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Ion Channels in Drug Discovery
Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden Thesis for doctoral degree (Ph.D.) 2008 Thesis for doctoral degree (Ph.D.) 2008 Ion Channels in Drug Discovery - focus on biological assays Ion Channels in Drug Discovery - focus on biological assays Kim Dekermendjian Ion Channels in Drug Discovery - focus on biological - focus on in Drug assays Channels Discovery Ion Kim Dekermendjian Kim Dekermendjian Stockholm 2008 Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden Ion Channels in Drug Discovery - focus on biological assays Kim Dekermendjian Stockholm 2008 Main Supervisor: Bertil B Fredholm, Professor Department of Physiology and Pharmacology Karolinska Institutet. Co-Supervisor: Olof Larsson, PhD Associated Director Department of Molecular Pharmacology, Astrazeneca R&D Södertälje. Opponent: Bjarke Ebert, Adjunct Professor Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark. and Department of Electrophysiology, H. Lundbeck A/S, Copenhagen, Denmark. Examination board: Ole Kiehn, Professor Department of Neurovetenskap, Karolinska Institutet. Bryndis Birnir, PhD Docent Department of Clinical Sciences, Lund University. Bo Rydqvist, Professor Department of Physiology and Pharmacology Karolinska Institutet. All previously published papers were reproduced with permission from the publisher. Front page (a) Side view of the GABA-A model; the trans membrane domain (TMD) (bottom) spans through the lipid membrane (32 Å) and partly on the extracellular side (12 Å), while the ligand binding domain (LBD) (top) is completely extracellular (60 Å). (b) The LBD viewed from the extracellular side (diameter of 80 Å). (c) The TMD viewed from the extracellular side. Arrows and ribbons (which correspond to ȕ-strands and Į- helices, respectively) are coloured according to position in each individual subunit sequence, as well as in the TM4 of each subunit which is not bonded to the rest of the model (with permission from Campagna-Slater and Weaver, 2007 Copyright © 2006 Elsevier Inc.). -
FDA Comments on CBD in Foods
Popular Content Public Health Focus FDA and Marijuana: Questions and Answers 1. How is marijuana therapy being used by some members of the medical community? 2. Why hasn’t the FDA approved marijuana for medical uses? 3. Is marijuana safe for medical use? 4. How does FDA’s role differ from NIH and DEA’s role when it comes to the investigation of marijuana for medical use? 5. Does the FDA object to the clinical investigation of marijuana for medical use? 6. What kind of research is the FDA reviewing when it comes to the efficacy of marijuana? 7. How can patients get into expanded access program for marijuana for medical use? 8. Does the FDA have concerns about administering a cannabis product to children? 9. What is FDA’s reaction to states that are allowing marijuana to be sold for medical uses without the FDA’s approval? 10. What is the FDA’s position on state “Right to Try” bills? 11. Has the agency received any adverse event reports associated with marijuana for medical conditions? 12. Can products that contain cannabidiol be sold as dietary supplements? 13. Is it legal, in interstate commerce, to sell a food to which cannabidiol has been added? 14. In making the two previous determinations, why did FDA conclude that substantial clinical investigations have been authorized for and/or instituted about cannabidiol, and that the existence of such investigations has been made public? 15. Will FDA take enforcement action regarding cannabidiol products that are marketed as dietary supplements? What about foods to which cannabidiol has been added? 16. -
Exploring Non-Covalent Interactions Between Drug-Like Molecules and the Protein Acetylcholinesterase
Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase Lotta Berg Doctoral Thesis, 2017 Department of Chemistry Umeå University, Sweden This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-644-2 Elektronisk version tillgänglig på http://umu.diva-portal.org/ Printed by: VMC-KBC Umeå Umeå, Sweden, 2017 “Life is a relationship between molecules, not a property of any one molecule” Emile Zuckerkandl and Linus Pauling 1962 i Table of contents Abstract vi Sammanfattning vii Papers covered in the thesis viii List of abbreviations x 1. Introduction 1 1.1. Drug discovery 1 1.2. The importance of non-covalent interactions 1 1.3. Fundamental forces of non-covalent interactions 2 1.4. Classes of non-covalent interactions 3 1.5. Hydrogen bonds 3 1.5.1. Definition of the hydrogen bond 3 1.5.2. Classical and non-classical hydrogen bonds 4 1.5.3. CH∙∙∙Y hydrogen bonds 5 1.6. Interactions between aromatic rings 6 1.7. Thermodynamics of binding 7 1.8. The essential enzyme acetylcholinesterase 8 1.8.1. The relevance of research focused on AChE 8 1.8.2. The structure of AChE 9 1.8.3. AChE in drug discovery 10 2. Scope of the thesis 12 3. Background to techniques and methods 13 3.1. Structure determination by X-ray crystallography 13 3.1.1. The significance of crystal structures of proteins 13 3.1.2. Data collection and structure refinement 13 3.1.3. Electron density maps 14 3.1.4. -
Vaccines, Diagnostics, and Treatments): Frequently Asked Questions
Development and Regulation of Medical Countermeasures for COVID-19 (Vaccines, Diagnostics, and Treatments): Frequently Asked Questions June 25, 2020 Congressional Research Service https://crsreports.congress.gov R46427 SUMMARY R46427 Development and Regulation of Medical June 25, 2020 Countermeasures for COVID-19 (Vaccines, Agata Dabrowska Diagnostics, and Treatments): Frequently Analyst in Health Policy Asked Questions Frank Gottron Specialist in Science and In recent months, the Coronavirus Disease 2019 (COVID-19) pandemic has spread globally, with Technology Policy the United States now reporting the highest number of cases of any country in the world. Currently, there are few treatment options available to lessen the health impact of the disease and no vaccines or other prophylactic treatments to curb the spread of the virus. Amanda K. Sarata Specialist in Health Policy The biomedical community has been working to develop new therapies or vaccines, and to repurpose already approved therapeutics, that could prevent COVID-19 infections or lessen Kavya Sekar severe outcomes in patients. In addition, efforts have been underway to develop new diagnostic Analyst in Health Policy tools (i.e., testing) to help better identify and isolate positive cases, thereby reducing the spread of the disease. To this end, Congress has appropriated funds for research and development into new medical countermeasures (MCMs) in several recent supplemental appropriations acts. MCMs are medical products that may be used to treat, prevent, or diagnose conditions associated with emerging infectious diseases or chemical, biological, radiological, or nuclear (CBRN) agents. MCMs include biologics (e.g., vaccines, monoclonal antibodies), drugs (e.g., antimicrobials, antivirals), and medical devices (e.g., diagnostic tests). -
Comparisons of Food and Drug Administration and European
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector VALUE IN HEALTH 15 (2012) 1108–1118 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/jval Health Policy Analyses Comparisons of Food and Drug Administration and European Medicines Agency Risk Management Implementation for Recent Pharmaceutical Approvals: Report of the International Society for Pharmacoeconomics and Outcomes Research Risk Benefit Management Working Group Yvonne Lis, PhD1, Melissa H. Roberts, MS2, Shital Kamble, PhD3, Jeff J. Guo, PhD4, Dennis W. Raisch, PhD5,* 1PAREXEL International, Uxbridge, UK; 2Lovelace Clinic Foundation Research, Albuquerque, New Mexico, USA; 3Quintiles-Outcome, Rockville, MD, USA; 4College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH, USA; 5College of Pharmacy, University of New Mexico, Albuquerque, NM, USA ABSTRACT Objective: 1) To compare the Food and Drug Administration’s (FDA’s) requirements not included in RMPs were patient medication guides Risk Evaluation and Mitigation Strategies (REMS) and European (100% of the drugs), provider communication plans (38%), and routine Medicines Agency’s (EMA’s) Risk Management Plan (RMP) guidances monitoring of REMS (66%). RMP requirements not included in REMS and 2) to compare REMS and RMPs for specific chemical entities and were specific adverse event reporting (45% of the drugs), prospective biological products. Methods: FDA, EMA, and pharmaceutical com- registry studies (34%), prospective epidemiology studies (24%), addi- pany Web sites were consulted for details pertaining to REMS and tional trial data (28%), and Summary of Product Characteristics RMPs. REMS requirements include medication guides, communication contraindications (76%). Conclusions: Both REMS and RMPs provide plans, elements to ensure safe use, implementation systems, and positive guidance for identification, monitoring, and minimization of specified assessment intervals. -
New Drugs Are Not Enough‑Drug Repositioning in Oncology: an Update
INTERNATIONAL JOURNAL OF ONCOLOGY 56: 651-684, 2020 New drugs are not enough‑drug repositioning in oncology: An update ROMINA GABRIELA ARMANDO, DIEGO LUIS MENGUAL GÓMEZ and DANIEL EDUARDO GOMEZ Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina Received August 15, 2019; Accepted December 16, 2019 DOI: 10.3892/ijo.2020.4966 Abstract. Drug repositioning refers to the concept of discov- 17. Lithium ering novel clinical benefits of drugs that are already known 18. Metformin for use treating other diseases. The advantages of this are that 19. Niclosamide several important drug characteristics are already established 20. Nitroxoline (including efficacy, pharmacokinetics, pharmacodynamics and 21. Nonsteroidal anti‑inflammatory drugs toxicity), making the process of research for a putative drug 22. Phosphodiesterase-5 inhibitors quicker and less costly. Drug repositioning in oncology has 23. Pimozide received extensive focus. The present review summarizes the 24. Propranolol most prominent examples of drug repositioning for the treat- 25. Riluzole ment of cancer, taking into consideration their primary use, 26. Statins proposed anticancer mechanisms and current development 27. Thalidomide status. 28. Valproic acid 29. Verapamil 30. Zidovudine Contents 31. Concluding remarks 1. Introduction 2. Artesunate 1. Introduction 3. Auranofin 4. Benzimidazole derivatives In previous decades, a considerable amount of work has been 5. Chloroquine conducted in search of novel oncological therapies; however, 6. Chlorpromazine cancer remains one of the leading causes of death globally. 7. Clomipramine The creation of novel drugs requires large volumes of capital, 8. Desmopressin alongside extensive experimentation and testing, comprising 9. Digoxin the pioneer identification of identifiable targets and corrobora- 10. -
Clinical Pharmacology of Antiмcancer Agents
A CLINI CLINICAL PHARMACOLOGY OF NTI- C ANTI-CANCER AGENTS C AL PHARMA AN Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren www.esmo.org C ER A This is a user-friendly handbook, designed for young GENTS medical oncologists, where they can access the essential C information they need for providing the treatment which could OLOGY OF have the highest chance of being effective and tolerable. By finding out more about pharmacology from this handbook, young medical oncologists will be better able to assess the different options available and become more knowledgeable in the evaluation of new treatments. ESMO ESMO Handbook Series European Society for Medical Oncology CLINICAL PHARMACOLOGY OF Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland Handbook Series ANTI-CANCER AGENTS Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren ESMO Press · ISBN 978-88-906359-1-5 ISBN 978-88-906359-1-5 www.esmo.org 9 788890 635915 ESMO Handbook Series handbook_print_NEW.indd 1 30/08/12 16:32 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS CM15 ESMO Handbook 2012 V14.indd1 1 2/9/12 17:17:35 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS Edited by Cristiana Sessa Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Luca Gianni Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Marina Garassino Oncology Department, Istituto Nazionale dei Tumori, Milan, Italy Henk van Halteren Department of Internal Medicine, Gelderse Vallei Hospital, Ede, The Netherlands ESMO Press CM15 ESMO Handbook 2012 V14.indd3 3 2/9/12 17:17:35 First published in 2012 by ESMO Press © 2012 European Society for Medical Oncology All rights reserved. -
Biological Target and Its Mechanism He Zuan* Department of Pharmacology, School of Medicine,Shenzhen University, Shenzhen 518000, China
OPEN ACCESS Freely available online Journal of Cell Signaling Editorial Biological Target and Its Mechanism He Zuan* Department of Pharmacology, School of Medicine,Shenzhen University, Shenzhen 518000, China EDITORIAL NOTE 1. There is no direct change in the biological target, but the binding of the substance stops other endogenous substances (such Biological target is whatsoever within an alive organism to which as triggering hormones) from binding to the target. Contingent some other entity (like an endogenous drug or ligand) is absorbed on the nature of the target, this effect is mentioned as receptor and binds, subsequent in a modification in its function or antagonism, ion channel blockade or enzyme inhibition. behaviour. For examples of mutual biological targets are nucleic acids and proteins. Definition is context dependent, and can refer 2. A conformational change in the target is induced by the stimulus to the biological target of a pharmacologically active drug multiple, which results in a change in target function. This change in function the receptor target of a hormone like insulin, or some other target can mimic the effect of the endogenous substance in which case of an external stimulus. Biological targets are most commonly the effect is referred to as receptor agonism or be the opposite of proteins such as ion channels, enzymes, and receptors. The term the endogenous substance which in the case of receptors is referred "biological target" is regularly used in research of pharmaceutical to as inverse agonism. to describe the nastive protein in body whose activity is altered Conservation Ecology: These biological targets are conserved by a drug subsequent in a specific effect, which may a desirable across species, making pharmaceutical pollution of the therapeutic effect or an unwanted adverse effect. -
Uncovering New Drug Properties in Target-Based Drug-Drug Similarity Networks
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.12.988600; this version posted March 12, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Uncovering new drug properties in target-based drug-drug similarity networks Lucret¸ia Udrescu1, Paul Bogdan2, Aim´eeChi¸s3, Ioan Ovidiu S^ırbu3,6, Alexandru Top^ırceanu4, Renata-Maria V˘arut¸5, Mihai Udrescu4,6* 1 Department of Drug Analysis, "Victor Babe¸s",University of Medicine and Pharmacy Timi¸soara,Timi¸soara,Romania 2 Ming Hsieh Department of Electrical Engineering, University of Southern California, Los Angeles, CA, USA 3 Department of Biochemistry, "Victor Babe¸s"University of Medicine and Pharmacy Timi¸soara,Timi¸soara,Romania 4 Department of Computer and Information Technology, Politehnica University of Timi¸soara,Timi¸soara,Romania 5 Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania 6 Timi¸soaraInstitute of Complex Systems, Timi¸soara,Romania * [email protected] Abstract Despite recent advances in bioinformatics, systems biology, and machine learning, the accurate prediction of drug properties remains an open problem. Indeed, because the biological environment is a complex system, the traditional approach { based on knowledge about the chemical structures { cannot fully explain the nature of interactions between drugs and biological targets. Consequently, in this paper, we propose an unsupervised machine learning approach that uses the information we know about drug-target interactions to infer drug properties. -
MDMA, MBDB' and I! I the Classichallucinogens
Differences Between the Mechanism I t of Action of MDMA, MBDB' and i! I the ClassicHallucinogens. i Identification of a New Therapeutic Class: Entactogens Jawi'ri", ! 7 U$ DAVID E. NICHOLS, PH.D.* The widespread use of psychedelic drugs, such as quantitative structure-activity relationships (QSARs). lysergic ac;.d diethylamide (LSD), during the 1960's and Simply stated, attempts are made to find quantitative 1970's IcC to severe reactions by governmental agencies correlations (or equations) that relate biological activity to and proscriptions against their use. However, with the fundamental properties of the molecule. This approach is high deg _e of interest in mind-altering drugs in the being widely developed in the pharmaceutical industry in United States, as evidenced by their widespread popular- order to understand more fully how particular types of ity, it wasonlyamatteroftimebeforenewdrugsappeared drugs work, and to be able to predict which additional that were developed outside of the pharmaceutical corn- molecules should be synthesized. It should also be added panics, that no equations have been developed that adequately j Nearly 70 years after its first synthesis, 3,4- correlate hallucinogenic or psychedelic activity with any methy'enedioxymethamphetamine (MDMA) was redis- particular molecular property. covered. Although it had its' more recent origin in the class In this context, it is important to define clearly the of dr. gs that is generally defined as psychedelic or hallu- type of biological activity that is being measured. It is cino enic, it clearly appears different from LSD. In hu- typical that if a molecule has several different sites of mar , MDMA induces a state of reduced anxiety and action in the brain, that each oneof these actions may be lc .red defensiveness that makes it attractive to thera- related to entirely different structural features or proper- pi . -
Drug Development and Clinical Trials 101
DRUG DEVELOPMENT AND CLINICAL TRIALS 101 March 27, 2021 A Resource of PWSA | USA | pwsausa.org DISCOVERY - PHASE 1 Dean S. Carson, PhD, Saniona, Inc. A Resource of PWSA | USA | pwsausa.org DRUG DISCOVERY AND DEVELOPMENT Why is it important? • Rare hormone producing tumor of the anterior pituitary gland • Cabergoline, an ergot derivative, is a potent dopamine D2 receptor agonist that blocks pituitary production of prolactin • Ergot is a fungus that grows on rye and related plants, and produces alkaloids that can cause ergotism in humans and animals that eat the contaminated grain • Painful seizures, mania, psychosis, headaches, nausea, vomiting A Resource of PWSA | USA | pwsausa.org 3 PHARMACOLOGY • Pharmacology is the science of how • Clinical Pharmacology applies the basic drugs and biologics act on biological science and principles of pharmacology to systems and how the system responds to the practice of medicine the drug Basic science Translational pharmacology Clinical practice Doctors, pharmacists, dentists, veterinarians use the information discovered from pharmacology to select the best medications to treat patients A Resource of PWSA | USA | pwsausa.org 4 MECHANISM OF ACTION • Modern drug discovery is a mechanism • What are the known consequences of that driven field mechanism in a disease state? ie. • Nearly all new experimental therapeutics potential efficacy have a defined mechanism-of-action and • What are the known consequences of that most have companion diagnostics allowing mechanism in healthy systems? ie. researchers to -
Research and Development in the Pharmaceutical Industry
Research and Development in the Pharmaceutical Industry APRIL | 2021 At a Glance This report examines research and development (R&D) by the pharmaceutical industry. Spending on R&D and Its Results. Spending on R&D and the introduction of new drugs have both increased in the past two decades. • In 2019, the pharmaceutical industry spent $83 billion dollars on R&D. Adjusted for inflation, that amount is about 10 times what the industry spent per year in the 1980s. • Between 2010 and 2019, the number of new drugs approved for sale increased by 60 percent compared with the previous decade, with a peak of 59 new drugs approved in 2018. Factors Influencing R&D Spending. The amount of money that drug companies devote to R&D is determined by the amount of revenue they expect to earn from a new drug, the expected cost of developing that drug, and policies that influence the supply of and demand for drugs. • The expected lifetime global revenues of a new drug depends on the prices that companies expect to charge for the drug in different markets around the world, the volume of sales they anticipate at those prices, and the likelihood the drug-development effort will succeed. • The expected cost to develop a new drug—including capital costs and expenditures on drugs that fail to reach the market—has been estimated to range from less than $1 billion to more than $2 billion. • The federal government influences the amount of private spending on R&D through programs (such as Medicare) that increase the demand for prescription drugs, through policies (such as spending for basic research and regulations on what must be demonstrated in clinical trials) that affect the supply of new drugs, and through policies (such as recommendations for vaccines) that affect both supply and demand.