Digitala Vetenskapliga Arkivet

Endre søk
Begrens søket
45678910 301 - 350 of 3715
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Treff pr side
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
Merk
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 301.
    Baverel, Paul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Savic, Rada
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Marshall, Scott
    Karlsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A novel covariate search method intended for PKPD models with nonparametric parameter distributionsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective. To develop a new covariate modeling approach adapted for nonparametric parameter distributions and to evaluate its statistical properties in terms of power and type-I error rate of covariate inclusion.

    Methods. The proposed methodology is articulated around the decomposition of the nonparametric joint density obtained in NONMEM into a set of unique individual probability density distributions. These individual probabilities are then exported into R and used as weighting factors of a generalized additive model (GAM) regressing support points on covariate distributions. A calibration of the method is undertaken by means of 1000 randomization tests automated with GAM analyses to derive a decision criterion based on the Akaike’s information criterion (AIC) given the null hypothesis and a user-defined confidence level α. Statistical properties of the proposed methodology were then evaluated through Monte-Carlo simulations with α=5%. Eight scenarios of 1000 stochastic simulations followed by estimations (SSEs) were performed under FOCE-NONP given a 1-compartment pharmacokinetic model and an informative design. Estimates of the statistical power of inclusion of both a continuous and a categorical covariates with varying correlation strengths on CL were obtained with associated estimates of type-I error rate. A comparison was then intended with likelihood ratio test statistics (LRTs) given FOCE parameter distributions. Errors in estimates of correlation coefficients were further assessed.

    Results. The methodology was successfully implemented by means of a Perl script calling PsN, NONMEM and R. Estimates of statistical power and type-I error rate of the proposed method were in close agreement with LRT statistics under ideal conditions of hypothesis-testing for the latter, and this, regardless of the correlation strengths and of the attributes of the covariate distribution investigated. Estimates of regression coefficients presented negligible bias and were as precise as the ones obtained with parametric models.

    Conclusions. The set of covariate analysis tools is extended with a new, calibrated, covariate identification technique intended for nonparametric population models.

  • 302.
    Baverel, Paul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Savic, Radojka
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wilkins, Justin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evaluation of the Nonparametric Estimation Method in NONMEM VI: Application to Real Data2009Inngår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 36, nr 4, s. 297-315Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of the study was to evaluate the nonparametric estimation methods available in NONMEM VI in comparison with the parametric first-order method (FO) and the first-order conditional estimation method (FOCE) when applied to real datasets. Four methods for estimating model parameters and parameter distributions (FO, FOCE, nonparametric preceded by FO (FO-NONP) and nonparametric preceded by FOCE (FOCE-NONP)) were compared for 25 models previously developed using real data and a parametric method. Numerical predictive checks were used to test the appropriateness of each model. Up to 1000 new datasets were simulated from each model and with each method to construct 90% and 50% prediction intervals. The mean absolute error and the mean error of the different outcomes investigated were computed as indicators of imprecision and bias respectively and formal statistical tests were performed. Overall, less imprecision and less bias were observed with nonparametric methods than with parametric methods. Across the 25 models, t-tests revealed that imprecision and bias were significantly lower (P < 0.05) with FOCE-NONP than with FOCE for half of the NPC outcomes investigated. Improvements were even more pronounced with FO-NONP in comparison with FO. In conclusion, when applied to real datasets and evaluated by numerical predictive checks, the nonparametric estimation methods in NONMEM VI performed better than the corresponding parametric methods (FO or FOCE).

  • 303.
    Bayatli, Meysun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Diskrepanser i läkemedelsunderlagen kan leda till felaktig läkemedelsbehandling i särskilda äldre boenden (SÄBO)2012Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [sv]

    Introduktion: Läkemedelsrelaterade problem (LRP) så som läkemedelsbiverkningar, oföljsamhet och läkemedelsinteraktioner, har på senare åren identifierats som en trolig orsak till ökad morbiditet och sjukvårdskonsumtion fram för allt hos den äldre befolkningen. Till läkemedelsrelaterade problem räknas även felmedicinering som uppkommer inom sjukvården på grund av olämplig läkemedelsval, otillräcklig behandling, överdosering och förväxling. Äldre är på grund av åldrandet och multisjukdom sköra och därmed särskilt känsliga för läkemedel. Därför löper äldre högre risk att drabbas av LRP på grund av felaktig läkemedelsbehandling. Syfte: Att kartlägga i vilken utsträckning förändringen av instruktioner och rutiner för läkemedelshantering har medfört att det är färre diskrepanser mellan läkemedelslistan eller dosreceptet i patientjournalen och sjuksköterskans underlag för läkemedelshanteringen och därmed minskad risk för felmedicinering. Material och metod: Studiepopulationen utgjordes av 361 patienter från 11 särskilda boenden i Stockholm och materialet utgjordes av kopior på sjuksköterskans underlag för läkemedelshanteringen samt patientjournalens läkemedelslista och/eller dosrecept. Alla patientuppgifter överfördes till en databas (Excel®) där dessa uppgifter registrerades och bearbetades med pivot-tabeller för att få fram resultaten. Resultat: Diskrepanser mellan sjuksköterskans dosrecept och läkarens dosrecept var 4 % och diskrepanserna mellan sjuksköterskans underlag och patientjournalens läkemedelslista var 38 % av de aktuella läkemedelsordinationerna. Konklusion: Trots att det är färre diskrepanser som förekom mellan läkemedelsunderlagen kan en viss förbättring endast ses mellan sjuksköterskans underlag och läkemedelslistan i journalen för patienter med läkemedelshantering från läkemedelsförråd enligt slutenvårdsmodellen.

  • 304.
    Baysal, Arife
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Toxicity screening of chemical substances and compounds by two model organisms A. salina and S. cerevisiae2014Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 305.
    Bazov, Igor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Epigenetic Dysregulations in the Brain of Human Alcoholics: Analysis of Opioid Genes2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Neuropeptides are special in their expression profiles restricted to neuronal subpopulations and low tissue mRNA levels. Genetic, epigenetic and transcriptional mechanisms that define spatiotemporal expression of the neuropeptide genes have utmost importance for the formation and functions of neural circuits in normal and pathological human brain. This thesis focuses on regulation of transcription of the opioid/nociceptin genes, the largest neuropeptide family, and on identification of adaptive changes in these mechanisms associated with alcoholism as model human pathology. Two epigenetic mechanisms, the common for most cells in the dorsolateral prefrontal cortex (dlPFC) and the neuron-subpopulation specific that may orchestrate prodynorphin (PDYN) transcription in the human dlPFC have been uncovered. The first, repressive mechanism may operate through control of DNA methylation/demethylation in a short, nucleosome size promoter CpG island (CGI). The second mechanism may involve USF2, the sequence–specific methylation–sensitive transcription factor which interaction with its target element in the CpG island results in USF2 and PDYN co-expression in the same neurons. The short PDYN promoter CGI may function as a chromatin element that integrates cellular and environmental signals through changes in methylation and transcription factor binding. Alterations in USF2–dependent PDYN transcription are affected by the promoter SNP (rs1997794: T>C) under transition to pathological state, i.e. in the alcoholic brain. This and two other PDYN SNPs that are most significantly associated with alcoholism represent CpG-SNPs, which are differentially methylated in the human dlPFC. The T, low risk allele of the promoter SNP forms a noncanonical AP-1–binding element. JUND and FOSB proteins, which may form homo- or heterodimers have been identified as dominant constituents of AP-1 complex. The C, non-risk variant of the PDYN 3′ UTR SNP (rs2235749 SNP: C>T) demonstrated significantly higher methylation in alcoholics compared to controls. PDYN mRNA and dynorphin levels significantly and positively correlated with methylation of the PDYN 3′ UTR CpG-SNP suggesting its involvement in PDYN regulation. A DNA–binding factor with differential binding affinity for the T allele and methylated and unmethylated C alleles of the PDYN 3′ UTR SNP (the T allele specific binding factor, Ta-BF) has been discovered, which may function as a regulator of PDYN transcription. These findings emphasize the complexity of PDYN regulation that determines its expression in specific neuronal subpopulations and suggest previously unknown integration of epigenetic, transcriptional and genetic mechanisms that orchestrate alcohol–induced molecular adaptations in the human brain. Given the important role of PDYN in addictive behavior, the findings provide a new insight into fundamental molecular mechanisms of human brain disorder. In addition to PDYN in the dlPFC, the PNOC gene in the hippocampus and OPRL1 gene in central amygdala that were downregulated in alcoholics may contribute to impairment of cognitive control over alcohol seeking and taking behaviour.

    Fulltekst (pdf)
    fulltext
    Download (jpg)
    presentationsbild
  • 306.
    Bazov, Igor
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Taqi, Mumtaz Malik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Stålhandske, Lada
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Verbeek, Dineke
    Rajkowska, Grazyna
    Syvänen, Ann-Christine
    Yakovleva, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Neuronal Expression of Opioid Gene is Regulated by Genetically Controlled Epigenetic and Transcriptional Mechanisms in Addicted Human BrainManuskript (preprint) (Annet vitenskapelig)
  • 307.
    Bazov, Igor
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kuntić, Vesna
    Sarkisyan, Daniil
    Taqi, Malik Mumtaz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hussain, Muhammad Zubair
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yakovleva, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction2013Inngår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 18, nr 1, s. 161-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The endogenous opioid system (EOS) plays a critical role in addictive processes. Molecular dysregulations in this system may be specific for different stages of addiction cycle and neurocircuitries involved and therefore may differentially contribute to the initiation and maintenance of addiction. Here we evaluated whether the EOS is altered in brain areas involved in cognitive control of addiction including the dorsolateral prefrontal cortex (dl-PFC), orbitofrontal cortex (OFC) and hippocampus in human alcohol-dependent subjects. Levels of EOS mRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and levels of dynorphins by radioimmunoassay (RIA) in post-mortem specimens obtained from 14 alcoholics and 14 controls. Prodynorphin mRNA and dynorphins in dl-PFC, κ-opioid receptor mRNA in OFC and dynorphins in hippocampus were up-regulated in alcoholics. No significant changes in expression of proenkephalin, and µ- and δ-opioid receptors were evident; pro-opiomelanocortin mRNA levels were below the detection limit. Activation of the κ-opioid receptor by up-regulated dynorphins in alcoholics may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control.

  • 308.
    Bazov, Igor
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hussain, M. Z.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karpyak, V. M.
    Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA..
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    THE ENDOGENOUS OPIOID SYSTEM: DYSREGULATION IN THE STRIATUM OF HUMAN ALCOHOLICS2015Inngår i: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50Artikkel i tidsskrift (Annet vitenskapelig)
  • 309.
    Bazov, Igor
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karpyak, Victor M.
    Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN 55905 USA.
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics2018Inngår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, artikkel-id 122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

    Fulltekst (pdf)
    fulltext
  • 310.
    Bazov, Igor
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Taqi, Malik Mumtaz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Faculty of Medicine, NORMENT, University of Oslo, Oslo, Norway.
    Stålhandske, Lada
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Verbeek, Dineke S
    Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
    Mulder, Jan
    Department of Neuroscience, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
    Rajkowska, Grazyna
    Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
    Sheedy, Donna
    Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney NSW, Australia.
    Kril, Jillian
    Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney NSW, Australia.
    Sun, Xueguang
    Zymo Research Corporation, 17062 Murphy Avenue, Irvine, CA, USA; Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain2018Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 28, nr 9, s. 3129-3142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.

  • 311.
    Bazov, Igor
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hansson, Anita C
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Sommer, Wolfgang H
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Spanagel, Rainer
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Inst Psychopharmacol, D-68159 Mannheim, Germany.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.2018Inngår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, nr 8, s. 7049-7061Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.

    Fulltekst (pdf)
    fulltext
  • 312.
    Behnan, Tamara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Validation of a new vancomycin dosing nomogram within a pharmacist- led therapeutic drug monitoring program2014Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Introduction: Vancomycin is a glycopeptide antibiotic used to treat different kinds of severe Gram positive infections. Alfred Health is the leading hospital in Australia in using vancomycin. Today, there are many guidelines for initiation of vancomycin but little evidence on maintenance dosing. Alfred Health has introduced a nomogram as a guideline for maintenance dosing. Aim: To measure the extent to which the clinical pharmacists have followed the nomogram to achieve the target trough range (15-20 mg/L) in vancomycin maintenance dosing at Alfred Health. Materials and Methods: Vancomycin levels from 161 patients in Alfred Health were collected. Patients’ clinical characteristics were recorded, as well as initiation and maintenance dosing of vancomycin using a Data Collection Tool. The data was then analyzed in Microsoft Excel 2003. Results: Of the 161 collected patients, 130 were included with a total of 491 levels taken. Of these levels, 32.8% were therapeutic, 57.6% were above minimum target and 15.2% were supratherapeutic. Twenty-nine patients (5.9%) had a new incidence of acute renal failure. There were a total of 113 patients that reached steady state with a total of 312 levels taken. Out of these levels, 86.5% were adjusted according to the nomogram. Conclusions: The majority of steady state levels were adjusted according to the nomogram. Opportunity exists to use this only as a pilot study and later repeat in larger population. It has been shown in the study that various dosage adjustment practices exist. Further work to improve today’s practice is required. 

  • 313. Bein, D.
    et al.
    Kuehn, E.
    Meuth, A. M.
    Amler, S.
    Haust, M.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sauerland, C.
    Luger, T. A.
    Bonsmann, G.
    Kuhn, A.
    Evaluation of disease activity and damage in different subtypes of cutaneous lupus erythematosus using the CLASI2011Inngår i: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 25, nr 6, s. 652-659Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a scoring system for patients with cutaneous lupus erythematosus (CLE) to assess disease activity and damage. Objective: The aim of this study was to evaluate whether the CLASI is a useful instrument which reflects the different subtypes of CLE comparably well in each parameter. Methods: A total of 50 patients (42 female, 8 male) with different subtypes of CLE, including acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE) and LE tumidus (LET), from the Departments of Dermatology, University of Dusseldorf, Germany, and Danderyd Hospital, Stockholm, Sweden, were evaluated using the CLASI at one time point. Results: The total CLASI activity score was significantly lower in patients with LET compared with ACLE (P < 0.05) and CCLE (P < 0.001), and the total CLASI damage score was significantly lower in patients with LET than with ACLE (P < 0.05), SCLE (P < 0.001) and CCLE (P < 0.001). The erythema score and the scale/hypertrophy score were significantly lower in LET than in ACLE (P < 0.05, both) and CCLE (P < 0.05 and P < 0.001, respectively). The dyspigmentation score was lowest in patients with LET, differing significantly from ACLE (P < 0.05), SCLE (P < 0.05) and CCLE (P < 0.001). The scarring/atrophy/panniculitis score was significantly higher in patients with CCLE in contrast to SCLE and LET (P < 0.05 and P < 0.001, respectively). Conclusion: These data characterize the CLASI as an overall useful instrument to analyse disease activity and damage in CLE. However, the CLASI does not give an accurate assessment of all disease subtypes; therefore, a revision of the CLASI with critical analysis of all parameters is recommended.

  • 314.
    Bell, Joanne
    et al.
    Pfizer Inc.
    ONeill, Brian
    Pfizer Inc.
    Brodney, Michael
    Pfizer Inc.
    Hajos-Korcsok, Eva
    Pfizer Inc.
    Lu, Yasong
    Pfizer Inc.
    Riddell, David
    Pfizer Inc.
    Ito, Kaori
    Pfizer Inc.
    Ueckert, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nicholas, Timothy
    Pfizer Inc.
    A novel BACE inhibitor (PF-05297909):: A two-part adaptive design to evaluate safety, pharmacokinetics and pharmacodynamics for modifying beta-amyloid in a first-in-human study2013Inngår i: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 9, nr 4, s. P287-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    The accumulation of amyloid beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration seen in the Alzheimer's disease (AD) brain. Given the central role of Aβ42 in AD pathogenesis, a therapeutic strategy to lower central Aβ42 (and Aβ40) levels via inhibition of BACE was adopted in a first in human trial in a 2-part adaptive design.

    Methods

    Part 1 evaluated PF-05297909 plasma PK and the PK/PD relationship for the reduction of plasma Aβ40, Aβ42 and AβX levels; Part 2 evaluated the exposure-response relationship between PF-05297909 and CSF levels of Aβ40, Aβ42 and AβX. Sufficient safety and tolerability, plasma exposure and reduction in plasma Aβ were necessary to initiate Part 2. Part 1 was a sequential parallel group dose escalation (25, 100, 250 and 325 mg) with n=8 (6:2, active:placebo) healthy volunteers (HV) in each cohort. Part 2 consisted of 3 cohorts of n=8 (6:2, active:placebo) HV. Doses selected for Part 2 started with the highest safe dose in Part 1 and then adapted for subsequent cohorts. The PK/PD relationship between PF-05297909 and Aβ42 was determined using a non-linear mixed effects (NLME) analysis. The doses for Part 2 - cohort 2 and 3 were to be chosen to improve the relative standard error in the estimate of the BACE IC50 as quantified by evaluating the determinant of the Fisher information matrix for the NLME model.

    Results

    PF-05297909 was well-tolerated. Reduction in plasma Aβ (Aβ40 and Aβ42) was exposure related with an apparent maximum at the 250 mg dose with a greater duration of activity at the 325 mg dose of PF-05297909. A 325 mg dose was selected for Part 2 - cohorts 1 and 2 without further cohorts being run, as stopping criteria for futility were met following analysis of cohort 2. A PK/PD relationship in CSF was not observed.

    Conclusions

    The adaptive designed PF-05297909 FIH study allowed efficient testing of safety and of the PK/PD relationship between PF-05297909 exposure and Aβ (Aβ40 and Aβ42). PF-05297909 was safe and well tolerated in HV at exposures tested. A robust effect on plasma Aβ did not translate to CSF pharmacodynamic effects.

  • 315.
    Bender, Brendan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmacometric Models for Antibody Drug Conjugates and Taxanes in HER2+ and HER2- Breast Cancer2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In oncology, there is a need to optimize drug treatment for efficient eradication of tumors, minimization of adverse effects (AEs), and prolonging patient survival. Pharmacometric models can be developed to streamline information between drug development phases, describe and quantify response to treatment, and determine dose regimens that balance toxicity and efficacy. In this thesis, data from trastuzumab emtansine (T-DM1) and taxane drug treatment were used to develop pharmacometric models of pharmacokinetics (PK), AEs, anti-tumor response, and survival, supporting drug development.

    T-DM1 is an antibody-drug conjugate (ADC) for treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. ADCs are a relatively new class of oncologic agents, and contain multiple drug-to-antibody ratio (DAR) moieties in their dose product. The complex distribution of T-DM1 was elucidated through PK models developed using in vitro and in vivo rat and cynomolgus monkey DAR data. Mechanism–based PK/pharmacodynamic (PKPD) models were also developed for T-DM1 that described the AEs thrombocytopenia (TCP) and hepatotoxicity in patients receiving T-DM1. Variable patterns of platelet and transaminase (ALT and AST) response were quantified, including an effect of Asian ethnicity that was related to higher incidences of TCP.  Model simulations, comparing dose intensities (DI) and Grade 3/4 incidences between the approved T-DM1 dose (3.6 mg/kg every three weeks) and weekly regimens, determined that 2.4 mg/kg weekly provided the highest DI.

    Docetaxel and paclitaxel are taxane treatment options for HER2–negative breast cancer. Tumor response data from these treatments were used to develop a mechanism–based model of tumor quiescence and drug–resistance. Subsequently, a parametric survival analysis found that tumor baseline and the model–predicted time to tumor growth (TTG) were predictors of overall survival (OS). This tumor and OS modeling approach can be applied to other anticancer treatments with similar patterns of drug–resistance.

    Overall, the pharmacometric models developed within this thesis present new modeling approaches and provide understanding on ADC PK and PKPD (TCP and hepatotoxicity), as well as drug–resistance tumor response. These models can inform simulation strategies and clinical study design, and be applied towards dose finding for anticancer drugs in development, especially ADCs.

    Fulltekst (pdf)
    fulltext
    Download (jpg)
    preview image
  • 316.
    Bender, Brendan C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Schaedeli-Stark, Franziska
    Koch, Reinhold
    Joshi, Amita
    Chu, Yu-Waye
    Rugo, Hope
    Krop, Ian E.
    Girish, Sandhya
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gupta, Manish
    A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer2012Inngår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 70, nr 4, s. 591-601Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEMA (R) 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. The model described the platelet data well and predicted the incidence of grade a parts per thousand yen3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the similar to 8 % incidence of grade a parts per thousand yen3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.

  • 317.
    Bender, Brendan C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Schindler, Emilie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Friberg, Lena E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Population pharmacokinetic pharmacodynamic modelling in oncology: a tool for predicting clinical response2015Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 79, nr 1, s. 56-71Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In oncology trials, overall survival (OS) is considered the most reliable and preferred endpoint to evaluate the benefit of drug treatment. Other relevant variables are also collected from patients for a given drug and its indication, and it is important to characterize the dynamic effects and links between these variables in order to improve the speed and efficiency of clinical oncology drug development. However, the drug-induced effects and causal relationships are often difficult to interpret because of temporal differences. To address this, population pharmacokinetic-pharmacodynamic (PKPD) modelling and parametric time-to-event (TTE) models are becoming more frequently applied. Population PKPD and TTE models allow for exploration towards describing the data, understanding the disease and drug action over time, investigating relevance of biomarkers, quantifying patient variability and in designing successful trials. In addition, development of models characterizing both desired and adverse effects in a modelling framework support exploration of risk-benefit of different dosing schedules. In this review, we have summarized population PKPD modelling analyses describing tumour, tumour marker and biomarker responses, as well as adverse effects, from anticancer drug treatment data. Various model-based metrics used to drive PD response and predict OS for oncology drugs and their indications are also discussed.

    Fulltekst (pdf)
    fulltext
  • 318.
    Bender, Brendan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jin, Jin
    Clinical Pharmacology, Genentech, Inc.
    Friberg, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A mechanism-based model of tumor quiescence and drug-resistance in HER2–negative metastatic breast cancer patients receiving docetaxel or paclitaxelManuskript (preprint) (Annet vitenskapelig)
  • 319.
    Bender, Brendan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Leipold, Douglas D.
    Xu, Keyang
    Shen, Ben-Quan
    Tibbitts, Jay
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A Mechanistic Pharmacokinetic Model Elucidating the Disposition of Trastuzumab Emtansine (T-DM1), an Antibody-Drug Conjugate (ADC) for Treatment of Metastatic Breast Cancer2014Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 16, nr 5, s. 994-1008Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) therapeutic for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. The T-DM1 dose product contains a mixture of drug-to-antibody ratio (DAR) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody. The pharmacokinetics (PK) underlying this system and other ADCs are complex and have not been elucidated. Accordingly, we have developed two PK modeling approaches from preclinical data to conceptualize and understand T-DM1 PK, to quantify rates of DM1 deconjugation, and to elucidate the link between trastuzumab, T-DM1, and DAR measurements. Preclinical data included PK studies in rats (n = 34) and cynomolgus monkeys (n = 18) at doses ranging from 0.3 to 30 mg/kg and in vitro plasma stability. T-DM1 and total trastuzumab (TT) plasma concentrations were measured by enzyme-linked immunosorbent assay. Individual DAR moieties were measured by affinity capture liquid chromatography-mass spectrophotometry. Two PK modeling approaches were developed for T-DM1 using NONMEM 7.2 software: a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and T-DM1 concentrations. DAR moieties were well described with a three-compartmental model and DM1 deconjugation in the central compartment. DM1 deconjugated fastest from the more highly loaded trastuzumab molecules (i.e., DAR moieties that are a parts per thousand yen3 DM1 per trastuzumab). T-DM1 clearance (CL) was 2-fold faster than TT CL due to deconjugation. The two modeling approaches provide flexibility based on available analytical measurements for T-DM1 and a framework for designing ADC studies and PK-pharmacodynamic modeling of ADC efficacy- and toxicity-related endpoints.

  • 320.
    Bender, Brendan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Quartino, Angelica
    Genentech, Inc..
    Li, Chunze
    Genentech, Inc.
    Chen, Shang-Chiung
    Genentech, Inc..
    Smitt, Melanie
    Genenetch, Inc..
    Strasak, Alexander
    F. Hoffman-La Roche Ltd..
    Chernyukhin, Natalia
    Genentech, Inc..
    Wang, Bei
    Genentech, Inc..
    Jin, Jin
    Clinical Pharmacology, Genentech, Inc.
    Girish, Sandhya
    Genentech, Inc..
    Friberg, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    An integrated pharmacokinetic-pharmacodynamic (PKPD) modeling analysis of trastuzumab emtansine (T-DM1)-induced thrombocytopenia (TCP) and hepatotoxicity in patients with HER2–positive metastatic breast cancerManuskript (preprint) (Annet vitenskapelig)
  • 321.
    Bendre, Megha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Comasco, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nilsson, Kent W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Early Life Stress and Voluntary Alcohol Consumption in Adulthood Affect Maoa Expression in the Nucleus Accumbens of Outbred Rats2015Inngår i: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50Artikkel i tidsskrift (Annet vitenskapelig)
  • 322.
    Bendre, Megha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Comasco, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nilsson, Kent W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation.: Maoa,ELS and alcohol2015Inngår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 5, artikkel-id e690Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.

    Fulltekst (pdf)
    fulltext
  • 323.
    Bendre, Megha
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Comasco: Neuropsykofarmakologi.
    Granholm, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Drennan, Ryan
    Meyer, Ann
    Yan, Liying
    Nilsson, Kent W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Comasco, Erika
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Comasco: Neuropsykofarmakologi.
    Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.2019Inngår i: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 79, s. 7-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions.

  • 324.
    Bendre, Megha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Nillson, Kent W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Granholm, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Comasco, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Maoa Methylation: A Molecular Mechanism Behind The Effect Of Early Life Stress And Voluntary Alcohol Consumption On Maoa Expression In Wistar Rats2017Inngår i: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 52Artikkel i tidsskrift (Annet vitenskapelig)
  • 325.
    Bengtsson, Andrea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effects of anabolic-androgenic steroid use on hippocampus and cortex: A controlled study of the anabolic-androgenic steroids testosterone, nandrolone, trenbolone and stanozolol in primary neuronal cultures.2014Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    Anabolic-androgenic steroids (AAS) have long been used to improve muscularity and athletic performance. Although several side-effects such as depression, anxiety, aggression and memory deficits have been reported, the effect of AAS on the brain is still not fully understood. The aim of this study was to investigate how different AAS affect neurons by monitoring neurite outgrowth (NO) and cell viability in primary neuronal cultures following exposure to various AAS. Primary cells isolated from the hippocampus and prefrontal cortex of embryonic day 17 Sprague Dawley rats were treated with five concentrations of AAS over four days. The steroids tested in this study were testosterone, nandrolone, trenbolone and stanozolol. To analyse NO, immunocytochemistry was performed and the length of neurites was measured. Cell viability was analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a measure of mitochondrial function. Results showed that a four-day treatment with testosterone significantly increased NO in prefrontal cortical cells. Nandrolone and trenbolone also induced an increase, however, stanozolol decreased NO at concentrations above 1 µM. Results using hippocampal cells showed a similar trend, but NO was less affected by the treatment regime. All four AAS decreased cell viability in both hippocampal and prefrontal cortical cells at concentrations above 1 µM. In conclusion, these results indicate that high concentrations of AAS negatively impact on the growth and viability of neurons isolated from the hippocampus and prefrontal cortex, regions of the brain associated with learning and memory. These affects could potentially induce cognitive impairments and need to be further elucidated in future studies.

  • 326.
    Bengtsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Developmental Aspects of Drug Transport Across the Blood-Brain Barrier2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The developmental aspect of drug transport across the blood-brain barrier (BBB) was investigated. Microdialysis was used to study unbound morphine BBB transport at different ages in sheep. An in vitro study was performed to find differentially expressed genes in brain capillary-rich fractions of the brain in rats of different ages. Microdialysis and brain-to-plasma ratios were used to study the contribution of breast cancer resistance protein (Bcrp) to the transport of nitrofurantoin (NTF) across the BBB of rats during development as well as in adult rats and mice.

    A method of analysing morphine and its metabolites in plasma and microdialysis samples was developed and validated. The in vivo recovery of deuterated morphine, used as a calibrator in microdialysis experiments, was not affected by the presence of morphine in the tissue. A net influx of morphine was observed in premature lambs and adult sheep, in contrast to the efflux seen in other species. This influx decreased with age, indicating that the morphine transport across the BBB changes with age. In contrast, the transport of the morphine metabolite morphine-3-glucuronide (M3G) did not change with age. Microarray data indicated that several active transporters are differentially expressed with age. Moreover, the mRNA expression levels of Abcg2 (Bcrp) and Slc22a8 (organic anion transporter 3) changed with age when quantified using real-time polymerase chain reaction. In contrast, the expression of Abcb1 (P-glycoprotein) and occludin (a tight junction protein) did not change with age. In rats, the brain distribution of NTF decreased with age due to increased protein binding in plasma. The concentration ratio of unbound NTF across the BBB was low in the adult rat, due to intra-brain metabolism and/or efflux by other transporters. Bcrp did not appear to have a significant contribution in the developing rat or in knock-out mice compared to wild-type controls with regard to NTF BBB transport.

    In conclusion, in vitro studies showed that the expression levels of some genes changed with age, presumably affecting subsequent drug distribution to the brain. Further, in vivo studies showed that distribution across the BBB changed with age for morphine but not for M3G or NTF.

    Fulltekst (pdf)
    FULLTEXT01
  • 327.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Boström, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    The use of a deuterated calibrator for in vivo recovery estimations in microdialysis studies2008Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, nr 8, s. 3433-3441Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One of the crucial issues in quantitative microdialysis is the reliability of recovery estimates to correctly estimate unbound drug tissue concentrations. If a deuterated calibrator is used for retrodialysis, the calibrator has the same properties as the study drug. However, recovery of the calibrator may be affected by the presence of the drug in the tissues. The aim of this study was to investigate the recovery of deuterated morphine with time in the absence and presence of morphine in rat tissues. Microdialysis probes were placed in the brain and blood of eight rats. Ringer's solution containing D3-morphine was perfused throughout the study and recovery was estimated. After a stabilization period of 3 h, an exponential infusion of morphine was administered over 4 h. The presence of morphine did not affect the recovery of D3-morphine from brain or blood. The average recovery values (SD) were 0.145 (0.039) and 0.131 (0.048) during the stabilization and infusion periods, respectively, for the brain probe and 0.792 (0.055) and 0.790 (0.084), respectively, for the blood probe. The recovery of deuterated morphine was stable over time in the brain and in blood, and was not affected by the presence of pharmacologically concentrations of morphine.

  • 328.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ederoth, P
    Ley, D
    Hansson, S
    Amer-Wåhlin, I
    Hellström-Westas, Lena
    Marsál, K
    Nordström, C-H
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep2009Inngår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 157, nr 6, s. 1085-1096Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose

     The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied.

    Experimental approach

     Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg.kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated.

     Key results

     Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups.

    Conclusions and implications

     The morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.

  • 329.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Engwall, Ann-Cathrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Jergil, Måns
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Differences in gene expression in the developing rat brain using cDNA microarray and real-time PCRManuskript (Annet vitenskapelig)
    Abstract [en]

    The blood-brain barrier (BBB) is formed by endothelial cells, connected by tight junction proteins restricting paracellular transport. Transport of substances into the brain may also be limited due to active efflux transporters. Not much is known about the development of tight junction proteins and active transporters in the BBB, and how this affects drug distribution to the brain at different ages. The aim of this study was to analyze possible differences in expression of tight junction proteins and active transporters in the BBB at different postnatal ages in the rat. Brain capillary-rich fractions (BCRF) were collected and gene expression levels were compared at three postnatal ages using microarray analysis. BCRF was also analyzed for the mRNA expression levels of P-gp Abcb1 (P-gp), Abcg2 (Bcrp), Slc22a8 (Oat3) and occludin using real-time PCR at 12 different postnatal ages between postnatal Day 1 and Adult. In the array analysis, 28 genes of interest were found to be differentially expressed. The mRNA levels of Abcg2 decreased to one seventh from postnatal Day 1 to Day 15. The levels of Slc22a8 increased from birth and reached a plateau at Day 3 - 12 followed by a decrease to Day 15. These findings show that active transporters are differentially expressed in the developing BBB, possibly affecting drug distribution to the brain. No change in the mRNA levels for Abcb1 or occludin was observed.

  • 330.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Jansson, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    On-line desalting and determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in microdialysis and plasma samples using column switching and liquid chromatography/tandem mass spectrometry2005Inngår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 19, nr 15, s. 2116-2122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A sensitive and reproducible method for the determination of morphine and the metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was developed. The method was validated for perfusion fluid used in microdialysis as well as for sheep and human plasma. A C18 guard column was used to desalt the samples before analytical separation on a ZIC HILIC (hydrophilic interaction chromatography) column and detection with tandem mass spectrometry (MS/MS). The mobile phases were 0.05% trifluoroacetic acid (TFA) for desalting and acetonitrile/5 mM ammonium acetate (70:30) for separation. Microdialysis samples (5 microL) were directly injected onto the system. The lower limits of quantification (LLOQ) for morphine, M3G and M6G were 0.50, 0.22 and 0.55 ng/mL, respectively, and the method was linear from LLOQ to 200 ng/mL. For plasma, a volume of 100 microL was precipitated with acetonitrile containing internal standards (deuterated morphine and metabolites). The supernatant was evaporated and reconstituted in 0.05% TFA before the desalting process. The LLOQs for sheep plasma were 2.0 and 3.1 ng/mL and the ranges were 2.0-2000 and 3.1-3100 ng/mL for morphine and M3G, respectively. For human plasma, the LLOQs were 0.78, 1.49 and 0.53 ng/mL and the ranges were 0.78-500, 1.49-1000 and 0.53-500 ng/mL for morphine, M3G and M6G, respectively.

  • 331.
    Bengtsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Mukai, Chisato
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Kitagaki, Shinji
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Miyakoshi, Naoki
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Terasaki, Tetsuya
    Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan..
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Bcrp does not influence transport of nitrofurantoin across the blood-brain barrier at different agesManuskript (Annet vitenskapelig)
    Abstract [en]

    In the blood-brain barrier (BBB), tight junction proteins together with active efflux transporters efficiently restrict access of many compounds to the brain. The contribution of breast cancer resistance protein (Bcrp, coded by Abcg2) for drug efflux in the BBB is not clear. The aim of this study was to investigate the contribution of Bcrp in the rat BBB and how development affects distribution of a Bcrp substrate with age. Nitrofurantoin (NTF) is a good substrate for Bcrp and was used as model substance. Brain-to-plasma concentration ratio (Kp) of NTF was measured at postnatal Day 1, Day 4, Day 11 and in adult rats. Microdialysis was used to measure concentration ratio of unbound NTF across the BBB (Kp,uu) with or without blockers for active transport (PSC833 and probenecid). To investigate the in vivo contribution of Bcrp, Kp was also measured in Bcrp-/- and wild-type control mice with or without the selective Bcrp blocker Ko143. The Kp decreased with age, but due to an increase in the protein binding. The Kp,uu was on average 0.047 and not affected by the presence of any blocker. Possible explanations for the low Kp,uu is intra-brain metabolism and/or efflux due to other transporter(s). No difference was observed in the Kp of NTF for Bcrp-/- compared to wild-type mice, independent of co-administration with Ko143. Thus, no in vivo contribution of Bcrp to the BBB brain transport of NTF was detected.

  • 332.
    Bereziat, Jean Claude
    et al.
    Biokemi.
    Schmezer, Peter
    Biokemi.
    Frei, Erica
    Biokemi.
    Geneste, Olivier
    Biokemi.
    lang, Matti
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Biokemi.
    Cytochrome P450 of nasal epithelium: regulation and role in carcinogen metabolism1995Inngår i: Molecular Carcinogenesis, Vol. 14, s. 130-139Artikkel i tidsskrift (Fagfellevurdert)
  • 333.
    Berg, Hampus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Method optimization for ImageXpres: Analysis of cell development in primary cells cultures2016Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    In many research fields accessible and accurate image analysis tools are essential. Morphometric analysis of cells and their cellular events can be classified into two categories: manual analysis and automated imaging analysis. In this study, a widefield automated microscope from Molecular Devices called ImageXpress, and its associated image acquisition and analysis software, called MetaXpress, were optimized for analysis of neurite outgrowth from cortical neurons taken from 17 days old embryonic fetal rats. To visualize the cells, immunocytochemistry was used. A primary antibody against the protein BIII tubulin was added along with it associated secondary antibody (Alexa 488) was used to detect the overall shape of the cells and DAPI was used to detect the nuclei. Different cell densities were tested to examine the optimum density for the cells and for the MetaXpress. A validation experiment for the MetaXpress was set up where cells were treated with 50 ng/ml BDNF once a day for one or two days. These cells were then analyzed both with the automated method in MetaXpress and manually with ImageJ. The automated analysis method was then compared to the manual tracing of the neurons. After optimization, the following settings were chosen for image capturing: exposure time for Alexa 488 was set to 750 ms, DAPI was set to 45 ms. Each well had one site in the middle. The images were captured with a 10x objective. The results demonstrated that both the MetaXpress and the manually analysis could not find a significant difference between the treated cells and the control group. The results indicate that the MetaXpress measures the neurites the same way as the manual analysis.

  • 334.
    Berg, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Transferrin receptor scFv ligands in mediation of therapeutics across the blood-brain barrier2016Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 335.
    Bergfeldt, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Electronic Health Records, social media and search logs future role in pharmacovigilance2018Independent thesis Advanced level (degree of Master (One Year)), 10 poäng / 15 hpOppgave
    Abstract [en]

    Introduction: Adverse Drug Reactions (ADR) are causing mortality and morbidity in our society. It is there for important that post-marketing surveillance systems are well functioning. The most common system is the spontaneous reporting system, but because of problems with under-reporting, other possible ADR detection strategies are being explored. Using big data sources could be valuable in the future post-marketing surveillance of drugs. Aim: This study’s aim is to get a better understanding on Electronic Health Records (EHR), social media and search logs possible contribution in the future post-marketing surveillance. Method: This study is based on relevant primary articles, mainly collected from the PubMed database. Result: A study analyzing EHR showed that Cilastazols black box warning may be inadequate. A study analyzing twitter and FDA Adverse Event Reporting System (FAERS) displayed almost three times more Adverse Events (AE) in Twitter. Another study demonstrated social medias real-time monitoring and showed that it could lead to earlier detection of AE than using FAERS. Combining FAERS and search logs have led to a 19% better identification of ADR. Conclusion: Possible areas for the big data sources in the future is to improve the accuracy in black box warnings, explore specific treatments and to use it in combination with traditional systems. Big Data’s large volume and its real-time monitoring are characteristics that could be useful in the future surveillance. Its limitation are the ethical and technical issues, which needs to be discussed and handled before fully implementing these sources in the future.

  • 336.
    Bergfeldt, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Geographical Variation in Drug Use: a Swedish Register-Based Study of the Total Population, 75 Years and Older2019Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
  • 337.
    Berggren, Jakob
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Skadliga effekter av nikotinexponering under graviditeten2017Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Bakgrund: Gravida kvinnor i Sverige får bland annat kunskap om rökningens skadliga effekter vid första besöket hos barnmorskan. Många har redan kunskapen och väljer att sluta innan eller i början av graviditeten. Det finns inte lika stor kunskap om snus eller Nicotine Replacement Therapy-produkter kan orsaka liknande skada på fostret som rökning gör. Uppgifter från socialstyrelsen i Sverige under 2014 visade att 5,5 % av de gravida kvinnorna rökte samt 1,3 % snusade. Andel gravida kvinnor som använder NRT-produkter under graviditeten registreras inte och är därmed okänt. Syfte: Att undersöka och jämföra skadliga effekter som uppstår på fostret under graviditeten från användning av cigaretter, snus, nikotin eller Nicotine Replacement Therapy-produkter. Hur induceras skadan? Om ingen fastställd mekanism är klarlagt, vilka hypoteser finns det?Metod: Källorna i arbetet har framförallt funnits via PubMed. Nyckelord i sökningarna var exempelvis nicotine och pregnancy som skrevs med olika komplikationer under graviditeten. Resultat: Tobaksanvändning under graviditeten orsakar prematur födsel, läpp-, käk- och gomspalt, tillväxtrestriktion på fostret, perinatal död, kardiovaskulära effekter och plötslig spädbarnsdöd och apné. Rökning orsakar även ektopiska graviditeter, spontan abort, placenta previa och placentaabruption. Studier på djur och in-vitro visar även på att nikotin kan ha en stor roll i den skadliga mekanismen, och därmed inducera samtliga utfall. Slutsats: Majoriteten av komplikationerna orsakas av tobak och nikotin är en av de skadliga komponenterna. Användning av NRT-produkter kan i teorin orsaka fosterskador, dock är dessa ändå ett bättre alternativ för gravida kvinnor som inte kan sluta röka eller snusa.

  • 338.
    Berglind, Frida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effects of combined use of nicotine and ethanol on human neuroblastoma cells2013Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Abstract

    According to the Swedish Public Health Institute, around 2 million swedes use some kind of tobacco product regularly. 90 % of the Swedish people also report that they drink alcohol. That nicotine and ethanol are often used together is a well-known fact and it seems that these drugs tend to increase the use of each other. Both nicotine and ethanol has shown both neuroprotective and neurotoxic properties in previous studies, depending on the doses used. Combination of low-dose ethanol and nicotine has, in contrast to some hypotheses, pointed towards a synergistic effect and an enhanced toxicity. Hence, the aim of this study was to investigate how a combined use of these substances could affect human neuroblastoma cells (SH-SY5Y). The cells were seeded onto 96 well plates and treated with different concentrations of ethanol, staurosporine or hydrogen peroxide. Staurosporine was used as a neurotoxic reference. A pre-treatment approach was also studied, where nicotine was added to the cells 24 hours prior to neurotoxic agent. The cell viability was measured using an MTT assay 48 hours later. The results showed that nicotine was unable to protect the cells against staurosporine toxicity, but a tendency of decreased toxicity was observed in cells treated with hydrogen peroxide. Concomitant administration of nicotine and ethanol showed a decreased viability compared to nicotine and ethanol alone, which was in line with previous studies. Pre-treatment with nicotine reduced the toxic effects, but the cell viability was still lowered compared to control. Since this study is based on a small number of repeats of each experiment, further research is needed to be able to draw conclusions about both the results and the mechanisms behind them. However, signs indicate that the concomitant use of ethanol and nicotine may induce a stronger neurotoxicity than if they are used separately.

  • 339.
    Berglund, Cathrine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Plasmaoxytocin och salivkortisol hos äldre patienter med depression – 3 patientfall vid Akademiska Sjukhuset2012Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [sv]

    Introduktion Hypotalamus-hypofys-binjurebarksaxeln (HPA-axeln) är det huvudsakliga endokrina systemet som aktiveras vid stress och det är välkänt att dess funktion är förändrad vid psykiatriska tillstånd såsom depression. Vid depression och ångest kan man därför se en förhöjd utsöndring av kortisol. Hormonet oxytocin har förutom dess perifera verkan vid födsel och amning visats fungera som neurotransmittor i det centrala nervsystemet och reglerar flera centrala funktioner. Flera studier har visat att oxytocin har en ångestdämpande effekt samt att oxytocinnivåer skiljer sig mellan patienter med depression och friska kontroller. Detta gör oxytocinsystemet till ett intressant område att studera ur farmakologisk synvinkel.

    Syfte Syftet med arbetet är att undersöka om någon förändring i oxytocin- och kortisolnivåer kan ses vid förbättringar av depressiva symtom hos äldre patienter.

    Material och metoder Tre patienter med depression på avdelning 1, äldrepsykiatriska verksamhetsområdet vid Akademiska Sjukhuset valdes ut. Provtagning av plasmaoxytocin och salivkortisol utfördes vid två olika tillfällen med så lång tid mellan mätningarna som möjligt, dock ej längre än en månad. I nära anslutning till provtagningstillfällena skattades även patienternas depression för att kunna följa sjukdomsförloppet och relatera resultaten från provtagningarna till graden av depressiva symtom.

    Resultat Inga trender i oxytocin- och kortisolnivåer kunde ses hos de tre patienterna relaterat till respektive depressionsgrad. 

    Slutsats För att ordentligt kunna studera och dra några slutsatser kring hur oxytocin- och kortisolnivåer förändras vid förbättringar av depressiva symtom, behöver en kontrollerad studie med ett större patientunderlag genomföras.

  • 340.
    Berglund, Kristina
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Roman, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Balldin, Jan
    Berggren, Ulf
    Eriksson, Matts
    Gustavsson, Petter
    Fahlke, Claudia
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Do men with excessive alcohol consumption and social stability have an addictive personality?2011Inngår i: Scandinavian Journal of Psychology, ISSN 0036-5564, E-ISSN 1467-9450, Vol. 52, nr 3, s. 257-260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The existence of an "addictive" personality has been extensively debated. The current study investigated personality in male individuals with excessive alcohol consumption (n = 100) in comparison to a population-based control group (n = 131). The individuals with excessive alcohol consumption were recruited by advertisements in a regional daily newspaper and controls from a population based Swedish Twin Registry. Personality was assessed by the Karolinska Scales of Personality (KSP). Comparisons were made with normative data. Furthermore, by using a multivariate projection-based approach (Principal Component Analysis; PCA), hidden structures of traits and possible relationships among the individuals with excessive consumption and the controls was investigated. The individuals with excessive alcohol consumption as well as the controls had mean values within the normative range in all scales of the KSP. Moreover, the PCA analysis revealed no systematic between-group separation. Taken together, this result demonstrates that male individuals with excessive alcohol consumption do not have a personality different from that of a general population, which supports the notion of no "addictive personality".

  • 341. Berglund, Kristina
    et al.
    Roman, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Balldin, Jan
    Berggren, Ulf
    Gustavsson, Petter
    Fahlke, Claudia
    Personality profile in male type 1 alcoholics2007Inngår i: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 42Artikkel i tidsskrift (Annet vitenskapelig)
  • 342.
    Bergman, Hilde-Marléne
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lundin, Erik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Andersson, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lanekoff, Ingela
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Quantitative mass spectrometry imaging of small-molecule neurotransmitters in rat brain tissue sections using nanospray desorption electrospray ionization2016Inngår i: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 141, nr 12, s. 3686-3695Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small molecule neurotransmitters are essential for the function of the nervous system, and neurotransmitter imbalances are often connected to neurological disorders. The ability to quantify such imbalances is important to provide insights into the biochemical mechanisms underlying the disorder. This proof-of-principle study presents online quantification of small molecule neurotransmitters, specifically acetylcholine, γ-aminobutyric acid (GABA) and glutamate, in rat brain tissue sections using nanospray desorption electrospray ionization (nano-DESI) mass spectrometry imaging. By incorporating deuterated internal standards in the nano-DESI solvent we show identification, accurate mapping, and quantification of these small neurotransmitters in rat brain tissue without introducing any additional sample preparation steps. We find that GABA is about twice as abundant in the medial septum-diagonal band complex (MSDB) as in the cortex, while glutamate is about twice as abundant in the cortex as compared to the MSDB. The study shows that nano-DESI is well suited for imaging of small molecule neurotransmitters in health and disease.

  • 343. Bergman, U
    et al.
    Brittebo, EB
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Methimazole toxicity in rodents: Covalent binding in the olfactory mucosa and detection of glial fibrillary acidic protein in the olfactory bulb1999Inngår i: TOXICOLOGY AND APPLIED PHARMACOLOGY, Vol. 155, s. 190-Artikkel i tidsskrift (Fagfellevurdert)
  • 344.
    Bergman, Ulrika
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Östergren, Anna
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Gustafson, Anne-Lee
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Brittebo, Eva B
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Differential effects of olfactory toxicants on olfactory regeneration.2002Inngår i: Arch Toxicol, Vol. 76, s. 104-Artikkel i tidsskrift (Fagfellevurdert)
  • 345. Bergmann, T. K.
    et al.
    Brasch-Andersen, C.
    Green, H.
    Mirza, M.
    Pedersen, R. S.
    Nielsen, F.
    Skougaard, K.
    Wihl, J.
    Keldsen, N.
    Damkier, P.
    Friberg, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Peterson, C.
    Vach, W.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brosen, K.
    Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer2011Inngår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, nr 2, s. 113-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 346.
    Bergqvist, M
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Brattstrom, D
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Stalberg, M
    Vaghef, H
    Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brodin, O
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Hellman, B
    Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evaluation of radiation-induced DNA damage and DNA repair in human lung cancer cell lines with different radiosensitivity using alkaline and neutral single cell gel electrophoresis1998Inngår i: Cancer Lett, Vol. 133, s. 9-Artikkel i tidsskrift (Fagfellevurdert)
  • 347.
    Bergstrand, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Application of Mixed-Effect Modeling to Improve Mechanistic Understanding and Predictability of Oral Absorption2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Several sophisticated techniques to study in vivo GI transit and regional absorption of pharmaceuticals are available and increasingly used. Examples of such methods are Magnetic Marker Monitoring (MMM) and local drug administration with remotely operated capsules. Another approach is the paracetamol and sulfapyridine double marker method which utilizes observed plasma concentrations of the two substances as markers for GI transit. Common for all of these methods is that they generate multiple types of observations e.g. tablet GI position, drug release and plasma concentrations of one or more substances. This thesis is based on the hypothesis that application of mechanistic nonlinear mixed-effect models could facilitate a better understanding of the interrelationship between such variables and result improved predictions of the processes involved in oral absorption.

    Mechanistic modeling approaches have been developed for application to data from MMM studies, paracetamol and sulfapyridine double marker studies and for linking in vitro and in vivo drug release. Models for integrating information about tablet GI transit, in vivo drug release and drug plasma concentrations measured in MMM studies was outlined and utilized to describe drug release and absorption properties along the GI tract for felodipine and the investigational drug AZD0837. A mechanistic link between in vitro and in vivo drug release was established by estimation of the mechanical stress in different regions of the GI tract in a unit equivalent to rotation speed in the in vitro experimental setup. The effect of atropine and erythromycin on gastric emptying and small intestinal transit was characterized with a semi-mechanistic model applied to double marker studies in fed and fasting dogs.

    The work with modeling of in vivo drug absorption has highlighted the need for, and led to, further development of mixed-effect modeling methodology with respect to model diagnostics and the handling of censored observations.

    Fulltekst (pdf)
    FULLTEXT01
  • 348.
    Bergstrand, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hooker, Andrew C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wallin, Johan E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Prediction-Corrected Visual Predictive Checks for Diagnosing Nonlinear Mixed-Effects Models2011Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 13, nr 2, s. 143-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Informative diagnostic tools are vital to the development of useful mixed-effects models. The Visual Predictive Check (VPC) is a popular tool for evaluating the performance of population PK and PKPD models. Ideally, a VPC will diagnose both the fixed and random effects in a mixed-effects model. In many cases, this can be done by comparing different percentiles of the observed data to percentiles of simulated data, generally grouped together within bins of an independent variable. However, the diagnostic value of a VPC can be hampered by binning across a large variability in dose and/or influential covariates. VPCs can also be misleading if applied to data following adaptive designs such as dose adjustments. The prediction-corrected VPC (pcVPC) offers a solution to these problems while retaining the visual interpretation of the traditional VPC. In a pcVPC, the variability coming from binning across independent variables is removed by normalizing the observed and simulated dependent variable based on the typical population prediction for the median independent variable in the bin. The principal benefit with the pcVPC has been explored by application to both simulated and real examples of PK and PKPD models. The investigated examples demonstrate that pcVPCs have an enhanced ability to diagnose model misspecification especially with respect to random effects models in a range of situations. The pcVPC was in contrast to traditional VPCs shown to be readily applicable to data from studies with a priori and/or a posteriori dose adaptations.

  • 349.
    Bergstrand, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Handling data below the limit of quantification in mixed effect models.2009Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 11, nr 2, s. 371-380Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study is to investigate the impact of observations below the limit of quantification (BQL) occurring in three distinctly different ways and assess the best method for prevention of bias in parameter estimates and for illustrating model fit using visual predictive checks (VPCs). Three typical ways in which BQL can occur in a model was investigated with simulations from three different models and different levels of the limit of quantification (LOQ). Model A was used to represent a case with BQL observations in an absorption phase of a PK model whereas model B represented a case with BQL observations in the elimination phase. The third model, C, an indirect response model illustrated a case where the variable of interest in some cases decreases below the LOQ before returning towards baseline. Different approaches for handling of BQL data were compared with estimation of the full dataset for 100 simulated datasets following models A, B, and C. An improved standard for VPCs was suggested to better evaluate simulation properties both for data above and below LOQ. Omission of BQL data was associated with substantial bias in parameter estimates for all tested models even for seemingly small amounts of censored data. Best performance was seen when the likelihood of being below LOQ was incorporated into the model. In the tested examples this method generated overall unbiased parameter estimates. Results following substitution of BQL observations with LOQ/2 were in some cases shown to introduce bias and were always suboptimal to the best method. The new standard VPCs was found to identify model misfit more clearly than VPCs of data above LOQ only.

  • 350.
    Bergstrand, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nosten, Francois
    Lwin, Khin Maung
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    White, Nicholas J.
    Tarning, Joel
    Characterization of an in vivo concentration-effect relationship for piperaquine in malaria chemoprevention2014Inngår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 6, nr 260, s. 260ra147-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A randomized, placebo-controlled trial conducted on the northwest border of Thailand compared malaria chemoprevention with monthly or bimonthly standard 3-day treatment regimens of dihydroartemisinin-piperaquine. Healthy adult male subjects (N = 1000) were followed weekly during 9 months of treatment. Using nonlinear mixed-effects modeling, the concentration-effect relationship for the malaria-preventive effect of piperaquine was best characterized with a sigmoidal E-max relationship, where plasma concentrations of 6.7 ng/ml [relative standard error (RSE), 23%] and 20 ng/ml were found to reduce the hazard of acquiring a malaria infection by 50% [that is, median inhibitory concentration (IC50)] and 95% (IC95), respectively. Simulations of monthly dosing, based on the final model and published pharmacokinetic data, suggested that the incidence of malaria infections over 1 year could be reduced by 70% with a recently suggested dosing regimen compared to the current manufacturer's recommendations for small children (8 to 12 kg). This model provides a rational framework for piperaquine dose optimization in different patient groups.

45678910 301 - 350 of 3715
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf