sent in October 2010 to a random sample of 13 931 Swedish residents aged ≥18 years. Self-reported ADEs experienced during the past month included ADRs, STEs, drug dependence, drug intoxications and morbidity due to drug-related untreated indication. ADEs could be associated with prescription, non-prescription or herbal drugs. The respondents estimated whether ADRs and STEs could have been prevented. ADE prevalences in age groups (18–44, 45–64, or ≥65 years) were compared.

    Results

    Of 7099 respondents (response rate 51.0%), ADEs were reported by 19.4% (95% confidence interval, 18.5–20.3%), and the prevalence did not differ by age group (p>0.05). The prevalences of self-reported ADRs, STEs, and morbidities due to drug-related untreated indications were 7.8% (7.2–8.4%), 7.6% (7.0–8.2%) and 8.1% (7.5–8.7%), respectively. The prevalence of self-reported drug dependence was 2.2% (1.9–2.6%), and drug intoxications 0.2% (0.1–0.3%). The respondents considered 19.2% (14.8–23.6%) of ADRs and STEs preventable. Although reported drugs varied between ADE categories, most ADEs were attributable to commonly dispensed drugs. Drugs reported for all and preventable events were similar.

    Conclusions

    One-fifth of the adult general public across age groups reported ADEs during the past month, indicating a need for prevention strategies beyond hospitalised patients. For this, the underlying causes of ADEs should increasingly be investigated. The high burden of ADEs and preventable ADEs from widely used drugs across care settings supports redesigning a safer healthcare system to adequately tackle the problem.

  • 33.
    Hakkarinen, Katja
    et al.
    Nordic School of Public Health NHV, Sweden .
    Olsson, Sten
    Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring Sweden.
    Hägg, Staffan
    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.
    Comments: Patient safety in developing countries: retrospective estimation of scale and nature of harm to patients in hospital (volume 344, article number e832, 2012)2012In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 344, article id 10.1136/bmj.e832Article in journal (Other academic)
    Abstract [en]

    We commend Wilson and colleagues1 for their excellent study providing valuable evidence on the frequency and nature of adverse events in hospitals in transitional economies. Wilson and colleagues defined an adverse event as “an unintended injury that resulted in temporary or permanent disability or death (including increased length of stay or readmission) and that was associated with healthcare management rather than the underlying disease”, and found that 8.2% of the 15 548 reviewed records included at least one adverse event. The most common adverse events were therapeutic errors (34% of all adverse events), diagnostic events (19%), and operation-related events (18%). Drug-related adverse events represented only 4% of all adverse events, and were present in 0.3% of all records. Thus, drug-related events were markedly less frequent than in western studies,2 as the authors acknowledge. Wilson and colleagues imply that less frequent use of medicines in transitional economies may contribute to fewer drug-related events, and argue that improvements are needed in the diagnostic and therapeutic steps in the care of patients.

  • 34.
    Hallbäck, Ida
    et al.
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    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.
    Eriksson, Andreas
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation2012In: Pharmacological Reports, ISSN 1734-1140, Vol. 64, no 4, p. 979-983Article in journal (Refereed)
    Abstract [en]

    Background: Although several studies show that there is an increased risk of bleeding events during antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs), few studies show direct effects in vitro of SSRIs on hemostasis. less thanbrgreater than less thanbrgreater thanMethods: This study was undertaken to investigate the effects on platelet adhesion and plasma coagulation (APTT and PT) of two common SSRIs, citalopram and sertraline, the selective noradrenaline reuptake inhibitor reboxetine, and the serotonin and noradrenaline reuptake inhibitor venlafaxine. less thanbrgreater than less thanbrgreater thanResults: None of the compounds affected plasma coagulation significantly but all compounds except for venlafaxine inhibited platelet adhesion by approximately 50% or more at the highest concentration (100 mu g/l, p andlt; 0.01). The potency of respective compound to inhibit platelet adhesion to both collagen and fibrinogen surfaces was in the following order; citalopram andgt; sertraline andgt; reboxetine. In contrast, venlafaxine caused a weak but statistically significant increased platelet adhesion to fibrinogen. less thanbrgreater than less thanbrgreater thanConclusion: This study showed that sertraline, citalopram and reboxetine direct and acutely decrease platelet adhesion to both collagen and fibrinogen in vitro. These results also indicate that increased risk for bleeding complications in antidepressant users may not only be explained by depletion of serotonin in platelets.

  • 35.
    Hannan, Johanna L.
    et al.
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Albersen, Maarten
    Urological Research Institute, San Raffaele Hospital, Vita-Salute University, Milan, Italy.
    Kutlu, Omer
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Gratzke, Christian
    Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
    Stief, Christian G.
    Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
    Burnett, Arthur L.
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Lysiak, Jeffrey J.
    Department of Urology, University of Virginia, Charlottesville, Virginia, USA.
    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.
    Bivalacqua, Trinity J.
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Inhibition of Rho-Kinase Improves Erectile Function, Increases Nitric Oxide Signaling and Decreases Penile Apoptosis in a Rat Model of Cavernous Nerve Injury2013In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 189, no 3, p. 1155-1161Article in journal (Refereed)
    Abstract [en]

    Purpose: Bilateral cavernous nerve injury results in up-regulation of ROCK signaling in the penis. This is linked to erectile dysfunction in an animal model of post-prostatectomy erectile dysfunction. We evaluated whether daily treatment with the ROCK inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri) would prevent erectile dysfunction in a rat model of bilateral cavernous nerve injury.Materials and Methods: Sprague-Dawley(R) rats underwent surgery to create sham (14) or bilateral (27) cavernous nerve injury. In the injury group 13 rats received treatment with Y-27632 (5 mg/kg twice daily) and 14 received vehicle. At 14 days after injury, rats underwent cavernous nerve stimulation to determine erectile function. Penes were assessed for neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase. ROCK2 was assessed by Western blot. Cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. Cavernous homogenates were tested for ROCK and protein kinase G enzymatic activity. Penile apoptosis was evaluated using the Apostain technique (Alexis, San Diego, California). Data were analyzed on ROCK using ANOVA and the t test.Results: While erectile function was decreased in rats with bilateral cavernous nerve injury, daily administration of Y-27632 improved erectile responses. Injury decreased neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase but ROCK2 was significantly increased. Y-27632 treatment restored neuronal nitric oxide synthase, nitric oxide synthase membrane-endothelial nitric oxide synthase and cyclic guanosine monophosphate levels, and protein kinase G activity. Treatment significantly decreased ROCK2 protein and ROCK activity. There were significantly fewer apoptotic cells after treatment than in injured controls.Conclusions: These results provide evidence for up-regulation of the RhoA/ROCK signaling pathway with detrimental effects on erectile function after bilateral cavernous nerve injury. ROCK inhibition improved erectile dysfunction associated with bilateral cavernous nerve injury by preserving penile nitric oxide bioavailability and decreasing penile apoptosis.

  • 36.
    Hannan, Johanna L.
    et al.
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Kutlu, Omer
    Karadeniz Technical University, Trabzon, Turkey.
    Stopak, Bernard L.
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Liu, Xiaopu
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Castiglione, Fabio
    San Raffaele Research Institute, Milan, Italy .
    Hedlund, Petter
    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. San Raffaele Research Institute, Milan, Italy .
    Burnett, Arthur L.
    Johns Hopkins School Med, MD 21287 USA .
    Bivalacqua, Trinity J.
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats2014In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 11, no 6, p. 1442-1451Article in journal (Refereed)
    Abstract [en]

    Introduction Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. Aims This study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. Methods Five groups of rats (8-10 weeks, n=10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-1 (TGF-1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (-SMA) antibodies. Main Outcome Measures We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-1 protein expression; penile fibrosis; penile -SMA content. Results There was a voltage-dependent decline (Pless than0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (Pless than0.05) 14 days after BCNI. There was a slight increase in TGF-1 protein expression after BCNI. Histological analysis showed increased (Pless than0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (Pless than0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile -SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (Pless than0.05). Conclusion HDAC-induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy.

  • 37.
    Hasan, Mohammad
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Plasma and Coating Physics. Linköping University, The Institute of Technology. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Pilch, Iris
    Linköping University, Department of Physics, Chemistry and Biology, Plasma and Coating Physics. Linköping University, The Institute of Technology. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Söderström, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Plasma and Coating Physics. Linköping University, The Institute of Technology. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Lundin, D.
    Royal Institute Technology KTH, Sweden.
    Helmersson, Ulf
    Linköping University, Department of Physics, Chemistry and Biology, Plasma and Coating Physics. Linköping University, The Institute of Technology. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Brenning, N.
    Royal Institute Technology KTH, Sweden.
    Modeling the extraction of sputtered metal from high power impulse hollow cathode discharges2013In: Plasma sources science & technology (Print), ISSN 0963-0252, E-ISSN 1361-6595, Vol. 22, no 3, p. 035006-Article in journal (Refereed)
    Abstract [en]

    High power impulse hollow cathode sputtering is studied as a means to produce high fluxes of neutral and ionized sputtered metal species. A model is constructed for the understanding and optimization of such discharges. It relates input parameters such as the geometry of the cathode, the electric pulse form and frequency, and the feed gas flow rate and pressure, to the production, ionization, temperature and extraction of the sputtered species. Examples of processes that can be quantified by the use of the model are the internal production of sputtered metal and the degree of its ionization, the speed and efficiency of out-puffing from the hollow cathode associated with the pulses, and the gas back-flow into the hollow cathode between pulses. The use of the model is exemplified with a special case where the aim is the synthesis of nanoparticles in an expansion volume that lies outside the hollow cathode itself. The goals are here a maximum extraction efficiency, and a high degree of ionization of the sputtered metal. It is demonstrated that it is possible to reach a degree of ionization above 85%, and extraction efficiencies of 3% and 17% for the neutral and ionized sputtered components, respectively.

  • 38.
    Hedlund, Petter
    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.
    Cannabinoids and the Endocannabinoid System in Lower Urinary Tract Function and Dysfunction2014In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 33, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    AimsTo review knowledge on cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. MethodsReview of MEDLINE using defined search terms, and manual analysis. Articles published in English were included. Results and DiscussionComponents of the endocannabinoid systemcannabinoid (CB) receptor types 1 and 2, anandamide, and fatty acid amide hydrolase (FAAH), which degrades anandamide and related fatty-acid amideshave been located to lower urinary tract tissues of mice, rats, monkeys, and humans. Studies have located CB receptors in urothelium and sensory nerves and FAAH in the urothelium. CB receptor- and FAAH-related activities have also been reported in the lumbosacral spinal cord. Data on supraspinal CB functions in relation to micturition are lacking. Cannabinoids are reported to reduce sensory activity of isolated tissues, cause antihyperalgesia in animal studies of bladder inflammation, affect urodynamics parameters reflecting sensory functions in animals models, and appear to have effects on storage symptoms in humans. FAAH inhibitors have affected sensory bladder functions and reduced bladder overactivity in rat models. Cannabinoids may modify nerve-mediated functions of isolated lower urinary tract tissues. ConclusionsEvidence suggests components of the endocannabinoid system are involved in regulation of bladder function, possibly at several levels of the micturition pathway. It is unclear if either CB receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites. Amplification of endocannabinoid activity by FAAH inhibitors may be an attractive drug target in specific pathways involved in LUTS.

  • 39.
    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.
    Combined Ibuprofen and Metamizole treatment - Acute renal failure2014In: WHO Pharmaceuticals Newsletter, Vol. 3, no 2, p. 10-13Article in journal (Other academic)
  • 40.
    Hägg, Staffan
    et al.
    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.
    Jönsson, Anna K
    Nordic School of Public Health, Gothenburg, Sweden.
    Spigset, Olav
    St Olav University Hospital, Department of Clinical Pharmacology, Trondheim, Norway.
    Risk of venous thromboembolism due to antipsychotic drug therapy.2009In: Expert opinion on drug safety, ISSN 1744-764X, Vol. 8, no 5, p. 537-47Article in journal (Refereed)
    Abstract [en]

    An increasing number of reports suggest a link between venous thromboembolism (VTE) and the use of antipsychotics. To better understand this association the available body of evidence has been critically scrutinised. Relevant articles were identified in the databases Scopus and PubMed. Several observational studies using different methodologies show an increased risk of VTE in psychiatric patients. This elevated risk seems to be related to the use of antipsychotic medication and in particular to the use of clozapine and low-potency first-generation drugs. Many studies investigating the association have, however, methodological limitations. The biological mechanisms involved in the pathogenesis of this possible adverse reaction are largely unknown but several hypotheses have been suggested such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinemia and hyperprolactinemia. The association may also be related to underlying risk factors present in psychotic patients. Physicians need to be aware of this possible adverse drug reaction. Although supporting evidence has not been published they should consider discontinuing or switching the antipsychotic treatment in patients experiencing VTE. In addition, although data is lacking, the threshold for considering prophylactic antithrombotic treatment should be low when risk situations for VTE arise, such as immobilisation, surgery and so on.

  • 41.
    Jacobsson, Ingela
    et al.
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Danell Boman, M
    Div of Clinical Pharmacology, Umeå.
    Jönsson, Anna
    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.
    Hägg, Staffan
    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.
    Who Reports Suspected Adverse Drug Reactions to the Spontaneous Reporting System in Sweden?2008Conference paper (Refereed)
  • 42.
    Jacobsson, Ingela
    et al.
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jönsson, Anna
    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.
    Gerdén, Barbro
    Läkemedelsverket, Uppsala.
    Axling, Cecilia
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    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.
    Spontaneously Reported Suspected Adverse Drug Reactions in Association with Complementary and Alternative Medicine Products2007In: Pharmacoepidemiology and Drug Safety, Wiley , 2007, p. 196-197Conference paper (Refereed)
  • 43.
    Jakobsen Falk, I. A.
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Green, K. H. Z.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    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.
    Fyrberg, Anna
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    CORRELATION BETWEEN CYTIDINE DEAMINASE SINGLE NUCLEOTIDE POLYMORPHISMS AND DNA METHYLATION IN ACUTE MYELOGENOUS LEUKEMIA in ANNALS OF ONCOLOGY, vol 23, issue , pp 14-142012In: ANNALS OF ONCOLOGY, Oxford University Press (OUP): Policy A1 , 2012, Vol. 23, p. 14-14Conference paper (Refereed)
    Abstract [en]

    n/a

  • 44.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Fyrberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Paul, Esbjorn
    Karolinska Institute, Sweden.
    Nahi, Hareth
    Karolinska Institute, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Hoglund, Martin
    Uppsala University, Sweden.
    Palmqvist, Lars
    University of Gothenburg, Sweden.
    Stockelberg, Dick
    Sahlgrens University Hospital, Sweden.
    Wei, Yuan
    Sahlgrens University Hospital, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. KTH Royal Institute Technology, Sweden.
    Lotfi, Kourosh
    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.
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, no 5, p. 671-680Article in journal (Refereed)
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199Ggreater thanA, 1236Cgreater thanT, 2677Ggreater thanT/A and 3435Cgreater thanT, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236Cgreater thanT and 2677Ggreater thanT may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

  • 45.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Fyrberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Paul, Esbjörn
    Karolinska Institutet, Stockholm, Sweden.
    Nahi, Hareth
    Karolinska Institutet, Stockholm, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Höglund, Martin
    University of Gothenburg, Sweden.
    Palmqvist, Lars
    University of Gothenburg, Sweden.
    Stockelberg, Dick
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wei, Yuan
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    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.
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed)
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and −451C>T rs532545), 5′-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3′UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and −451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML

  • 46.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jain, Mayur V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Lotfi, Kourosh
    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.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, p. 10134-10145Article in journal (Refereed)
    Abstract [en]

    Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

  • 47.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Panigrahi, Soumya
    Case Western Reserve University, Cleveland, OH, USA.
    Lotfi, Kourosh
    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.
    Yadav, Manisha
    CSIR-Central Drug Research Institute, Lucknow, India.
    Maddika, Subbareddy
    Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
    Tripathi, Anil Kumar
    King George's Medical University, Lucknow, India.
    Sanyal, Sabyasachi
    CSIR-Central Drug Research Institute, Lucknow, India.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 16, p. 7198-7211Article in journal (Refereed)
    Abstract [en]

    Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.

  • 48.
    Jensen, Lasse Dahl
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Department of Microbiology, Tumor and Cell Biology, The Karolinska Institute, tockholm, Sweden.
    Gyllenhaal, Charlotte
    The Block Center for Integrative Cancer Treatment, 60077 Skokie, IL, USA.
    Block, Keith
    The Block Center for Integrative Cancer Treatment, 60077 Skokie, IL, USA.
    Circadian angiogenesis2014In: Biomolecular concepts, ISSN 1868-503X, Vol. 5, no 3, p. 245-56Article in journal (Refereed)
    Abstract [en]

    Daily rhythms of light/darkness, activity/rest and feeding/fasting are important in human physiology and their disruption (for example by frequent changes between day and night shifts) increases the risk of disease. Many of the diseases found to be associated with such disrupted circadian lifestyles, including cancer, cardiovascular diseases, metabolic disorders and neurological diseases, depend on pathological de-regulation of angiogenesis, suggesting that disrupting the circadian clock will impair the physiological regulation of angiogenesis leading to development and progression of these diseases. Today there is little known regarding circadian regulation of pathological angiogenesis but there is some evidence that supports both direct and indirect regulation of angiogenic factors by the cellular circadian clock machinery, as well as by circulating circadian factors, important for coordinating circadian rhythms in the organism. Through highlighting recent advances both in pre-clinical and clinical research on various diseases including cancer, cardiovascular disorders and obesity, we will here present an overview of the available knowledge on the importance of circadian regulation of angiogenesis and discuss how the circadian clock may provide alternative targets for pro- or anti-angiogenic therapy in the future.

  • 49.
    Johansson, Marie-Louise
    et al.
    Sahlgrenska University Hospital.
    Hägg, Staffan
    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.
    Wallerstedt, Susanna M
    Sahlgrenska University Hospital.
    Impact of information letters on the reporting rate of adverse drug reactions and the quality of the reports: a randomized controlled study2011In: BMC clinical pharmacology, ISSN 1472-6904, Vol. 11, no 14Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Spontaneous reporting of adverse drug reactions (ADRs) is an important method for pharmacovigilance, but under-reporting and poor quality of reports are major limitations. The aim of this study was to evaluate if repeated one-page ADR information letters affect (i) the reporting rate of ADRs and (ii) the quality of the ADR reports.

    METHODS: All 151 primary healthcare units in the Region Västra Götaland, Sweden, were randomly allocated (1:1) to an intervention (n = 77) or a control group (n = 74). The intervention consisted of one-page ADR information letters administered at three occasions during 2008 to all physicians and nurses in the intervention units. The number of ADR reports received from the 151 units was registered, as was the quality of the reports, which was defined as high if the ADR was to be reported according to Swedish regulations, that is, if the ADR was (i) serious, (ii) unexpected, and/or (iii) related to the use of new drugs and not labelled as common in the Summary of Product Characteristics. A questionnaire was administered to evaluate if the ADR information letter had reached the intended recipient.

    RESULTS: Before the intervention, no significant differences in reporting rate or number of high quality reports could be detected between the randomization groups. In 2008, 79 reports were sent from 37 intervention units and 52 reports from 30 control units (mean number of reports per unit ± standard deviation: 1.0 ± 2.5 vs. 0.7 ± 1.2, P = 0.34). The number of high quality reports was higher in intervention units than in control units (37 vs. 15 reports, 0.5 ± 0.9 vs. 0.2 ± 0.6, P = 0.048). According to the returned questionnaires (n = 1,292, response rate 57%), more persons in the intervention than in the control group had received (29% vs. 19%, P < 0.0001) and read (31% vs. 26%, P < 0.0001) an ADR information letter.

    CONCLUSIONS: This study suggests that repeated ADR information letters to physicians and nurses do not increase the ADR reporting rate, but may increase the number of high quality reports.

  • 50.
    Josefine, Palle
    et al.
    Uppsala Univ Hospital.
    Britt-Marie, Frost
    Uppsala Univ Hospital.
    Curt, Petersson
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Henrik, Hasle
    Aarhus Univ Hosp.
    Marit, Hellebostad
    Ullevaal Univ Hosp.
    Jukka, Kanerva
    Univ Helsinki.
    Kjeld, Schmiegelow
    Rigshospital.
    Gudmar, Loenerholm
    Uppsala University Hospital.
    Thioguanine pharmacokinetics in induction therapy of children with acute myeloid leukemia2009In: ANTI-CANCER DRUGS, ISSN 0959-4973, Vol. 20, no 1, p. 7-14Article in journal (Refereed)
    Abstract [en]

    We studied the pharmacokinetics of 6-thioguanine (6TG) in 50 children treated for newly diagnosed acute myeloid leukemia, four of them with Down syndrome (DS). They received oral 6TG 100 mg/m(2) body surface area twice daily for 4 days. Etoposide, 100 mg/m(2)/24 h, and cytarabine, 200 mg/m(2)/24 h, were administered concomitantly by intravenous infusion. On day 5, doxorubicin 75 mg/m2 was given as an 8-h infusion. The concentration of thioguanine nucleotides (TGN) in erythrocytes, the active metabolites of 6TG, was determined by high-performance liquid chromatography. The mean TGN concentration from 72, 95, and 106-h samples was used as a measure of drug exposure for each individual. The median TGN concentration in non-DS children above 2 years of age was 2.30 mu mol/mmol Hb (range 0.57-25.3). The TGN concentrations varied widely (30-fold) also after dose normalization. We found no correlation with demographic, clinical, or biochemical parameters, and differences in bioavailability might be the most important explanation to interpatient variability. Children with high TGN concentration tended to have longer treatment interval to the next course, but we found no correlation with our predefined parameters for clinical response, that is, remission and relapse rate. Therefore, 6TG does not seem to be a candidate for therapeutic drug monitoring by TGN measurement, at least not in the setting of short multidrug treatment courses. Children with DS had significantly higher TGN concentrations, indicating that dose reduction might be considered to reach the same drug exposure as in non-DS children.

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