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  • 1.
    Abdulmahdi, Rasha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion

    Rasha Abdulmahdi

    Handledare: Björn Wettermark, Docent, Apotekare, Utvecklingsavdelningen, SLL. Yvonne Freund-Levi, MD PhD Överläkare KI. Tero Shemiekka, överläkare Avdelningen för E-hälsa, SLL. Examinator: Margareta Hammarlund-Udenaes, Professor i farmakokinetik och farmakodynamik. Institutionen för farmaceutisk biovetenskap. Examensarbete i Farmakoterapi D, 30hp, Uppsala universitet.

     

    Introduktion: Äldre patienter löper större risk att utveckla läkemedelsbiverkningar p.g.a. avtagande njurfunktion. Flera publicerade studier tyder på att många patienter läggs in akut på sjukhus för att de använder läkemedel som inte anpassas efter deras njurfunktion. Syfte: Att kartlägga förskrivning av statiner hos äldre hypertonipatienter med avseende på njurfunktion i Skaraborg och sydvästra Stockholms Län. Material och metoder: En tvärsnittstudie baserad på data hämtade från SPCCD (Swedish Primary Care Cardiovascular Database). Patienter ≥ 65 år som hade minst ett registrerat S-kreatinin under år 2006-2008 inkluderades och andelen som hämtade ut statiner under perioden 2006-2009 analyserades. GFR (Glomerular Filtration Rate) beräknades med CKD-EPI-formeln (Chronic Kidney Disease Epidemiology Collaboration). Läkemedelssubstanserna lämplighet eller behov av dosjustering i relation till njurfunktion granskades enligt RenBase, en databas med dokumentation av läkemedel vid nedsatt njurfunktion. Resultat. Totalt identifierades 38 239 individer och av dessa hade 23,8 % behandlats med statiner. De mest förskrivna statinerna var simvastatin (84,2 %) och atorvastatin (10,5 %). Det var signifikant färre (95 % C.I.) som behandlades med de båda statinerna vid en jämförelse mellan GFR < 30 och >30. Det fanns ingen korrelation mellan snittdosering (mg/dag) och njurfunktion. Konklusion: Många äldre hypertonipatienter i primärvården med nedsatt njurfunktion får statinbehandling. Det förefaller dock som om simvastatin inte dosjusteras hos patienter med svårt nedsatt njurfunktion.

                 

  • 2.
    Akcan, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Smärtstillande läkemedelsbehandling hosäldre i Uppsala län - en retrospektiv studie2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Hos äldre är smärta relativt vanligt då det med ökad ålder uppkommerproblem i muskler, leder, senor och skelett, t.ex. artros, osteoporos och sarkopeni.Socialstyrelsen utformade 2004 en mall för god läkemedelsterapi hos äldre, s.k.kvalitetsindikatorer. T.ex. får paracetamol inte överstiga en dygnsdos på 4 g/dygn ochNSAID bör endast användas vid inflammatorisk smärta. När lätta analgetika inte hjälperrekommenderas behandling med starka opioider direkt utan att först använda lättaopioider lätta opioider då dessa anses olämpliga för äldre. Vid perifer neuropatisksmärta rekommenderas i första hand TCA (amitriptylin, nortriptylin) eller gabapentin.Syfte: Det övergripande syftet är att värdera kvaliteten i äldres smärtstillandeläkemedelsbehandling genom att relatera den till rekommenderad behandling för att ökakunskapen om hur behandling med smärtstillande läkemedel ser ut inom äldrevårdenidag. Material och metoder: Läkemedelslistor från 434 patienter från olikaäldreboenden i Uppsala län inkluderas i studien. Insamlade, avidentifierade data fördesin i Excel med information som student-ID, patient-ID, ålder, kön, substansnamn,stående dos, vidbehovsdos och stående + vidbehovsdos. Resultat: Gruppen bestod av299 kvinnor och 135 män med medelåldern 85,4 år. Totalt förskrevs 485 smärtstillandeläkemedel till de 434 patienterna. 75.8 % patienter förskrevs paracetamol, 27,2 %opioider, 3,45 % NSAID, 0,92 % amitriptylin respektive 1,61 % gabapentin.Rekommenderad dygnsdos av paracetamol överskreds hos 13 patienter, av diklofenakhos en patient medan 33 patienter inte hade maximal dygnsdos angiven. Förskrivning avett analgetikum var vanligast och förekom hos 179 patienter. Två analgetika förskrevstill 119 patienter medan två, en man och en kvinna, förskrevs 5 analgetika vardera.Totalt 94 personer, 21,4 %, använde inga smärtstillande läkemedel alls. Konklusion:Studien visar att smärtstillande läkemedelsbehandling hos äldre i Uppsala län inteskiljer sig markant från studier gjorda i övriga Sverige och Europa. Dock var det någrasom, enligt Socialstyrelsen kvalitetsindikatorer, överskred dygnsdosen och stod påläkemedel som anses vara olämpliga för äldre, vilket visar att det fortfarande finnsproblem med äldres läkemedelsterapi.

  • 3.
    Akin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    En undersökning gällande val av antibiotika för behandling av nedre UVI hos kvinnor2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    En undersökning gällande val av antibiotika för behandling av nedre UVI hos kvinnor Berivan Akin Handledare: Margareta Hammarlund-Udenaes – Institution för farmaceutisk biovetenskap Examinator: Agneta Freijs – Institution för farmaceutisk biovetenskap

    Introduktion: Nedre UVI är en infektion som lokaliseras till urinröret och orsakas till mestadels av de primära patogenerna E. coli eller S. saprophyticus. Infektionen kan diagnostiseras endast baserad på symtomen eller med tillägg av tester som leukocytesterastest, nitrittest samt urinodling. Användning av de testerna ger en säkrare diagnos och förskrivaren kan därmed ge patienten en lämpligare behandling. Detta kan skilja sig om det är sporadisk eller recidiverande nedre UVI. Antibiotika som förskrivs för nedre UVI är huvudsakligen nitrofurantoin, pivmecillinam, trimetoprim och ciprofloxacin. Syfte: Huvudsyftet med arbetet var att klargöra hur förskrivaren resonerar kring valet av tester och antibiotika för att behandla en patient med misstänkt nedre UVI. Metod: Förskrivare med olika bakgrund och erfarenhet intervjuades för att undersöka bakomliggande motiv tillbehandlingsvalet. En litteraturstudie genomfördes för att erhålla information om resistensproblematiken samt miljövänligheten av preparaten. Förskrivningsstatistik togs fram via Socialstyrelsens databas för läkemedel. Resultat: Det konstaterades att labprov och teststickor inte nödvändigtvis behövs för att förskriva läkemedel mot nedre UVI. Förskrivningsstatistiken visade att antalet recept med nitrofurantoin och pivmecillinam har ökat markant från år 2006 och framåt, medan trimetoprim och ciprofloxacin har minskat. Slutsats: Pivmecillinam förskrivs mest och därefter nitrofurantoin. Förskrivarna resonerar olika vid valet av antibiotika beroende på erfarenheten. Resistensproblematiken tas hänsyn till, men miljöproblematiken prioriteras lågt.

  • 4.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study2013In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, no 1, p. 185-191Article in journal (Refereed)
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

  • 5.
    Alenius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Treatment Response in Psychotic Patients in a Naturalistic Setting: Classification, Genes, Drugs, Insight and Social Networks2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many patients with psychotic symptoms respond poorly to treatment. Various approaches have been made to classify these patients according to treatment response. However, existing classifications have been criticized for various reasons and a new classification system is needed. Further, no satisfactory explanation of the poor treatment response has been apparent. The general aim of this thesis was therefore to develop and validate a new classification method of functional remission in a naturalistic population of patients with psychosis and to utilize this classification to investigate the population from genetic, drug treatment, insight and social network points of view.

    Data for this cross-sectional study of patients (n=123) attending the Psychosis Outpatient Care clinic in the county of Jönköping, Sweden, were obtained from patient interviews, blood samples and information from patient files. The new classification method CANSEPT, which combines the CAN rating scale (CAN), the UKU side effect rating scale (SE) and the patient’s previous treatment history (PT), showed validity in discriminating the patients and was accepted well by the patients. CANSEPT was used to group the patients in the other studies in this thesis.

    The results indicated that the gene polymorphism ABCB1 3435T, was related to worse significant social and clinical needs for patients on olanzapine, while the polymorphism DRD2 Taq1 A1 was related to a greater risk of significant side effects; especially if male, or taking strong dopamine D2-receptor antagonistic drugs. Drug treatment factors were also related to treatment response; longer duration of untreated prodromal and early psychosis was seen for patients with current significant social and clinical needs and non-adherence to treatment was associated with worse significant side effects. Worse treatment outcomes also appeared to be associated with smaller social network groups, worse insight into illness, poorer knowledge of warning signs and worse coping strategies.

    In summary, CANSEPT was shown to be a useful valid, multidimensional tool for classification of treatment response. Gene polymorphisms, duration of untreated illness, non-adherence to treatment, social networks and knowledge should be taken into consideration when investigating inadequate treatment response.

    List of papers
    1. Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Open this publication in new window or tab >>Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Show others...
    2009 (English)In: Comprehensive Psychiatry, ISSN 0010-440X, E-ISSN 1532-8384, Vol. 50, no 5, p. 453-462Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. CONCLUSION: In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98078 (URN)10.1016/j.comppsych.2008.11.001 (DOI)000269251100009 ()19683616 (PubMedID)
    Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2017-12-13Bibliographically approved
    2. Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Open this publication in new window or tab >>Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Show others...
    2008 (English)In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, no 11, p. 884-893Article in journal (Refereed) Published
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

    Keywords
    DRD2, 5-HT2, ABCB1, Cytochrome P-450 CYP2D6, Antipsychotic agents, Schizophrenia
    National Category
    Pharmaceutical Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98079 (URN)10.1016/j.jpsychires.2007.10.007 (DOI)000258798300002 ()18086475 (PubMedID)
    Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2018-01-13
    3. Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    Open this publication in new window or tab >>Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    2009 (English)Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-98080 (URN)
    Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2011-05-11Bibliographically approved
    4. Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    Open this publication in new window or tab >>Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    2010 (English)In: Social Psychiatry and Psychiatric Epidemiology, ISSN 0933-7954, E-ISSN 1433-9285, Vol. 45, no 5, p. 523-529Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Patients with psychotic symptoms often respond poorly to treatment. Outcomes can be affected by biological, physiological and psychological factors according to the vulnerability-stress model. The patient's coping strategies and beliefs have been correlated with outcomes. OBJECTIVES: To investigate the knowledge and insight in relation to treatment response. METHODS: A naturalistic study was performed using patient interviews and information gathered from patient drug charts. Apart from the rating scales used for classification of treatment response (CANSEPT method), the SPKS knowledge of illness and drugs rating scale was utilized. RESULTS: In the group of patients in functional remission (FR; n = 38), 37% had insight into their illness as compared to 10% among those not in functional remission (non-FR; n = 78; P < 0.01). As much as 23% of the non-FR group had no strategy for responding to warning signs versus 8% in the FR group (P < 0.05). CONCLUSIONS: Better treatment outcomes appear to be associated with better insight into illness, higher knowledge of warning signs and better coping strategies.

    Keywords
    Health knowledge, Treatment outcome, Schizophrenia, Psychotic disorders, Insight
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-123011 (URN)10.1007/s00127-009-0096-3 (DOI)000275422700002 ()19626260 (PubMedID)
    Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
  • 6.
    Alenius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hartvig, Per
    Lindström, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, no 11, p. 884-893Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

  • 7.
    Al-zaibari, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Visualization of metabotropic glutamate receptor 5 (mGluR5) expression and function during progression of Alzheimer’s disease2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 8.
    Bengtsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Boström, Emma
    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.
    The use of a deuterated calibrator for in vivo recovery estimations in microdialysis studies2008In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, p. 3433-3441Article in journal (Refereed)
    Abstract [en]

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

  • 9.
    Bengtsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Engwall, Ann-Cathrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Jergil, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Differences in gene expression in the developing rat brain using cDNA microarray and real-time PCRManuscript (preprint) (Other academic)
    Abstract [en]

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

  • 10.
    Bengtsson, Jörgen
    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.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    On-line desalting and determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in microdialysis and plasma samples using column switching and liquid chromatography/tandem mass spectrometry2005In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 19, no 15, p. 2116-2122Article in journal (Refereed)
    Abstract [en]

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

  • 11.
    Bengtsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Mukai, Chisato
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Kitagaki, Shinji
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Miyakoshi, Naoki
    Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
    Terasaki, Tetsuya
    Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan..
    Björkman, Sven
    Uppsala 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.
    Bcrp does not influence transport of nitrofurantoin across the blood-brain barrier at different agesManuscript (preprint) (Other academic)
    Abstract [en]

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

  • 12.
    Berg, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Transferrin receptor scFv ligands in mediation of therapeutics across the blood-brain barrier2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 13.
    Bergström, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yates, Roger
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kågedal, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Syvänen, Stina
    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.
    Blood-brain barrier penetration of zolmitriptan--modelling of positron emission tomography data2006In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 33, no 1, p. 75-91Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography (PET) with the drug radiolabelled allows a direct measurement of brain or other organ kinetics, information which can be essential in drug development. Usually, however, a PET-tracer is administered intravenously (i.v.), whereas the therapeutic drug is mostly given orally or by a different route to the PET-tracer. In such cases, a recalculation is needed to make the PET data representative for the alternative administration route. To investigate the blood-brain barrier penetration of a drug (zolmitriptan) using dynamic PET and by PK modelling quantify the brain concentration of the drug after the nasal administration of a therapeutic dose. [11C]Zolmitriptan at tracer dose was administered as a short i.v. infusion and the brain tissue and venous blood kinetics of [11C]zolmitriptan was measured by PET in 7 healthy volunteers. One PET study was performed before and one 30 min after the administration of 5 mg zolmitriptan as nasal spray. At each of the instances, the brain radioactivity concentration after subtraction of the vascular component was determined up to 90 min after administration and compared to venous plasma radioactivity concentration after correction for radiolabelled metabolites. Convolution methods were used to describe the relationship between arterial and venous tracer concentrations, respectively between brain and arterial tracer concentration. Finally, the impulse response functions derived from the PET studies were applied on plasma PK data to estimate the brain zolmitriptan concentration after a nasal administration of a therapeutic dose. The studies shows that the PET data on brain kinetics could well be described as the convolution of venous tracer kinetics with an impulse response including terms for arterial-to-venous plasma and arterial-to-brain impulse responses. Application of the PET derived impulse responses on the plasma PK from nasal administration demonstrated that brain PK of zolmitriptan increased with time, achieving about 0.5 mg/ml at 30 min and close to a maximum of 1.5 mg/ml after 2 hr. A significant brain concentration was observed already after 5 min. The data support the notation of a rapid brain availability of zolmitriptan after nasal administration.

  • 14.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    A comment on the application of drug tissue-plasma partition coefficients Kp in eliminating organs to calculation of volume of distribution at steady state2005In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 32, no 5-6, p. 655-658Article in journal (Refereed)
  • 15.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children: how accurate are available scaling methods?2006In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 45, no 1, p. 1-11Article, review/survey (Other academic)
    Abstract [en]

    Correct dosing of drugs in neonates, infants and children is hampered by a general lack of knowledge about drug disposition in this population. Suggested methods to improve our knowledge without performing conventional full-scale investigations include population pharmacokinetic studies, allometric scaling of drug disposition according to bodyweight and in silico prediction of pharmacokinetics. The last method entails scaling of pharmacokinetic parameters according to age-dependent changes in drug absorption and elimination capacity, plasma protein binding and physiological characteristics of the subjects. Maturation (or ontogeny) of the drug-metabolising part of the cytochrome P450 (CYP) enzyme system is thus an important factor in the calculations for most drugs. The aim of this commentary is to test and critically examine the proposed methods to estimate hepatic clearance (CL) as a function of age (0-20 years), with CYP3A-mediated metabolism as the case in point. Midazolam and alfentanil were used as model drugs.Allometric scaling failed to predict the CL of midazolam and alfentanil in neonates. Calculations using in vitro findings on CYP maturation gave better estimates for neonates but very divergent ones for older infants and children. This was chiefly due to very different data on CYP3A4/5 ontogeny in three published studies. In the age range where full adult CYP activity per gram of liver could be assumed, allometric scaling and in silico predictions gave similar results. These predictions were also in approximate agreement with clinical data.The findings with the two model drugs can very probably be generalised to most drugs cleared by CYP-dependent hepatic metabolism. Allometric scaling accounts for development of body size and function but not for the fact that the drug-metabolising capacity of the liver is generally low at birth. The crucial question in the prediction of CL is thus when the activity of the applicable CYP isoform(s) attains adult levels. There are still not enough data on this, particularly when different studies even on the same CYP isoform have given very divergent results. It may also be pointed out that CYP ontogeny is an area where we have at least some information. There are several other important developmental changes about which we know practically nothing. Thus, while allometric scaling is generally unreliable for prediction in neonates and infants, the alternative method of in silico prediction can at present be used only to obtain tentative initial estimates of drug CL. Neither of the methods can be used as a substitute for actual clinical studies.

  • 16.
    Björkman, Sven E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Folkesson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Berntorp, E.
    In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting2007In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 13, no 1, p. 2-8Article in journal (Refereed)
    Abstract [en]

    In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL−1 per U kg−1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5–67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13–69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.

  • 17.
    Boström, Emma
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Pharmacokinetics and Pharmacodynamics of Oxycodone and Morphine with Emphasis on Blood-Brain Barrier Transport2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The pharmacokinetics and pharmacodynamics of oxycodone and morphine was investigated and related to the transport across the blood-brain barrier (BBB) in rats. The influence of a P-glycoprotein (P-gp) inhibitor on the plasma pharmacokinetics and pharmacodynamics of oxycodone was evaluated. Microdialysis experiments were conducted to evaluate the unbound pharmacokinetics, including the rate and extent of transport across the BBB, of oxycodone and morphine. Mathematical models were used to assess the pharmacokinetics and also the relationship between pharmacokinetics and pharmacodynamics of the drugs.

    Oxycodone clearance, volume of distribution at steady-state, half-life, total brain tissue concentrations and tail-flick latency were all unaffected when a P-gp inhibitor was co-administered with oxycodone as compared to a control group. The lack of differences between the groups indicates that oxycodone BBB transport is not affected by P-gp inhibition. Investigating the unbound concentrations of oxycodone in brain and blood using microdialysis revealed an exciting finding. At steady-state, the unbound concentration in brain was 3 times higher than in blood (i.e. a Kp,uu of 3), indicating that active influx is involved in the BBB transport of oxycodone. In contrast, the Kp,uu of morphine was estimated to 0.56, which is an indication that active efflux mechanisms are involved in the BBB transport of morphine. This means that based on the same unbound concentration in blood, an approximately 6-fold higher unbound concentration of oxycodone compared to morphine will be reached in the brain. Using pharmacokinetic-pharmacodynamic modelling, the unbound brain concentrations of oxycodone and morphine were correlated to the tail-flick latency in vivo. The relative potency of the drugs was found to be concentration dependent with an infliction point of 55 nM.

    In summary, this thesis emphasise the importance of taking the local brain pharmacokinetics into consideration when investigating the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationships of centrally acting drugs.

    List of papers
    1. The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue
    Open this publication in new window or tab >>The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue
    2004 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, no 21, p. 2565-2576Article in journal (Refereed) Published
    Abstract [en]

    Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95634 (URN)10.1002/rcm.1658 (DOI)000224872500007 ()15468158 (PubMedID)
    Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2018-01-13Bibliographically approved
    2. Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC833
    Open this publication in new window or tab >>Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC833
    2005 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, no 5, p. 1060-1066Article in journal (Refereed) Published
    Abstract [en]

    The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood-brain barrier (BBB) with concomitantly administered P-gp substrates.

    Keywords
    P-glycoprotein, pharmacokineties/pharmacodynamics, blood-brain barrier, efflux pumps, active transports, transporters, CNS, clearance
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95635 (URN)10.1002/jps.20327 (DOI)000228792200014 ()15799017 (PubMedID)
    Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2018-01-13Bibliographically approved
    3. In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics
    Open this publication in new window or tab >>In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics
    2006 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 34, no 9, p. 1624-1631Article in journal (Refereed) Published
    Abstract [en]

    The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL(in) and K(p,uu). CL(in) describes the clearance of oxycodone across the BBB into the brain, whereas K(p,uu) describes the extent of drug equilibration across the BBB. CL(in) across the BBB was estimated to 1910 microl/min x g brain. K(p,uu) was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95636 (URN)10.1124/dmd.106.009746 (DOI)000239938500025 ()16763013 (PubMedID)
    Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2018-01-13Bibliographically approved
    4. Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine
    Open this publication in new window or tab >>Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine
    2008 (English)In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 108, no 3, p. 495-505Article in journal (Refereed) Published
    Abstract [en]

    Background The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic relations of un-bound oxycodone and morphine to investigate the influence of blood-brain barrier transport on differences in potency between these drugs. Methods: Microdialysis was used to obtain unbound concentrations in brain and blood. The antinociceptive effect of each drug was assessed using the hot water tail-flick method. Population pharmacokinetic modeling was used to describe the bloodbrain barrier transport of morphine as the rate (Cl.) and extent (K-p,K-uu) of equilibration, where CLin is the influx clearance across the blood-brain barrier and Kp,,,, is the ratio of the unbound concentration in brain to that in blood at steady state. Results: The six-fold difference in K-p,K-uu between oxycodone and morphine implies that, for the same unbound concentration in blood, the concentrations of unbound oxycodone in brain will be six times higher than those of morphine. A joint pharmacokinetic-pharmacodynamic model of oxycodone and morphine based on unbound brain concentrations was developed and used as a statistical tool to evaluate differences in the pharmacodynamic parameters of the drugs. A power model using Effect = Baseline + Slope center dot C-gamma best described the data. Drug-specific slope and gamma parameters made the relative potency of the drugs concentration dependent. Conclusions: For centrally acting drugs such as opioids, pharmacokinetic-pharmacodynamic relations describing the interaction with the receptor are better obtained by correlating the effects to concentrations of unbound drug in the tissue of interest rather than to blood concentrations.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95637 (URN)10.1097/ALN.0b013e318164cf9e (DOI)000253395800021 ()18292687 (PubMedID)
    Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2018-01-13Bibliographically approved
  • 18.
    Boström, Emma
    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.
    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.
    Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine2008In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 108, no 3, p. 495-505Article in journal (Refereed)
    Abstract [en]

    Background The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic relations of un-bound oxycodone and morphine to investigate the influence of blood-brain barrier transport on differences in potency between these drugs. Methods: Microdialysis was used to obtain unbound concentrations in brain and blood. The antinociceptive effect of each drug was assessed using the hot water tail-flick method. Population pharmacokinetic modeling was used to describe the bloodbrain barrier transport of morphine as the rate (Cl.) and extent (K-p,K-uu) of equilibration, where CLin is the influx clearance across the blood-brain barrier and Kp,,,, is the ratio of the unbound concentration in brain to that in blood at steady state. Results: The six-fold difference in K-p,K-uu between oxycodone and morphine implies that, for the same unbound concentration in blood, the concentrations of unbound oxycodone in brain will be six times higher than those of morphine. A joint pharmacokinetic-pharmacodynamic model of oxycodone and morphine based on unbound brain concentrations was developed and used as a statistical tool to evaluate differences in the pharmacodynamic parameters of the drugs. A power model using Effect = Baseline + Slope center dot C-gamma best described the data. Drug-specific slope and gamma parameters made the relative potency of the drugs concentration dependent. Conclusions: For centrally acting drugs such as opioids, pharmacokinetic-pharmacodynamic relations describing the interaction with the receptor are better obtained by correlating the effects to concentrations of unbound drug in the tissue of interest rather than to blood concentrations.

  • 19.
    Boström, Emma
    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.
    Hammarlund-Udenaes, Margareta
    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.
    The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue2004In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, no 21, p. 2565-2576Article in journal (Refereed)
    Abstract [en]

    Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

  • 20.
    Boström, Emma
    et al.
    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.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics2006In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 34, no 9, p. 1624-1631Article in journal (Refereed)
    Abstract [en]

    The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL(in) and K(p,uu). CL(in) describes the clearance of oxycodone across the BBB into the brain, whereas K(p,uu) describes the extent of drug equilibration across the BBB. CL(in) across the BBB was estimated to 1910 microl/min x g brain. K(p,uu) was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.

  • 21.
    Boström, Emma
    et al.
    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.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC8332005In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, no 5, p. 1060-1066Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood-brain barrier (BBB) with concomitantly administered P-gp substrates.

  • 22.
    Bouw, M. René
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Xie, Rujia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Tunblad, Karin
    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.
    Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats: pharmacokinetic/pharmacodynamic modelling2001In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 134, no 8, p. 1796-1804Article in journal (Refereed)
    Abstract [en]

    1. The objective of this study was to investigate the contribution of the blood-brain barrier (BBB) transport to the delay in antinociceptive effect of morphine-6-glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations. 2. On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml(-1) (6.5 microM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration. 3. The half-life of M6G was 23+/-5 min in arterial blood, 26+/-10 min in venous blood and 58+/-17 min in brain ECF (P<0.05; brain vs blood). The BBB equilibration, expressed as the unbound steady-state concentration ratio, was 0.22+/-0.09, indicating active efflux in the BBB transport of M6G. A two-compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20+/-0.02 ml g brain(-1). The concentration-antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half-life of 103 min in relation to blood concentrations and a remaining effect delay half-life of 53 min in relation to brain ECF concentrations. 4. Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate-limiting mechanisms at the receptor level.

  • 23.
    Callmar, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    The impact of a pharmacy technician on medicines management and skill mix at the Emergency Department of Antrim Area Hospital2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The impact of a pharmacy technician on medicines management and skill mix at the Emergency Department of Antrim Area Hospital

    Marika Callmar

    Division for Pharmacokinetics and Drug Therapy, 30 hp. Examiner: Margareta Hammarlund-Udenaes. Supervisor: Prof. Michael Scott, Head of Pharmacy & Medicines Management NHSCT, Northern Ireland.

    Introduction: It has previously been shown that integrating pharmaceutical care in hospitals reduces the average length of hospital stay and number of readmissions, which leads to cost savings. To enable pharmaceutical care at an early stage, the pharmacists in the Emergency Department (ED) must be freed from non-clinical tasks, such as stock management and dispensing medicines. These tasks are better performed by a pharmacy technician. A pharmacy technician can also manage patients own drugs (PODs) that are brought in to ED instead of relying on nurses to undertake this task.

    Aim:  The aim of the study was to investigate if medicines management is improved by introducing a pharmacy technician in the ED. Improving medicines management may improve the treatment of patients as well as reduce costs for the hospital.

    Materials and Methods:  Improvements in medicines management were measured in two ways. Data was gathered on how much time the pharmacists spent on different tasks to investigate if a better skill mix in ED could free time for pharmaceutical care. Information regarding storage of any PODs brought in to ED and whether they were transferred with the patient was also gathered. This was compared before and after introducing a technician in ED.

     Results:  The percentage of time the pharmacists spent on stock management was cut in half, which corresponded to a 5.2 % decrease of their total working time. No other time changes due to the introduction of a technician were observed. The number of correctly stored PODs was increased by 37.9 % but no significant improvement was seen regarding PODs transferred to the wards.

    Conclusions:  Introducing a technician in ED can improve the management of PODs. In order to achieve time savings for the pharmacists the skill mix must be further assessed.

  • 24.
    Chammas, Nancy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Avvikelser mellan journalens läkemedelslista och sjuksköterskans underlag för läkemedelshanteringen hos yngre-äldre och äldre-äldre i särskilda boende2011Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 25.
    Cullberg, Marie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Direct Thrombin Inhibitors in Treatment and Prevention of Venous Thromboembolism: Dose – Concentration – Response Relationships2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE).

    Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT).

    The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication.

    The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.

    List of papers
    1. Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease
    Open this publication in new window or tab >>Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease
    2001 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 51, no 1, p. 71-79Article in journal (Refereed) Published
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94472 (URN)10.1046/j.1365-2125.2001.01326.x (DOI)
    Available from: 2006-05-02 Created: 2006-05-02 Last updated: 2018-01-13Bibliographically approved
    2. Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct thrombin inhibitor melagatran
    Open this publication in new window or tab >>Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct thrombin inhibitor melagatran
    (English)Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-94473 (URN)
    Available from: 2006-05-02 Created: 2006-05-02 Last updated: 2011-06-21Bibliographically approved
    3. Pharmacokinetics of ximelagatran and relationship to clinical response in acute vein thrombosis
    Open this publication in new window or tab >>Pharmacokinetics of ximelagatran and relationship to clinical response in acute vein thrombosis
    Show others...
    2005 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 77, no 4, p. 279-290Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:

    Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.

    METHODS:

    A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models.

    RESULTS:

    The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat.

    CONCLUSIONS:

    The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94474 (URN)10.1016/j.clpt.2004.11.001 (DOI)15903126 (PubMedID)
    Available from: 2006-05-02 Created: 2006-05-02 Last updated: 2017-12-14Bibliographically approved
    4. Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical events
    Open this publication in new window or tab >>Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical events
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94475 (URN)
    Available from: 2006-05-02 Created: 2006-05-02 Last updated: 2011-03-01
  • 26.
    Cullberg, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Eriksson, Ulf G.
    Larsson, Marita
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease2001In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 51, no 1, p. 71-79Article in journal (Refereed)
  • 27.
    Cullberg, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Eriksson, Ulf G.
    Wåhlander, Karin
    Eriksson, Henry
    Schulman, Sam
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetics of ximelagatran and relationship to clinical response in acute vein thrombosis2005In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 77, no 4, p. 279-290Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.

    METHODS:

    A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models.

    RESULTS:

    The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat.

    CONCLUSIONS:

    The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

  • 28.
    Cullberg, Marie
    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
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Eriksson, Ulf G.
    Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct thrombin inhibitor melagatranArticle in journal (Refereed)
  • 29.
    Cullberg, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wåhlander, Karin
    Lundström, Torbjörn
    Wall, Ulrika
    Eriksson, Ulf G.
    Karlsson, Mats O.
    Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical eventsManuscript (Other academic)
  • 30.
    Dansirikul, Chantaratsamon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Silber, Hanna E
    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.
    Approaches to handling pharmacodynamic baseline responses2008In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 3, p. 269-283Article in journal (Refereed)
    Abstract [en]

    A few approaches for handling baseline responses are available for use in pharmacokinetic (PK)-pharmacodynamic (PD) analysis. They include: (method 1-B1) estimation of the typical value and interindividual variability (IIV) of baseline in the population, (B2) inclusion of the observed baseline response as a covariate acknowledging the residual variability, (B3) a more general version of B2 as it also takes the IIV of the baseline in the population into account, and (B4) normalization of all observations by the baseline value. The aim of this study was to investigate the relative performance of B1-B4. PD responses over a single dosing interval were simulated from an indirect response model in which a drug acts through stimulation or inhibition of the response according to an Emax model. The performance of B1-B4 was investigated under 22 designs, each containing 100 datasets. NONMEM VI beta was used to estimate model parameters with the FO and the FOCE method. The mean error (ME, %) and root mean squared error (RMSE, %) of the population parameter estimates were computed and used as an indicator of bias and imprecision. Absolute ME (|ME|) and RMSE from all methods were ranked within the same design, the lower the rank value the better method performance. Average rank of each method from all designs was reported. The results showed that with B1 and FOCE, the average of |ME| and RMSE across all typical individual parameters and all conditions was 5.9 and 31.8%. The average rank of |ME| for B1, B2, B3, and B4 was 3.7, 3.8, 3.3, and 5.2 for the FOCE method, and 4.6, 4.3, 4.7, and 6.4 for the FO method. The smallest imprecision was noted with the use of B1 (rank of 3.1 for FO, and 2.9 for FOCE) and increased, in order, with B3 (3.9-FO and 3.6-FOCE), B2 (4.8-FO; 4.7-FOCE), and B4 (6.4-FO; 6.5-FOCE). We conclude that when considering both bias and imprecision B1 was slightly better than B3 which in turn was better than B2. Differences between these methods were small. B4 was clearly inferior. The FOCE method led to a smaller bias, but no marked reduction in imprecision of parameter estimates compared to the FO method.

  • 31. Dyhre, Henrik
    et al.
    Söderberg, Lars
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Carlsson, Christer
    Local anesthetics in lipid-depot formulations--neurotoxicity in relation to duration of effect in a rat model2006In: Regional anesthesia and pain medicine, ISSN 1098-7339, E-ISSN 1532-8651, Vol. 31, no 5, p. 401-408Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the possible local neurotoxicity of a number of lipid-depot formulations of local anesthetics in relation to their duration of action in sciatic-nerve block. METHODS: Formulations that contain 2%, 4%, 8%, 16%, 32%, or 64% of a mixture of bupivacaine and lidocaine base 4:1 in medium-chain triglyceride were prepared and evaluated, together with 0.5%, 1.0%, and 2.0% bupivacaine HCl solutions, bupivacaine 4.2% or 7.0% in medium-chain triglyceride, and 20% lidocaine base in a polar lipid vehicle. The duration of sensory and motor sciatic-nerve block was determined in rats. A week later, the sciatic nerves were dissected and removed for histopathologic examination by light microscopy. RESULTS: The duration of sensory and motor-nerve block was prolonged almost 4 times with the 32% and 13 times with the 64% bupivacaine:lidocaine formulation, in comparison to the 0.5% aqueous solution. The 64% formulation was applied by injection and also placed directly on the nerve with similar results. Slight to moderate signs of neurotoxicity were only found after administration of the 64% formulation. CONCLUSIONS: The findings suggest that depot formulations of local anesthetics with advantageous pharmaceutical and pharmacologic properties can be prepared by use of bupivacaine as the active component and natural lipids as carriers. A favorable balance between effects and toxicity may conceivably be obtained. After supplemental testing in more sensitive models for toxicity, such formulations could be candidates for clinical trials.

  • 32.
    Ebrahimi, Nadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Användning av inhalationssteroider och risk för pneumoni hos KOL-patienter: en retrospektiv studie vid Lungkliniken, Karolinska Universitetssjukhuset2015Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis