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  • 1.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Orphan Drugs and Their Impact on Pharmaceutical Development2018In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 6, p. 525-535Article, review/survey (Refereed)
    Abstract [en]

    High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.

  • 2.
    Högberg, Liselotte Diaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Heddini, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The global need for effective antibiotics: challenges and recent advances2010In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 31, no 11, p. 509-515Article, review/survey (Refereed)
    Abstract [en]

    The emerging problem of antibiotic resistance is a serious threat to global public health. The situation is aggravated by a substantial decline in the research and development of antibacterial agents. Hence, very few new antibacterial classes are brought to market when older classes lose their efficacy. There has been renewed and growing attention within policy groups to: (i) address the problem; (ii) discuss incentives for the development of urgently needed new treatments; (iii) preserve the efficacy of existing therapeutic options. We briefly review the basic principles of antibiotic resistance, and contrast the increasing resistance to the dwindling antibacterial 'pipeline'. We also highlight some recent policy initiatives aiming to secure the future need of effective antibiotics.

  • 3.
    Jespers, Willem
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Leiden Amsterdam Ctr Drug Res, Drug Discovery & Safety, Leiden.; Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen.
    Schiedel, Anke C.
    PharmaCtr Bonn, Pharmaceut Inst, Pharmaceut Chem 1, Bonn.
    Heitman, Laura H.
    Leiden Amsterdam Ctr Drug Res, Drug Discovery & Safety, Leiden.
    Cooke, Robert M.
    Heptares Therapeut, Biopk, Broadwater Rd, Welwyn Garden City, Herts.
    Kleene, Lisa
    PharmaCtr Bonn, Pharmaceut Inst, Pharmaceut 1, Bonn.
    van Westen, Gerard J. P.
    Leiden Amsterdam Ctr Drug Res, Drug Discovery & Safety, Leiden.
    Gloriam, David E.
    Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen.
    Müller, Christa E.
    PharmaCtr Bonn, Pharmaceut Inst, Pharmaceut Chem 1, Bonn.
    Sotelo, Eddy
    Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biolox & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.; Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela.
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms2018In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 1, p. 75-89Article, review/survey (Refereed)
    Abstract [en]

    The four adenosine receptors (ARs), A(1), A(2A), A(2B), and A(3), constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A(2A) and inactive conformations of the A(1) ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www.gpcrdb.org). This analysis provides novel insights into ligand binding, allosteric modulation, and signaling of the AR family.

  • 4.
    Kurland, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Using genotyping to predict responses to anti-hypertensive treatment2005In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 26, no 9, p. 443-7Article in journal (Refereed)
    Abstract [en]

    Hypertension is prevalent and affects approximately 1 in every 4 adults in the Western world. Although many drugs are effective in treating hypertension, an individual's response to treatment is unpredictable. Pharmacogenetics holds the promise of becoming a tool to predict this response but obstacles and shortcomings need to be overcome. Significant developments in molecular biology, including the sequencing of the genome, the cataloguing of genetic variation and the development of microarray techniques, enable analysis of many genotypes simultaneously. However, despite these technical advances there are, as yet, no clinical applications of pharmacogenetics in anti-hypertensive treatment. It is therefore necessary to design prospective pharmacogenetic studies that aim to identify a genetic profile that will predict the response to anti-hypertensive treatment.

  • 5.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fenu, Luca A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundquist, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wisniewski, Jacek R.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany..
    Kansy, Manfred
    F Hoffmann La Roche & Co Ltd, Roche Innovat Ctr Basel, Pharmaceut Sci, Roche Pharmaceut Res & Early Dev, CH-4070 Basel, Switzerland..
    Artursson, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Addendum to 'Quantifying the impact of transporters on cellular drug permeability'2015In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 36, no 9, p. 559-559Article in journal (Refereed)
  • 6.
    Matsson, Pär
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fenu, Luca A
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundquist, Patrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wiśniewski, Jacek R
    Kansy, Manfred
    Artursson, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quantifying the impact of transporters on cellular drug permeability.2015In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 35, no 5, p. 255-262Article in journal (Refereed)
    Abstract [en]

    The conventional model of drug permeability has recently been challenged. An alternative model proposes that transporter-mediated flux is the sole mechanism of cellular drug permeation, instead of existing in parallel with passive transmembrane diffusion. We examined a central assumption of this alternative hypothesis; namely, that transporters can give rise to experimental observations that would typically be explained with passive transmembrane diffusion. Using systems-biology simulations based on available transporter kinetics and proteomic expression data, we found that such observations are possible in the absence of transmembrane diffusion, but only under very specific conditions that rarely or never occur for known human drug transporters.

  • 7.
    Matsson, Pär X.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundquist, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Need for Speed-Kinetic Limits of Drug Transporters2016In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 37, no 4, p. 243-245Article in journal (Refereed)
  • 8.
    Perland, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Classification Systems of Secondary Active Transporters2017In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 38, no 3, p. 305-315Article, review/survey (Refereed)
    Abstract [en]

    Membrane-bound solute carrier (SLC) transporter proteins are vital to the human body, as they sustain homeostasis by moving soluble molecule as nutrients, drugs, and waste across lipid membranes. Of the 430 identified secondary active transporters in humans, 30% are still orphans, and systematic research has been requested to elaborate on their possible involvement in diseases and their potential as drug targets. To enable this, the various classification systems in use must be understood and used correctly. In this review, we describe how various classification systems for human SLCs are constructed, and how they overlap and differ. To facilitate communication between researchers and to avoid ambiguities, everyone must clearly state which classification system they are referring to when writing scientific articles.

  • 9. Pirmohamed, Munir
    et al.
    Kamali, Farhad
    Daly, Ann K.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Oral anticoagulation: a critique of recent advances and controversies2015In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 36, no 3, p. 153-163Article, review/survey (Refereed)
    Abstract [en]

    There have recently been significant advances in the field of oral anticoagulation, but these have also led to many controversies. Warfarin is still the commonest drug used for clotting disorders but its use is complicated owing to wide inter-individual variability in dose requirement and its narrow therapeutic index. Warfarin dose requirement can be influenced by both genetic and environmental factors. Two recent randomized controlled trials (RCTs) came to different conclusion regarding the utility of genotype-guided dosing; we critically explore the reasons for the differences. The new generation of oral anticoagulants have been demonstrated to be as efficacious as warfarin, but further work is needed to evaluate their safety in real clinical settings.

  • 10.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhang, Jin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fabbro, Doriano
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Advances in kinase targeting: current clinical use and clinical trials2014In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 35, no 11, p. 604-620Article, review/survey (Refereed)
    Abstract [en]

    Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec®) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.

  • 11. Tulp, Martin
    et al.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Functional versus chemical diversity: is biodiversity important for drug discovery?2002In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 23, no 5, p. 225-231Article in journal (Refereed)
    Abstract [en]

    Prospecting the full biodiversity of nature to find leads for new drugs is not necessary. Because finding leads is aimed at identifying biological activity, structure is of secondary importance. Furthermore, although natural chemical diversity might be unrivalled, functional diversity is bound to be considerably less. It is likely that many millions of chemically distinct molecules exist in nature but it is inconceivable that the number of different biological functions is near this number. This is corroborated by knowledge obtained from the genome sequences of an increasing number of species. It is unlikely that ligands for specific molecular targets are restricted to one species and even individual compounds are often found in more than one species. Important molecular mechanisms are likely to be ubiquitous and there are no a priori reasons to assume that some are restricted to, for example, tropical rainforests. Thus, there are no obvious advantages of ‘biodiversity prospecting’, which will, possibly, endanger fragile ecosystems in the search for rare species.

  • 12. Tulp, Martin
    et al.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rediscovery of known natural compounds: nuisance or goldmine?2005In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 26, no 4, p. 175-177Article in journal (Other academic)
1 - 12 of 12
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