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  • 101.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sinha, Vikash
    Mackie, Claire
    van Peer, Achiel
    Drinkenburg, Wilhelmus
    Vermeulen, An
    Heald, Donald
    Margareta, Hammarlund-Udenaes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wassvik, Carola
    Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates2015In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, p. 520-532Article in journal (Refereed)
    Abstract [en]

    In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood-brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (Kp,uu,brain), intracellular accumulation (Kp,uu,cell) and binding and distribution in the brain (Vu,brain) for a set of 40 compounds were identified using partial least squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties.

  • 102.
    Lundquist, Pinelopi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hartvig, Per
    Hospital Pharmacy, Uppsala University Hospital.
    Blomquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Långström, Bengt
    5-hydroxy-L-[beta-C-11]tryptophan versus alpha-[C-11]methyl-L-tryptophan for positron emission tomography imaging of serotonin synthesis capacity in the rhesus monkey brain2007In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 27, no 4, p. 821-830Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to compare two positron emission tomography (PET) tracers that were developed to follow serotonin (5HT) synthesis by performing sequential PET scanning of the same rhesus monkey (n=4) on the same day. α-[11C]Methyl-L-tryptophan ([11C]AMT) and 5-Hydroxy-L-[β-11C]tryptophan ([11C]HTP) are substrates in the first and second enzymatic steps, respectively, in the biosynthesis of 5HT. Regional net accumulation rate constants were derived from kinetic (two-tissue compartment model with irreversible tracer trapping) and graphic (Patlak) analyses, using the arterial plasma concentrations as input. The kinetic data analysis showed that the rate constant for the transfer of [11C]HTP into the brain (K1) was higher than that for [11C]AMT in the striatum and thalamus but was similar in other brain regions. The rate constant for tracer trapping (k3) was also higher for [11C]HTP than for [11C]AMT in the striatum (0.046±0.024 versus 0.019±0.006 min-1) and thalamus (0.039±0.013 versus 0.016±0.007 min-1). In agreement with previously reported regional HTP accumulation rates, the net accumulation rate constant (Kacc) for [11C]HTP was also higher in these regions than in other brain regions; this is in contrast to the uniform distribution of [11C]AMT Kacc values. This suggests that the regional net accumulation rates obtained with these two PET tracers will be of different magnitude, which might be related to the activity of each targeted enzyme.

  • 103.
    Lundquist, Pinelopi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wilking, Helena
    Höglund, A Urban
    Sandell, Johan
    Bergström, Mats
    Hartvig, Per
    Långström, Bengt
    Potential of [11C]DASB for measuring endogenous serotonin with PET: binding studies2005In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 32, no 2, p. 129-136Article in journal (Refereed)
    Abstract [en]

    The serotonin transporter radioligand [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [11C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [11C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [11C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [11C]DASB for transporter binding.

  • 104.
    Madsen, Jacob
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Merachtsaki, Pinelopi
    Davoodpour, Padideh
    Bergström, Mats
    Långström, Bengt
    Andersen, Kim
    Thomsen, Christian
    Martiny, Lars
    M. Knudsen, Gitte
    Synthesis and Biological Evaluation of Novel Carbon-11-Labelled Analogues of Citalopram as Potential Radioligands for the Serotonin Transporter2003In: Bioorganic & Medicinal Chemistry, Vol. 11, no 16, p. 3447-56Article in journal (Refereed)
  • 105. Magnusson, Marie
    et al.
    Bergstrand, Ingar C
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Heijl, Anders
    Roth, Bodil
    Höglund, Peter
    A placebo-controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans2006In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 61, no 2, p. 138-147Article in journal (Refereed)
    Abstract [en]

    AIM: To investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans. METHODS: A randomized, placebo-controlled, four-period cross-over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min(-1). Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R-M1, S-M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses. RESULTS: Mean AUCs (ng h ml(-1)) were significantly increased for pentoxifylline (1964 vs. 1453) and S-M1 (5804 vs. 4227), but not R-M1 when pentoxifylline was co-administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1-systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co-administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R-M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S-M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline. CONCLUSION: The R-M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.

  • 106. Magnusson, Marie
    et al.
    Gunnarsson, Margoth
    Berntorp, Erik
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Höglund, Peter
    Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans2008In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 581, no 3, p. 290-5Article in journal (Refereed)
    Abstract [en]

    It is known that pentoxifylline inhibits platelet aggregation in vitro, but the effects from pentoxifylline and its main metabolites: 3,7-dimetyl-1(5 hydroxyhexyl)xanthine (R-M1 and S-M1), 3,7-dimetyl -1(4-carboxybutyl)xanthine (M4), 3,7-dimetyl -1(3-carboxypropyl)xanthine (M5), on platelet aggregation in whole blood in vitro and in vivo have not been studied. We found that pentoxifylline, rac-M1, R-M1, S-M1 and M4 significantly inhibit ADP induced platelet aggregation in whole blood in vitro in a concentration-dependent manner, R-M1 being the most potent followed by rac-M1, S-M1, pentoxifylline, and M4. In this series of experiments the effects on aggregation induced ATP-release were less pronounced and were only significant after treatment with pentoxifylline, rac-M1 and R-M1, but the potency order appears to be the same. Since the metabolites are not available for use in humans, and also since each substance would be extensively metabolised in vivo, we made an attempt to estimate the relative contribution of each substance to the total effect of pentoxifylline in vivo. Previously published concentrations of pentoxifylline and these metabolites in humans, after administration of pentoxifylline, were used in combination with the potency ratios from this study. The findings from these calculations were that the main effect in vivo comes from S-M1 followed by pentoxifylline, the other metabolites contribute less than 10% each. In conclusion: in the following potency order R-M1, rac-M1, pentoxifylline, S-M1 and M4 all have significant effects on platelet aggregation in whole blood in vitro. However, it appears that the main effects in vivo are caused by S-M1 and pentoxifylline.

  • 107.
    Magnusson, Mats O.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Pharmacodynamics of Enzyme Induction and its Consequences for Substrate Elimination2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enzyme induction is a process whereby a molecule enhances the expression of enzymes. If the affected enzymes are involved in the elimination of a drug, this may result in a drug interaction. Induction is therefore of major concern during drug development and in clinical practice.

    The induction process depends on the half-life of the induced enzyme, the pharmacokinetics of the inducing agent, and the relationship between the inducer’s concentration and the induction stimulus. The aim of the conducted research was to investigate these key aspects of enzyme induction and the consequences that induction has for substrate elimination.

    Successful investigations of the induction process presuppose the existence of appropriate methods for the estimation of the metabolic activity. Enzyme activity measurements can be conducted in tissues with low enzyme content using the analytical method presented here.

    A model was developed describing the changes in the pharmacokinetics of clomethiazole and its metabolite NLA-715, that are attributable to carbamazepine induction. The consequences of the induction was explained using a mechanistic approach, acknowledging food-induced changes in the blood flow to the liver, and interpreting in vitro generated metabolic information.

    The time course of the induction process was examined in two investigations. In the first of these, the pharmacokinetics of the autoinducing drug phenobarbital and its effect on several enzymes were described in rats. This was accomplished by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner. In the final investigation, the time course of the increase and cessation in enzyme activity was studied in healthy volunteers treated with carbamazepine. This investigation allowed the half-lives of CYP3A and CYP1A2 to be estimated.

    The key aspects of the enzyme induction process have been examined using mechanistic induction models. These novel models improve the understanding of the induction process and its consequences for substrate elimination.

    List of papers
    1. Quantitative analysis of eight testosterone metabolites using column switching and liquid chromatography/tandem mass spectrometry
    Open this publication in new window or tab >>Quantitative analysis of eight testosterone metabolites using column switching and liquid chromatography/tandem mass spectrometry
    2004 In: Rapid Commun Mass Spectrom, Vol. 18, no 10, p. 1089-94Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95737 (URN)
    Available from: 2007-04-13 Created: 2007-04-13Bibliographically approved
    2. A mechanistic model describing the impact of carbamazepine on the pharmacokinetics of clomethiazole and its metabolite NLA-715
    Open this publication in new window or tab >>A mechanistic model describing the impact of carbamazepine on the pharmacokinetics of clomethiazole and its metabolite NLA-715
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-95738 (URN)
    Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2011-03-01
    3. A mechanism-based integrated pharmacokinetic enzyme model describing the time course and magnitude of phenobarbital-mediated enzyme induction in the rat
    Open this publication in new window or tab >>A mechanism-based integrated pharmacokinetic enzyme model describing the time course and magnitude of phenobarbital-mediated enzyme induction in the rat
    2006 (English)In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 23, no 3, p. 521-532Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE:

    To characterize the magnitude, time course, and specificity of phenobarbital (PB)-mediated enzyme induction, and further, to develop an integrated pharmacokinetic (PK)-enzyme model describing the changes in the activities of CYP enzymes as well as in the PK of PB.

    METHODS:

    PB plasma concentrations and in vitro activities of several CYP enzymes were measured in rats treated with PB between 0 and 14 days. A PB PK-enzyme induction model was developed using the program NONMEM: .

    RESULTS:

    PB treatment both induces and reduces the activity of CYP enzymes by stimulating the enzymes' formation or elimination rates. Certain CYP enzymes affected the PB PK through autoinduction. The half-life of the induction process was estimated to be 2 days for CYP1A2, CYP3A1/2, and CYP2B1/2, and 3 days for androstenedione producing enzymes. The CYP2C11 activity was rapidly reduced by PB treatment. A lag time for the PB autoinduction was observed. This lag time is explained by the rate difference between induction and reduction in CYP activities.

    CONCLUSION:

    To our knowledge, this is the first example of an induction model that simultaneously describes plasma PK and in vitro data. It does so by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-95739 (URN)10.1007/s11095-005-9571-z (DOI)16525862 (PubMedID)
    Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2017-12-14Bibliographically approved
    4. Pharmacodynamics of enzyme induction attributable to carbamazepine treatment using midazolam, caffeine and digoxin as probe substrates
    Open this publication in new window or tab >>Pharmacodynamics of enzyme induction attributable to carbamazepine treatment using midazolam, caffeine and digoxin as probe substrates
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-95740 (URN)
    Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2011-03-01
    Download full text (pdf)
    FULLTEXT01
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    COVER01
  • 108.
    Magnusson, Mats O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Dahl, Marja-Liisa
    Cederberg, Jonas
    Karlsson, Mats O.
    Sandström, Rikard
    Pharmacodynamics of enzyme induction attributable to carbamazepine treatment using midazolam, caffeine and digoxin as probe substratesManuscript (Other academic)
  • 109.
    Magnusson, Mats O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, Rikard
    A mechanism-based integrated pharmacokinetic enzyme model describing the time course and magnitude of phenobarbital-mediated enzyme induction in the rat2006In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 23, no 3, p. 521-532Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To characterize the magnitude, time course, and specificity of phenobarbital (PB)-mediated enzyme induction, and further, to develop an integrated pharmacokinetic (PK)-enzyme model describing the changes in the activities of CYP enzymes as well as in the PK of PB.

    METHODS:

    PB plasma concentrations and in vitro activities of several CYP enzymes were measured in rats treated with PB between 0 and 14 days. A PB PK-enzyme induction model was developed using the program NONMEM: .

    RESULTS:

    PB treatment both induces and reduces the activity of CYP enzymes by stimulating the enzymes' formation or elimination rates. Certain CYP enzymes affected the PB PK through autoinduction. The half-life of the induction process was estimated to be 2 days for CYP1A2, CYP3A1/2, and CYP2B1/2, and 3 days for androstenedione producing enzymes. The CYP2C11 activity was rapidly reduced by PB treatment. A lag time for the PB autoinduction was observed. This lag time is explained by the rate difference between induction and reduction in CYP activities.

    CONCLUSION:

    To our knowledge, this is the first example of an induction model that simultaneously describes plasma PK and in vitro data. It does so by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner.

  • 110.
    Magnusson, Mats O.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sandström, Rikard
    Quantitative analysis of eight testosterone metabolites using column switching and liquid chromatography/tandem mass spectrometry2004In: Rapid Commun Mass Spectrom, Vol. 18, no 10, p. 1089-94Article in journal (Refereed)
  • 111.
    Magnusson, Mats O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Zingmark, Per-Henrik
    Fransson, Bo
    Karlsson, Mats O.
    Sandström, Rikard
    A mechanistic model describing the impact of carbamazepine on the pharmacokinetics of clomethiazole and its metabolite NLA-715Manuscript (Other academic)
  • 112.
    Maloney, Alan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Optimal adaptive design in clinical drug development: a simulation example2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 10, p. 1231-1243Article in journal (Refereed)
    Abstract [en]

    The objective of this article is to demonstrate optimal adaptive design as a methodology for improving the performance of phase II dose-response studies. Optimal adaptive design uses both information prior to the study and data accrued during the study to continuously update and refine the study design. Dose-response models include linear, log-linear, 4-parameter sigmoidal E-max, and exponential models. Where the response has both a placebo effect and plateau at higher doses, only the 4-parameter sigmoidal E-max model behaves acceptably and hence is used to illustrate the methodology. Across 13 hypothetical dose-response scenarios considered, it was shown that the capability of the adaptive designs to "learn" the true dose response resulted in performances up to 180% more efficient than the best fixed optimal designs, This work exposes the common misconception that adaptive designs are somehow "risky." As shown in this simple simulation example, the converse is true. Adaptive designs perform extremely well both when prior information is accurate and inaccurate. This leads to improved dose-response models and dose selection in phase III. This benefits sponsors, regulators, and subjects alike by reducing sample size, increasing information, and providing better dose guidance.

  • 113.
    Masete, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Frequency and impact of hospital admissions due to anticoagulant-related bleeding: a cohort study2017Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Anticoagulants used in the community have an important role as they may be life-saving in patients with, or at risk for, thromboembolic conditions. However, adverse effects (AEs) such as bleeding can also potentially be life-threatening. With a growing elderly population, use of these medications increases, therefore it is important to identify patients who require closer attention to minimise the incidence and impact of AEs.

    Aim:  To determine the frequency and impact of admissions to a tertiary care hospital through the emergency department with bleeding associated with over-anticoagulation.

    Materials and Methods:  A retrospective cohort study was conducted at Alfred Health. Patients were identified using anticoagulant-bleeding related diagnostic codes (ICD-10 AM: D68.3; Y44.2; Y44.3). Patients discharged between July 2015-June 2016 with an anticoagulant-bleed diagnosis and minimum one-night hospital admission were included.

    Results:  From the 220 patient episodes identified through coding, 81 satisfied the inclusion criteria. The median age was 79 (IQR 70-85) and 49% had major bleeds. Most patients (80%) were admitted on warfarin and managed by withholding anticoagulants and administering reversal agents (97%). Almost 20% required surgery, and ten patients died. Length of stay was approximately 6 days, with a median total episode cost of $8,600.

    Conclusions:  These findings identify the current burden for patients at risk of having a bleed due to anticoagulation. With the recent introduction of an Anticoagulation Stewardship Program at Alfred Health, improvements in the way the hospital provides care and follow-up may reduce the incidence of anticoagulant-related bleeding, as well as associated morbidity and mortality.

  • 114.
    Mikhail, Sandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Användning av Aciklovir på Astrid Lindgrens Barnsjukhus – En djupanalys2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: De flesta läkemedel som finns på marknaden idag har bristfällig information till barn vad gäller säkerhet, dosering, indikation och effekt. Nyfödda barn genomgår stora fysiologiska förändringar och därför är det nödvändigt att ta hänsyn till ett barns farmakokinetiska utveckling för att kunna dosera korrekt. Eftersom informationen om läkemedel till barn kan vara otillräcklig har det lett till en ökad erfarenhetsbaserad kunskap kring läkemedel. ePed är en Erfarenhetsbaserad och Evidensbaserad Databas där relevant information om läkemedel samlas. Aciklovir är ett virushämmande läkemedel som används mot Herpes simplex virus 1 och 2, Varicella-zoster virus, Epstein-Barr virus och Cytomegalovirus. Syfte: Att analysera användningen av aciklovir med avseende på barn samt skapa bakgrundsinformation för erfarenhetsbaserade rekommendationer i ePeds databas. Genom att analysera doseringen och användningen av aciklovir uppmärksammas eventuella fel och därmed finns det möjlighet till förbättring. Material och metoder: Litteratursökning, inleveransstatistik från sjukhusapotek, retrospektiv journalgenomgång samt intervju med vårdpersonal. Resultat: 41 % av alla inkluderade patienter har fått rätt dos och 59 % av alla inkluderade patienter har fått avvikande dos, där majoriteten av åldersgruppen 2 månader – 12 år blivit doserade efter kroppsvikt när de bör doseras efter kroppsyta. För 79 % av patienterna var behandlingsorsak inte inrapporterat. Konklusion: Majoriteten av doseringarna med aciklovir stämde inte överens med referenslitteraturen samt att det beställs mer aciklovir än vad som administreras. 

  • 115.
    Nacke, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    External validation of a tool to assess medication-related admissions in four Swedish hospitals2019Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    External validation of a tool to assess medication-related admissions in four Swedish hospitals

    Background

    The MedBridge trial is a large ongoing clinical trial on medication reviews in elderly patients in Sweden with participating hospitals from Uppsala, Enköping, Västerås and Gävle. A tool for assessing medication-related admissions (MRAs) has been developed and validated in Uppsala: Assessment Tool for identifying Hospital Admissions Related to Medications (AT-HARM10). MRAs is often used as an outcome for medication reviews and similar interventions. Validation of AT-HARM10 outside of Uppsala is therefore warranted.

    Aim

    The aim was to externally validate AT-HARM10. This was needed since AT-HARM10 was for the first time used outside Uppsala.

    Materials and methods

    The readmissions of elderly patients within the MedBridge trial were collected from all participating hospitals. The assessors in this study were two final-year pharmacy students. First, the assessors assessed the readmissions independently of each other and then a consensus meeting was held where the readmissions were discussed, and a consensus was reached. The outcomes in this study were the assessment time, inter-rater reliability and content validity between the hospitals from Uppsala, Enköping, Västerås, and Gävle. The time was measured every day during the assessment period. The inter-rater reliability was calculated for every consensus meeting. The content validity was based on the questions from AT-HARM10 and was collected for each of the assessed readmissions and compared between the four participating hospitals. The content validity of the distribution of questions U1-P10 between the hospitals was tested with a χ2-test.

    Results

    In this study, 1687 unplanned readmissions from 893 patients were assessed. Uppsala University Hospital had 6.6 minutes as total mean assessment time including consensus meeting. The total mean time from Enköping, Västerås and Gävle were 6.48, 6.32 and 6.16 minutes respectively. The strength of agreement between the two assessors was substantial in Uppsala, Västerås and Gävle (ĸ 0.80, 0.79 and 0.76 respectively) and perfect in Enköping (ĸ 0.89). For the content validity were there no differences between the hospitals in the distribution of question U1-P10.

    Conclusion

    AT-HARM10 was for the first time used outside Uppsala and has been externally validated with data from the hospitals in Enköping, Västerås, and Gävle. The time needed per admission for the two assessors was low which confirms that it is possible to have final-year pharmacy students as assessors. This information is important both within the MedBridge trial and if the tool would be used in outer clinical studies.

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    fulltext
  • 116.
    Nielsen, Elisabet I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Viberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sandström, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments2007In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 51, no 1, p. 128-136Article in journal (Refereed)
    Abstract [en]

    Dosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of Streptococcus pyogenes exposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (Emax) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.

  • 117.
    Nieves, Migxania
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hemtjänstens syn på farmaceutiskt stöd vid utskrivning: en kommunöverskridande kartläggning med fokus på att utvärdera dess vidare behov och utveckling2016Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: I dagens samhälle är det alltmer viktigt att öka patientsäkerheten inom vården. Den farmaceutiska tjänsten, Utskrivningshjälpen, har visats kunna minska felaktigheter i läkemedelslistor och andra problem vid patientutskrivningar till korttidsboendet i Uppsala län. Under sommaren 2015 utökades tjänsten till att även inkludera patienter som skrivs ut till hemsjukvård i Uppsala kommun. Syfte: Att kartlägga hemtjänstens syn på farmaceutiskt stöd vid utskrivning samt belysa de problem hemtjänsten upplever vid utskrivningar från sjukhuset, för att kunna utveckla farmaceuttjänsten. Material och metoder: En kvalitativ undersökning med kvantitativa inslag utfördes med hjälp av halvstrukturerade intervjuer med sjuksköterskor från hemtjänst/hemsjukvård från olika kommuner i Uppsala län. Intervjuerna utfördes, spelades in, transkriberades manuellt och analyserades med hjälp av innehållsanalys. Resultat: Totalt utfördes 13 intervjuer. En majoritet på 69 % hade haft erfarenhet av Utskrivningshjälpen och av dessa var det 89 % som upplevde en nytta med tjänsten. Det var 46 % som ansåg att klinikapotekaren kunde underlätta deras arbete i hemtjänst/hemsjukvård. Samma antal upplevde i dagsläget dålig patientsäkerhet. Konklusion: Utskrivningshjälpen fokuserar på sådant som anses kunna öka patientsäkerheten och underlättar sjuksköterskornas arbete i hemtjänst/hemsjukvård. Förutom att kontrollera läkemedelslistor och rensa läkemedel, var det önskvärt att förbättra tjänstens kommunikation med hemsjukvården och anhöriga. Generellt fanns det en positiv syn på Utskrivningshjälpen inom hemsjukvården. 

  • 118. Norrgren, Kristina
    et al.
    Sjölin, Maria
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Areberg, Johan
    Johnsson, Anders
    Johansson, L
    Mattsson, Sören
    Comparative renal, hepatic, and bone marrow toxicity of Cisplatin and radioactive Cisplatin (191Pt) in Wistar rats2006In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 21, no 5, p. 528-534Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate the possibility to increase the therapeutic gain of the cytotoxic agent, cisplatin, by incorporation of radioactive platinum. In this study, we investigated how organs at risk (i.e., kidneys, bone marrow, and liver) are affected by treatment with 191Pt-cisplatin, compared to treatment with conventional cisplatin. Rats (total, n = 69) were divided into three groups and given 5 mg/kg 191Pt-cisplatin and 5 mg/kg nonradioactive cisplatin or saline. The weight of the animals and blood samples, including analysis of creatinine, bilirubin, alanine and aspartate aminotransferases and platelet count, was followed for 6 weeks after treatment. Histopathology examinations of kidney and liver tissues were performed. An initial decrease in weight gain was seen from 3 days after treatment with cisplatin and 191Pt-cisplatin and for 1 week onward; thereafter, the weight gain continued, following the same pattern as for the control group. Concentration of plasma creatinine was increased for both cisplatin groups but with no significant difference between treatment groups. No other significant differences in effect parameters were found. There was no increase in toxicity for radioactive cisplatin on liver, kidneys, and bone marrow, compared to conventional cisplatin. Further experimental and clinical studies on preparations of this type are thus warranted.

  • 119.
    Persson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Aspekter på läkemedelsförskrivning till äldre patienter: en analys baserad på data från Läkemedelsregistret2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Aging is accompanied by an increased vulnerability to drug-related problems, and certain drugs are due to unfavorable benefit-risk balances of special concern. The Swedish National Board of Health and Welfare has developed a list of substances that are potentially inappropriate for elderly, including anticholinergic drugs, tramadol, propiomazine and long-acting benzodiazepines.

    Aim: To create a foundation for interventions by illuminating aspects regarding extent and quality of drug prescribing for patients 75 years and older in Sweden, focusing on potentially inappropriate drugs, hypnotics, drugs for urinary incontinence, neuroleptics and analgesics.

    Materials and Methods: Data were ordered from the Swedish Prescribed Drug Register which contains individual-based information about all out-patient prescriptions dispensed at Swedish pharmacies since July 2005. Data were processed using Microsoft Office Excel and results were analyzed using current Swedish treatment guidelines and quality indicators.

    Results: During August 2011- July 2012 almost 22 % of the Swedish population aged 75 years and older were dispensed one or more potentially inappropriate drug, the most frequent being tramadol. Nearly 5 % of the elderly were introduced on hypnotics, of which the majority received zopiclone according to Swedish recommendations. Among patients introduced on drugs for urinary incontinence, treatment was often not continuous over time. Regular use of neuroleptics was seen among 4 % of patients. About 9 % were introduced on opioids, of which codeine combinations and tramadol were the most common substances.

    Conclusions: Compliance to treatment guidelines is generally fairly good, but there are still potentials for improvements in prescribing for elderly patients.

  • 120.
    Rana, Munita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Följsamhet till nationella riktlinjer vid läkemedelsbehandling av vänsterkammarsvikt vid Akademiska sjukhuset i Uppsala2017Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Följsamhet till nationella riktlinjer vid läkemedelsbehandling av vänsterkammarsvikt vid Akademiska sjukhuset i Uppsala

     

    Munita Rana

    Fördjupningsprojekt 30 hp, Apotekarprogrammet

    Institution för Farmaceutisk biovetenskap, Handledare: Henrik Toss och Examinator: Margareta Hammarlund-Udenaes

     

    Introduktion: Evidens för behandling av Heart Failure with Reduced Ejection Fraction (HFrEF) är väl underbyggda och tydliga behandlingsriktlinjer finns att följa för diagnostik, behandling samt uppföljning. Däremot finns det bristande evidens för hur Heart Failure with Preserved Ejection Fraction (HFpEF) skall handläggas. Därför har nya nationella riktlinjer tagits fram för att bättre kunna diagnostisera och behandla HFpEF.

    Syfte: Att kartlägga hur diagnostik, läkemedelsbehandling och uppföljning skiljer sig mellan patienter med HFrEF och HFpEF vid Akademiska sjukhuset i Uppsala, samt undersöka hur god följsamheten är till Socialstyrelsens nya nationella riktlinjer för hjärtsviktsvården.

    Material och metod: En deskriptiv, retrospektiv studie utfördes i form av en journalgranskning bestående av patienter med huvuddiagnos hjärtsvikt inlagda på Akademiska sjukhuset i Uppsala. Patienterna följdes från det första inskrivningstillfället under året 2016 och förloppet följdes sedan under följande sex månader efter inläggningen.

    Resultat: Studien visar att en lika stor andel av patienterna i de båda grupperna behandlades med ACE-hämmare, ARB respektive diuretika. Man fann inte heller någon signifikant skillnad i behandling med betablockerare.

    Slutsats: Andelen som behandlats med ACE-hämmare, ARB, betablockerare och diuretika var lika vid jämförelse av de två grupperna.

  • 121.
    Ribbing, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jonsson, E. Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Power, Selection Bias and Predictive Performance of the Population Pharmacokinetic Covariate Model2004In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 31, no 2, p. 109-134Article in journal (Refereed)
    Abstract [en]

    Identification and quantification of covariate relations is often an important part of population pharmacokinetic/pharmacodynamic (PK/PD) modelling. The covariate model is regularly built in a stepwise manner. With such methods, selection bias may be a problem if only statistically significant covariates are accepted into the model. Competition between multiple covariates may further increase selection bias, especially when there is a moderate to high correlation between the covariates. This can also result in a loss of power to find the true covariates. The aim of this simulation study was to investigate the effect on power, selection bias and predictive performance of the covariate model, when altering study design and system-related quantities. Data sets with 20-1000 subjects were investigated. Five covariates were created by sampling from a multivariate standard normal distribution. The true covariate was set up to have no, low, moderate and high correlation to the other four covariates, respectively. Data sets, in which each individual had two or three PK observations, were simulated using a one-compartment i.v. bolus model. The true covariate influenced clearance according to one of several magnitudes. Different magnitudes of residual error and inter-individual variability in the structural model parameters were also introduced to the simulation model. A total of 7400 replicate data sets were simulated independently for each combination of the above conditions. Models with one of the five simulated covariates influencing clearance and the model without any covariate were fitted to the data. The probability of selecting (according to a pre-specified P-value) the different covariates, along with the estimated covariate coefficient, was recorded. The results show that selection bias is very high for small data sets (< or = 50 subjects) simulated with a weak covariate effect. If selected under these circumstances, the covariate coefficient is on average estimated to be more than twice its true value, making the covariate model useless for predictive purposes. Surprisingly, even though competition from false covariates caused substantial loss in the power of selecting the true covariate, the already high selection bias increased only marginally. This means that the bias due to competition is negligible if statistical significance is also required for covariate selection. Bias and predictive performance are direct functions of power, only indirectly affected by study design and system-related quantities. Mainly because of selection bias, low-powered covariates can be expected to harm the predictive performance when selected. For the same reason these low-powered covariates may falsely appear to be clinically relevant when selected. If the aim of an analysis is predictive modelling, we do not recommend stepwise selection or significance testing of covariates to be performed on small or moderately sized data sets (<50-100 subjects).

  • 122.
    Sandström, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lidbrink, Elisabet
    Bergh, Jonas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Model describing the relations between pharmacokinetics and hematological toxicity of the epirubicin-docetaxel regimen in breast cancer2005In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 23, no 3, p. 413-421Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients.

    PATIENTS AND METHODS:

    Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m(2). Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m(2)) or reduced (minimum, 40/50 mg/m(2)). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment.

    RESULTS:

    In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data.

    CONCLUSION:

    The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.

  • 123.
    Savic, Radojka M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jonker, Daniël M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Kerbusch, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Implementation of a Transit Compartment Model for Describing Drug Absorption in Pharmacokinetic Studies2007In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 34, no 5, p. 711-726Article in journal (Refereed)
    Abstract [en]

    Purpose: To compare the performance of the standard lag time model (LAG model) with the performance of an analytical solution of the transit compartment model (TRANSIT model) in the evaluation of four pharmacokinetic studies with four different compounds. Methods: The population pharmacokinetic analyses were performed using NONMEM on concentration–time data of glibenclamide, furosemide, amiloride, and moxonidine. In the TRANSIT model, the optimal number of transit compartments was estimated from the data. This was based on an analytical solution for the change in drug concentration arising from a series of transit compartments with the same first-order transfer rate between each compartment. Goodness-of-fit was assessed by the decrease in objective function value (OFV) and by inspection of diagnostic graphs. Results: With the TRANSIT model, the OFV was significantly lower and the goodness-of-fit was markedly improved in the absorption phase compared with the LAG model for all drugs. The parameter estimates related to the absorption differed between the two models while the estimates of the pharmacokinetic disposition parameters were similar. Conclusion: Based on these results, the TRANSIT model is an attractive alternative for modeling drug absorption delay, especially when a LAG model poorly describes the drug absorption phase or is numerically unstable.

  • 124.
    Silber, Hanna E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jauslin, Petra M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Frey, Nicolas
    Gieschke, Ronald
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    An integrated model for glucose and insulin regulation in healthy volunteers and type 2 diabetic patients following intravenous glucose provocations2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 9, p. 1159-1171Article in journal (Refereed)
    Abstract [en]

    An integrated model for the regulation of glucose and insulin concentrations following intravenous glucose provocations in healthy volunteers and type 2 diabetic patients was developed. Data from 72 individuals were included. Total glucose, labeled glucose, and insulin concentrations were determined. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM. Integrated models for glucose, labeled glucose, and insulin were developed. Control mechanisms for regulation of glucose production, insulin secretion, and glucose uptake were incorporated. Physiologically relevant differences between healthy volunteers and patients were identified in the regulation of glucose production, elimination rate of glucose, and secretion of insulin. The model was able to describe the insulin and glucose profiles well and also showed a good ability to simulate data. The features of the present model are likely to be of interest for analysis of data collected in antidiabetic drug development and for optimization of study design.

  • 125.
    Simonsen, Lena E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wählby, Ulrika
    Sandström, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Freijs, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats2000In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 20, no 3A, p. 1519-1525Article in journal (Refereed)
    Abstract [en]

    AIM

    To study the effects of single and fractionated doses of 5-fluorouracil and epirubicin on the leukocyte counts in rats.

    METHODS

    Six different dosing patterns of each drug were injected within one day. The leukocytes were followed for 11-15 days. Pharmacokinetic models were developed using NONMEM. Quantitative and qualitative pharmacokinetic-pharmacodynamic relationships were investigated.

    RESULTS

    A one-compartment model with non-linear elimination described 5-fluorouracil pharmacokinetics and a three-compartment model described epirubicin concentration data. Sigmoidal or basic Emax-models quantified the relationships between individual AUCs and decreases in leukocytes, for both drugs. Similar relationships between AUC and toxicity were found, regardless of whether the drugs were given as single or fractionated doses.

    CONCLUSION

    Quantitative relationships between AUC and the effect on leukocytes were established for 5-fluorouracil and epirubicin. However, no schedule dependence was indicated for the schedules used in the study.

  • 126.
    Simonsson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. Stockholms läns landsting.
    Multipel skleros - en kartläggning av tidigare immunsuppressiva behandlingar hos patienter som behandlas med Tecfidera i Stockholms läns landsting2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Multipel skleros (MS) är en kronisk autoimmun sjukdom i det centrala nervsystemet som orsakar skador i myelin och axoner, vilket leder till försämrad nervimpulsöverföring. I Sverige finns närmare 17 500 MS-patienter. Syfte: Studiens syfte är att identifiera patienter som behandlas med MS-läkemedlet Tecfidera i Stockholms läns landsting (SLL) och kartlägga deras behandlingshistorik. Ett ytterligare syfte är att studera hur läkemedelsbehandlingen för MS-patienter i SLL varierar över tid. Material och metoder: Observationsstudien omfattar alla patienter i SLL som expedierats Tecfidera på apotek. Individdata inhämtas från VAL:s datalager under tidsperioden juli 2010 till februari 2015. För att studera hur läkemedelsbehandlingen för MS-patienter varierar över tid användes försäljningsdata från www.gups.sll.se för samtliga MS-läkemedel som expedierats på apotek i Stockholms län under tidsperioden januari 2011 till februari 2015. Resultat: Under perioden maj 2014 till februari 2015 expedierades 236 patienter, tillhörande SLL, Tecfidera. Majoriteten, 63% (n=148), hade tidigare expedierats andra MS-läkemedel varav Avonex var det vanligast förekommande läkemedlet (n=75). En betydande andel, 37% (n=88), var behandlingsnaiva dvs de hade tidigare inte expedierats andra MS-läkemedel. Under perioden januari 2011 till februari 2015 var Avonex det mest expedierade MS-läkemedlet, mätt i AUP, i SLL. Sedan introduktionen av Tecfidera, maj 2014, har Tecfidera snabbt tagit en stor del av marknaden och Avonex särställning har minskat. Konklusion: Tecfidera används inte bara av behandlingsnaiva patienter som första linjens behandling utan den används även hos patienter som har en behandlingshistoria med andra MS-läkemedel. Tecfidera håller på att ersätta Avonex på marknaden.

  • 127.
    Simonsson, Ulrika S H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hai, Trinh Ngoc
    Huong, Dinh Xuan
    Tybring, Gunnel
    Ashton, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C92003In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 74, no 1, p. 32-43Article in journal (Other academic)
    Abstract [en]

    AIM: Our goal was to investigate whether artemisinin autoinduction is caused by an increase in cytochrome P450 (CYP) 2B6 or CYP2C9 activities, we evaluated the effects of multiple-dose artemisinin administration on S-mephenytoin N-demethylation in healthy subjects. METHODS: Fourteen subjects, 6 poor metabolizers of CYP2C19 and 8 extensive metabolizers, received a single oral dose of 200 mg racemic mephenytoin (CYP2B6 in vivo marker) before (day -28) and during multiple-dose artemisinin administration (250 mg/d orally for 9 days and 500 mg on the tenth day). A 500-mg single dose of artemisinin was administered on day -28. The CYP2C9 in vivo marker tolbutamide was administered on day -28 and on days 7, 12, and 17 to monitor the minor involvement of CYP2C9 in S-mephenytoin N-demethylation. RESULTS: Artemisinin oral clearance increased 5.3-fold (P <.001) by the tenth day of administration. Its pharmacokinetics was not different in the 2 CYP2C19 phenotypes. The oral clearance of R-mephenytoin increased 1.7-fold (P <.05) in both phenotypes during the period of artemisinin administration. The area under the concentration-time curve ratio of S-nirvanol/S-mephenytoin, an index of CYP2B6 activity, increased 1.9-fold (P <.05) in CYP2C19 poor metabolizers during artemisinin multiple-dose administration, whereas the urinary excretion ratio of hydroxytolbutamide plus carboxytolbutamide/tolbutamide remained constant during the study period. CONCLUSIONS: These results indicate that artemisinin induces the N-demethylation of S-mephenytoin probably by an increased capacity of CYP2B6. The autoinduction phenomenon of artemisinin may, therefore, be attributed, at least in part, to induction of CYP2B6, because this is the isozyme primarily involved in its metabolism. In addition, artemisinin alters the disposition of R-mephenytoin by an unidentified isozyme.

  • 128.
    Skare, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Integrated Medicines Management (IMM) på Medisinsk Avdeling.2016Independent thesis Advanced level (degree of Master (One Year)), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Integrated Medicines Management (IMM) at medical ward.

    Author: Skare, Erik.

    Supervisior: Lagerkrantz, Ronny.

    Examinator: Nielsen, Elisabeth.

    Magister of Clinical Pharmacy 2016.

    Department of Pharmaceutical Biosciences, division of Pharmacokinetics and drug therapy.

    Faculty of Pharmacy, Uppsala University, Sweden.

    Abstract

    Background and objective:

    Sykehusapotekene HF introduced IMM- method in Norway in 2010. The aim of this study is to survey the incidence of drug related problems (LRP) among medical patients and the extent to which these are accepted by the treating health professional. Secondary goal is to survey LRP according to drug administration, age and renal function.

    Design:

    Descriptive, quantitative study. Patients underwent drug accordance and drug examination pursuant to validated IMM- method. Patients were grouped according to I: MDD (Ia), non- MDD (Ib), II: age ≥ 65 years (IIa), age < 65 years (IIb), III: GFR < 60 ml/ min (IIIa), GFR ≥ 60 ml/ min (IIIb). Occurrence of prescribed drugs, identified LRP and acceptance rate were identified by groups. Statistical analysis were performed using t- test and 95 % CI to identify differences in drug treatment for each group.

    Setting:

    The ward of general internal medicine, Sykehuset Østfold HF, Norway.

    Main outcome measures:

    Number of identified LRP from the IMM- tool and acceptance rate from presented LRP.

    Results:

    Patient sample had average 12,0 prescribed drugs and 6,41 identified LRP per patient respectively, with an average acceptance rate at 73 %. There was a statistically significant difference in the number of prescribed drugs inwards group I and II respectively (P < 0,05). There was no statistically significant difference in the number of identified LRP or  acceptance rate inwards group I, II and III respectively (P > 0,05).

    Conclusion:

    The study indicates high occurrence of LRP at medical ward, where clinical utility of the IMM- method seems independent of drug administration, age and renal function.

  • 129.
    Skoog, Carolin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    RCT pilot - Effects of clinical pharmacists at hospital wards2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Many elderly receive multiple medication treatments, with a risk of drug-related problems. Clinical pharmacist services, such as the performance of medication reviews at hospital wards, can reduce these drug-related problems. Currently a multicentre randomised controlled trial (RCT) is being planned to optimise these clinical services and study the effects after implementation in daily practice.

    Aim: To study the feasibility of the planned RCT within a pilot phase, and to propose solutions to encountered problems during this phase in order to improve the methodological quality of the RCT.

    Materials and Methods: Prospective RCT pilot study at three hospital wards at Uppsala University Hospital during nearly seven weeks. Patients aged 65 years or older were randomised into two different intervention groups and one control group. Clinical pharmacists performed different activities on the patients. The feasibility was studied and any problems that arose during the pilot study were evaluated.

    Results: Informative documents and standard operating procedures (SOPs) were successfully developed and refined. In total 136 out of 186 patients (73.1%) gave consent to participate. Eventually only 52.2% of the included patients received all predefined treatment activities, mainly due to a lack of pharmacist resources and concordance with other ward staff. All encountered problems were solved and/or suggestions for solutions were made, although it was not possible to develop a reliable method to assess drug-related hospital admissions within the time frame of this study.

    Conclusions: It is feasible to conduct the planned RCT. However, some issues need to be improved before starting the study, such as the involvement of and concordance with other healthcare professionals and the availability of clinical pharmacists at the wards.

  • 130.
    Standing, Joseph F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Howard, Richard F.
    Johnson, Atholl
    Savage, Imogen
    Wong, Ian C. K.
    Population pharmacokinetics of oral diclofenac for acute pain in children2008In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 66, no 6, p. 846-853Article in journal (Refereed)
    Abstract [en]

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

    center dot Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range.center dot Diclofenac is frequently used 'off-label' in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5-2.5 mg kg(-1)). There is currently no licensed oral paediatric formulation of diclofenac.

    WHAT THIS STUDY ADDS

    center dot Using a new diclofenac oral suspension, a dose of 1 mg kg(-1) in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses.To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml(-1)) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children.Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg(-1) dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults.A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V-D/F were 53.98 l h(-1) 70 kg(-1) and 4.84 l 70 kg(-1) respectively. Allometric size models appeared to predict adequately changes in CL and V-D with age. Of the simulated doses investigated, 1 mg kg(-1) gave paediatric AUC((0,12 h)) to adult 50 mg AUC((0,12 h)) ratios of 1.00, 1.08 and 1.18 for ages 1-3, 4-6 and 7-12 years respectively.This study has shown 1 mg kg(-1) diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.

  • 131.
    Strömberg, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Förskrivning av neuroleptika på särskilda boenden i Stockholms läns landsting2012Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Förskrivningen av läkemedel till äldre har ökat markant de senaste tjugo åren. Den ökade läkemedelsanvändningen är särskilt påtaglig hos äldre som bor i särskilda boenden (SÄBO) där multimedicinering är vanligt. Många äldre är känsliga för läkemedel och nationella satsningar görs nu för att minska användningen av olämpliga läkemedel hos äldre. Syfte: Att undersöka förskrivningen av neuroleptika till äldre på SÄBO med dosdispensering eller rekvisition till förråd i Stockholms län under 2011. Material och metoder: Retrospektiv tvärsnittstudie med data över uthämtade Apodos® recept och expedierade rekvisitioner för utvalda SÄBO i Stockholms län för helår 2011. Boendena klassades efter typ och efter den läkemedelsförsörjningsform som tillämpades. Användningen av neuroleptika mättes i antal definierade dygnsdoser (DDD) per 1000 boende per dag. Resultat: Av sjukhemmen hade 55 Apodos® och 36 hade rekvisition till förråd. Totalanvändningen av neuroleptika var högre på sjukhem med förråd, 35,2 respektive 32,8 DDD/1000boende/dag. Av de 10 korttidsboendena hade 7 Apodos® och 3 hade rekvisition till läkemedelsförråd. Här var totalanvändningen marginellt högre på hem med förråd, 35,7 resp 35,6 DDD/1000 boende/dag. De 6 servicehusen hade endast uppgifter för Apodos ®. De vanligaste substanserna som förskrevs eller rekvirerades var risperdion, olanzapin och haloperidol. Mellan alla enskilda SÄBO fanns variationer i användningen av olika neuroleptika. Konklusion: Totalanvändningen av neuroleptika var marginellt större på sjukhem med förråd och förskrivning av neuroleptika varierade mellan enskilda boenden.

  • 132.
    Svensson, Ulrika S H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Mäki-Jouppila, Mika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hoffmann, Kurt-J
    Ashton, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto-induction in the rat by use of nonlinear mixed effects modelling.2003In: Biopharmaceutics & drug disposition, ISSN 0142-2782, E-ISSN 1099-081X, Vol. 24, no 2, p. 71-85Article in journal (Refereed)
    Abstract [en]

    Aims: The aims of the study were to characterise the metabolic pattern of artemisinin in human and rat liver microsomes and to assess the magnitude of auto-induction in the rat.

    Methods14C-artemisinin was incubated with human liver microsomes and with liver microsomes from rats pretreated with oral artemisinin or placebo. The metabolic fate of 14C-artemisinin in microsomes from human B-lymphoblastoid cell lines transformed with CYP2A6, CYP2B6 and CYP3A4 was also investigated. The human liver microsome data and the rat liver microsomes data were analysed by nonlinear mixed effects modelling and naïve pooling using NONMEM, respectively.

    Results: Four metabolites were radiometrically detected in experiments with rat liver microsomes. The model that best described the data involved three primary metabolites of which one metabolite was further metabolised to a secondary metabolite. The formation of the four metabolites was induced 2.8, 7.2, 4.8 and 2.5-fold, respectively, in liver microsomes from rats pre-treated with artemisinin. Three metabolites were formed in human liver microsomes; having the same retention times as three of the metabolites formed in the rat. The final model consisted of two primary metabolites and a secondary metabolite with CYP2B6 and CYP2A6 influencing the formation rates of the major and minor primary metabolites, respectively.

    Conclusions: CYP2B6 and CYP2A6 activities described variability in the formation of the major and minor primary metabolites, respectively, in human liver microsomes. All artemisinin metabolic pathways in rat liver microsomes were induced in artemisinin pretreated animals. We suggest modelling as a method for the discrimination and detection of more complex metabolic patterns from in vitrometabolism rate data. 

  • 133.
    Syawish, Triva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Användning av generiska läkemedel hos personer 75 år och äldre2012Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Abstract

    Introduktion: Generiska läkemedel definieras som medicinskt likvärdiga läkemedel som kan säljas billigare än originalläkemedel. Generisk substitution infördes i oktober 2002. För äldre patienter kan det vara förvirrande med generiska läkemedel, då de kan få flera olika läkemedelsnamn med samma aktiva substans vilket kan leda till överdosering. Det är bara 9 % av Sveriges befolkning som är 75 år och äldre, men de står förmer än 25 % av all läkemedelsförbrukning.

    Syfte: Att studera användning av generiska läkemedel hos personer 75 år och äldre, hur detta har förändrats under ett 10-års period och om det finns könsskillnader.

    Material och metoder: Retrospektiv studie baserad på data från Stockholms läns landstings VAL- databasen och data från Socialstyrelsens läkemedelsregister. Studien inkluderar äldre personer (≥ 75 år) i hela Sverige under perioden 2001 till 2011.

    Resultat: De vanligaste använda ATC-grupper med störst andel byte samt stor volym är: A02, A06, A10, C07, C08, C09, C10, J01, M01, M05, R01, R03, S01. Andelen byte har ökat successivt för dessa ATC-grupper mellan 2002 och 2011 från 0 till 31 %. Det finns tydliga könsskillnader i andelen byte med högre andel byten för män.. De många läkemedelsnamnen för samma aktiva substans medför att en person med 6 förskrivna läkemedel kan under en 12-månadersperiod få mer än 15 olika läkemedelsnamn utskrivna.

    Konklusion: Användning av generiska läkemedel har ökat successivt sedan introduktion av generisk substitution 2002, men den varierar mellan olika läkemedelsgrupper. Andelen utbyte är högre hos män.

  • 134.
    Syvänen, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Blomquist, Gunnar
    Appel, Lieuwe
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Predicting brain concentrations of drug using positron emission tomography and venous input: modeling of arterial-venous concentration differences2006In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 62, no 10, p. 839-848Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    In a positron emission tomography (PET) study, the concentrations of the labeled drug (radiotracer) are often different in arterial and venous plasma, especially immediately following administration. In a PET study, the transfer of the drug from plasma to brain is usually described using arterial plasma concentrations, whereas venous sampling is standard in clinical pharmacokinetic studies of new drug candidates. The purpose of the study was to demonstrate the modeling of brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform (T(av)).

    METHODS

    Brain kinetics (C(br)) was described as the convolution of arterial plasma kinetics (C(ar)) with an arterial-to-brain impulse response function (T(br)). The arterial plasma kinetics was obtained as venous plasma kinetics (C(ve)) convolved with the inverse of the arterio-venous transform (T(av) (-1)). The brain kinetics was then given by C(br)=C(ve)*T(av) (-1)*T(br). This concept was applied on data from a clinical PET study in which both arterial and venous plasma sampling was done in parallel to PET measurement of brain drug kinetics. The predictions of the brain kinetics based on an arterial input were compared with predictions using a venous input with and without an arterio-venous transform.

    RESULTS

    The venous based models for brain distribution, including a biexponential arterio-venous transform, performed comparably to models based on arterial data and better than venous based models without the transform. It was also shown that three different brain regions with different shaped concentration curves could be modeled with a common arterio-venous transform together with an individual brain distribution model.

    CONCLUSION

    We demonstrated the feasibility of modeling brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform. Such a model can in turn be used for the calculation of brain kinetics resulting from an arbitrary administration mode by applying this model on venous plasma pharmacokinetics. This would be an important advantage in the development of drugs acting in the brain, and in other circumstances when the effect is likely to be closer related to the brain than the plasma concentration.

  • 135. Söderberg, Lars
    et al.
    Dyhre, Henrik
    Roth, Bodil
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    The "inverted cup": a novel in vitro release technique for drugs in lipid formulations2006In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 113, no 1, p. 80-88Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop a membrane-free in vitro release method for drugs in lipid formulations. It was intended to be applicable to as wide a range as possible of preparations, independently of their polarity and viscosity. The principle of the novel technique is to keep the sample suspended in the release medium in an inverted glass cup, allowing a possible phase transition or swelling. Thirteen formulations containing bupivacaine, lidocaine and/or prilocaine in lipid vehicles with different physical properties were prepared and examined. When possible, in vitro release profiles obtained by the new method were compared to profiles obtained by earlier techniques. For three formulations of either bupivacaine or lidocaine in polar lipid formulations, in vitro release profiles were evaluated in relation to in vivo data, from nerve block and pharmacokinetic studies in rats. Preparations that could be investigated both by the "inverted cup" and by the earlier published "single drop" technique generally showed good agreement between the two release profiles. In the case of the polar lipid formulations, arterial blood concentration curves in rats could reasonably be predicted from the in vitro release profiles. In conclusion, the "inverted cup" technique should potentially be applicable to a wide range of lipid formulations of drugs, both for physico-chemical characterisation and for obtaining in vitro - in vivo correlations.

  • 136. Söderberg, Lars
    et al.
    Dyhre, Henrik
    Roth, Bodil
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ultralong peripheral nerve block by lidocaine:prilocaine 1:1 mixture in a lipid depot formulation: Comparison of in vitro, in vivo and effect kinetics2006In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 104, no 1, p. 110-121Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to develop stable and easily injectable lipid depot preparations of local anesthetics in which the drug concentration can be varied according to desired duration of action. METHODS: The formulations contained a 2.0, 5.0, 10, 20, 40, 60, 80, or 100% eutectic mixture of lidocaine and prilocaine base in medium-chain triglyceride. Duration of sciatic nerve block and local neurotoxicity was investigated in rats with 2.0% lidocaine:prilocaine HCl solution and 99.5% ethanol as controls. The rate of release of local anesthetic from the site of administration and the possibility to predict in vivo depot characteristics from in vitro release data were investigated for the 20 and 60% formulations. RESULTS: The duration of sensory sciatic block was prolonged 3 times with the 20% formulation and approximately 180 times with the 60% formulation, in comparison with the 2% aqueous solution. With the 80 and 100% formulations, all animals still showed nerve block after 2 weeks. The in vivo release of local anesthetic could be approximately predicted from in vitro data for the 20% but not for the 60% formulation. The formulations of 60% or greater and ethanol showed neurotoxic effects. CONCLUSIONS: The pharmaceutical properties of these formulations compare favorably with those of other depot preparations. The high-percentage ones showed the longest duration of action yet reported for sciatic nerve block in rats. The possibility of using a high-concentration local anesthetic depot formulation as an alternative to ethanol or phenol for long-term nerve blocks in chronic pain merits further investigation.

  • 137.
    Söderberg, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Följsamhet till nyinsatt behandling med betareceptorblockerande och serumlipidsänkande medel2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Följsamhet till nyinsatt behandling med betareceptorblockerande och serumlipidsänkande medel

    Matilda Söderberg

    Handledare: Anders Ekedahl och Carola Bardage, Läkemedelsverket. Institutionen för farmaceutiskt biovetenskap,  avdelningen för  farmakokinetik och läkemedelsterapi.  15 hp. Examinator: Margareta Hammarlund-Udenaes.

    Introduktion: Bristande följsamhet inom långtsidsbehandlingar hänger samman med höga kostnader, onödigt lidande och, många gånger, misslyckad behandling. Trots detta vet man lite om hur följsamheten ser ut inom långtidsbehandlingar i Sverige.

    Syfte: Syftet är att undersöka hur vanligt det är med tidigt avbrytande av nyinsatta behandlingar med betareceptorblockerande medel (ATC-grupp C07) och medel som påverkar serumlipidnivåerna (ATC-grupp C10).

    Material och metoder: Registerundersökning med material från läkemedelsregistret (Socialstyrelsen). Undersökningen gällde patienter med ett första uttag av läkemedel inom ATC-grupperna C07 och C10 under januari och februari 2011. De studerade utfallen var hur stor andel av patienterna som gjort ett respektive fyra eller färre uttag under perioden januari 2011 till och med mars 2013. Pearsons chi-två-test användes för att beräkna statistiska skillnader.

    Resultat: Bland patienterna med betareceptorblockerare (n=18134) gjorde 24,0% ett uttag och 44,5% gjorde fyra eller färre  uttag. Av patienterna med lipidsänkare (n=17005) gjorde 17,0% ett uttag och 39,4% gjorde fyra eller färre uttag. Andelarna terapiavbrott var signifikant större bland patienter med betablockerare jämfört med lipidsänkare, yngre jämfört med äldre och kvinnor jämfört med män.

    Konklusion: Nära hälften av patienterna avbröt sin behandling under uppföljnignsperioden. Resultaten tyder på att det finns behov av insatser för att förbättra följsamheten inom långtidsbehandlingar och att sådana insatser bör sättas in tidigt i behandlingen.

  • 138.
    Truong, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Kartläggning av nyinsättning av DPP-4-hämmare vid typ 2-diabetes inom Landstinget i Uppsala län2016Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Kartläggning av nyinsättning av DPP-4-hämmare vid typ 2-diabetes inom Landstinget i Uppsala län

    Joakim Truong

    Fördjupningsprojekt i Farmakoterapi D, 30 hp, Hösterminen 2016

    Handledare: Jonatan Alvan, Landstinget i Uppsala län 

    Examinator: Margareta Hammarlund-Udenaes

    Institutionen för Farmaceutisk biovetenskap, Avdelningen för Farmakokinetik och läkemedelsterapi,

    Farmaceutiska fakulteten, Uppsala universitet

    Introduktion: Dipeptidylpeptidas-4-hämmare (DPP-4-hämmare) är en läkemedelsgrupp som används som tredjehandsval vid farmakologisk blodsockersänkandebehandling för typ 2-diabetes. Behandlingen är lågt prioriterat enligt Socialstyrelsens riktlinjer och är ett dyrt läkemedel som ökat i användning i Uppsala län. 

    Syfte: Att kartlägga nyinsättningar av DPP-4-hämmare vid typ 2-diabetes inom Landstinget i Uppsala län under 2015, för att kvalitetsgranska den ökade förskrivningen. 

    Material och metod: En retrospektiv journalbaserad tvärsnittsstudie genomfördes, där totalt 796 patienter erhöll en nyinsättning. Av dessa valdes 285 patienter slumpmässigt och granskades vid insättning med avseende på bland annat ålder, diabetesduration och HbA1c. Dessutom insamlades data om sjukvården utfört en uppföljning av HbA1c efter insättningen, som också användes för en effektutvärdering.

    Resultat: Totalt inkluderades 186 patienter i studien som var i genomsnitt 65 år gamla, hade en diabetesduration på 9 år och ett HbA1c på 74 mmol/mol. Totalt hade 83 % prövat metformin innan insättningen och 49 % en sulfonureid samt 41 % insulin. Av dessa patienter hade 20 % ett HbA1c ≤59 mmol/mol med en genomsnittlig ålder och diabetesduration på 65 år respektive 7 år. Majoriteten (84 %) av de 186 patienterna fick en uppföljning av sjukvården inom ett år och effektutvärderingen visade en medelminskning på 7,5 mmol/mol (95 % KI 4,5 – 10 mmol/mol). 

    Konklusion: Många i studiepopulationen hade höga HbA1c-värden och majoriteten hade redan provat flera andra blodsockersänkande läkemedel, vilket gör att insättningen av läkemedlet i många fall kan bedömas adekvat. Däremot kan nyttan med en ytterligare blodsockersänkande behandling diskuteras för de patienter som fått en nyinsättning trots lång diabetesduration och relativt låga HbA1c-värden. Vidare följde sjukvården upp patienterna väl efter insättningen. 

  • 139.
    Tunblad, Karin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Blood-Brain Barrier Transport of Drugs Across Species with the Emphasis on Health, Disease and Modelling2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The transport of drugs across the blood-brain barrier (BBB) has been investigated in different species using morphine and morphine-6-glucuronide (M6G) as model compounds. The influence of probenecid on the BBB transport of morphine and M6G was investigated, and the consequences of meningitis and severe brain injury on the concentrations of morphine in the brain were examined. All data were obtained by microdialysis, and data analysis using mathematical models was emphasised.

    Morphine is exposed to active efflux at the BBB in rats, pigs and humans. In addition, the half-life of morphine is longer in the brain than in blood in these species. These interspecies similarities show the predictive potential of the two animal models for the BBB transport of morphine in humans. In the pig the exposure of the brain to morphine was higher in the presence of meningitis than when healthy. This was interpreted as a decrease in the active efflux and an increase in the passive diffusion over the injured BBB. In contrast, there was no significant difference in the concentrations of morphine in the “better” (uninjured) or the “worse” (injured) brain tissue in brain trauma patients. The extent of the transport across the BBB is similar for morphine and M6G. However, co-administration of probenecid only increased the brain concentrations of morphine, demonstrating that morphine and M6G are substrates for different efflux transporters at the BBB. An integrated model for the analysis of data obtained by microdialysis was developed. This model makes fewer assumptions about the recovery, the protein binding and the time of the dialysate observation than a previous model and traditional non-compartmental analysis and should, therefore, yield more reliable parameter estimates.

    Knowledge of the consequences of efflux transporters and disease on the brain concentrations of a drug can be useful for individualising the dosing regimen in patients.

    List of papers
    1. Morphine blood-brain barrier transport is influenced by probenecid co-administration
    Open this publication in new window or tab >>Morphine blood-brain barrier transport is influenced by probenecid co-administration
    2003 In: Pharmaceutical Research, Vol. 20, no 4, p. 618-623Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91383 (URN)
    Available from: 2004-02-12 Created: 2004-02-12Bibliographically approved
    2. Influence of probenecid on the delivery of morphine-6-glucuronide to the brain
    Open this publication in new window or tab >>Influence of probenecid on the delivery of morphine-6-glucuronide to the brain
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91384 (URN)
    Available from: 2004-02-12 Created: 2004-02-12 Last updated: 2010-01-13Bibliographically approved
    3. Altered brain exposure of morphine in experimental meningitis studied with microdialysis
    Open this publication in new window or tab >>Altered brain exposure of morphine in experimental meningitis studied with microdialysis
    Show others...
    2004 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 48, no 3, p. 294-301Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed.

    METHODS:

    Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated.

    RESULTS:

    The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis.

    CONCLUSION:

    This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91385 (URN)10.1111/j.0001-5172.2003.0311.x (DOI)14982561 (PubMedID)
    Available from: 2004-02-12 Created: 2004-02-12 Last updated: 2017-12-14Bibliographically approved
    4. Blood-brain barrier transport of morphine in patients with severe brain trauma
    Open this publication in new window or tab >>Blood-brain barrier transport of morphine in patients with severe brain trauma
    Show others...
    2004 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 57, no 4, p. 427-435Article in journal (Refereed) Published
    Abstract [en]

    AIMS: In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood-brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics. METHODS: Patients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as 'better' and 'worse' brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10-min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3-h period with microdialysis and regular blood sampling. RESULTS: The area under the concentration-time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in 'better' brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in 'worse' brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half-life and T(max) were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in 'better' than in 'worse' brain tissue. The T(max) value tended to be shorter in 'worse' brain tissue. CONCLUSIONS: The unbound AUC ratio below unity in the 'better' human brain tissue demonstrates an active efflux of morphine across the blood-brain barrier. The 'worse' brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood-brain barrier.

    Keywords
    blood-brain barrier, brain injury, human, microdialysis, morphine, pharmacokinetics
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91386 (URN)10.1046/j.1365-2125.2003.02032.x (DOI)000220272800008 ()15025740 (PubMedID)
    Available from: 2004-02-12 Created: 2004-02-12 Last updated: 2017-12-14Bibliographically approved
    5. An integrated model for the analysis of pharmacokinetic data from microdialysis experiments
    Open this publication in new window or tab >>An integrated model for the analysis of pharmacokinetic data from microdialysis experiments
    2004 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 21, no 9, p. 1698-1707Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: To develop an integrated model for microdialysis data that incorporates all data including the recovery measurements in one model, and to compare this model to a previous model and the results from a noncompartmental analysis. METHODS: The models were developed in NONMEM. The modes of analysis were compared with respect to parameter estimates, model structures, gained mechanistic insight, and practical aspects. RESULTS: Both modeling approaches resulted in similar model structures. The parameter estimates in blood and brain from the models and the results from the noncompartmental analysis were comparable. Using the integrated model all data, that is, the total arterial concentrations, the venous and brain dialysate concentrations, and the recovery measurements, were analyzed simultaneously. CONCLUSION: The theoretical benefits of the integrated model are related to the inclusion of the recovery in the model and the use of all collected data as it was observed. Thus, all data are described in a single model, corrections for the recovery and the protein binding are done within the model, and the dialysate observations are described by the integral over each collection interval. Thereby, the variability and the uncertainty in the model parameters are handled correctly to give more reliable parameter estimates.

    Keywords
    Animals, Blood-Brain Barrier/drug effects, Comparative Study, Microdialysis, Models; Biological, Morphine/pharmacokinetics, Pharmacokinetics, Probenecid/pharmacology, Rats, Research Support; Non-U.S. Gov't
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-91387 (URN)10.1023/B:PHAM.0000041468.00587.c6 (DOI)15497699 (PubMedID)
    Available from: 2004-02-12 Created: 2004-02-12 Last updated: 2018-01-13Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 140.
    Tunblad, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ederoth, Per
    Gärdenfors, Anna
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Nordström, Carl-Henrik
    Altered brain exposure of morphine in experimental meningitis studied with microdialysis2004In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 48, no 3, p. 294-301Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed.

    METHODS:

    Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated.

    RESULTS:

    The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis.

    CONCLUSION:

    This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.

  • 141.
    Tunblad, Karin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Jonsson, E. Niclas
    Influence of probenecid on the delivery of morphine-6-glucuronide to the brainManuscript (Other academic)
  • 142.
    Tunblad, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jonsson, Niclas E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    An integrated model for the analysis of pharmacokinetic data from microdialysis experiments2004In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 21, no 9, p. 1698-1707Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To develop an integrated model for microdialysis data that incorporates all data including the recovery measurements in one model, and to compare this model to a previous model and the results from a noncompartmental analysis. METHODS: The models were developed in NONMEM. The modes of analysis were compared with respect to parameter estimates, model structures, gained mechanistic insight, and practical aspects. RESULTS: Both modeling approaches resulted in similar model structures. The parameter estimates in blood and brain from the models and the results from the noncompartmental analysis were comparable. Using the integrated model all data, that is, the total arterial concentrations, the venous and brain dialysate concentrations, and the recovery measurements, were analyzed simultaneously. CONCLUSION: The theoretical benefits of the integrated model are related to the inclusion of the recovery in the model and the use of all collected data as it was observed. Thus, all data are described in a single model, corrections for the recovery and the protein binding are done within the model, and the dialysate observations are described by the integral over each collection interval. Thereby, the variability and the uncertainty in the model parameters are handled correctly to give more reliable parameter estimates.

  • 143.
    Tunblad, Karin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jonsson, E. Niclas
    Hammarlund-Udenaes, Margareta
    Morphine blood-brain barrier transport is influenced by probenecid co-administration2003In: Pharmaceutical Research, Vol. 20, no 4, p. 618-623Article in journal (Refereed)
  • 144.
    Tunblad, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lindbom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    McFadyen, Lynn
    Jonsson, E. Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Marshall, Scott
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data2008In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 5, p. 503-526Article in journal (Refereed)
    Abstract [en]

    To characterise the pharmacokinetics of dofetilide in patients and to identify clinically relevant parameter-covariate relationships. To investigate three different modelling strategies in covariate model building using dofetilide as an example: (1) using statistical criteria only or in combination with clinical irrelevance criteria for covariate selection, (2) applying covariate effects on total clearance or separately on non-renal and renal clearances and (3) using separate data sets for covariate selection and parameter estimation. Pooled concentration-time data (1,445 patients, 10,133 observations) from phase III clinical trials was used. A population pharmacokinetic model was developed using NONMEM. Stepwise covariate model building was applied to identify important covariates using the strategies described above. Inclusion and exclusion of covariates using clinical irrelevance was based on reduction in interindividual variability and changes in parameters at the extremes of the covariate distribution. Parametric separation of the elimination pathways was accomplished using creatinine clearance as an indicator of renal function. The pooled data was split in three parts which were used for covariate selection, parameter estimation and evaluation of predictive performance. Parameter estimations were done using the first-order (FO) and the first-order conditional estimation (FOCE) methods. A one-compartment model with first order absorption adequately described the data. Using clinical irrelevance criteria resulted in models containing less parameter-covariate relationships with a minor loss in predictive power. A larger number of covariates were found significant when the elimination was divided into a renal part and a non-renal part, but no gain in predictive power could be seen with this data set. The FO and FOCE estimation methods gave almost identical final covariate model structures with similar predictive performance. Clinical irrelevance criteria may be valuable for practical reasons since stricter inclusion/exclusion criteria shortens the run times of the covariate model building procedure and because only the covariates important for the predictive performance are included in the model.

  • 145.
    Vedia Fuentes, Sabina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Antibiotic Prescribing at Advanced Care at Home in Stockholms Sjukhem: Compliance with National Guidelines2018Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Irrational use of antibiotics has been reported in nursing homes and hospice care worldwide, although guidelines for appropriate antibiotic use are available. Information about antibacterial drug usage and factors influencing their use are required in order to improve the quality of prescription practices.

    Purpose: The aim of this report was to assess whether or not antibiotic prescriptions in ASIH-units were in accordance with national guidelines. This study was conducted since there are no previous studies on antibiotic use in Stockholms Sjukhem advanced healthcare at home (ASIH) units in relation to Swedish guidelines.

    Methods: Methodology triangulation was used to combine quantitative and qualitative method for the collection of data. In qualitative section, a face-to-face interview was conducted with two physicians. In quantitative section, medicament lists, medical – and laboratory records of residents prescribed systemic antibiotics during a period of three months were reviewed. Data was collected via point prevalence study (PPS) questionnaires. Use of systemic antibiotics (ATC group J01) were evaluated based on Swedish guidelines.

    Results: A total 102 of 184 residents received antibacterial drugs, of whom 63 residents were prescribed antibiotics in ASIH. Of the 63 residents receiving antibiotics, 57 residents (85%) were prescribed antibiotics for a suspected infection, 7 residents (10%) were prescribed prophylactic treatment and 3 (5%) patients received both prophylaxis and treatment simultaneously. Indication for antibiotics were in 38% of the cases urinary tract infections (UTI), in 18% skin and soft tissue infection, in 17% missing diagnosis, 12% respiratory tract infections (RTI) and in 15 % other infections. The antibiotics most frequently used were penicillins (47%), followed by cephalosporins (16%) and nitrofurantoin (10%). Irrational use of antibiotics was common in ASIH-units (95% CI 0.69-0.89, c2 =10.2, p=0.0014). Inappropriate antibiotic use was more common in RTIs (86%) and UTIs (82%). The compliance to guidelines for empirical treatment and selection of antibiotics for infection treatments were low and it was followed by duration of therapy and dosage. Incorrect route of administration and non-performed bacteriological cultures were not common in ASIH. Results from the interview indicate factors that may have influenced the observed prescription pattern.

    Conclusion: The high proportion of inappropriate antibiotic use in Stockholms Sjukhem ASIH-units underlines the need for increased focus on rational prescribing in the ASIH-units. Prescribing antibacterial drugs according to bacteriological test results and national guidelines, whenever it is possible, could decrease the inappropriate use of antibiotics. Further studies should focus on developing guidelines for this patient population in order to be able to use antibiotics in the best possible manner. 

  • 146.
    Viberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Using Pharmacokinetic and Pharmacodynamic Principles to Evaluate Individualisation of Antibiotic Dosing – Emphasis on Cefuroxime2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cefuroxime is a renally eliminated antibiotic used against a variety of different bacterial infections. The pharmacokinetics (PK) for cefuroxime was studied in 97 hospitalized patients using population analysis. To be able to measure cefuroxime in human serum a new sensitive analytical method was developed using mass spectrometry detection. The method was validated and shown to be sensitive and selective. Cystatin C was found to be a better covariate for cefuroxime clearance compared to the traditionally used creatinine clearance (CLcr). This relation might be useful when designing dosing strategies for cefuroxime and other renally eliminated drugs.

    The time-courses of the biomarkers C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and body temperature were studied for the first 72 hours of cefuroxime treatment and was related to the duration of illness previous treatment with cefuroxime and to time to step-down of treatment. When duration of illness was short, CRP and SAA were showed increasing levels. None of the biomarkers could be used to differentiate between early or late step-down of therapy.

    By use of known PK and pharmacodynamic (PD) principles, dosing strategies based on CLcr for cefuroxime were estimated using minimization of a risk function. The risk function was constructed with the aim to expose patients to cefuroxime concentration above minimum inhibitory concentration (MIC) for 50 % of the dosing interval and to minimize the amount of drug administered in excess to reach the aim. Based on evaluation using wild type MIC distributions for Escherichia coli and Streptococcus pneumoniae improved dosing strategies were selected.

    In vitro experiments were performed exposing Streptococcus pyogenes to constant concentration of benzylpenicillin, cefuroxime, erythromycin, moxifloxacin or vancomycin. A semi-mechanistic PK/PD model characterizing the time-course of the antibacterial effect was developed using all data simultaneously. Internal validation showed the model being predictive and robust.

    List of papers
    1. Determination of cefuroxime in human serum or plasma by liquid chromatography with electrospray tandem mass spectrometry
    Open this publication in new window or tab >>Determination of cefuroxime in human serum or plasma by liquid chromatography with electrospray tandem mass spectrometry
    2004 In: Rapid Commun Mass Spectrom, Vol. 18, no 6, p. 707-710Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94165 (URN)
    Available from: 2006-03-31 Created: 2006-03-31Bibliographically approved
    2. A population pharmacokinetic model for cefuroxime using cystatin C as a marker of renal function
    Open this publication in new window or tab >>A population pharmacokinetic model for cefuroxime using cystatin C as a marker of renal function
    Show others...
    2006 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 62, no 3, p. 297-303Article in journal (Refereed) Published
    Abstract [en]

    Aims: Since cefuroxime mainly is excreted by renal filtration, dosing is currently based on serum creatinine (Scr) or creatinine clearance (CLcr). However, it has been suggested that cystatin C (CysC) is superior to Scr as a marker of renal function. The aim of this prospective study was to develop a population model that describes the pharmacokinetics of cefuroxime and to investigate the usefulness of CysC as a covariate of the model parameters.

    Methods: Ninety-seven patients were studied (CLcr range 6.5-115 ml min(-1)). Blood samples (n = 407) for the determination of cefuroxime were withdrawn according to a sparse data sampling schedule and analysed by liquid chromatography mass spectrometry. The population analysis was performed in NONMEM.

    Results: A two-compartment model described the data well. The biomarkers Scr, CLcr and CysC were evaluated as covariates on clearance (CL). The model that included CysC generated the best fit. In the final population model CL was a function of CysC and body weight, whereas V-1 was only a function of body weight. Final parameter estimates (relative standard errors) were 6.00 (3.2%) l h(-1), 11.4 (5.3%) l and 5.11 (11%) l for CL, V-1 and V-2, respectively.

    Conclusion: Based on the results of the present study, and because CysC is practical to use in the clinic, it is suggested that individual dosing of cefuroxime may be based on CysC rather than on Scr or CLcr. Furthermore, our final population model may be useful as a tool when designing new dosing schedules for cefuroxime.

    Keywords
    cefuroxime, cystatin C, NONMEM, pharmacokinetics
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94166 (URN)10.1111/j.1365-2125.2006.02652.x (DOI)000239694000007 ()16934045 (PubMedID)
    Available from: 2006-03-31 Created: 2006-03-31 Last updated: 2018-01-13Bibliographically approved
    3. The time course of the biomarkers body temperature, serum amyloid A protein (SAA), C-reactive protein (CRP) and interleukin- (IL) 6 during initial treatment with cefuroxime in patients with bacterial infections
    Open this publication in new window or tab >>The time course of the biomarkers body temperature, serum amyloid A protein (SAA), C-reactive protein (CRP) and interleukin- (IL) 6 during initial treatment with cefuroxime in patients with bacterial infections
    Show others...
    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94167 (URN)
    Available from: 2006-03-31 Created: 2006-03-31 Last updated: 2010-04-26Bibliographically approved
    4. Individualization of Cefuroxime Dosage using Pharmacodynamic targets, MIC distributions and Minimization of a Risk Function
    Open this publication in new window or tab >>Individualization of Cefuroxime Dosage using Pharmacodynamic targets, MIC distributions and Minimization of a Risk Function
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94168 (URN)
    Available from: 2006-03-31 Created: 2006-03-31 Last updated: 2011-03-01
    5. Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments
    Open this publication in new window or tab >>Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments
    Show others...
    2007 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 51, no 1, p. 128-136Article in journal (Refereed) Published
    Abstract [en]

    Dosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of Streptococcus pyogenes exposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (Emax) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94169 (URN)10.1128/AAC.00604-06 (DOI)000243214200016 ()17060524 (PubMedID)
    Available from: 2006-03-31 Created: 2006-03-31 Last updated: 2018-01-13Bibliographically approved
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  • 147.
    Viberg, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Cars, Otto
    Karlsson, Mats O
    Jönsson, Siv
    Individualization of Cefuroxime Dosage using Pharmacodynamic targets, MIC distributions and Minimization of a Risk FunctionManuscript (Other academic)
  • 148.
    Viberg, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lannergård, Anders
    Cars, Otto
    Karlsson, Mats O
    Sandström, Marie
    Larsson, Anders
    The time course of the biomarkers body temperature, serum amyloid A protein (SAA), C-reactive protein (CRP) and interleukin- (IL) 6 during initial treatment with cefuroxime in patients with bacterial infectionsManuscript (Other academic)
  • 149.
    Viberg, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lannergård, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sandström, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    A population pharmacokinetic model for cefuroxime using cystatin C as a marker of renal function2006In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 62, no 3, p. 297-303Article in journal (Refereed)
    Abstract [en]

    Aims: Since cefuroxime mainly is excreted by renal filtration, dosing is currently based on serum creatinine (Scr) or creatinine clearance (CLcr). However, it has been suggested that cystatin C (CysC) is superior to Scr as a marker of renal function. The aim of this prospective study was to develop a population model that describes the pharmacokinetics of cefuroxime and to investigate the usefulness of CysC as a covariate of the model parameters.

    Methods: Ninety-seven patients were studied (CLcr range 6.5-115 ml min(-1)). Blood samples (n = 407) for the determination of cefuroxime were withdrawn according to a sparse data sampling schedule and analysed by liquid chromatography mass spectrometry. The population analysis was performed in NONMEM.

    Results: A two-compartment model described the data well. The biomarkers Scr, CLcr and CysC were evaluated as covariates on clearance (CL). The model that included CysC generated the best fit. In the final population model CL was a function of CysC and body weight, whereas V-1 was only a function of body weight. Final parameter estimates (relative standard errors) were 6.00 (3.2%) l h(-1), 11.4 (5.3%) l and 5.11 (11%) l for CL, V-1 and V-2, respectively.

    Conclusion: Based on the results of the present study, and because CysC is practical to use in the clinic, it is suggested that individual dosing of cefuroxime may be based on CysC rather than on Scr or CLcr. Furthermore, our final population model may be useful as a tool when designing new dosing schedules for cefuroxime.

  • 150.
    Viberg, Anders
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sandström, Marie
    Jansson, Britt
    Determination of cefuroxime in human serum or plasma by liquid chromatography with electrospray tandem mass spectrometry2004In: Rapid Commun Mass Spectrom, Vol. 18, no 6, p. 707-710Article in journal (Refereed)
1234 101 - 150 of 160
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