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  1. 1. Benefits of Non-Linear Mixed Effect Modeling and Optimal Design : Pre-Clinical and Clinical Study Applications

    Författare :Charles Ernest II; Andrew Hooker; Mats Karlsson; Bart Ploeger; Uppsala universitet; []
    Nyckelord :MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; Pharmacometrics; optimal design; nonlinear mixed effects models; population models; Pharmaceutical Science; Farmaceutisk vetenskap;

    Sammanfattning : Despite the growing promise of pharmaceutical research, inferior experimentation or interpretation of data can inhibit breakthrough molecules from finding their way out of research institutions and reaching patients. This thesis provides evidence that better characterization of pre-clinical and clinical data can be accomplished using non-linear mixed effect modeling (NLMEM) and more effective experiments can be conducted using optimal design (OD). LÄS MER

  3. 2. Finding improved drug strategies for schizophrenia : Preclinical studies on lumateperone and sodium nitroprusside

    Författare :Joep Titulaer; Åsa Konradsson-Geuken; Anne-Lie Svensson; Erika Roman; Kent Jardemark; Joshua Beckmann; Uppsala universitet; []
    Nyckelord :MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; schizophrenia; lumateperone; sodium nitroprusside; antipsychotic drugs; Farmaceutisk vetenskap; Pharmaceutical Science; Pharmacology; Farmakologi; Psychiatry; Psykiatri;

    Sammanfattning : Schizophrenia is a severe psychiatric disorder affecting approximately 20 million people worldwide. The disease consists of positive symptoms e.g. hallucinations, negative symptoms such as anhedonia, and cognitive deficits, e. LÄS MER

  4. 3. Development and Evaluation of Nonparametric Mixed Effects Models

    Författare :Paul Baverel; Mats Karlsson; Radojka Savic; Nils Hoem; Uppsala universitet; []
    Nyckelord :NATURVETENSKAP; NATURAL SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; nonparametric; model; pharmacometrics; pharmacokinetics; pharmacodynamic; imprecision; covariate analysis; parameter distribution; Statistics; computer and systems science; Statistik; data- och systemvetenskap; Pharmaceutical pharmacology; Farmaceutisk farmakologi; Biopharmaceutics; Biofarmaci; Clinical Pharmacology; Klinisk farmakologi; Computer Systems; Datorteknik; Farmakologi; Pharmacology; Statistics; Statistik;

    Sammanfattning : A nonparametric population approach is now accessible to a more comprehensive network of modelers given its recent implementation into the popular NONMEM application, previously limited in scope by standard parametric approaches for the analysis of pharmacokinetic and pharmacodynamic data. The aim of this thesis was to assess the relative merits and downsides of nonparametric models in a nonlinear mixed effects framework in comparison with a set of parametric models developed in NONMEM based on real datasets and when applied to simple experimental settings, and to develop new diagnostic tools adapted to nonparametric models. LÄS MER

  5. 4. Development of Methods for Assessing Unbound Drug Exposure in the Brain : In vivo, in vitro and in silico

    Författare :Markus Fridén; Margareta Hammarlund-Udenaes; Ulf Bredberg; Yuichi Sugiyama; Uppsala universitet; []
    Nyckelord :MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; Blood-brain barrier; Drug transport; Tissue distribution; Transporters; Pharmacokinetics; Other pharmacy; Övrig farmaci; Biopharmacy; Biofarmaci; Pharmaceutical pharmacology; Farmaceutisk farmakologi; Pharmacokinetics and Drug Therapy; Farmakokinetik och läkemedelsterapi;

    Sammanfattning : The blood-brain barrier is formed by tightly joined capillary cells with transporter proteins and acts as to regulate the brain concentration of nutrients as well as many drugs. When developing central nervous system drugs it is necessary to measure the unbound drug concentration in the brain, i.e. the unbound brain exposure. LÄS MER

  7. 5. Catalytic and Structural Properties of Heme-containing Fatty Acid Dioxygenases : Similarities of Fungal Dioxygenases and Cyclooxygenases

    Författare :Ulrike Garscha; Ernst Oliw; Per-Johan Jakobsson; Uppsala universitet; []
    Nyckelord :MEDICIN OCH HÄLSOVETENSKAP; MEDICAL AND HEALTH SCIENCES; dioxygenase; prostaglandin H synthase; Gaeumannomyces graminis; Aspergilli; hydroperoxide isomerase; linoleate diol synthase; cytochrome P450; oxylipin; Pharmaceutical pharmacology; Farmaceutisk farmakologi; Farmaceutisk farmakologi; Pharmaceutical Pharmacology;

    Sammanfattning : 7,8-Linoleate diol synthase (7,8-LDS) of the take-all pathogen of wheat, Gaeumannomyces graminis, converts linoleic acid to 8R-hydroperoxyoctadecadienoic acid (8-HPODE) by 8-dioxygenase activity (8-DOX), and further isomerizes the hydroperoxide to 7S,8S-dihydroxyoctadecadienoic acid (7,8-DiHODE) by hydroperoxide isomerase activity. Sequence alignment showed homology to prostaglandin H synthase (PGHS), and both enzymes share structural and catalytic properties. LÄS MER