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  • 1.
    Bergqvist, Filip
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Ossipova, Elena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Idborg, Helena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Raouf, Joan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Checa, Antonio
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Englund, Karin
    Stockholm Univ, Dept Analyt Chem, Stockholm, Sweden.
    Englund, Petter
    Stockholm Univ, Dept Analyt Chem, Stockholm, Sweden.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Larsson, Karin
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Korotkova, Marina
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Jakobsson, Per-Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 636Article in journal (Refereed)
    Abstract [en]

    Pharmacological inhibition of microsomal prostaglandin E synthase (mPGES)-1 for selective reduction in prostaglandin E-2 (PGE(2)) biosynthesis is protective in experimental models of cancer and inflammation. Targeting mPGES-1 is envisioned as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Herein, we compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1 beta-induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE(2) production and increased PGF(2 alpha) and thromboxane B-2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways. Moreover, pathway analysis predicted that CIII increased cell death of cancer cells (Z = 3.8, p = 5.1E-41) while NS-398 decreased the same function (Z = -5.0, p = 6.5E-35). In our lipidomics analyses, we found alterations in nine phospholipids between the two inhibitors, with a stronger alteration in the lysophospholipid (LPC) profile with NS-398 compared to CIII. Inhibition of mPGES-1 increased the concentration of sphinganine and dihydroceramide (C16:0D hCer), while inhibition of COX-2 caused a general decrease in most ceramides, again suggesting different effects on cell death between the two inhibitors. We showed that CIII decreased proliferation and potentiated the cytotoxic effect of the cytostatic drugs cisplatin, etoposide, and vincristine when investigated in a live cell imaging system. Our results demonstrate differences in protein and lipid profiles after inhibition of mPGES-1 or COX-2 with important implications on the therapeutic potential of mPGES-1 inhibitors as adjuvant treatment in cancer. We encourage further investigations to illuminate the clinical benefit of mPGES-1 inhibitors in cancer.

  • 2.
    Borroto-Escuela, Dasiel O.
    et al.
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Rodriguez, David
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Romero Fernandez, Wilber
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kapla, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jaiteh, Mariama
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ranganathan, Anirudh
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Lazarova, Tzvetana
    Autonomous Univ Barcelona, Fac Med, Dept Biochem & Mol Biol, Inst Neurosci, Barcelona, Spain.
    Fuxe, Kjell
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Carlsson, Jens
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mapping the Interface of a GPCR Dimer: A Structural Model of the A(2A) Adenosine and D-2 Dopamine Receptor Heteromer2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 829Article in journal (Refereed)
    Abstract [en]

    The A(2A) adenosine (A(2A)R) and D-2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A(2A)R-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A(2A)R-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A(2A)R-D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on A(2A)R-D2R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A(2A)R blocked heterodimer interactions and disrupted the allosteric effect of A(2A)R activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A(2A)R-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A(2A)R-D2R interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A(2A)R-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.

  • 3. Borroto-Escuela, Dasiel O.
    et al.
    Rodriguez, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Romero-Fernandez, Wilber
    Kapla, Jon
    Jaiteh, Mariama
    Ranganathan, Anirudh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lazarova, Tzvetana
    Fuxe, Kjell
    Carlsson, Jens
    Mapping the Interface of a GPCR Dimer: A Structural Model of the A(2A) Adenosine and D-2 Dopamine Receptor Heteromer2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 829Article in journal (Refereed)
    Abstract [en]

    The A(2A) adenosine (A(2A)R) and D-2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A(2A)R-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A(2A)R-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A(2A)R-D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on A(2A)R-D2R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A(2A)R blocked heterodimer interactions and disrupted the allosteric effect of A(2A)R activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A(2A)R-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A(2A)R-D2R interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A(2A)R-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.

  • 4.
    Che, Karlhans Fru
    et al.
    Karolinska Inst, Inst Environm Med, Unit Lung & Airway Res, Stockholm, Sweden.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Inst Environm Med, Unit Lung & Airway Res, Stockholm, Sweden;.
    Linden, Anders
    Karolinska Inst, Inst Environm Med, Unit Lung & Airway Res, Stockholm, Sweden;Karolinska Univ Hosp Solna, Dept Resp Dis & Allergy, Stockholm, Sweden.
    Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 956Article in journal (Refereed)
    Abstract [en]

    Background: Interleukin (IL)-26 is a neutrophil-mobilizing and bactericidal cytokine that is enhanced in human airways in vivo in response to endotoxin from Gram-negative bacteria. This cytokine is also enhanced in the airways during exacerbations of chronic obstructive pulmonary disease (COPD). Here, we investigated whether human primary lung fibroblasts (HLF) release IL-26 constitutively and in response to TLR4 stimulation by endotoxin and characterized the effects of bronchodilatory and anti-inflammatory drugs utilized in COPD. Methods: The HLF were stimulated with different concentrations of endotoxin. Cells were also treated with different concentrations of bronchodilatory and anti-inflammatory drugs, with and without endotoxin stimulation. Cytokine protein concentrations were quantified in the cell-free conditioned media [enzyme-linked immunosorbent assay (ELISA)], and the phosphorylation levels of intracellular signaling molecules were determined (phosphoELISA). Results: Whereas HLF displayed constitutive release of IL-26 into the conditioned medium, endotoxin markedly enhanced this release, as well as that of IL-6 and IL-8. This cytokine release was paralleled by increased phosphorylation of the intracellular signaling molecules NF-kappa B, c-Jun N-terminal kinase (JNK) 1-3, p38, and extracellular signal-regulated kinase (ERK) 1/2. The glucocorticoid hydrocortisone caused substantial inhibition of the endotoxin-induced release of IL-26, IL-6, and IL-8, an effect paralleled by a decrease of the phosphorylation of NF-kappa B, p38, and ERK1/2. The muscarinic receptor antagonist (MRA) tiotropium, but not aclidinium, caused minor inhibition of the endotoxin-induced release of IL-26 and IL-8, paralleled by a decreased phosphorylation of NF-kappa B. The beta 2-adrenoceptor agonist salbutamol caused modest inhibition of the endotoxin-induced release of IL-26 and IL-8, paralleled by a decreased phosphorylation of NF-kappa B, JNK1-3, and p38. Similar pharmacological effects were observed for the constitutive release of IL-26. Conclusions: The HLF constitute an abundant source of IL-26 that may contribute to local host defense against Gram-negative bacteria. Among the tested drugs, the glucocorticoid displayed the most powerful inhibitory effect, affecting the NF-kappa B, p38, and ERK1/2 signaling pathways. Whether or not this inhibition of IL-26 contributes to an increased risk for local infections in COPD requires further evaluation.

  • 5. de Bruijn, Winnie
    et al.
    Ibanez, Cristina
    Frisk, Pia
    Pedersen, Hanne Bak
    Alkan, Ali
    Bonanno, Patricia Vella
    Brkicic, Ljiljana S.
    Bucsicsa, Anna
    Dedet, Guillaume
    Eriksen, Jaran
    Fadare, Joseph O.
    Furst, Jurij
    Gallego, Gisselle
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. School of Medicine, The University of Notre Dame Australia, Darlinghurst, NSW, Australia.
    Godoi, Isabella P.
    Guerra Junior, Augusto A.
    Gursoz, Hakki
    Jan, Saira
    Jones, Jan
    Joppi, Roberta
    Kerman, Saim
    Laius, Ott
    Madzikwa, Newman
    Magnusson, Einar
    Maticic, Mojca
    Markovic-Pekovic, Vanda
    Massele, Amos
    Ogunleye, Olayinka
    O'Leary, Aisling
    Piessnegger, Jutta
    Sermet, Catherine
    Simoens, Steven
    Tiroyakgosi, Celda
    Truter, Ilse
    Thyberg, Magnus
    Tomekova, Kristina
    Wladysiuk, Magdalena
    Vandoros, Sotiris
    Vural, Elif H.
    Zara, Corinne
    Godman, Brian
    Introduction and Utilization of High Priced HCV Medicines across Europe: Implications for the Future2016In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 7, article id 197Article in journal (Refereed)
    Abstract [en]

    Background: Infection with the Hepatitis C Virus (HCV) is a widespread transmittable disease with a diagnosed prevalence of 2.0%. Fortunately, it is now curable in most patients. Sales of medicines to treat HCV infection grew 2.7% per year between 2004 and 2011, enhanced by the launch of the protease inhibitors (Hs) boceprevir (BCV) and telaprevir (TVR) in addition to ribavirin and pegylated interferon (pegIFN). Costs will continue to rise with new treatments including sofosbuvir, which now include interferon free regimens. Objective: Assess the uptake of BCV and TVR across Europe from a health authority perspective to offer future guidance on dealing with new high cost medicines. Methods: Cross-sectional descriptive study of medicines to treat HCV (pegIEN, ribavirin, BCV and TVR) among European countries from 2008 to 2013. Utilization measured in defined daily doses (DDDs)/1000 patients/quarter (DIOs) and expenditure in Euros/DDD. Health authority activities to influence treatments categorized using the 4E methodology (Education, Engineering, Economics and Enforcement). Results: Similar uptake of BCV and TVR among European countries and regions, ranging from 0.5 DIQ in Denmark, Netherlands and Slovenia to 1.5 DIQ in Tayside and Catalonia in 2013. However, different utilization of the new Pls vs. ribavirin indicates differences in dual vs. triple therapy, which is down to factors including physician preference and genotypes. Reimbursed prices for BCV and TVR were comparable across countries. Conclusion: There was reasonable consistency in the utilization of BCV and TVR among European countries in comparison with other high priced medicines. This may reflect the social demand to limit the transmission of HCV. However, the situation is changing with new curative medicines for HCV genotype 1 (GT1) with potentially an appreciable budget impact. These concerns have resulted in different prices across countries, with their impact on budgets and patient outcomes monitored in the future to provide additional guidance.

  • 6.
    Eriksson, Irene
    et al.
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Wettermark, Bjorn
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Persson, Marie
    Stockholm County Council, Sweden.
    Edström, Morgan
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Godman, Brian
    University of Liverpool, England; Karolinska University Hospital, Sweden; University of Strathclyde, Scotland.
    Lindhe, Anna
    Regional Vastra Gotaland, Sweden.
    Malmstrom, Rickard E.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Ramstrom, Helena
    Stockholm County Council, Sweden.
    von Eulerz, Mia
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bergkvist Christensen, Anna
    Regional Skåne, Sweden.
    The Early Awareness and Alert System in Sweden: History and Current Status2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 674Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Over the past decades, early awareness and alert (FAA) activities and systems have gained importance and become a key early health technology assessment (HTA) tool. While a pioneer in HTA, Sweden had no national level EAA activities until 2010. We describe the evolution and current status of the Swedish EAA System. Methods: This was a historical analysis based on the knowledge and experience of the authors supplemented by a targeted review of published and gray literature as well as documents relating to EM activities in Sweden. Key milestones and a description of the current state of the Swedish FAA System is presented. Results: Initiatives to establish a system for the identification and assessment of emerging health technologies in Sweden date back to the 1980s. In the 1990s, the Swedish Agency for HTA and Assessment of Social Services (SBU) supported the development of EuroScan as one of its founder members. In the mid-2000s, an independent regional initiative, driven by the Stockholm County Drug and Therapeutics Committee, resulted in the establishment of a regional horizon scanning function. By 2009, this work had expanded to a collaboration between the four biggest counties in Sweden. The following year it was further expanded to the national level and since then the Swedish EAA System has been carrying out identification, filtration and prioritization of new medicines, early assessment of the prioritized medicines, and dissemination of information. In 2015, the EAA System was incorporated into the Swedish national process for managed introduction and follow-up of new medicines. Outputs from the EAA System are now used to select new medicines for inclusion in this process. Conclusions: The Swedish FAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the system today is its complete integration into the national process for managed introduction and follow-up of new medicines. The system will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international level.

  • 7.
    Eriksson, Irene
    et al.
    Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Solna, Sweden.
    Wettermark, Björn
    Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Solna, Sweden.
    Persson, Marie
    Healthcare Administration, Stockholm County Council, Stockholm, Sweden.
    Edström, Morgan
    Department of Clinical Pharmacology, County Council of Östergötland, Linköping University Hospital, Linköping, Sweden.
    Godman, Brian
    Health Economics Unit, University of Liverpool Management School, Liverpool, United Kingdom; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, United Kingdom.
    Lindhé, Anna
    Department of Healthcare, Regional Head Office, Region Västra Götaland, Gothenburg, Sweden.
    Malmström, Rickard E.
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Ramström, Helena
    Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden.
    von Euler, Mia
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Solna, Sweden.
    Bergkvist Christensen, Anna
    Department of Medicines Management and Informatics, Regional Head Office, Region Skåne, Malmö, Sweden.
    The Early Awareness and Alert System in Sweden: History and Current Status2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 674Article, review/survey (Refereed)
    Abstract [en]

    The Swedish EAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the system today is its complete integration into the national process for managed introduction and follow-up of new medicines. The system will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international level.

  • 8.
    Eriksson, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wallin, Philip
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Clinical Experience of Sirolimus Regarding Efficacy and Safety in Systemic Lupus Erythematosus2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 82Article in journal (Refereed)
    Abstract [en]

    New treatment options constitute unmet needs for patients diagnosed with systemic lupus erythematosus (SLE). Inhibition of the mammalian target of rapamycin (mTOR) pathway by sirolimus, a drug approved and in clinical use to prevent transplant rejection, has shown promising effects in lupus animal models as well as in patients with both antiphospholipid syndrome and SLE. Sirolimus inhibits antigen-induced T cell proliferation and increases the number of circulating regulatory T cells. Recently, sirolimus was tested in an open label phase 1/2 trial, including 43 patients with active SLE, resistant or intolerant to conventional medications. The results were encouraging showing a progressive improvement, including mucocutaneous and musculoskeletal manifestations. At our university unit, we have more than 16 years experience of sirolimus as treatment for non-renal manifestations of SLE. Herein, we retrospectively evaluated data on tolerance, dosage, affected organ systems, disease activity measures, corticosteroid reduction, concomitant immunosuppressive therapies, and patient-reported outcome measures (PROMs) such as pain intensity, fatigue, well-being and quality-of-life (QoL) in 27 Caucasian patients with mildly active SLE. Musculoskeletal manifestation was the main reason for sirolimus treatment followed by skin involvement and leukocytopenia. Mean time on sirolimus was 47.1 (range 2-140) months. Decreasing global disease activity was observed, as measured by the clinical SLE disease activity index-2000, with a mean reduction of 2.5 points (range -10 to 0) and a corresponding mean reduction of the physicians global assessment (0-4) of 0.64 (range -2 to 0). The mean daily dose of corticosteroids (prednisolone) was reduced by 3.3 mg (-12.5 to 0). Non-significant trends toward improvements of QoL and pain intensity were found. Serious side-effects were not seen during sirolimus treatment, but early withdrawal due to nausea (n = 4) and non-serious infections (n = 2) appeared. This observational study, including longtime real-life use of sirolimus in SLE, is the largest to date and it essentially confirms the results of the recent phase 1/2 trial. Our data indicate that sirolimus is efficient in patients with musculoskeletal SLE manifestations, particularly arthritis and tendinitis. Further randomized controlled trials evaluating the potential benefits of sirolimus in SLE are warranted, but should aim to enroll patients with shorter disease duration, less accrued damage, and more diverse ethnicities.

  • 9. Godman, Brian
    et al.
    Malmstrom, Rickard E.
    Diogene, Eduardo
    Jayathissa, Sisira
    McTaggart, Stuart
    Cars, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Alvarez-Madrazo, Samantha
    Baumgaertel, Christoph
    Brzezinska, Anna
    Bucsics, Anna
    Campbell, Stephen
    Eriksson, Irene
    Finlayson, Alexander
    Fuerst, Jurij
    Garuoliene, Kristina
    Gutierrez-Ibarluzea, Inaki
    Hviding, Krystyna
    Herholz, Harald
    Joppi, Roberta
    Kalaba, Marija
    Laius, Ott
    Malinowska, Kamila
    Pedersen, Hanne B.
    Markovic-Pekovic, Vanda
    Piessnegger, Jutta
    Selke, Gisbert
    Sermet, Catherine
    Spillane, Susan
    Tomek, Dominik
    Voncina, Luka
    Vlahovic-Palcevski, Vera
    Wale, Janet
    Wladysiuk, Magdalena
    van Woerkom, Menno
    Zara, Corinne
    Gustafsson, Lars L.
    Dabigatran - a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs2014In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 5, article id 109Article, review/survey (Refereed)
    Abstract [en]

    Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are effectiveness, safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies showed dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. These concerns resulted in extensive activities pre- to post-launch to manage its introduction. Objective: To (i) review authority activities across countries, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications based on post-launch activities. Methodology: (i) Descriptive review and appraisal of activities regarding dabigatran, (ii) development of guidance for key stakeholder groups through an iterative process, (iii) refining guidance following post launch studies. Results: Plethora of activities to manage dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions and monitoring of prescribing post launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Post-launch activities include increasing use of patient registries to monitor the safety and effectiveness of new drugs in clinical practice. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.

  • 10.
    Houde, Martin
    et al.
    Univ Sherbrooke, Fac Med & Sci Sante, Dept Pharmacol Physiol, Sherbrooke, PQ, Canada; Leiden Univ, Leiden Acad, Ctr Drug Res, Div BioTherapeut, Leiden, Netherlands.
    Schwertani, Adel
    McGill Univ, Dept Med, Montreal, PQ, Canada.
    Touil, Hanene
    Univ Sherbrooke, Fac Med & Sci Sante, Dept Pharmacol Physiol, Sherbrooke, PQ, Canada.
    Desbiens, Louisane
    Univ Sherbrooke, Fac Med & Sci Sante, Dept Pharmacol Physiol, Sherbrooke, PQ, Canada.
    Sarrhini, Otman
    Univ Sherbrooke, CRCHUS, Sherbrooke Mol Imaging Ctr, Dept Nucl Med & Radiobiol, Sherbrooke, PQ, Canada.
    Lecomte, Roger
    Univ Sherbrooke, CRCHUS, Sherbrooke Mol Imaging Ctr, Dept Nucl Med & Radiobiol, Sherbrooke, PQ, Canada.
    Lepage, Martin
    Univ Sherbrooke, CRCHUS, Sherbrooke Mol Imaging Ctr, Dept Nucl Med & Radiobiol, Sherbrooke, PQ, Canada.
    Gagnon, Hugo
    PhenoSwitch Biosci Inc, Sherbrooke, PQ, Canada.
    Takai, Shinji
    Osaka Med Coll, Dept Innovat Med, Osaka, Japan.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Jacques, Danielle
    Univ Sherbrooke, Fac Med & Sci Sante, Dept Anat & Cell Biol, Sherbrooke, PQ, Canada.
    Gobeil, Fernand, Jr.
    Univ Sherbrooke, Fac Med & Sci Sante, Dept Pharmacol Physiol, Sherbrooke, PQ, Canada.
    Day, Robert
    Univ Sherbrooke, Fac Med & Sci Sante, Dept Surg, Sherbrooke, PQ, Canada.
    D'Orleans-Juste, Pedro
    Univ Sherbrooke, Fac Med & Sci Sante, Dept Pharmacol Physiol, Sherbrooke, PQ, Canada.
    Mouse Mast Cell Protease 4 Deletion Protects Heart Function and Survival After Permanent Myocardial Infarction2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 868Article in journal (Refereed)
    Abstract [en]

    Chymase, a mast cell serine protease involved in the generation of multiple cardiovascular factors, such as angiotensin II and endothelin-1 (ET-1), is elevated and participates in tissue degeneration after permanent myocardial infarction (PMI). Anesthetized 4-month old male wild-type (WT) C57BL/6J mice and mouse mast cell protease-4 knockout (mMCP-4 KO) congeners were subjected to ligation of the left anterior descending (LAD) coronary artery. A group of mice was then subjected to Kaplan-Meier 28-day survival analysis. In another group of mice, F-18-fluorodeoxyglucose positron emission tomography (PET) was performed to evaluate heart function and the infarcted zone 3 days post-PMI surgery. Cardiac morphology following PMI was evaluated on formalin-fixed heart slices and glycoproteomic analysis was performed using mass spectrometry. Finally, cardiac and lung tissue content of immunoreactive ET-1 was determined. PMI caused 60% mortality in WT mice, due to left ventricular wall rupture, and 7% in mMCP-4 KO mice. Cardiac PET analysis revealed a significant reduction in left ventricular volume (systolic and diastolic) and preserved the ejection fraction in mMCP-4 KO compared to WT animals. The infarcted area, apoptotic signaling and wall remodeling were significantly decreased in mMCP-4 KO mice compared to their WT congeners, while collagen deposition was increased. Glycoproteomic analysis showed an increase in apolipoprotein A1, an established chymase substrate in mMCP-4 KO mice compared to WT mice post-PMI. ET-1 levels were increased in the lungs of WT, but not mMCP-4 KO mice, 24 h post-PMI. Thus, the genetic deletion of mMCP-4 improved survival and heart function post-PMI.

  • 11.
    Klawonn, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rådberg, Carl F.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindström, Sarah
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Ericson, Mia
    University of Gothenburg, Sweden.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Fritz, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 714Article in journal (Refereed)
    Abstract [en]

    Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatmentresistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and in vivo microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via in vivo microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.

  • 12.
    Korinek, Michal
    et al.
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan.;Kaohsiung Med Univ, Dept Biotechnol, Coll Life Sci, Kaohsiung, Taiwan..
    Tsai, Yi-Hong
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan..
    El-Shazly, Mohamed
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan.;Ain Shams Univ, Dept Pharmacognosy, Fac Pharm, Cairo, Egypt..
    Lai, Kuei-Hung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wu, Shou-Fang
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan.;Dev Ctr Biotechnol, Nat Resource Dev Inst Pharmaceut, New Taipei, Taiwan..
    Lai, Wan-Chun
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan..
    Wu, Tung-Ying
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan..
    Chen, Shu-Li
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan..
    Wu, Yang-Chang
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan.;Kaohsiung Med Univ, Res Ctr Nat Prod & Drug Dev, Kaohsiung, Taiwan.;Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung, Taiwan..
    Cheng, Yuan-Bin
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan.;Kaohsiung Med Univ, Res Ctr Nat Prod & Drug Dev, Kaohsiung, Taiwan.;Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan..
    Hwang, Tsong-Long
    Chang Gung Univ, Grad Inst Nat Prod, Coll Med, Taoyuan, Taiwan.;Chang Gung Univ Sci & Technol, Res Ctr Chinese Herbal Med, Res Ctr Food & Cosmet Safety, Coll Human Ecol, Taoyuan, Taiwan.;Chang Gung Univ Sci & Technol, Coll Human Ecol, Grad Inst Hlth Ind Technol, Taoyuan, Taiwan.;Chang Gung Mem Hosp, Dept Anesthesiol, Taoyuan, Taiwan..
    Chen, Bing-Hung
    Kaohsiung Med Univ, Dept Biotechnol, Coll Life Sci, Kaohsiung, Taiwan.;Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung, Taiwan.;Natl Sun Yat Sen Univ, Inst Biomed Sci, Kaohsiung, Taiwan..
    Chang, Fang-Rong
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung, Taiwan.;Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan.;Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung, Taiwan.;Kaohsiung Med Univ, Res Ctr Environm Med, Kaohsiung, Taiwan.;Kaohsiung Med Univ Hosp, Canc Ctr, Kaohsiung, Taiwan..
    Anti-allergic Hydroxy Fatty Acids from Typhonium blumei Explored through ChemGPS-NP2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 356Article in journal (Refereed)
    Abstract [en]

    Increasing prevalence of allergic diseases with an inadequate variety of treatment drives forward search for new alternative drugs. Fatty acids, abundant in nature, are regarded as important bioactive compounds and powerful nutrients playing an important role in lipid homeostasis and inflammation. Phytochemical study on Typhonium blumei Nicolson and Sivadasan (Araceae), a folk anti-cancer and anti-inflammatory medicine, yielded four oxygenated fatty acids, 12R-hydroxyoctadec-9Z, 13E-dienoic acid methyl ester (1) and 10R-hydroxyoctadec-8E, 12Z-dienoic acid methyl ester (2), 9R-hydroxy-10E-octadecenoic acid methyl ester (3), and 12R *-hydroxy-10E-octadecenoic acid methyl ester (4). Isolated compounds were identified by spectroscopic methods along with GC-MS analysis. Isolated fatty acids together with a series of saturated, unsaturated and oxygenated fatty acids were evaluated for their anti-inflammatory and anti-allergic activities in vitro. Unsaturated (including docosahexaenoic and eicosapentaenoic acids) as well as hydroxylated unsaturated fatty acids exerted strong anti-inflammatory activity in superoxide anion generation (IC50 2.14-3.73 mu M) and elastase release (IC50 1.26-4.57 mu M) assays. On the other hand, in the anti-allergic assays, the unsaturated fatty acids were inactive, while hydroxylated fatty acids showed promising inhibitory activity in A23187-and antigen-induced degranulation assays (e.g., 9S-hydroxy-10E, 12Z-octadecadienoic acid, IC50 92.4 and 49.7 mu M, respectively). According to our results, the presence of a hydroxy group in the long chain did not influence the potent anti-inflammatory activity of free unsaturated acids. Nevertheless, hydroxylation of fatty acids (or their methyl esters) seems to be a key factor for the anti-allergic activity observed in the current study. Moreover, ChemGPS-NP was explored to predict the structure-activity relationship of fatty acids. The anti-allergic fatty acids formed different cluster distant from clinically used drugs. The bioactivity of T. blumei, which is historically utilized in folk medicine, might be related to the content of fatty acids and their metabolites.

  • 13. Lallement, Pierre-Alexandre
    et al.
    Brouwer, Bastiaan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Keech, Olivier
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Hecker, Arnaud
    Rouhier, Nicolas
    The still mysterious roles of cysteine-containing glutathione transferases in plants2014In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 5, p. 192-Article, review/survey (Refereed)
    Abstract [en]

    Glutathione transferases (GSTs) represent a widespread multigenic enzyme family able to modify a broad range of molecules. These notably include secondary metabolites and exogenous substrates often referred to as xenobiotics, usually for their detoxification, subsequent transport or export. To achieve this, these enzymes can bind non-substrate ligands (ligandin function) and/or catalyze the conjugation of glutathione onto the targeted molecules, the latter activity being exhibited by GSTs having a serine or a tyrosine as catalytic residues. Besides, other GST members possess a catalytic cysteine residue, a substitution that radically changes enzyme properties. Instead of promoting GSH-conjugation reactions, cysteine-containing GSTs (Cys-GSTs) are able to perform deglutathionylation reactions similarly to glutaredoxins but the targets are usually different since glutaredoxin substrates are mostly oxidized proteins and Cys-GST substrates are metabolites. The Cys-GSTs are found in most organisms and form several classes. While Beta and Omega GSTs and chloride intracellular channel proteins (CLICs) are not found in plants, these organisms possess microsomal ProstaGlandin E-Synthase type 2, glutathionyl hydroquinone reductases, Lambda, Iota and Hemerythrin GSTs and dehydroascorbate reductases (DHARs); the four last classes being restricted to the green lineage. In plants, whereas the role of DHARs is clearly associated to the reduction of dehydroascorbate to ascorbate, the physiological roles of other Cys-GSTs remain largely unknown. In this context, a genomic and phylogenetic analysis of Cys-GSTs in photosynthetic organisms provides an updated classification that is discussed in the light of the recent literature about the functional and structural properties of Cys-GSTs. Considering the antioxidant potencies of phenolic compounds and more generally of secondary metabolites, the connection of GSTs with secondary metabolism may be interesting from a pharmacological perspective.

  • 14.
    Lampa, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alvarsson, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arvidsson Mc Shane, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ahlberg, Ernst
    Predictive Compound ADME & Safety, Drug Safety & Metabolism, AstraZeneca IMED Biotech Unit, Mölndal, Sweden.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Predicting off-target binding profiles with confidence using Conformal Prediction2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 1256Article in journal (Refereed)
    Abstract [en]

    Ligand-based models can be used in drug discovery to obtain an early indication of potential off-target interactions that could be linked to adverse effects. Another application is to combine such models into a panel, allowing to compare and search for compounds with similar profiles. Most contemporary methods and implementations however lack valid measures of confidence in their predictions, and only providing point predictions. We here describe the use of conformal prediction for predicting off-target interactions with models trained on data from 31 targets in the ExCAPE dataset, selected for their utility in broad early hazard assessment. Chemicals were represented by the signature molecular descriptor and support vector machines were used as the underlying machine learning method. By using conformal prediction, the results from predictions come in the form of confidence p-values for each class. The full pre-processing and model training process is openly available as scientific workflows on GitHub, rendering it fully reproducible. We illustrate the usefulness of the methodology on a set of compounds extracted from DrugBank. The resulting models are published online and are available via a graphical web interface and an OpenAPI interface for programmatic access.

  • 15.
    Li, Junhao
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China.
    Zhang, Hongxiao
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Liu, Guixia
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Tang, Yun
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Tu, Yaoquan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Li, Weihua
    East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
    Computational Insight Into Vitamin K-1 omega-Hydroxylation by Cytochrome P450 4F22018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 1065Article in journal (Refereed)
    Abstract [en]

    Vitamin K-1 (VK1) plays an important role in the modulation of bleeding disorders. It has been reported that omega-hydroxylation on the VK1 aliphatic chain is catalyzed by cytochrome P450 4F2 (CYP4F2), an enzyme responsible for the metabolism of eicosanoids. However, the mechanism of VK1 omega-hydroxylation by CYP4F2 has not been disclosed. In this study, we employed a combination of quantum mechanism (QM) calculations, homology modeling, molecular docking, molecular dynamics (MD) simulations, and combined quantum mechanism/molecular mechanism (QM/MM) calculations to investigate the metabolism profile of VK1 omega-hydroxylation. QM calculations based on the truncated VK1 model show that the energy barrier for omega-hydroxylation is about 6-25 kJ/mol higher than those at other potential sites of metabolism. However, results from the MD simulations indicate that hydroxylation at the omega-site is more favorable than at the other potential sites, which is in accordance with the experimental observation. The evaluation of MD simulations was further endorsed by the QM/MM calculation results. Our studies thus suggest that the active site residues of CYP4F2 play a determinant role in the omega-hydroxylation. Our results provide structural insights into the mechanism of VK1 omega-hydroxylation by CYP4F2 at the atomistic level and are helpful not only for characterizing the CYP4F2 functions but also for looking into the omega-hydroxylation mediated by other CYP4 enzymes.

  • 16.
    Malmström, Rickard E.
    et al.
    Karolinska University Hospital Solna, Sweden.
    Godman, Brian B.
    Karolinska University Hospital Huddinge, Sweden; University of Liverpool, England; University of Strathclyde, Scotland.
    Diogene, Eduard
    Catalan Institute Heatlh, Spain.
    Baumgartel, Christoph
    Austrian Medical and Medical Dev Agency, Austria.
    Bennie, Marion
    University of Strathclyde, Scotland; NHS National Serv Scotland, Scotland.
    Bishop, Iain
    NHS National Serv Scotland, Scotland.
    Brzezinska, Anna
    Agency Health Technology Assessment, Poland.
    Bucsics, Anna
    Hauptverband Osterreichischen Sozialversicherung, Austria.
    Campbell, Stephen
    University of Manchester, England.
    Ferrario, Alessandra
    LSEHealth, England.
    Finlayson, Alexander E.
    Weston Educat Centre, England.
    Furst, Jurij
    Health Insurance Institute, Slovenia.
    Garuoliene, Kristina
    National Health Insurance Fund, Lithuania.
    Gomes, Miguel
    Institute Nacl Farmacia and Med, Portugal.
    Gutierrez-Ibarluzea, Inaki
    Ministry Health Basque Country, Spain.
    Haycox, Alan
    University of Liverpool, England.
    Hviding, Krystyna
    Norwegian Medical Agency, Norway.
    Herholz, Harald
    Kassenarztliche Vereinigung Hessen, Germany.
    Hoffmann, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jan, Saira
    Horizon Blue Cross Blue Shield New Jersey, NJ USA.
    Jones, Jan
    NHS Tayside, Scotland.
    Joppi, Roberta
    Local Health Unit Verona, Italy.
    Kalaba, Marija
    Republ Institute Health Insurance, Serbia.
    Kvalheim, Christina
    Norwegian Medical Agency, Norway.
    Laius, Ott
    State Agency Med, Estonia.
    Langner, Irene
    Wissenschaftliches Institute AOK, Germany.
    Lonsdale, Julie
    Lancashire Commissioning Support Unit, England.
    Lööv, Sven-Åke
    Stockholm County Council, Sweden.
    Malinowska, Kamila
    HTA Consulting, Poland; Medical Centre Postgrad Educat, Poland.
    McCullagh, Laura
    St James Hospital, Ireland.
    Paterson, Ken
    Scottish Medical Consortium, Scotland.
    Markovic-Pekovic, Vanda
    University of Banja Luka, Bosnia and Herceg; Ministry Health and Social Welfare, Bosnia and Herceg.
    Martin, Andrew
    NHS Bury, England.
    Piessnegger, Jutta
    Hauptverband Osterreichischen Sozialversicherung, Austria.
    Selke, Gisbert
    State Agency Med, Estonia.
    Sermet, Catherine
    Institute Rech and Documentat Econ St, France.
    Simoens, Steven
    Katholieke University of Leuven, Belgium.
    Tulunay, Cankat
    President Turkish Rational Drug Use Platform, Turkey.
    Tomek, Dominik
    Comenius University, Slovakia; Slovak Medical University, Slovakia.
    Voncina, Luka
    Minist Heatlh, Croatia.
    Vlahovic-Palcevski, Vera
    University Hospital Rijeka, Croatia.
    Wale, Janet
    Independent Consumer Advocate, Australia.
    Wilcock, Michael
    Royal Cornwall Hospital NHS Trust, England.
    Wladysiuk, Magdalena
    HTA Consulting, Poland.
    van Woerkom, Menno
    Dutch Institute Rational Use Med, Netherlands.
    Zara, Corrine
    Catalan Health Serv, Spain.
    Gustafsson, Lars L.
    Karolinska University Hospital Huddinge, Sweden.
    Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs2013In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 4, article id 39Article in journal (Refereed)
    Abstract [en]

    Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.

  • 17.
    Olivier, Jocelien D A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Vinkers, Christiaan H
    Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Netherlands.
    Olivier, Berend
    Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Netherlands.
    The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders2013In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 4, no Article 74, p. 1-17Article in journal (Refereed)
    Abstract [en]

    There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies.

  • 18.
    Philippot, Gaetan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Forsberg, Erica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tahan, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Single delta(9)-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 1156Article in journal (Refereed)
    Abstract [en]

    delta(9)-tetrahydrocannabinol (THC) is one of the most used drugs during pregnancy and lactation and efficiently crosses the placental and blood-brain barriers. Despite the recent legalization initiatives worldwide, the adverse outcome pathway (AOP) of THC following exposure during brain development is incompletely understood. We have previously reported that a single injection of THC on postnatal day (PND) 10 altered adult spontaneous behavior and habituation rates in adult mice. Similar behavioral alterations have been reported following PND 10 exposure to the commonly used over-the-counter analgesic acetaminophen (AAP; also known as paracetamol); as both THC and AAP interact with the endocannabinoid system, we hypothesize that this system might be involved in the AOP of both these pharmaceuticals/drugs. Here, we report that a single THC dose on PND 10 decreased transcript levels of tropomyosin receptor kinase b (Trkb) 24 h after exposure in both the frontal and parietal cortex, and in the hippocampus in mice. An increase in the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) ratio were also found in both the parietal cortex and hippocampus following neonatal exposure to THC. In addition, THC exposure increased transcript levels of cannabinoid receptor type 1 (Cb1r) in the parietal cortex and increased the apoptosis regulator BAX in the frontal cortex. This study is important for mainly 3 reasons: 1) we are starting to get information on the developmental neurotoxic AOP of PND 10 exposure to THC, where we suggest that transcriptional changes of the neurotrophic receptor Trkb are central, 2) our PND 10 exposure model provides information relevant to human exposure and 3) since PND 10 exposure to AAP also decreased Trkb transcript levels, we suggest THC and AAP may share key events in their respective AOP through endocannabinoid-mediated alterations of the brain-derived neurotrophic factor (BDNF)TRKB signaling pathway.

  • 19.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy.
    Squassina, Alessio
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy;Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    Treatment-Resistant Schizophrenia: Insights From Genetic Studies and Machine Learning Approaches2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 617Article, review/survey (Refereed)
    Abstract [en]

    Schizophrenia (SCZ) is a severe psychiatric disorder affecting approximately 23 million people worldwide. It is considered the eighth leading cause of disability according to the Wood Health Organization and is associated with a significant reduction in life expectancy. Antipsychotics represent the first-choice treatment in SCZ, but approximately 30% of patients fail to respond to acute treatment. These patients are generally defined as treatment-resistant and are eligible for clozapine treatment. Treatment-resistant patients show a more severe course of the disease, but it has been suggested that treatment-resistant schizophrenia (TRS) may constitute a distinct phenotype that is more than just a more severe form of SCZ. TRS is heritable, and genetics has been shown to play an important role in modulating response to antipsychotics. Important efforts have been put into place in order to better understand the genetic architecture of TRS, with the main goal of identifying reliable predictive markers that might improve the management and quality of life of TRS patients. However, the number of candidate gene and genome-wide association studies specifically focused on TRS is limited, and to date, findings do not allow the disentanglement of its polygenic nature. More recent studies implemented polygenic risk score, gene-based and machine learning methods to explore the genetics of TRS, reporting promising findings. In this review, we present an overview on the genetics of TRS, particularly focusing our discussion on studies implementing polygenic approaches.

  • 20.
    Raclariu, Ancuta C.
    et al.
    Univ Oslo, Nat Hist Museum, Plant Evolut & Metabarcoding Grp, Oslo, Norway.;Natl Inst Res & Dev Biol Sci NIRDBS, Stejarul Res Ctr Biol Sci, Piatra Neamt, Romania..
    Mocan, Andrei
    Iuliu Hatieganu Univ Med & Pharm, Fac Pharm, Dept Pharmaceut Bot, Cluj Napoca, Romania.;Univ Agr Sci & Vet Med Cluj Napoca, ICHAT, Cluj Napoca, Romania.;Univ Agr Sci & Vet Med Cluj Napoca, Inst Life Sci, Cluj Napoca, Romania..
    Popa, Madalina O.
    Natl Inst Res & Dev Biol Sci NIRDBS, Stejarul Res Ctr Biol Sci, Piatra Neamt, Romania..
    Vlase, Laurian
    Univ Oslo, CEES, Dept Biosci, Oslo, Norway..
    Ichim, Mihael C.
    Natl Inst Res & Dev Biol Sci NIRDBS, Stejarul Res Ctr Biol Sci, Piatra Neamt, Romania..
    Crisan, Gianina
    Iuliu Hatieganu Univ Med & Pharm, Fac Pharm, Dept Pharmaceut Bot, Cluj Napoca, Romania..
    Brysting, Anne K.
    CEES, Dept Biosci, Oslo, Norway..
    de Boer, Hugo J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Univ Oslo, Nat Hist Museum, Plant Evolut & Metabarcoding Grp, Oslo, Norway.
    Veronica officinalis Product Authentication Using DNA Metabarcoding and HPLC-MS Reveals Widespread Adulteration with Veronica chamaedrys2017In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 8, article id 378Article in journal (Refereed)
    Abstract [en]

    Studying herbal products derived from local and traditional knowledge and their value chains is one of the main challenges in ethnopharmacology. The majority of these products have a long history of use, but non-harmonized trade and differences in regulatory policies between countries impact their value chains and lead to concerns over product efficacy, safety and quality. Veronica officinalis L. (common speedwell), a member of Plantaginaceae family, has a long history of use in European traditional medicine, mainly in central eastern Europe and the Balkans. However, no specified control tests are available either to establish the quality of derived herbal products or for the discrimination of its most common substitute, V. chamaedrys L. (germander speedwell). In this study, we use DNA metabarcoding and high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) to authenticate sixteen V. officinalis herbal products and compare the potential of the two approaches to detect substitution, adulteration and the use of unreported constituents. HPLC-MS showed high resolution in detecting phytochemical target compounds, but did not enable detection of specific plant species in the products. DNA metabarcoding detected V. officinalis in only 15% of the products, whereas it detected V. chamaedrys in 62% of the products. The results confirm that DNA metabarcoding can be used to test for the presence of Veronica species, and detect substitution and/or admixture of other Veronica species, as well as simultaneously detect all other species present. Our results confirm that none of the herbal products contained exactly the species listed on the label, and all included substitutes, contaminants or fillers. This study highlights the need for authentication of raw herbals along the value chain of these products. An integrative methodology can assess both the quality of herbal products in terms of target compound concentrations and species composition, as well as admixture and substitution with other chemical compounds and plants.

  • 21.
    Saul, Meike J.
    et al.
    Tech Univ Darmstadt, Dept Biol, Darmstadt, Germany;Goethe Univ Frankfurt, Inst Pharmaceut Chem, Frankfurt, Germany.
    Hegewald, Anett B.
    Tech Univ Darmstadt, Dept Biol, Darmstadt, Germany.
    Emmerich, Anne C.
    Tech Univ Darmstadt, Dept Biol, Darmstadt, Germany;Goethe Univ Frankfurt, Inst Pharmaceut Chem, Frankfurt, Germany.
    Ossipova, Elena
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Vogel, Marc
    Tech Univ Darmstadt, Dept Biol, Darmstadt, Germany.
    Baumann, Isabell
    Tech Univ Darmstadt, Dept Biol, Darmstadt, Germany;Goethe Univ Frankfurt, Inst Pharmaceut Chem, Frankfurt, Germany.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lengqivst, Johan
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Steinhilber, Dieter
    Goethe Univ Frankfurt, Inst Pharmaceut Chem, Frankfurt, Germany.
    Jakobsson, Per Johan
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Mass Spectrometry-Based Proteomics Approach Characterizes the Dual Functionality of miR-328 in Monocytes2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 640Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRs) are small noncoding RNAs which control the expression of target genes by either translational repression or RNA degradation, known as canonical miR functions. The recent discovery that miR-328 has a noncanonical function and can activate gene expression by antagonizing the activity of heterogeneous ribonuclear protein E2 (hnRNP E2) opens an unexplored and exciting field of gene expression regulation. The global importance of such noncanonical miR function is not yet known. In order to achieve a better understanding of the new miR activity, we performed a compartment specific tandem mass tag (TMT)-based proteomic analysis in differentiated MonoMac6 (MM6) cells, to monitor gene expression variations in response to miR-328 knockdown. We identified a broad spectrum of novel potential miR-328/hnRNP E2 and miR-328 targets involved in regulation of compartment specific cellular processes, such as inflammation or RNA splicing. This study provides first insights of the global significance of noncanonical miR function.

  • 22. Stiedl, Oliver
    et al.
    Pappa, Elpiniki
    Konradsson-Geuken, Åsa
    Ögren, Sven Ove
    The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory.2015In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 6Article in journal (Refereed)
    Abstract [en]

    Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with the development of anxiety, depression and cognitive function linked to mechanisms of emotional learning and memory. In rodents fear conditioning and passive avoidance (PA) are associative learning paradigms to study emotional memory. This review assesses the role of 5-HT1AR and 5-HT7R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT1ARs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT1AR facilitates memory retention possibly via 5-HT7R activation and evidence is provided that 5HT7R can facilitate emotional memory upon reduced 5-HT1AR transmission. These findings highlight the differential role of these 5-HTRs in cognitive/emotional domains of behavior. Moreover, the results indicate that tonic and phasic 5-HT release can exert different and potentially opposing effects on emotional memory, depending on the states of 5-HT1ARs and 5-HT7Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role for the responsiveness to drug treatment, e.g., by SSRIs which increase intrasynaptic 5-HT levels thereby activating multiple pre- and postsynaptic 5-HTR subtypes.

  • 23.
    van Overbeeke, Eline
    et al.
    Clinical Pharmacology and Pharmacotherapy, KU Leuven, Leuven, Belgium.
    Janssens, Rosanne
    Clinical Pharmacology and Pharmacotherapy, KU Leuven, Leuven, Belgium.
    Whichello, Chiara
    School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, Netherlands.
    Schölin Bywall, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Sharpe, Jenny
    Muscular Dystrophy UK, London, United Kingdom.
    Nikolenko, Nikoletta
    John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle, United Kingdom.
    Philips, Berkeley S.
    Pfizer, Tadworth, United Kingdom.
    Guiddi, Paolo
    Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology, Milan, Italy.
    Pravettoni, Gabriella
    Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology, Milan, Italy; Department of Oncology and Hematology Oncology, Faculty of Medicine and Surgery, University of Milan, Milan, Italy.
    Vergani, Laura
    Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology, Milan, Italy; Department of Oncology and Hematology Oncology, Faculty of Medicine and Surgery, University of Milan, Milan, Italy.
    Marton, Giulia
    Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology, Milan, Italy; Department of Oncology and Hematology Oncology, Faculty of Medicine and Surgery, University of Milan, Milan, Italy.
    Cleemput, Irina
    Belgian Health Care Knowledge Centre, Brussels, Belgium.
    Simoens, Steven
    Clinical Pharmacology and Pharmacotherapy, KU Leuven, Leuven, Belgium.
    Kübler, Jürgen
    Quantitative Scientific Consulting, Marburg, Germany.
    Juhaeri, Juhaeri
    Sanofi, Bridgewater, NJ, United States.
    Levitan, Bennet
    Janssen Research & Development, Titusville, NJ, United States.
    de Bekker-Grob, Esther W.
    School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, Netherlands.
    Veldwijk, Jorien
    School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, Netherlands.
    Huys, Isabelle
    Clinical Pharmacology and Pharmacotherapy, KU Leuven, Leuven, Belgium.
    Design, Conduct, and Use of Patient Preference Studies in the Medical Product Life Cycle: A Multi-Method Study2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, no 1395Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate stakeholder perspectives on how patient preference studies (PPS) should be designed and conducted to allow for inclusion of patient preferences in decision-making along the medical product life cycle (MPLC), and how patient preferences can be used in such decision-making.

    Methods: Two literature reviews and semi-structured interviews (n = 143) with healthcare stakeholders in Europe and the US were conducted; results of these informed the design of focus group guides. Eight focus groups were conducted with European patients, industry representatives and regulators, and with US regulators and European/Canadian health technology assessment (HTA) representatives. Focus groups were analyzed thematically using NVivo.

    Results: Stakeholder perspectives on how PPS should be designed and conducted were as follows: 1) study design should be informed by the research questions and patient population; 2) preferred treatment attributes and levels, as well as trade-offs among attributes and levels should be investigated; 3) the patient sample and method should match the MPLC phase; 4) different stakeholders should collaborate; and 5) results from PPS should be shared with relevant stakeholders. The value of patient preferences in decision-making was found to increase with the level of patient preference sensitivity of decisions on medical products. Stakeholders mentioned that patient preferences are hardly used in current decision-making. Potential applications for patient preferences across industry, regulatory and HTA processes were identified. Four applications seemed most promising for systematic integration of patient preferences: 1) benefit-risk assessment by industry and regulators at the marketing-authorization phase; 2) assessment of major contribution to patient care by European regulators; 3) cost-effectiveness analysis; and 4) multi criteria decision analysis in HTA.

    Conclusions: The value of patient preferences for decision-making depends on the level of collaboration across stakeholders; the match between the research question, MPLC phase, sample, and preference method used in PPS; and the sensitivity of the decision regarding a medical product to patient preferences. Promising applications for patient preferences should be further explored with stakeholders to optimize their inclusion in decision-making.

  • 24.
    Whichello, Chiara
    et al.
    Erasmus School of Health Policy & Management and Erasmus Choice Modelling Centre, Erasmus University, Rotterdam, Netherlands.
    van Overbeeke, Eline
    Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
    Janssens, Rosanne
    Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
    Schölin Bywall, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Russo, Selena
    4Applied Research Division for Cognitive and Psychological Science, IEO European Institute of Oncology IRCCS, Milan, Italy.
    Weldwijk, Jorien
    Erasmus School of Health Policy & Management and Erasmus Choice Modelling Centre, Erasmus University, Rotterdam, Netherlands.
    Cleemput, Irina
    Belgian Health Care Knowledge Centre, Brussels, Belgium.
    Juhaeri, Juhaeri
    Sanofi, Bridgewater, NJ, United States.
    Levitan, Bennet
    Global R&D Epidemiology, Janssen Research & Development, Titusville, United States.
    Kübler, Jürgen
    Quantitative Scientific Consulting, Marburg, Germany.
    Smith, Meredith
    Global Patient Safety and Labeling, Amgen Inc., Thousand Oaks, CA, United States.
    Hermann, Richard
    Astra Zeneca, Gaithersburg, MD, United States.
    Engelbrecht, Matthias
    Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
    Heuber, Alex J.
    Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
    Comanescu, Alina
    Community Health Association, Bucharest, Romania.
    Harding, Sarah
    Global Patient Safety, Takeda, London, United Kingdom.
    Simoens, Steven
    Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
    Huys, Isabelle
    Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
    de Bekker-Grob, Esther
    Erasmus School of Health Policy & Management and Erasmus Choice Modelling Centre, Erasmus University, Rotterdam, Netherlands.
    Factors and Situations Affecting the Value of Patient Preference Studies: Semi-Structured Interviews in Europe and the US2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 1009Article in journal (Refereed)
    Abstract [en]

    Objectives: Patient preference information (PPI) is gaining recognition among the pharmaceutical industry, regulatory authorities, and health technology assessment (HTA) bodies/payers for use in assessments and decision-making along the medical product lifecycle (MPLC). This study aimed to identify factors and situations that influence the value of patient preference studies (PPS) in decision-making along the MPLC according to different stakeholders.

    Methods: Semi-structured interviews (n = 143) were conducted with six different stakeholder groups (physicians, academics, industry representatives, regulators, HTA/payer representatives, and a combined group of patients, caregivers, and patient representatives) from seven European countries (the United Kingdom, Sweden, Italy, Romania, Germany, France, and the Netherlands) and the United States. Framework analysis was performed using NVivo 11 software.

    Results: Fifteen factors affecting the value of PPS in the MPLC were identified. These are related to: study organization (expertise, financial resources, study duration, ethics and good practices, patient centeredness), study design (examining patient and/or other preferences, ensuring representativeness, matching method to research question, matching method to MPLC stage, validity and reliability, cognitive burden, patient education, attribute development), and study conduct (patients’ ability/willingness to participate and preference heterogeneity). Three types of situations affecting the use of PPS results were identified (stakeholder acceptance, market situations, and clinical situations).

    Conclusion: The factors and situation types affecting the value of PPS, as identified in this study, need to be considered when designing and conducting PPS in order to promote the integration of PPI into decision-making along the MPLC.

  • 25.
    Wilhelms, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Dock, Hua
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Brito, Haissa O.
    Not Found:Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden.
    Pettersson, Emma
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Stojakovic, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Zajdel, Joanna
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hammar, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Spetz Holm, Anna-Clara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    CGRP Is Critical for Hot Flushes in Ovariectomized Mice2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 1452Article in journal (Refereed)
    Abstract [en]

    Hot flushes are common and troublesome symptoms of menopause. The neuropeptide calcitonin gene-related peptide (CGRP) is increased in plasma during hot flushes but it has not been clear if CGRP is causally involved in the mechanism underpinning the flushes. Here, we examined the effect of interventions with CGRP in a mouse model of hot flushes based on flush-like temperature increases triggered by forced physical activity in ovariectomized mice. Compared to normal mice, ovariectomized mice reacted with an exaggerated, flush-like, temperature increase after physical exercise. This increase was completely blocked by the non-peptide CGRP-antagonist MK-8825 (-0.41 degrees Celsius, 95% CI: -0,83 to 0,012, p amp;lt; 0.0001) at a dose that had no obvious effects on locomotor activity (50 mg/kg). Further, the flush-like temperature increases were strongly attenuated in ovariectomized mice lacking alpha CGRP due to a genetic modification. Collectively, our findings suggest that CGRP is an important mediator of experimentally induced hot flushes and they identify CGRP antagonists as promising treatment candidates for women and possibly also men with hot flushes.

  • 26.
    Zhang, Xiaoqun
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Mantas, Ioannis
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Alvarsson, Alexandra
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Yoshitake, Takashi
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomolecular Mass Spectrometry Imaging, National Resource for Mass Spectrometry Imaging, Uppsala, Sweden.
    Pereira, Marcela
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Kehr, Jan
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Millan, Mark J.
    Ctr Rech Croissy, Ctr Therapeut Innovat CNS, Inst Rech Servier, Paris, France..
    Chergui, Karima
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Mol Neurophysiol, Solna, Sweden..
    Svenningsson, Per
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or beta-Phenylethylamine2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 166Article in journal (Refereed)
    Abstract [en]

    The trace amine-associated receptor 1 (TAAR1) is expressed by dopaminergic neurons, but the precise influence of trace amines upon their functional activity remains to be fully characterized. Here, we examined the regulation of tyrosine hydroxylase (TH) by tyramine and beta-phenylethylamine (beta-PEA) compared to 3-iodothyronamine (T(1)AM). Immunoblotting and amperometry were performed in dorsal striatal slices from wildtype (WT) and TAAR1 knockout (KO) mice. T(1)AM increased TH phosphorylation at both Ser(19) and Ser(40), actions that should promote functional activity of TH. Indeed, HPLC data revealed higher rates of L-dihydroxyphenylalanine (DOPA) accumulation in WT animals treated with T(1)AM after the administration of a DOPA decarboxylase inhibitor. These effects were abolished both in TAAR1 KO mice and by the TAAR1 antagonist, EPPTB. Further, they were specific inasmuch as Ser(845) phosphorylation of the post-synaptic GluA1 AMPAR subunit was unaffected. The effects of T1AM on TH phosphorylation at both Ser(19) (CamKII-targeted), and Ser40 (PKA-phosphorylated) were inhibited by KN-92 and H-89, inhibitors of CamKII and PKA respectively. Conversely, there was no effect of an EPAC analog, 8-CPT-2Me-cAMP, on TH phosphorylation. In line with these data, T(1)AM increased evoked striatal dopamine release in TAAR1 WT mice, an action blunted in TAAR1 KO mice and by EPPTB. Mass spectrometry imaging revealed no endogenous T(1)AM in the brain, but detected T(1)AM in several brain areas upon systemic administration in both WT and TAAR1 KO mice. In contrast to T1AM, tyramine decreased the phosphorylation of Ser40-TH, while increasing Ser(845)-GluA1 phosphorylation, actions that were not blocked in TAAR1 KO mice. Likewise, beta-PEA reduced Ser(40)-TH and tended to promote Ser845-GluA1 phosphorylation. The D-1 receptor antagonist SCH23390 blocked tyramine-induced Ser(845)-GluA1 phosphorylation, but had no effect on tyramine-or beta-PEA-induced Ser(40)-TH phosphorylation. In conclusion, by intracellular cascades involving CaMKII and PKA, T(1)AM, but not tyramine and beta-PEA, acts via TAAR1 to promote the phosphorylation and functional activity of TH in the dorsal striatum, supporting a modulatory influence on dopamine transmission.

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