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  • 1.
    Arvidsson, Per I.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Sandberg, Kristian
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Open for collaboration: an academic platform for drug discovery and development at SciLifeLab2016Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 21, nr 10, s. 1690-1698Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The Science for Life Laboratory Drug Discovery and Development (SciLifeLab DDD) platform reaches out to Swedish academia with an industry-standard infrastructure for academic drug discovery, supported by earmarked funds from the Swedish government. In this review, we describe the build-up and operation of the platform, and reflect on our first two years of operation, with the ambition to share learnings and best practice with academic drug discovery centers globally. We also discuss how the Swedish Teacher Exemption Law, an internationally unique aspect of the innovation system, has shaped the operation. Furthermore, we address how this investment in infrastructure and expertise can be utilized to facilitate international collaboration between academia and industry in the best interest of those ultimately benefiting the most from translational pharmaceutical research - the patients.

  • 2.
    Bohlin, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Rosén, Börje
    Podophyllotoxin derivatives: drug discovery and development1996Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 1, nr 8, s. 343-351Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The exploration and exploitation of podophyllin formulations provide an example of how a plant extract with established ethnomedical use, but also causing toxicity, can provide a basis for new drug discovery and development. Applications and potential applications include the treatment of venereal warts, psoriasis, rheumatoid arthritis, malaria and Alzheimer's disease. This review addresses the history and pharmacological action of these natural products and outlines the preclinical development and clinical trials of drugs in the pipeline and with marketing approval.

  • 3.
    Bruhn, Jan G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Molecular Pharmacognosy: an explanatory model1997Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 2, nr 6, s. 243-246Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Increased interest in the study of natural products as potential drugs and rapidly changing research strategies are driving us to reassess the role of pharmacognosy in the wider context of pharmaceutical research. The authors propose a new definition and an explanatory model of modern pharmacognosy that can be used as a theoretical foundation for future development of this classical branch of the life sciences.

  • 4.
    Colcloughl, Nicola
    et al.
    AstraZeneca, IMED Biotech Unit, Oncol, DMPK, Cambridge, England.
    Chen, Kan
    AstraZeneca, IMED Biotech Unit, Asia IMED, DMPK, Shanghai, Peoples R China.
    Johnstrom, Peter
    Karolinska Inst, AstraZeneca, IMED Biotech Unit, PET Sci Ctr,Precis Med & Genom, Stockholm, Sweden.
    Fridén, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. AstraZeneca, IMED Biotech Unit, DMPK, RIA, Gothenburg, Sweden.
    McGinnity, Dermot F.
    AstraZeneca, IMED Biotech Unit, Oncol, DMPK, Cambridge, England.
    Building on the success of osimertinib: achieving CNS exposure in oncology drug discovery2019Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 24, nr 5, s. 1067-1073Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Due to the blood-brain barrier (BBB) limiting the exposure of therapeutics to the central nervous system (CNS), patients with brain malignancies are challenging to treat, typically have poor prognoses, and represent a significant unmet medical need. Preclinical data report osimertinib to have significant BBB penetration and emerging clinical data demonstrate encouraging activity against CNS malignancies. Here, we discuss the oncology drug candidates AZD3759 and AZD1390 as case examples of discovery projects designing in BBB penetrance. We demonstrate how these innovative kinase inhibitors were recognized as brain penetrant and outline our view of experimental approaches and strategies that can facilitate the discovery of new brain-penetrant therapies for the treatment of primary and secondary CNS malignancies as well as other CNS disorders.

  • 5. Davis, Andrew M.
    et al.
    St-Gallay, Stephen A.
    Kleywegt, Gerard J.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Strukturell molekylärbiologi.
    Limitations and lessons in the use of X-ray structural information in drug design2008Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 13, nr 19-20, s. 831-841Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The use of X-ray crystal structure models continues to provide a strong stimulus to drug discovery, through the direct visualisation of ligand-receptor interactions. There is sometimes a limited appreciation of the uncertainties introduced during the process of deriving an atomic model from the experimentally observed electron density. Here, some of these uncertainties are highlighted with recent examples from the literature, together with snippets of advice for the medicinal chemist embarking on using X-ray crystal structure information in a drug discovery programme.

  • 6. Di, Li
    et al.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Avdeef, Alex
    Ecker, Gerhard F.
    Faller, Bernard
    Fischer, Holger
    Houston, J. Brian
    Kansy, Manfred
    Kerns, Edward H.
    Kraemer, Stefanie D.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sugano, Kiyohiko
    Evidence-based approach to assess passive diffusion and carrier-mediated drug transport2012Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 17, nr 15-16, s. 905-912Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization.

  • 7.
    Flodmark, Charlotte A
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bruhn, Jan G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    One-third of Swedish food plants has anti-inflammatory records2001Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 6, nr 9, s. 455-456Artikel i tidskrift (Övrigt vetenskapligt)
  • 8.
    Hosseinimehr, Seyed Jalal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
    Flavonoids and genomic instability induced by ionizing radiation2010Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 15, nr 21-22, s. 907-918Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    DNA is the cellular target that has the most damage induced by ionizing radiation (IR). If genomic instability resulting from this DNA damage is not correctly repaired, it leads to mutation, cancer and cell death. Flavonoids are a family of natural products that affect oxidative stress and enhance genomic stability through DNA interaction. Although flavonoids exert protective effects against IR in normal cells, they enhance genotoxicity effects of this radiation in cancer cells, a beneficial effect that is of interest in the design of new anticancer pharmaceuticals. This review describes the molecular effects of IR on DNA structure and mechanisms by which flavonoids exert their effect on ionizing-radiation-induced genomic instability.

  • 9.
    Hosseinimehr, Seyed Jalal
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Liver uptake of radiolabeled targeting proteins and peptides: considerations for targeting peptide conjugate design2012Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 17, nr 21-22, s. 1224-1232Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Radionuclide imaging of molecular targets for cancer therapy is likely to be a powerful tool for patient stratification and response monitoring, allowing more personalized cancer treatment. Radiolabeled proteins and peptides are a promising class of imaging probes for visualization of molecular targets in vivo. However, hepatic uptake and hepatobiliary excretion of radioactivity can decrease imaging contrast, reducing the detection sensitivity of hepatic and extrahepatic abdominal metastases, respectively. In this article, we review factors that influence the hepatic uptake of radioactivity (e.g. the chemical nature of radiocatabolites and physicochemical properties of targeting peptides and linkers) to provide input for the rational design of peptide-based imaging probes.

  • 10. Larhed, M
    et al.
    Hallberg, A
    Microwave-assisted high-speed chemistry: a new technique in drug discovery2001Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 6, nr 8, s. 406-416Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    In both lead identification and lead optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds. The fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery; within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry.

  • 11.
    Molavipordanjani, Sajjad
    et al.
    Mazandaran Univ Med Sci, Dept Radiopharm, Pharmaceut Sci Res Ctr, Fac Pharm, Sari, Iran;Mazandaran Univ Med Sci, Student Res Comm, Fac Pharm, Sari, Iran.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Hosseinimehr, Seyed Jalal
    Mazandaran Univ Med Sci, Dept Radiopharm, Pharmaceut Sci Res Ctr, Fac Pharm, Sari, Iran.
    Basic and practical concepts of radiopharmaceutical purification methods2019Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 24, nr 1, s. 315-324Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The presence of radiochemical impurities in a radiopharmaceutical contributes to an unnecessary radiation burden for the patients or to an undesirable high radioactivity background, which reduces the imaging contrast or therapeutic efficacy. Therefore, if the radiolabeling process results in unsatisfactory radiochemical purity, a purification step is unavoidable. A successful purification process requires a profound knowledge about the radiopharmaceuticals of interest ranging from structural features to susceptibility to different conditions. Most radiopharmaceutical purification methods are based on solid phase extraction (SPE), high-performance liquid chromatography (HPLC), size exclusion chromatography (SEC), ion-exchange chromatography (IEC), and liquid-liquid extraction (LLE). Here, we discuss the basic and applied concepts of these purifications methods as well as their advantages and limitations.

  • 12.
    Muliaditan, Morris
    et al.
    UCL, Sch Life & Med Sci, London, England..
    Davies, Geraint R.
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England..
    Simonsson, Ulrika S.H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gillespie, Stephen H.
    Univ St Andrews, Sch Med, St Andrews, Fife, Scotland..
    Della Pasqua, Oscar
    UCL, Sch Life & Med Sci, London, England.;GlaxoSmithKline, London, England..
    The implications of model-informed drug discovery and development for tuberculosis2017Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 22, nr 3, s. 481-486Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Despite promising advances in the field and highly efficacious first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokineticpharmacodynamic (PKPD) relationships. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development. The aim of the consortium is to develop new preclinical tools in concert with an in silico model-based approach, grounded in PKPD principles. Here, we highlight the potential impact of such an integrated framework on the various stages of TB drug development and on the dose rationale for drug combinations.

  • 13.
    Soekhai, Vikas
    et al.
    Erasmus School of Health Policy & Management, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands; Erasmus Choice Modelling Centre, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands; Department of Public Health, Erasmus MC – University Medical Centre, Dr. Molewaterplein 40, 3000 CA Rotterdam.
    Whichello, Chiara
    Erasmus School of Health Policy & Management, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands; Erasmus Choice Modelling Centre, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands.
    Levitan, Bennet
    Janssen Research & Development, 1125 Trenton-Harbourton Road, PO Box 200, Titusville, NJ, 08560, USA.
    Veldwijk, Jorien
    Erasmus School of Health Policy & Management, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands; Erasmus Choice Modelling Centre, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands.
    Pinto, Cathy Anne
    Merck, Sharpe & Dome, 2000 Galloping Hill Rd., Kenilworth, NJ, 07033, USA.
    Donkers, Bas
    Department of Business Economics, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands; Erasmus Choice Modelling Centre, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands.
    Huys, Isabelle
    Clinical Pharmacology and Pharmacotherapy, University of Leuven, Herestraat 49 Box 521, Leuven, 3000 Belgium.
    van Overbeeke, Eline
    Clinical Pharmacology and Pharmacotherapy, University of Leuven, Herestraat 49 Box 521, Leuven, 3000 Belgium.
    Juhaeri, Juhaeri
    Sanofi, 55 Corporate Drive Bridgewater, NJ, 08807, USA.
    de Bekker-Grob, Esther W.
    Erasmus School of Health Policy & Management, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands; Erasmus Choice Modelling Centre, Erasmus University Rotterdam, P.O. Box 1738, Rotterdam, 3000 DR the Netherlands.
    Methods for exploring and eliciting patient preferences in the medical product lifecycle: a literature review2019Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Highlights

    • Preference studies are becoming increasingly important within the medical product decision-making context.
    • Currently, there is limited understanding of the range of methods to gain insights into patient preferences.
    • We developed a compendium and taxonomy of preference exploration (qualitative) and elicitation (quantitative) methods.
    • We identified 32 unique preference methods.
    • Our results can serve as an important resource for determining which preference methods are most promising in the medical product lifecycle.
  • 14. Tulp, Martin
    et al.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Unconventional natural sources for future drug discovery2004Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 9, nr 10, s. 450-458Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    ‘There are more things between heaven and earth…’ Despite the progress of science during the past four centuries, Shakespeare's words did not lose their actuality. Knowledge about the etiology of diseases is still limited, and for many life-threatening illnesses no effective treatments exist. Nature always has been a valuable source of drugs and, despite the unprecedented opportunities afforded by medicinal chemistry, continues to deliver lead compounds. Traditionally, research on natural sources was focused on terrestrial plants and microorganisms. More recently, however, organisms of marine origin are also being investigated. Here, the possibilities of unconventional and hardly explored sources are discussed.

  • 15. Tulp, Martin
    et al.
    Bruhn, Jan G
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Food for thought2006Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 11, nr 23-24, s. 1115-1121Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Do certain kinds of food contain pharmacologically active substances in concentrations that are high enough to have druglike effects when consumed? Are biologically active compounds in food indicative of therapeutic value? Is traditional drug development suitable for testing the merits of food? Is it ethical to test food as a drug on patients? Will dietary disease management remain a pipedream? Is it a fact or fantasy that the Mediterranean diet is beneficial to health? Is a vegetarian diet an elimination therapy, or one of supplementation? What can be learned from animals? Are humans losing the capability of listening to their bodies? In this review, we will address these questions-providing food for thought.

  • 16.
    van Overbeeke, Eline
    et al.
    Clinical Pharmacology and Pharmacotherapy, University of Leuven, Herestraat 49 Box 521, 3000 Leuven, Belgium.
    Whichello, Chiara
    Erasmus School of Health Policy & Management (ESHPM) and Erasmus Choice Modelling Centre (ECMC), Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
    Janssens, Rosanne
    Erasmus School of Health Policy & Management (ESHPM) and Erasmus Choice Modelling Centre (ECMC), Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
    Veldwijk, Jorien
    Erasmus School of Health Policy & Management (ESHPM) and Erasmus Choice Modelling Centre (ECMC), Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
    Cleemput, Irina
    Belgian Health Care Knowledge Centre (KCE), Kruidtuinlaan 55, 1000 Brussels, Belgium.
    Simoens, Steven
    Clinical Pharmacology and Pharmacotherapy, University of Leuven, Herestraat 49 Box 521, 3000 Leuven, Belgium.
    Juharei, Juharei
    Sanofi, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
    Levitan, Bennett
    Janssen Research & Development, 1125 Trenton-Harbourton Road, P.O. Box 200, Titusville, NJ 08560, USA.
    Kübler, Jürgen
    Quantitative Scientific Consulting, Europabadstr. 8, 35041 Marburg, Germany.
    de Bekker-Grob, Esther
    Erasmus School of Health Policy & Management (ESHPM) and Erasmus Choice Modelling Centre (ECMC), Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
    Huys, Isabelle
    Clinical Pharmacology and Pharmacotherapy, University of Leuven, Herestraat 49 Box 521, 3000 Leuven, Belgium.
    Factors and situations influencing the value of patient preference studies along the medical product lifecycle: a literature review2018Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Industry, regulators, health technology assessment (HTA) bodies, and payers are exploring the use of patient preferences in their decision-making processes. In general, experience in conducting and assessing patient preference studies is limited. Here, we performed a systematic literature search and review to identify factors and situations influencing the value of patient preference studies, as well as applications throughout the medical product lifecyle. Factors and situations identified in 113 publications related to the organization, design, and conduct of studies, and to communication and use of results. Although current use of patient preferences is limited, we identified possible applications in discovery, clinical development, marketing authorization, HTA, and postmarketing phases.

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