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151.
  • Silber, Hanna E, 1977-, et al. (författare)
  • The impact of misspecification of residual error or correlation structure on the type I error rate for covariate inclusion
  • 2009
  • Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 36:1, s. 81-99
  • Tidskriftsartikel (refereegranskat)abstract
    • It has been shown that when using the FOCE method in NONMEM, the likelihood ratio test (LRT) can be sensitive to the use of an inappropriate estimation method in that ignoring an existing eta-epsilon interaction leads to actual significance levels for type I errors being higher than the nominal levels. The objective of this study was to assess through simulations the LRT sensitivity to various types of residual error model misspecifications in both continuous and categorical data. The study contained two parts, simulations based on continuous and categorical data. Data sets containing 250 individuals with up to 24 observations per individual were simulated multiple times (1000) with different types of residual error models for the continuous data and different strength of correlation between observations for the categorical data. The data sets were analyzed using either the correct or a simpler (incorrect) model with or without addition of a covariate. The type I error rate of inclusion of the non-informative covariate on the 5% level was calculated as the number of runs where the drop in the objective function value (OFV) was larger than 3.84 when the covariate relationship was included in the model using the correct or the incorrect model. The difference in OFV between the model with the correct and the incorrect structure was also calculated as a measure of the residual error model misspecification. For continuous data the FOCE method was used in most cases (with interaction when appropriate). The Laplacian estimation method was used for one of the continuous models and for categorical data. The results showed that the residual error model misspecifications when the erroneous model was used were pronounced, as indicated by the OFV being substantially higher than for the corresponding correct models. The significance levels of the LRT with the incorrect model were appropriate in all cases but ignoring (serial) correlations between observations (continuous and categorical data) as well as when the eta-epsilon interaction was ignored (which has previously been shown, continuous data). When ignoring correlation, the type I error rates were shown to be sensitive to the correlation strength, the number of observations per individual and the magnitude of the inter-individual variability on clearance. We conclude that the LRT appears robust towards all tested cases, but ignoring (serial) correlations between observations and eta-epsilon interaction.
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152.
  • Sjögren, Erik, et al. (författare)
  • The multiple depletion curves method provides accurate estimates of intrinsic clearance (CLint), maximum velocity of the metabolic reaction (Vmax), and Michaelis constant (Km) : accuracy and robustness evaluated through experimental data and Monte Carlo simulations
  • 2009
  • Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 37:1, s. 47-58
  • Tidskriftsartikel (refereegranskat)abstract
    • The use of multiple depletion curves for the estimation of maximum velocity of the metabolic reaction (V(max)), the Michaelis constant (K(m)), and intrinsic clearance (CL(int)) was thoroughly evaluated by means of experimental data and through a series of Monte Carlo simulations. The enzyme kinetics of seven compounds were determined using the multiple depletion curves method (MDCM), the traditional initial formation rate of metabolite method (IFRMM), and the "in vitro t(1/2)" method, and the parameter estimates that were derived from the three methods were compared. The impact of a change in enzyme activity during the incubation period on the parameter estimates and the possibility to correct for this were also investigated. The MDCM was in good overall agreement with the IFRMM. Correction for a change in enzyme activity was possible and resulted in a better concordance in CL(int) estimates. The robustness of the method in coping with different rates of substrate turnover and variable starting concentrations were also demonstrated through Monte Carlo simulations. Furthermore, the limitations imposed by assumptions inherent in the in vitro t(1/2) method were demonstrated both experimentally and by simulations. This study demonstrates that the MDCM is a robust and efficient method for estimating enzyme kinetic variables with high accuracy and precision. The method may potentially be used in a wide range of applications, from pure enzyme kinetics to in vitro-based predictions of the pharmacokinetics of compounds with multiple and/or unknown metabolic pathways.
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153.
  • Skårberg, Kurt, 1951-, et al. (författare)
  • Multisubstance use as a feature of addiction to anabolic-androgenic steroids
  • 2009
  • Ingår i: European Addiction Research. - Basel : S. Karger AG. - 1022-6877 .- 1421-9891. ; 15:2, s. 99-106
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to explore and describe total drug use among anabolic-androgenic steroid (AAS) users and the reasons given for the use of these drugs. The study was based on semi-structured interviews and questionnaires involving 32 patients who were attending an addiction centre in Orebro, Sweden, for AAS use. The results indicated that a history of polysubstance use among the patients was frequent. Over half were using drugs of abuse and also taking various other pharmaceuticals. Almost half of the patients took human growth hormones, and almost half of the interviewed persons were drinking alcohol to a hazardous or harmful extent. The most common reason given for taking AAS and other hormones was to increase muscle mass and strength, but some participants also used insulin as a means of losing fat. Cannabis was used to improve sleep, heroin to decrease pain and amphetamine to increase endurance and burn fat. Our data suggest that most of the current AAS users who have been admitted to a treatment programme are multiple drug users with polysubstance dependence. The study stresses the importance of carefully examining total drug use as part of the assessment regimen for this group.
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154.
  • Sokka, Tuulikki, et al. (författare)
  • Women, men, and rheumatoid arthritis : analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study
  • 2009
  • Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 11:1, s. R7-
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). Methods The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. Results Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies. Conclusions In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.
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155.
  • Spjuth, Ola, 1977-, et al. (författare)
  • Bioclipse 2: A scriptable integration platform for the life sciences
  • 2009
  • Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 10, s. 397-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Contemporary biological research integrates neighboring scientific domains to answer complex ques- tions in fields such as systems biology and drug discovery. This calls for tools that are intuitive to use, yet flexible to adapt to new tasks. Results: Bioclipse is a free, open source workbench with advanced features for the life sciences. Version 2.0 constitutes a complete rewrite of Bioclipse, and delivers a stable, scalable integration platform for developers and an intuitive workbench for end users. All functionality is available both from the graphical user interface and from a built-in novel domain-specific language, supporting the scientist in interdisciplinary research and reproducible analyses through advanced visualization of the inputs and the results. New components for Bioclipse 2 include a rewritten editor for chemical structures, a table for multiple molecules that supports gigabyte-sized files, as well as a graphical editor for sequences and alignments. Conclusions: Bioclipse 2 is equipped with advanced tools required to carry out complex analysis in the fields of bio- and cheminformatics. Developed as a Rich Client based on Eclipse, Bioclipse 2 leverages on today’s powerful desktop computers for providing a responsive user interface, but also takes full advantage of the Web and networked (Web/Cloud) services for more demanding calculations or retrieval of data. That Bioclipse 2 is based on an advanced and widely used service platform ensures wide extensibility, and new algorithms, visualizations as well as scripting commands can easily be added. The intuitive tools for end users and the extensible architecture make Bioclipse 2 ideal for interdisciplinary and integrative research. Bioclipse 2 is released under the Eclipse Public License (EPL), a flexible open source license that allows additional plugins to be of any license. Bioclipse 2 is implemented in Java and supported on all major platforms; Source code and binaries are freely available at http://www.bioclipse.net.
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156.
  • Standing, Joseph F., et al. (författare)
  • Diclofenac for acute pain in children
  • 2009
  • Ingår i: Cochrane Database of Systematic Reviews. - 1469-493X .- 1469-493X. ; :4
  • Forskningsöversikt (refereegranskat)abstract
    • BACKGROUND: Diclofenac is commonly used for acute pain in children, but is not licensed for this indication in all age groups. OBJECTIVES: 1) Assess the efficacy of diclofenac for acute pain in children. 2) Assess the safety of diclofenac for short-term use in children. 3) Identify gaps in the evidence to direct future research. SEARCH STRATEGY: Seventeen databases indexing clinical trial reports were searched in February 2005 (with an update search as part of this first review in May 2008). A hand search of Paediatric Anaesthesia was undertaken and summaries obtained of adverse reaction reports from the UK Yellow Card Scheme and World Health Organization (WHO) Monitoring Centre. The reference lists of included studies were also searched. SELECTION CRITERIA: Any published report, in any language, involving the administration of diclofenac to a patient aged 18 years or younger for acute pain and detailing either monitoring of efficacy or safety. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study quality and extracted the data. Authors were contacted where necessary. Review Manager version 5 was used for analysis. MAIN RESULTS: 1) Efficacy: randomised controlled trials (RCTs) comparing diclofenac with placebo/any other treatment by using pain scores (assessed or reported), or need for rescue analgesia.2) Safety: any type of study seeking adverse events (regardless of cause). An adverse event was defined as any reported adverse or untoward happening to a patient being treated with diclofenac for acute pain.Seven publications on diclofenac efficacy and 79 on safety (74 studies plus five case reports) were included in the final analysis. Compared with placebo/no treatment, diclofenac significantly reduced need for post-operative rescue analgesia (relative risk [RR] 0.6; number needed to treat to benefit [NNT] 3.6; 95% confidence interval [CI] 2.5 to 6.3).Compared with any other non-NSAID, patients receiving diclofenac suffered less nausea or vomiting, or both (RR 0.6; NNT 7.7 [5.3 to 14.3]). There appeared to be no increase in bleeding requiring surgical intervention in patients receiving diclofenac in the peri-operative period. Serious diclofenac adverse reactions occurred in fewer than 0.24% of children treated for acute pain. The types of serious adverse reactions were similar to those reported in adults. AUTHORS' CONCLUSIONS: Diclofenac is an effective analgesic for perioperative acute pain in children. It causes similar types of serious adverse reactions in children as in adults, but these are rare. More research on optimum dosing and safety in asthmatic children is required.
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157.
  • Standing, Joseph F, et al. (författare)
  • Prospective observational study of adverse drug reactions to diclofenac in children
  • 2009
  • Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 68:2, s. 243-251
  • Tidskriftsartikel (refereegranskat)abstract
    • center dot Diclofenac is frequently used off-label in children for acute pain, but little information is available on diclofenac adverse   drug reactions in this population.   WHAT THIS STUDY ADDS   center dot The common adverse drug reactions of diclofenac for acute   pain in children are of a similar type to those seen in adults. center dot Serious adverse reactions occur in < 0.8% of children and   the incidence of diclofenac-induced bronchospasm in asthmatic children   is < 2.7%.   AIM  The aim of this study was to investigate the type of common (occurring   in > 1% of patients) adverse reactions caused by diclofenac when given   to children for acute pain.   METHODS   A prospective observational study was undertaken on paediatric surgical   patents aged < 12 years at Great Ormond Street and University College   London Hospitals. All adverse events were recorded, and causality   assessment used to judge the likelihood of them being due to   diclofenac. Prospective recruitment meant not all patients were   prescribed diclofenac, allowing an analysis of utilization. Causality   of all serious adverse events was reviewed by an expert panel.   RESULTS   Children prescribed diclofenac were significantly older, and stayed in   hospital for shorter periods than those who were not. Diclofenac was   not avoided in asthmatic patients. Data on 380 children showed they   suffer similar types of nonserious adverse reactions to adults. The   incidence (95% confidence interval) of rash was 0.8% (0.016, 2.3);   minor central nervous system disturbance 0.5% (0.06, 1.9); rectal   irritation with suppositories 0.3% (0.009, 1.9); and diarrhoea 0.3%   (0.007, 1.5). No serious adverse event was judged to be caused by   diclofenac, meaning the incidence of serious adverse reactions to   diclofenac in children is < 0.8%.   CONCLUSION   Children given diclofenac for acute pain appeared to suffer similar   types of adverse reactions to adults; the incidence of serious adverse   reaction is < 0.8%.
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158.
  • Strömstedt, Adam A, 1977- (författare)
  • Antimicrobial Peptide Interactions with Phospholipid Membranes : Effects of Peptide and Lipid Composition on Membrane Adsorption and Disruption
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The interactions between antimicrobial peptides and phospholipid membranes were investigated, in terms of lipid headgroup variations and the role of cholesterol, as well as peptide composition and structure. Also strategies for increasing proteolytic stability were evaluated. The interactions were studied on model membranes in the form of liposomes and supported bilayers, through a combination of ellipsometry, fluorescence spectroscopy, circular dichroism, dynamic light scattering, electrophoresis, electron cryomicroscopy, and bacterial/cell culture experiments. The findings showed that membrane tolerance against the lytic activity of melittin, was increased on anionic membranes by electrostatic arrest in the headgroup region, and was reduced by hydration repulsion. The presence of cholesterol caused a reduction in melittin adsorption, while at the same time reducing membrane tolerance per adsorbed peptide. Differences in membrane leakage mechanisms were also attributed to cholesterol, where large scale structural effects contributed to the leakage, while other membranes followed the pore formation model. Substituting specific amino acids for tryptophan on an LL-37 derivative, was shown to increase stability against bacterial proteases, while at the same time significantly increasing antibacterial properties. These substitutions, as well as terminal modifications, increased adsorption and membrane lytic properties in a way that was less dependent on electrostatics. Furthermore, by comparing short cationic peptides with oligotryptophan end-tagged versions, the lytic mechanism of end-tagged peptides, and the different contributions of arginine and lysine to membrane adsorption and disruption were demonstrated. This thesis is a contribution to the development of antimicrobial peptides as therapeutic alternatives to conventional antibiotics.
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159.
  • Strömstedt, Adam A., et al. (författare)
  • Evaluation of strategies for improving proteolytic resistance of antimicrobial peptides by using variants of EFK17, an internal segment of LL-37
  • 2009
  • Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 53:2, s. 593-602
  • Tidskriftsartikel (refereegranskat)abstract
    • Methods for increasing the proteolytic stability of EFK17 (EFKRIVQRIKDFLRNLV), a new peptide sequence with antimicrobial properties derived from LL-37, were evaluated. EFK17 was modified by four d-enantiomer or tryptophan (W) substitutions at known protease cleavage sites as well as by terminal amidation and acetylation. The peptide variants were studied in terms of proteolytic resistance, antibacterial potency, and cytotoxicity but also in terms their adsorption at model lipid membranes, liposomal leakage generation, and secondary-structure behavior. The W substitutions resulted in a marked reduction in the proteolytic degradation caused by human neutrophil elastase, Staphylococcus aureus aureolysin, and V8 protease but not in the degradation caused by Pseudomonas aeruginosa elastase. For the former two endoproteases, amidation and acetylation of the terminals also reduced proteolytic degradation but only when used in combination with W substitutions. The d-enantiomer substitutions rendered the peptides indigestible by all four proteases; however, those peptides displayed little antimicrobial potency. The W- and end-modified peptides, on the other hand, showed an increased bactericidal potency compared to that of the native peptide sequence, coupled with a moderate cytotoxicity that was largely absent in serum. The bactericidal, cytotoxic, and liposome lytic properties correlated with each other as well as with the amount of peptide adsorbed at the lipid membrane and the extent of helix formation associated with the adsorption. The lytic properties of the W-substituted peptides were less impaired by increased ionic strength, presumably by a combination of W-mediated stabilization of the largely amphiphilic helix conformation and a nonelectrostatic W affinity for the bilayer interface. Overall, W substitutions constitute an interesting means to reduce the proteolytic susceptibility of EFK17 while also improving antimicrobial performance.
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160.
  • Strömstedt, Adam A., 1977-, et al. (författare)
  • Oligotryptophan-tagged antimicrobial peptides and the role of the cationic sequence
  • 2009
  • Ingår i: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier BV. - 0005-2736 .- 1879-2642. ; 1788:9, s. 1916-1923
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of varying the cationic sequence of oligotryptophan-tagged antimicrobial peptides were investigated in terms of peptide adsorption to model lipid membranes, liposome leakage induction, and antibacterial potency. Heptamers of lysine (K7) and arginine (R7) were lytic against Escherichia coli bacteria at low ionic strength. In parallel, both peptides adsorbed on to bilayers formed by E. coli phospholipids, and caused leakage in the corresponding liposomes. K7 was the more potent of the two peptides in causing liposome leakage, although the adsorption of this peptide on E. coli membranes was lower than that of R7. The bactericidal effect, liposome lysis, and membrane adsorption were all substantially reduced at physiological ionic strength. When a tryptophan pentamer tag was linked to the C-terminal end of these peptides, substantial peptide adsorption, membrane lysis, and bacterial killing was observed also at high ionic strength, and also for a peptide of lower cationic charge density (KNKGKKN-W5). Strikingly, the order of membrane lytic potential of the cationic peptides investigated was reversed when tagged. This and other aspects of peptide behavior and adsorption, in conjunction with effects on liposomes and bacteria, suggest that tagged and untagged peptides act by different lytic mechanisms, which to some extent counterbalance each other. Thus, while the untagged peptides act by generating negative curvature strain in the phospholipid membrane, the tagged peptides cause positive curvature strain. The tagged heptamer of arginine, R7W5, was the best candidate for E. coli membrane lysis at physiological salt conditions and proved to be an efficient antibacterial agent.
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