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  • 1.
    Abelson, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Höglund, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat2004In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 94, no 4, p. 153-60Article in journal (Refereed)
    Abstract [en]

    Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinalacetylcholine. The cholinergic receptor system interacts with several other receptor types, such as a2-adrenergic receptors.To fully understand these interactions, the effects of various receptor ligands on the cholinergic system must be investigatedin detail. This study was initiated to investigate the effects of the a2-adrenergic receptor agonists clonidine and rilmenidineand the a2-adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors in the rat. Spinalmicrodialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or withoutnicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptorswere investigated. It was found that clonidine and rilmenidine increased, while yohimbine decreased spinal acetylcholinerelease. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade atten-uated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand, allligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curveand rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested a2-adrenergicreceptor ligands affect intraspinal acetylcholine release in the rat evoked by nicotinic receptor mechanisms in vivo, andthat they possess binding affinity to nicotinic receptors in vitro. The binding of a2-adrenergic receptor ligands to nicotinicreceptors might affect the intraspinal release of acetylcholine.

  • 2.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Björkblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Isaksson, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Impact of nandrolone decanoate on gene expression in endocrine systems related to the adverse effects of anabolic androgenic steroids2009In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 105, no 5, p. 307-314Article in journal (Refereed)
    Abstract [en]

    Elite athletes, body builders and adolescents misuse anabolic-androgenic steroids (AAS) in order to increase muscle mass or to enhance physical endurance and braveness. The high doses misused are associated with numerous adverse effects. The purpose of this study was to evaluate the impact of chronic supratherapeutic AAS treatment on circulating hormones and gene expression in peripheral tissues related to such adverse effects. Quantitative real-time PCR was used to measure expression levels of in total 37 genes (including peptide hormones, cell membrane receptors, nuclear receptors, steroid synthesising enzymes and other enzymes) in the pituitary, testes, adrenals, adipose tissue, kidneys and liver of male Sprague-Dawley rats after 14-day administration of the AAS nandrolone decanoate, 3 or 15 mg/kg. Plasma glucose and levels of adrenocorticotropic hormone (ACTH), adiponectin, corticosterone, ghrelin, insulin and leptin were also measured. We found several expected effects on the hypothalamic-pituitary-gonadal axis, while the treatment also caused a number of other not previously identified changes in circulating factors and gene transcription levels such as the dose-dependent reduction of the beta(3)-adrenergic receptor in adipose tissue, reduction of both circulating and mRNA levels of adiponectin, up-regulation of both hydroxymethylglutaryl-CoA-reductase, the rate-limiting enzyme in de novo synthesis of cholesterol, and the receptor for ACTH in the adrenals. The results provide evidence for wide ranging effects of AAS on the hypothalamic-pituitary-adrenal axis, adipose tissue and substrates of the renal control of blood pressure.

  • 3.
    Azarbayjani, Faranak
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Borg, L. A. Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Danielsson, Bengt R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Increased susceptibility to phenytoin teratogenicity: Excessive generation of reactive oxygen species or impaired antioxidant defense?2006In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 99, no 4, p. 305-311Article in journal (Refereed)
    Abstract [en]

    Phenytoin is a human and animal teratogen. Accumulating evidence suggests that the teratogenicity is associated with a potential of phenytoin to cause embryonic cardiac arrhythmia and resultant generation of toxic reactive oxygen species via hypoxia-reoxygenation mechanisms. The A/J mouse is more susceptible to phenytoin teratogenicity than other mouse strains. The aim of this study was to investigate whether A/J mice have other antioxidant enzyme activities than C57BL/6J and CD-1 mice. Also, strain differences in phenytoin effects on embryonic heart rate and rhythm were determined. Another objective was to determine whether a spin trapping agent with capacity to capture reactive oxygen species alter the developmental toxicity of phenytoin. Treatment with this agent resulted in a marked decrease in phenytoin teratogenicity, which supports the idea that reactive oxygen species are important mediators for the teratogenic action of phenytoin. The A/J mice embryos were most susceptible to the adverse cardiac effects of phenytoin and had the highest activity of superoxide dismutase and glutathione peroxidase, while the activity of catalase was the same in embryos of the three different strains. The high activities of antioxidant enzymes in the A/J stain indicate that the sensitivity to develop malformations is caused by excessive arrhythmia-related generation of reactive oxygen species rather than impaired antioxidant defense.

  • 4.
    Bjorklund, Geir
    et al.
    Council Nutr & Environm Med CONEM, Toften 24, N-8610 Mo I Rana, Norway.
    Chirumbolo, Salvatore
    Univ Verona, Dept Neurosci Biomed & Movement Sci, Verona, Italy;CONEM Sci Secretary, Verona, Italy.
    Dadar, Maryam
    AREEO, Razi Vaccine & Serum Res Inst, Karaj, Iran.
    Pivina, Lyudmila
    Semey Med Univ, Semey, Kazakhstan;Semey Med Univ, CONEM Kazakhstan Environm Hlth & Safety Res Grp, Semey, Kazakhstan.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Butnariu, Monica
    Banats Univ Agr Sci & Vet Med King Michael I Roma, Timisoara, Romania;Banats Univ Agr Sci & Vet Med King Michael I Roma, CONEM Romania Biotechnol & Environm Sci Grp, Timisoara, Romania.
    Aaseth, Jan
    Innlandet Hosp Trust, Res Dept, Brumunddal, Norway;Inland Norway Univ Appl Sci, Elverum, Norway.
    Mercury exposure and its effects on fertility and pregnancy outcome2019In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 125, no 4, p. 317-327Article, review/survey (Refereed)
    Abstract [en]

    Mercury (Hg), a highly toxic environmental pollutant, shows harmfulness which still represents a big concern for human health, including hazards to fertility and pregnancy outcome. Research has shown that Hg could induce impairments in the reproductive function, cellular deformation of the Leydig cells and the seminiferous tubules, and testicular degeneration as well as abnormal menstrual cycles. Some studies investigated spontaneous abortion and complicated fertility outcome due to occupational Hg exposure. Moreover, there is a relation between inhaled Hg vapour and reproductive outcome. This MiniReview evaluates the hypothesis that exposure to Hg may increase the risk of reduced fertility, spontaneous abortion and congenital deficits or abnormalities.

  • 5.
    Björklund, Geir
    et al.
    Council Nutr & Environm Med, Toften 24, N-8610 Mo I Rana, Norway.
    Hilt, Björn
    St Olavs Univ Hosp, Dept Occupat Med, Trondheim, Norway;Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, Trondheim, Norway.
    Dadar, Maryam
    AREEO, Razi Vaccine & Serum Res Inst, Karaj, Iran.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Aaseth, Jan
    Innlandet Hosp Trust, Res Dept, Brumunddal, Norway;Inland Norway Univ Appl Sci, Fac Hlth & Social Sci, Elverum, Norway.
    Neurotoxic effects of mercury exposure in dental personnel2019In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 124, no 5, p. 568-574Article, review/survey (Refereed)
    Abstract [en]

    Numerous studies have reported neurobehavioural effects in dental personnel occupationally exposed to chronic low levels of mercury (Hg). Hg exposure from dental work may also induce various chronic conditions such as elevation of amyloid protein expression, deterioration of microtubules and increase or inhibition of transmitter release at motor nerve terminal endings. Therefore, clinical studies of Hg toxicity in dentistry may provide new knowledge about disturbed metal homeostasis in neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis and mood disorders. The purpose of this MiniReview is to evaluate the evidence of possible relevance between Hg exposure in dentistry and idiopathic disturbances in motor functions, cognitive skills and affective reactions, as well as dose-response relationships.

  • 6.
    Bouchene, Salim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marchand, Sandrine
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Couet, William
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gobin, Patrice
    INSERM, U 1070, Pole Biol Sante, Poitiers, France.
    Lamarche, Isabelle
    INSERM, U 1070, Pole Biol Sante, Poitiers, France.
    Gregoire, Nicolas
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 4, p. 407-422Article in journal (Refereed)
    Abstract [en]

    Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram-negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K-p. Colistin and its prodrug, colistin methanesulfonate (CMS) K-p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting invivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K-p was estimated using in silico K-p priors (I) or K-p was estimated using experimental K-p priors (II) or K-p was fixed to the experimental values (III). The WB-PBPK model best described colistin and CMS plasma concentration-time profiles in scenario II. Colistin-predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K-p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K-p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.

  • 7.
    Cao, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Marttila, Petra S. K. (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J. (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B. (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster2016In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843Article in journal (Refereed)
    Abstract [en]

    Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed toDEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects fromDEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP mayhave detrimental effects on metabolic functions.

  • 8.
    Cao, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wiemerslage, Lyle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Marttila, Petra S. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster2016In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 119, no 3, p. 309-316Article in journal (Refereed)
    Abstract [en]

    Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long-term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions.

  • 9.
    Cars, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Wettermark, Bjorn
    Malmstrom, Rickard E.
    Ekeving, Gunnar
    Vikstrom, Bo
    Bergman, Ulf
    Neovius, Martin
    Ringertz, Bo
    Gustafsson, Lars L.
    Extraction of Electronic Health Record Data in a Hospital Setting: Comparison of Automatic and Semi-Automatic Methods Using Anti-TNF Therapy as Model2013In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 112, no 6, p. 392-400Article in journal (Refereed)
    Abstract [en]

    There is limited experience and methods for extractions of drug therapy data from electronic health records (EHR) in the hospital setting. We have therefore developed and evaluated completeness and consistency of an automatic versus a semi-automatic extraction procedure applied on prescribing and administration of the TNF inhibitor infliximab using a hospital EHR system in Karolinska University Hospital, Sweden. Using two different extraction methods (automatic and semi-automatic), all administered infusions of infliximab between 2007 and 2010 were extracted from a database linked to the EHR system. Extracted data included encrypted personal identity number (PIN), date of birth, sex, time of prescription/administration, healthcare units, prescribed/administered dose and time of admission/discharge. The primary diagnosis (ICD-10) for the treatment with infliximab was extracted by linking infliximab infusions to their corresponding treatment episode. A total of 13,590 infusions of infliximab were administered during the period of 2007 to 2010. Of those were 13,531 (99.6%) possible to link to a corresponding treatment episode, and a primary diagnosis was extracted for 13,530 infusions. Information on encrypted PIN, date of birth, time of prescription/administration, time of admission/discharge and healthcare unit was complete. Information about sex was missing in one patient only. Calculable information about dosage was extracted for 13,300 (98.3%) of all linked infusions. This methodological study showed the potential to extract drug therapy data in a hospital setting. The semi-automatic procedure produced an almost complete pattern of demographics, diagnoses and dosages for the treatment with infliximab.

  • 10. Choong, Eva
    et al.
    Loryan, Irena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Institutet, Yerevan State Medical University.
    Lindqvist, Marja
    Nordling, Åsa
    el Bouazzaoui, Samira
    van Schaik, Ron H
    Johansson, Inger
    Jakobsson, Jan
    Ingelman-Sundberg, Magnus
    Sex difference in formation of propofol metabolites: a replication study2013In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 113, no 2, p. 126-131Article in journal (Refereed)
    Abstract [en]

    Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men - an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose- and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-β-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-β-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women - a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.

  • 11. Dahl, Svein G.
    et al.
    Aarons, Leon
    Gundert-Remy, Ursula
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schneider, Yves-Jacques
    Steimer, Jean-Louis
    Troconiz, Inaki F.
    Incorporating Physiological and Biochemical Mechanisms into Pharmacokinetic-Pharmacodynamic Models: A Conceptual Framework2010In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 1, p. 2-12Article, review/survey (Refereed)
    Abstract [en]

    The aim of this conceptual framework paper is to contribute to the further development of the modelling of effects of drugs or toxic agents by an approach which is based on the underlying physiology and pathology of the biological processes. In general, modelling of data has the purpose (1) to describe experimental data, (2a) to reduce the amount of data resulting from an experiment, e.g. a clinical trial and (2b) to obtain the most relevant parameters, (3) to test hypotheses and (4) to make predictions within the boundaries of experimental conditions, e.g. range of doses tested (interpolation) and out of the boundaries of the experimental conditions, e.g. to extrapolate from animal data to the situation in man. Describing the drug/xenobiotic-target interaction and the chain of biological events following the interaction is the first step to build a biologically based model. This is an approach to represent the underlying biological mechanisms in qualitative and also quantitative terms thus being inherently connected in many aspects to systems biology. As the systems biology models may contain variables in the order of hundreds connected with differential equations, it is obvious that it is in most cases not possible to assign values to the variables resulting from experimental data. Reduction techniques may be used to create a manageable model which, however, captures the biologically meaningful events in qualitative and quantitative terms. Until now, some success has been obtained by applying empirical pharmacokinetic/pharmacodynamic models which describe direct and indirect relationships between the xenobiotic molecule and the effect, including tolerance. Some of the models may have physiological components built in the structure of the model and use parameter estimates from published data. In recent years, some progress toward semi-mechanistic models has been made, examples being chemotherapy-induced myelosuppression and glucose-endogenous insulin-antidiabetic drug interactions. We see a way forward by employing approaches to bridge the gap between systems biology and physiologically based kinetic and dynamic models. To be useful for decision making, the 'bridging' model should have a well founded mechanistic basis, but being reduced to the extent that its parameters can be deduced from experimental data, however capturing the biological/clinical essential details so that meaningful predictions and extrapolations can be made.

  • 12.
    Emanuelsson, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikvall, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friman, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 2, p. 130-136Article in journal (Refereed)
    Abstract [en]

    The active form of vitamin D (1,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose-dependently, in concentrations between 1 nM and 10 M. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound-healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle-treated cells. However, they had no effect on caspase-3 and -7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.

  • 13.
    Gunes, Arzu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bilir, Erhan
    Zengil, Hakan
    Babaoglu, Melih O
    Bozkurt, Atila
    Yasar, Umit
    Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients2007In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 100, no 6, p. 383-386Article in journal (Refereed)
    Abstract [en]

    Drug interactions constitute a major problem in the treatment of epilepsy because drug combinations are so common. Valproic acid is a widely used anticonvulsant drug with a broad therapeutic spectrum. Case reports suggest interaction between valproic acid and other drugs metabolized mainly by cytochrome P450 isoforms. The aim of this study was to evaluate the inhibitory effect of valproic acid on cytochrome P450 2C9 (CYP2C9) activity by using losartan oxidation as a probe in epilepsy patients. Patients were prescribed sodium valproate (mean 200 mg/day for the first week and 400 mg/day in the following period) according to their clinical need. A single oral dose of 25 mg losartan was given to patients before and after the first dose, first week and 4 weeks of valproic acid treatment. Losartan and E3174, the CYP2C9-derived carboxylic acid metabolite of losartan in 8 hr urine were assayed by using high pressure liquid chromatography. Urinary losartan/E3174 ratio did not change significantly on the first day (0.9, 0.3–3.5; median, range), and first week (0.6, 0.2–3.8; median, range), while a significant increase was observed after 4 weeks of valproic acid treatment (1.1, 0.3–5.7; median, range) as compared to that of measured before valproic acid administration (0.6, 0.1–2.1; median, range) (P = 0.039). The degree of inhibition was correlated with the steady-state plasma concentrations of valproic acid (r2 = 0.70, P = 0.04). The results suggest an inhibitory effect of valproic acid on CYP2C9 enzyme activity in epilepsy patients at steady state. The risk of pharmacokinetic drug–drug interactions should be taken into account during concomitant use of valproic acid and CYP2C9 substrates.

  • 14.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Active-Site Concentrations of Chemicals: Are They a Better Predictor of Effect than Plasma/Organ/Tissue Concentrations?2010In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 3, p. 215-220Article, review/survey (Refereed)
    Abstract [en]

    Active-site concentrations can be defined as the concentrations of unbound, pharmacologically active substances at the site of action. In contrast, the total concentrations of the drug in plasma/organ/tissue also include the protein- or tissue-bound molecules that are pharmacologically inactive. Plasma and whole tissue concentrations are used as predictors of effects and side effects because of their ease of sampling, while the concentrations of unbound drug in tissue are more difficult to measure. However, with the introduction of microdialysis and subsequently developed techniques, it has become possible to test the free drug hypothesis. The brain is an interesting organ in this regard because of the presence of the blood-brain barrier with its tight junctions and active efflux and influx transporters. We have proposed that research into brain drug delivery be divided into three main areas: the rate of delivery (PS, CL(in)), the extent of delivery (K(p,uu)) and the non-specific affinity of the drug to brain tissue, described by the volume of distribution of unbound drug in the brain (V(u,brain)). In this way, the concentration of unbound drug at the target site can be estimated from the total brain concentration and the plasma concentration after measuring the fraction of unbound drug. Results so far fully support the theory that active site concentrations are the best predictors when active transport is present. However, there is an urgent need to collect more relevant data for predicting active site concentrations in tissues with active transporters in their plasma membranes.

  • 15.
    Kohonen, Pekka
    et al.
    Karolinska Institutet.
    Ceder, Rebecca
    Karolinska Institutet.
    Smit, Ines
    Karolinska Institutet.
    Vesa, Hongisto
    VTT Technical Research Centre of Finland.
    Glenn, Myatt
    Leadscope.
    Barry, Hardy
    Douglas connect.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grafström, Roland
    Karolinska Institutet.
    Cancer Biology, Toxicology and Alternative Methods Development Go Hand-in-Hand2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 1, p. 50-58Article, review/survey (Refereed)
    Abstract [en]

    Toxicological research faces the challenge of integrating knowledge from diverse fields and novel technological developments generally in the biological and medical sciences. We discuss herein the fact that the multiple facets of cancer research, including discovery related to mechanisms, treatment and diagnosis, overlap many up and coming interest areas in toxicology, including the need for improved methods and analysis tools. Common to both disciplines, in vitro and in silico methods serve as alternative investigation routes to animal studies. Knowledge on cancer development helps in understanding the relevance of chemical toxicity studies in cell models, and many bioinformatics-based cancer biomarker discovery tools are also applicable to computational toxicology. Robotics-aided cell-based high throughput screening, microscale immunostaining techniques, and gene expression profiling analyses are common tools in cancer research, and when sequentially combined, form a tiered approach to structured safety evaluation of thousands of environmental agents, novel chemicals or engineered nanomaterials. Comprehensive tumour data collections in databases have been translated into clinically useful data, and this concept serves as template for computer-driven evaluation of toxicity data into meaningful results. Future “cancer research-inspired knowledge management” of toxicological data will aid the translation of basic discovery results and chemicals- and materials-testing data to information relevant to human health and environmental safety.

  • 16. Konstandi, Maria
    et al.
    Lang, Matti A
    Kostakis, Dimitris
    Johnson, Elizabeth O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Marselos, Marios
    Predominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyrene2008In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 102, no 1, p. 35-44Article in journal (Refereed)
    Abstract [en]

    The potential involvement of catecholamines and in particular of alpha(2)-adrenoceptor-related signalling pathways, in the regulation of drug-metabolizing enzymes by stress was investigated in Wistar rats after exposure to the environmental pollutant benzo(alpha)pyrene. For this purpose, total cytochrome P450 content, the CYP1A2 mRNA levels, 7-methoxyresorufin-O-dealkylase (MROD), 7-pentoxyresorufin-O-dealkylase (PROD) and p-nitrophenol hydroxylase activity levels were determined in the livers of rats exposed to repeated restraint stress after treatment with benzo(alpha)pyrene coupled with pharmacological manipulations of peripheral and/or central catecholamines and alpha(2)-adrenoceptors. The data show that stress is a significant factor in the regulation of CYP1A2 induction and that catecholamines play a central role in the stress-mediated modulation of hepatic CYP1A2 inducibility by benzo(alpha)pyrene. The up-regulating effect of stress on benzo(alpha)pyrene-induced CYP1A2 gene expression was eliminated after a generalized catecholamine depletion with reserpine. Similarly, in a state where only peripheral catecholamines were depleted and central catecholamines remained intact after guanethidine administration, the up-regulating effect of stress was eliminated. It is apparent that stress up-regulates the induction of CYP1A2 by benzo(alpha)pyrene mainly via peripheral catecholamines, while central catecholamines hold a minor role in the regulation. Pharmacological manipulations of alpha(2)-adrenoceptors appear to interfere with the effect of stress on the regulation of CYP1A2 inducibility. Either blockade or stimulation of alpha(2)-adrenoceptors with atipamezole and dexmedetomidine respectively, eliminated the up-regulating effect of stress on CYP1A2 benzo(alpha)pyrene-induced expression, while it enhanced MROD activity. In contrast, stress and pharmacological manipulations of catecholamines and alpha(2)-adrenoceptors did not affect total P450 content, the CYP2B1/2-dependent PROD and the CYP2E1-dependent p-nitrophenol hydroxylase activities. In conclusion, stress is a significant factor in the regulation of the CYP1A2 inducibility by benzo(alpha)pyrene, which in turn is involved in the metabolism of a large spectrum of toxicants, drugs and carcinogenic agents. Although the mechanism underlying the stress effect on CYP1A2 induction has not been clearly elucidated, it appears that peripheral catecholamines hold a predominant role, while central catecholamines and in particular, central noradrenergic pathways hold a minor role.

  • 17.
    Larsen, Michael D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Cars, Thomas
    Hallas, Jesper
    A MiniReview of the Use of Hospital-based Databases in Observational Inpatient Studies of Drugs2013In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 112, no 1, p. 13-18Article, review/survey (Refereed)
    Abstract [en]

    The majority of pharmacoepidemiological data resources are based on data generated in primary health care. Although inpatient data resources have existed since the 1960s, inpatient pharmacoepidemiological studies are relatively scarce. The objectives of this MiniReview were to describe pharmacoepidemiological studies in hospital settings and the underlying databases to provide an overview of research questions addressed by such databases. The studies were retrieved by chain searching. We included pharmacoepidemiological studies in hospital settings containing data on inpatient drug use. Twelve inpatient databases in Asia, the United States and Europe were found. Most databases were automatically collected from claims data or generated from electronic medical records. The contents of the databases varied as well as the potential for linkage with other data sources such as laboratory and outpatient data. Twenty studies were selected and discussed to illustrate the diversity of inpatient pharmacoepidemiological studies. Hospital-based databases had mainly been used for drug utilization studies and research in adverse drug reactions. Five studies within comparative effectiveness were found. The number of pharmacoepidemiological studies in inpatient settings was low compared with studies from primary healthcare settings. These resources may be under-utilized.

  • 18.
    Muceniece, Ruta
    et al.
    Faculty of Medicine, University of Latvia, Riga, Latvia.
    Zvejniece, Liga
    Vilskersts, Reinis
    Liepinsh, Edgars
    Baumane, Larisa
    Kalvinsh, Ivars
    Wikberg, Jarl E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Dambrova, Maija
    Latvian Institute of Organic Synthesis, Riga, Latvia.
    Functional evaluation of THIQ, a melanocortin 4 receptor agonist, in models of food intake and inflammation2007In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 101, no 6, p. 416-420Article in journal (Refereed)
    Abstract [en]

    The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro. The results showed that THIQ (0.1, 0.3 and 1 nmol/rat, intracerebroventricularly) is less effective in reducing food intake and body weights of rats than the non-selective melanocortin receptor agonist melanotan II. Electron paramagnetic resonance measurements in mice brain tissue showed that THIQ at doses of 0.001 and 0.01 nmol/mouse (intracisternally) increased the concentration of nitric oxide, which is not typical for melanocortin receptor agonists. In an experimental brain inflammation model, THIQ only weakly antagonized lipopolysaccharide-induced nitric oxide overproduction in brain tissue at a dose of 0.01 nmol/mouse. Our findings provide new insight into the in vivo pharmacological profile of the in vitro selective melanocortin-4 receptor agonist THIQ and give grounds for caution when interpreting and predicting melanocortin receptor selective agonist activity in vivo.

  • 19.
    Norlin, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lundqvist, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ellfolk, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hellström Pigg, Maritta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Wikvall, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Drug-mediated gene regulation of vitamin D3 metabolism in primary human dermal fibroblasts2017In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 120, no 1, p. 59-63Article in journal (Refereed)
    Abstract [en]

    Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug-mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25-hydroxyvitamin D3 and 1a,25-dihydroxyvitamin D3. The results demonstrate that primary dermal fibroblasts have an active vitamin D3 metabolising system. High incidence of low bone mineral density is a concern for HIV-infected patients treated with antiretroviral drugs. Osteomalacia and severe vitamin D deficiency have been reported. We investigated whether drug-mediated gene regulation could be a possible mechanism behind these adverse drug effects. Fibroblasts were treated with different drugs used in HIV therapy and the 1a,25-dihydroxyvitamin D3 levels and relative mRNA-levels for crucial enzymes were determined. Efavirenz, stavudine and ritonavir significantly downregulated the bioactivating CYP2R1 and upregulated the catabolic CYP24A1. The drugs reduced bioactivating enzyme activities and cellular levels of 1a,25-dihydroxyvitamin D3. The current results indicate that effects on gene expression may lead to disturbed vitamin D-metabolism and decreased cellular levels of active vitamin D3. The data are consistent with the impaired bone health in patients treated with certain antiretroviral drugs.

  • 20. Pickering, Chris
    et al.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Rosendahl, Sofi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fex-Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    A low ethanol dose affects all types of cells in mixed long-term embryonic cultures of the cerebellum2010In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 6, p. 472-478Article in journal (Refereed)
    Abstract [en]

    The beneficial effect of the '1-drink-a-day' lifestyle is suggested by studies of cardiovascular health, and this recommendation is increasingly followed in many countries. The main objective of this study was to determine whether this pattern of ethanol use would be detrimental to a pregnant woman. We exposed a primary culture of rat cerebellum from embryonic day 17 (corresponding to second trimester in humans) to ethanol at a concentration of 17.6 mM which is roughly equivalent to one glass of wine. Acutely, there was no change in cell viability after 5 or 8 days of exposure relative to control. By 11 days, a reduction in the number of viable cells was observed without an accompanying change in caspase-3 activity (marker of apoptotic cell death), suggesting changes in cell proliferation. As the proportion of nestin-positive cells was higher in the ethanol-treated cultures after 5 days, we hypothesized that an increase in differentiation to neurons would compensate for the ongoing neuronal death. However, there were limits to this compensatory ability as the relative proportion of nestin-positive cells was decreased after 11 days. To further illustrate the negative long-term effects of this ethanol dose, cultures were exposed for 30 days. After this period, virtually no neurons or myelinating oligodendrocytes were present in the ethanol-treated cultures. In conclusion, chronic exposure to ethanol, even at small doses, dramatically and persistently affects normal development.

  • 21.
    Pierozan, Paula
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jernerén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ransome, Yusuf
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    The Choice of Euthanasia Method Affects Metabolic Serum Biomarkers2017In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 21, p. 113-118Article in journal (Refereed)
    Abstract [en]

    The impact of euthanasia methods on endocrine and metabolic parameters in rodent tissues and biological fluids is highly relevant for the accuracy and reliability of the data collected. However, few studies concerning this issue are found in the literature. We compared the effects of three euthanasia methods currently used in animal experimentation (i.e. decapitation, CO2 inhalation and pentobarbital injection) on the serum levels of corticosterone, insulin, glucose, triglycerides, cholesterol and a range of free fatty acids in rats. The corticosterone and insulin levels were not significantly affected by the euthanasia protocol used. However, euthanasia by an overdose of pentobarbital (120 mg/kg intraperitoneal injection) increased the serum levels of glucose, and decreased cholesterol, stearic and arachidonic acids levels compared with euthanasia by CO2 inhalation and decapitation. CO2 inhalation appears to increase the serum levels of triglycerides, while euthanasia by decapitation induced no individual discrepant biomarker level. We conclude that choice of the euthanasia methods is critical for the reliability of serum biomarkers and indicate the importance of selecting adequate euthanasia methods for metabolic analysis in rodents. Decapitation without anaesthesia may be the most adequate method of euthanasia when taking both animal welfare and data quality in consideration.

  • 22. Rodriguez Carracedo, J.
    et al.
    de la Fuente Gonzalez, R. A.
    Varela Lara, I
    Brea Floriani, J.
    Rodriguez Diaz, D.
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Loza Garcia, M. , I
    Castro Perez, M.
    Residue HIS264 in Extracellular Loop 3 of Adenosine A(2A) Receptor is Critical for the Kinetics of Ligand Binding2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no S2, p. 22-22, article id 56Article in journal (Other academic)
  • 23. Roos, Per M
    et al.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mercury in the Spinal Cord after Inhalation of Mercury2012In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 111, no 2, p. 126-132Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) affects anterior horn cells of the spinal cord causing an indolent slow and steady deterioration of muscle strength leading inevitably to death in respiratory failure. ALS is a model condition for neurodegenerative disorders. Exposure to different agents dispersed in the environment has been suggested to cause neurodegeneration but no convincing evidence for such a link has yet been presented. Respiratory exposure to metallic mercury (Hg0) from different sources may be suspected. Body distribution of metallic mercury is fast and depends on solubility properties. Routes of transport, metabolism, excretion and biological half-life determine the overall toxic effects. Inhalation experiments were performed in 1984 where small marmoset monkeys (Callithrix jacchus) were exposed to 203Hg0 vapour mixed into the breathing air (4–5 μg/l). After 1 hr of exposure, they were killed and whole body autoradiograms prepared to study the distribution of mercury within organs. Autoradiograms showed that Hg was deposited inside the spinal cord. Areas of enhanced accumulation anatomically corresponding to motor nuclei could be observed. This study describes a reinvestigation, with new emphasis on the spinal cord, of these classical metal exposure data in a primate, focusing on their relevance for the causation of neurodegenerative disorders. A comparison with more recent rodent experiments with similar findings is included. The hypothesis that long-time low-dose respiratory exposure to metals, for example, Hg, contributes to neurodegenerative disorders is forwarded and discussed.

  • 24.
    Røge, Rikke Meldgaard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Novo Nordisk AS, Soborg, Denmark.
    Bagger, Jonatan I.
    Univ Copenhagen, Ctr Diabet Res, Gentofte Hosp, Hellerup, Denmark.; Univ Copenhagen, NNF Ctr Basic Metab Res, Copenhagen, Denmark.; Univ Copenhagen, Dept Biomed Sci, Panum Inst, Copenhagen, Denmark..
    Alskär, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kristensen, Niels R.
    Novo Nordisk AS, Soborg, Denmark.
    Klim, Søren
    Novo Nordisk AS, Soborg, Denmark.
    Holst, Jens J.
    Univ Copenhagen, NNF Ctr Basic Metab Res, Copenhagen, Denmark.; Univ Copenhagen, Dept Biomed Sci, Panum Inst, Copenhagen, Denmark..
    Ingwersen, Steen H.
    Novo Nordisk AS, Soborg, Denmark.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Knop, Filip K.
    Univ Copenhagen, Ctr Diabet Res, Gentofte Hosp, Hellerup, Denmark.; Univ Copenhagen, NNF Ctr Basic Metab Res, Copenhagen, Denmark.; Univ Copenhagen, Dept Biomed Sci, Panum Inst, Copenhagen, Denmark.; Univ Copenhagen, Dept Clin Med, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Vilsbøll, Tina
    Univ Copenhagen, Ctr Diabet Res, Gentofte Hosp, Hellerup, Denmark.; Univ Copenhagen, Dept Clin Med, Fac Hlth & Med Sci, Copenhagen, Denmark.; Univ Copenhagen, Steno Diabet Ctr Copenhagen, Gentofte, Denmark..
    Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose2017In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 121, no 4, p. 290-297Article in journal (Refereed)
    Abstract [en]

    The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP-1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.

  • 25.
    Schiöth, Helgi B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Muceniece, Ruta
    Mutule, Ilga
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    New melanocortin 1 receptor binding motif based on the C-terminal sequence of alpha-melanocyte-stimulating hormone2006In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 99, no 4, p. 287-293Article in journal (Refereed)
    Abstract [en]

    The C-terminal tripeptide of the alpha-melanocyte stimulating hormone (alpha-MSH11-13) possesses strong antiinflammatory activity without known cellular target. In order to better understand the structural requirements for function of such motif, we designed, synthesized and tested out Trp- and Tyr-containing analogues of the alpha-MSH11-13. Seven alpha-MSH11-13 analogues were synthesized and characterized for their binding to the melanocortin receptors recombinantly expressed in insect (Sf9) cells, infected with baculovirus carrying corresponding MC receptor DNA. We also tested these analogues on B16-F1 mouse melanoma cells endogenously expressing the MC1 receptor for binding and for ability to increase cAMP levels as well as on COS-7 cells transfected with the human MC receptors. The data indicate that HS401 (Ac-Tyr-Lys-Pro-Val-NH2) and HS402 (Ac-Lys-Pro-Val-Tyr-NH2) selectively bound to the MC1 receptor and stimulated cAMP generation in a concentration dependent way while the other Tyr- and Trp-containing alpha-MSH11-13 analogues neither bound to MC receptors nor stimulated cAMP. We have thus identified new MC receptor binding motif derived from the C-terminal sequence of alpha-MSH. The tetrapeptides have novel properties as the both act via MC-ergic pathways and also carry the anti-inflammatory alpha-MSH11-13 message sequence.

  • 26.
    Scordo, M.G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Clinical Applications of CYP450 Genotyping. Seven Years’ Experience in a Swedish Clinical Setting2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no S1, p. 11-11Article in journal (Other academic)
  • 27.
    Silber, Hanna E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jauslin, Petra M.
    Frey, Nicolas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An Integrated Model for the Glucose-Insulin System2010In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 3, p. 189-194Article, review/survey (Refereed)
    Abstract [en]

    The integrated glucose-insulin model was originally developed on a variety of intravenous glucose provocation experiments in healthy volunteers and type 2 diabetic patients. The model, which simultaneously describes time-courses of glucose and insulin based on mechanism-based components for production, elimination and homeostatic feedback, has been further extended to oral glucose provocations, meal tests and insulin administration. The model has been used to describe experiments ranging from 4 to 24 hr. Applications of the integrated glucose-insulin model include the clinical assessment of the mechanism of action of anti-diabetic drugs and the magnitude of their effects. Finally, the model was used for optimizing the design of provocation experiments.

  • 28.
    Sjöholm, Louise K
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Ransome, Yusuf
    Harvard T.H. Chan School of Public Health, Boston, USA.
    Ekström, Tomas J
    Karolinska Institute, Stockholm, Sweden.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evaluation of Post-Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation.2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 122, no 2, p. 208-213Article in journal (Refereed)
    Abstract [en]

    The number of epigenetic studies on brain functions and diseases are dramatically increasing, but little is known about the impact of post-mortem intervals and post-sampling effects on DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Here, we examined post-mortem-induced changes in global brain 5mC and 5hmC levels at post-mortem intervals up to 540 min., and studied effects of tissue heat stabilization, using LUMA and ELISA. The global 5mC and 5hmC levels were generally higher in the cerebellum of adult rats than neonates. When measured by ELISA, the global 5mC content in adults, but not neonates, decreased with the post-mortem interval reaching a significantly lower level in cerebellum tissue at the post-mortem interval 540 min. (2.9 ± 0.7%; mean ± S.E.M.) compared to control (3.7 ± 0.6%). The global 5hmC levels increased with post-mortem interval reaching a significantly higher level at 540 min. (0.29 ± 0.06%) compared to control (0.19 ± 0.03%). This suggests that the post-mortem interval may confound 5mC and 5hmC analysis in human brain tissues as the post-mortem handling could vary substantially. The reactive oxygen species (ROS) level in cerebellum also increased over time, in particular in adults, and may be part of the mechanism that causes the observed post-mortem changes in 5mC and 5hmC. The global 5mC and 5hmC states were unaffected by heat stabilization, allowing analysis of tissues that are stabilized to preserve more labile analytes. Further studies in human samples are needed to confirm post-mortem effects on DNA methylation/hydroxymethylation and elucidate details of the underlying mechanisms.

  • 29.
    Stage, Tore Bjerregaard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19,2, DK-5000 Odense C, Denmark..
    Lee, Moa P.
    Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Hallas, Jesper
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19,2, DK-5000 Odense C, Denmark..
    Christensen, Mette Marie Hougaard
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19,2, DK-5000 Odense C, Denmark..
    Brosen, Kim
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19,2, DK-5000 Odense C, Denmark..
    Christensen, Kaare
    Univ Southern Denmark, Inst Publ Hlth, Dept Epidemiol Biostat & Biodemog, Odense, Denmark..
    Gagne, Joshua J.
    Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Pottegard, Anton
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19,2, DK-5000 Odense C, Denmark..
    Early Discontinuation of Metformin in Individuals Treated with Inhibitors of Transporters of Metformin2016In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 118, no 6, p. 487-495Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to examine the risk of early discontinuation of metformin as a proxy for intolerance, associated with use of drugs known to inhibit transporters involved in metformin distribution. We analysed all incident users of metformin in Denmark between 2000 and 2012 (n = 132,221) and in a cohort of US patients (n = 296,903). Risk of early discontinuation of metformin was assessed using adjusted logistic regression for 28 drugs putatively inhibiting metformin transporters and four negative controls. Increased odds ratio of early discontinuation of metformin was only associated with codeine, an inhibitor of organic cation transporter 1 in both cohorts [adjusted odds ratio (OR) in Danish cohort (95% CI): 1.13 (1.021.26), adjusted OR in American cohort (95% CI): 1.32 (1.19-1.47)]. The remaining drugs were not associated with increased odds ratio of early discontinuation and, surprisingly, four drugs were associated with a decreased risk. These findings indicate that codeine use may be associated with risk of early discontinuation of metformin and could be used as a basis for further investigation.

  • 30.
    Stage, Tore Bjerregaard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol & Pharm, Odense, Denmark.
    Wellhagen, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Christensen, Mette Marie Hougaard
    Odense Univ Hosp, Dept Clin Biochem & Pharmacol, Odense, Denmark.
    Guiastrennec, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brosen, Kim
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol & Pharm, Odense, Denmark.
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Using a semi-mechanistic model to identify the main sources of variability of metformin pharmacokinetics2019In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 124, no 1, p. 105-114Article in journal (Refereed)
    Abstract [en]

    Metformin pharmacokinetics (PK) is highly variable, and researchers have for years tried to shed light on determinants of inter-individual (IIV) and inter-occasion variability (IOV) of metformin PK. We set out to identify the main sources of PK variability using a semi-mechanistic model. We assessed the influence of subject characteristics, including seven genetic variants. Data from three studies of healthy individuals with PK measurements of plasma and urine after single dose or at steady-state were used in this study. In total, 87 subjects were included (16 crossover subjects). Single nucleotide polymorphisms in ATM, OCT1, OCT2, MATE1 and MATE2-K were investigated as dominant, recessive or additive. A three-compartment model with transit absorption and renal elimination with a proportional error was fitted to the data using NONMEM 7.3. Oral parameters were separated from disposition parameters as dose-dependent absolute bioavailability was determined with support from urine data. Clearance was expressed as net renal secretion and filtration, assuming full fraction unbound and fraction excreted. Mean transit time and peripheral volume of distribution were identified as the main sources of variability according to estimates, with 94% IOV and 95% IIV, respectively. Clearance contributed only with 16% IIV. Glomerular filtration rate and body-weight were the only covariates found to affect metformin net secretion, reducing IIV to 14%. None of the genetic variants were found to affect metformin PK. Based on our analysis, finding covariates explaining absorption of metformin is much more valuable in understanding variability and avoiding toxicity than elimination.

  • 31. Stark, Katarina
    et al.
    Schauer, Lydia
    Sahlén, Göran E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Urologi.
    Ronquist, Gunnar
    Oliw, Ernst H.
    Expression of CYP4F12 in gastrointestinal and urogenital epithelia2004In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 94, no 4, p. 177-83Article in journal (Other academic)
    Abstract [en]

    Cytochrome P450 4F12 (CYP4F12) was originally cloned from human liver and small intestine. CYP4F12 can oxidize arachidonic acid, two stable prostaglandin H2 analogues, and an antihistamine, ebastine, but the tissue distribution and catalytic properties of CYP4F12 have not been fully investigated. An antipeptide polyclonal antibody was raised against the C-terminal of CYP4F12 (PLNVGLQ), evaluated by Western blot analysis and used for immunohistological analysis of 50 human tissues. Western blot analysis of recombinant CYP4F12, expressed in yeast, and microsomal proteins from adult and foetal liver, kidney, placenta at term, seminal vesicles, the prostate gland and purified prostasomes showed that the polyclonal antibody detected a protein of the expected size, approximately 60 kDa. CYP4F12 mRNA could be detected in seminal vesicles and prostate gland by reverse transcription-PCR. Prominent CYP4F12 immunoreactivity occurred, inter alia, in the epithelial cells of the gastrointestinal tract (stomach, small intestine, and colon), collecting tubules, transitional epithelium, ovarian follicles, the endothelium of microvessels of placental villi (first trimester), and epidermis. We screened recombinant CYP4F12 for catalytic activity. Arachidonic acid (20:4n-6) was hydroxylated at C18 and laurate at C11, but significant amounts of metabolites of 18:2n-6, 20:3n-9, 20:5n-3, 22:5n-6, and some prostaglandins could not be detected. We conclude that CYP4F12 is widely distributed in gastrointestinal and urogenital epithelia and exhibits a narrow substrate specificity.

  • 32. Stern, Natalia
    et al.
    Korotkova, Marina
    Strandvik, Birgitta
    Oxlund, Hans
    Oberg, Mattias
    Håkansson, Helen
    Lind, Monica
    Institute of Environmental Medicine, Karolinska Institutet.
    Subchronic toxicity of baltic herring oil and its fractions in the rat (III) bone tissue composition and dimension, and ratio of n-6/n-3 fatty acids in serum phospholipids.2005In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 96, no 6, p. 453-464Article in journal (Refereed)
    Abstract [en]

    Changes in total bone mineral density determined by the bone-ash method were recently demonstrated in rats, exposed to Herring oil from the contaminated southern part of the Baltic Sea. In the present study more detailed analysis of bone structure and biomechanics was performed and obtained results were evaluated in the context of dietary factors, such as polyunsaturated fatty acids, vitamin D and vitamin A. Baltic Sea herring oil was fractionated into one relatively pollutant-free fraction (F1), and two fractions with pronounced enrichment of pollutants (F2 and F3). Female Sprague-Dawley rats were fed diets supplemented with Baltic Herring oil, its fractions, Nordic Sea capelin oil or soy oil. Femur was scanned with peripheral quantitative computed tomography (pQCT) and also tested by a mechanical compression analysis. Polyunsaturated fatty acids, vitamin A and D were analysed in serum. Rats fed the high dose of herring oil exhibited shorter femur length with decreased diaphyseal cortical bone mineral density, as well as lowered metaphyseal cross-sectional area compared to the soy oil group. Rats fed the high dose of F1 diet had increased cortical and decreased trabecular area, and higher total and trabecular bone mineral density. Rats fed the low dose of F2 diet showed similar changes associated with increased maximum load and energy absorption in compression test of the femoral metaphysis. In summary, our findings in changes of bone geometry and density could not be linked to any isolated exposure parameter, suggesting synergistic or antagonistic effects of several components of the test diets.

  • 33.
    Uustalu, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Abelson, Klas S. P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Drug distribution in spinal cord during administration with spinal loop dialysis probes in anaesthetized rats2007In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 100, no 3, p. 196-200Article in journal (Refereed)
    Abstract [en]

    The present investigation aimed to study two methodological concerns of an experimental model, where a spinal loop dialysis probe is used for administration of substances to the spinal cord and sampling of neurotransmitters by microdialysis from the same area of anaesthetized rats. [3H]Epibatidine in concentrations of 1, 10 and 100 nM was dissolved in Ringer's solution and administered through the dialysis membrane into the dorsal region of the cervical spinal cord. First, the outflow of [3H]epibatidine from the probe into the spinal cord was examined with respect to different concentrations and changes over time. Then, the distribution of the different [3H]epibatidine concentrations along the spinal cord was studied. It was found that the percentage of [3H]epibatidine entering the spinal cord did not differ between different administered concentrations after a stabilization period of 60 min. The administered [3H]epibatidine was found to be distributed to the area closest to the dialysis probe and not dispersed along the spinal cord, and the distribution was equal for all concentrations. The data presented in this investigation provide information, which is important for interpretation of data from intraspinal administration of substances through the spinal loop dialysis probe.

  • 34.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Smedje, H.
    Karolinska Inst, Div Child & Adolescent Psychiat, Stockholm, Sweden.
    Yue, Q. -Y
    Med Prod Agcy, Uppsala, Sweden.
    Magnusson, P. K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome‐Wide Association Study of Pandemrix‐Induced Narcolepsy in Sweden – A Possible Role for Glial Derived Neurotrophic Factor (GDNF)2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no S1, p. 12-13Article in journal (Other academic)
  • 35.
    Wallin, Johan E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Model-Based Neutrophil-Guided Dose Adaptation in Chemotherapy: Evaluation of Predicted Outcome with Different Types and Amounts of Information2010In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 3, p. 234-242Article, review/survey (Refereed)
    Abstract [en]

    One of the most employed approaches to reduce severe neutropenia following anticancer drug regimens is to reduce the consecutive dose in fixed steps, commonly by 25%. Another approach has been to use pharmacokinetic (PK) sampling to tailor dosing, but only rarely have model-based computer approaches utilizing collected PK and/or pharmacodynamic (PD) data been used. A semi-mechanistic model for myelosuppression that can characterize the interindividual and interoccasion variability in the time-course of neutrophils following administration of a wide range of anticancer drugs may be used in a clinical setting for model-based dose individualization. The aim of this study was to compare current stepwise procedures to model-based dose adaptation by simulations, and investigate if the overall dose intensity in the population could be increased without increasing the risk of severe toxicity. The value of various amounts of PK- and/or PD-information was compared to standard dosing strategies using a maximum a posteriori procedure in NONMEM. The results showed that when information on neutrophil counts was available, the additional improvement from PK sampling was negligible. Using neutrophil sampling at baseline and an observation near the predicted nadir increased the number of patients in the target range by 27% in comparison with a one-sided 25% dose adjustment schedule, while keeping the number of patients experiencing severe toxicity at a comparable low level after five courses of treatment. High interindividual variability did not limit the benefit of model-based dose adaptation, whereas high interoccasion variability was predicted to make any dose adaptation method less successful. This study indicates that for successful model-based dose adaptation clinically, there is no need for drug concentration sampling, and that one extra neutrophil measurement in addition to the pre-treatment value is sufficient to limit severe neutropenia while increasing dose intensity.

  • 36.
    Wegler, Christine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikvall, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of osteoporosis-inducing drugs on vitamin D-related gene transcription and mineralization in MG-63 and Saos-2 cells2016In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 119, no 5, article id BCPT12612Article in journal (Refereed)
    Abstract [en]

    Vitamin D3 is important for calcium and phosphate homeostasis. To exert its effects, vitamin D3 has to be enzymatically activated into 1,25D3 (1,25-dihydroxyvitamin D3). Regulation by endogenous vitamin D metabolites of the activation and inactivation of 1,25D3 is important to maintain adequate amounts of active vitamin D3. Vitamin D deficiency and low bone mineral density have been linked to treatments with antiretroviral drugs and glucocorticoids. However, the causes of drug-induced osteoporosis remain unclear. The antiretroviral drugs efavirenz and ritonavir as well as the glucocorticoid dexamethasone were included in this study. Their effects on transcription of vitamin D-regulating enzymes in MG-63 cells were investigated. Ritonavir and dexamethasone both induced transcription of CYP27B1, the enzyme responsible for formation of 1,25D3. Efavirenz, however, suppressed CYP27B1 expression. When administered together with endogenous vitamin D metabolites, dexamethasone and efavirenz counteracted the 1,25D3-mediated up-regulation of CYP24A1, which inactivates 1,25D3. This suggests that the drugs may interfere with local regulation of the vitamin D metabolizing system in osteoblasts. Studies on mineralization were performed in MG-63 cells and Saos-2 cells by measuring calcium concentrations accumulated over time. The effects of efavirenz, ritonavir and dexamethasone and/or vitamin D metabolites were examined. 1,25D3 induced mineralization in both cell lines. Efavirenz administered alone did not affect mineralization but abrogated the inducing effects of 1,25D3 on mineralization in both MG-63 cells and Saos-2 cells. In summary, the results suggest that antiretroviral drugs and glucocorticoids may adversely affect bone by interference with the vitamin D-system in osteoblasts.

  • 37.
    Williams, Michael J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wang, Yi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klockars, Anica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Exposure to Bisphenol A Affects Lipid Metabolism in Drosophila melanogaster2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 114, no 5, p. 414-420Article in journal (Refereed)
    Abstract [en]

    Exposure to bisphenol A (BPA) in rodents was shown to induce obesity, yet the mechanism by which BPA might induce obesity is still unclear. We employed the genetically tractable model organism, Drosophila melanogaster, to test the effects of raising them on food containing various concentrations of BPA. Of note, raising males on food containing BPA were susceptible to starvation, possibly by inhibiting their ability to perform lipolysis during starvation, leading to significantly increased lipid content after 24 hr of fasting. Furthermore, feeding males with BPA significantly inhibited the expression of insulin-like peptides. From these results, we conclude that BPA may inhibit lipid recruitment during starvation in Drosophila.

  • 38.
    Wuttke, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lipid Signalling Dynamics at the beta-cell Plasma Membrane2015In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 116, no 4, p. 281-290Article, review/survey (Refereed)
    Abstract [en]

    Pancreatic -cells are clustered in islets of Langerhans and secrete insulin in response to increased concentrations of circulating glucose. Insulin in turn acts on liver, muscle and fat tissue to store energy and normalize the blood glucose level. Inappropriate insulin release may lead to impaired glucose tolerance and diabetes. In addition to glucose, other nutrients, neural stimuli and hormonal stimuli control insulin secretion. Many of these signals are perceived at the plasma membrane, which is also the site where insulin granules undergo exocytosis. Therefore, it is not surprising that membrane lipids play an important role in the regulation of insulin secretion. -cells release insulin in a pulsatile fashion. Signalling lipids integrate the nutrient and neurohormonal inputs to fine-tune, shape and co-ordinate the pulsatility. An important group of signalling lipids are phosphoinositides and their downstream messengers. This MiniReview will discuss new insights into lipid signalling dynamics in -cells obtained from live-cell imaging experiments with fluorescent translocation biosensors. The plasma membrane concentration of several phosphoinositides and of their downstream messengers changes rapidly upon nutrient or neurohormonal stimulation. Glucose induces the most complex spatio-temporal patterns, typically involving oscillations of messenger concentrations, which sometimes are locally restricted. The tightly controlled levels of lipid messengers can mediate specific binding of downstream effectors to the plasma membrane, contributing to the appropriate regulation of insulin secretion.

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