A Live Cell Nanobret Binding Assay Allows the Study of Ligand-Binding Kinetics to the Adenosine A3 Receptor
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CPT Fellowship Psychopharm Focus
Clinical Pharmacology and Toxicology Residency Program, McGill University One year Fellowship in Clinical Pharmacology and Toxicology: Psychopharmacology Focus Fellowship Director: Dr. Theodore Kolivakis, MD, FRCPC Program Director: Dr. Howard Margolese Location: MUHC (70-90%) JGH (10-20%) DH (10-20%) (% Depends on Selectives chosen based on interest of the Fellow) Number of Positions: 1 Length of Program: 1 year. The ‘academic’ year is July 1 to June 30, however ‘off-cycle’ candidates will also be considered Program General Information: The Clinical Pharmacology and Toxicology Fellowship: Psychopharmacology Focus is a one-year supervised training program open to qualified psychiatry residents who have completed their Psychiatry Postgraduate training and are eligible for practice in Canada. This fellowship program is based in the Clinical Psychopharmacology and Therapeutics Unit of the McGill University Health Centre (MUHC), Department of Psychiatry, McGill University, and is carried out in collaboration with a number of University hospitals and centers, namely the Clinical Toxicology Service of the MUHC, Alan Edwards Centre for Research on Pain at the MUHC, Internal Medicine at the MUHC or JGH (Hypertension clinic), Douglas Mental Health University Institute, and the Montreal Neurological Hospital and Institute; as well as the Department of Pharmacy of the MUHC. The objective of this program is to provide advanced training in clinical pharmacology and toxicology with a psychopharmacology focus to residents interested in gaining an expertise in the pharmacological treatment of their patients. Specifically they will learn best practices for 1. patients with complex medication regimes, 2. treatment resistant patients, 3. adverse drug reactions including iatrogenic ADR 4. consultation based care and practices After successfully completing the fellowship it is expected that fellows will become experts in the management of the most difficult psychiatric patients who are often those with significant other medical co-morbidities. -
Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development
Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development Gerlie Gieser, Ph.D. Office of Clinical Pharmacology, Div. IV Objectives • Outline the Phase 1 studies conducted to characterize the Clinical Pharmacology of a drug; describe important design elements of and the information gained from these studies. • List the Clinical Pharmacology characteristics of an Ideal Drug • Describe how the Clinical Pharmacology information from Phase 1 can help design Phase 2/3 trials • Discuss the timing of Clinical Pharmacology studies during drug development, and provide examples of how the information generated could impact the overall clinical development plan and product labeling. Phase 1 of Drug Development CLINICAL DEVELOPMENT RESEARCH PRE POST AND CLINICAL APPROVAL 1 DISCOVERY DEVELOPMENT 2 3 PHASE e e e s s s a a a h h h P P P Clinical Pharmacology Studies Initial IND (first in human) NDA/BLA SUBMISSION Phase 1 – studies designed mainly to investigate the safety/tolerability (if possible, identify MTD), pharmacokinetics and pharmacodynamics of an investigational drug in humans Clinical Pharmacology • Study of the Pharmacokinetics (PK) and Pharmacodynamics (PD) of the drug in humans – PK: what the body does to the drug (Absorption, Distribution, Metabolism, Excretion) – PD: what the drug does to the body • PK and PD profiles of the drug are influenced by physicochemical properties of the drug, product/formulation, administration route, patient’s intrinsic and extrinsic factors (e.g., organ dysfunction, diseases, concomitant medications, -
Affinity-Based, Biophysical Methods to Detect and Analyze Ligand Binding
Journal of Structural Biology 172 (2010) 142–157 Contents lists available at ScienceDirect Journal of Structural Biology journal homepage: www.elsevier.com/locate/yjsbi Affinity-based, biophysical methods to detect and analyze ligand binding to recombinant proteins: Matching high information content with high throughput Geoff A. Holdgate a, Malcolm Anderson a, Fredrik Edfeldt b, Stefan Geschwindner b,* a Lead Generation Sciences, AstraZeneca R&D Alderley Park, 50F49 Mereside, Alderley Park, United Kingdom b Lead Generation Sciences, AstraZeneca R&D Mölndal, S-43183 Mölndal, Sweden article info abstract Article history: Affinity-based technologies have become impactful tools to detect, monitor and characterize molecular Available online 4 July 2010 interactions using recombinant target proteins. This can aid the understanding of biological function by revealing mechanistic details, and even more importantly, enables the identification of new improved Keywords: ligands that can modulate the biological activity of those targets in a desired fashion. The selection of the Affinity appropriate technology is a key step in that process, as each one of the currently available technologies Thermodynamic offers a characteristic type of biophysical information about the ligand-binding event. Alongside the Interaction indisputable advantages of each of those technologies they naturally display diverse restrictions that Fragment are quite frequently related to the target system to be studied but also to the affinity, solubility and Ligand Screening molecular size of the ligands. This paper discusses some of the theoretical and experimental aspects of the most common affinity-based methods, what type of information can be gained from each one of those approaches, and what requirements as well as limitations are expected from working with recombinant proteins on those platforms and how those can be optimally addressed. -
Recommendations for the Bioanalytical Method Validation Of
Pharmaceutical Research, Vol. 20, No. 11, November 2003 (© 2003) Research Paper Recommendations for the studies was held more than a decade ago in Crystal City, VA (1,2). The proceedings and recommendations of that meeting Bioanalytical Method Validation of essentially became a de facto guideline for bioanalytical meth- Ligand-binding Assays to Support ods validation within the pharmaceutical industry. The con- ference addressed validation of bioanalytical methods in gen- Pharmacokinetic Assessments eral, but acknowledged differences between chromatographic of Macromolecules and nonchromatographic assays, including immunoassays and microbiological-based methods. After the original Crystal City conference, bioanalytical methods validation was ad- dressed subsequently several times at meetings and in publi- Binodh DeSilva,1 Wendell Smith,2 Russell Weiner,3 cations (3–6). Most emphasis to date has been on validation of Marian Kelley,4,11 JoMarie Smolec,5 Ben Lee,6 bioanalytical methods for conventional small molecular Masood Khan,7 Richard Tacey,8 Howard Hill,9 and weight drugs, principally due to the rapid growth during the Abbie Celniker10 1990s in the use of hyphenated mass-spectrometry as a rou- tine analytical tool. Because of the evolution in divergent analytical tech- Received July 2, 2003; accepted July 30, 2003 nologies for conventional small molecules and macromol- Purpose. With this publication a subcommittee of the AAPS Ligand ecules and the growth in the interest of macromolecular Binding Assay Bioanalytical Focus Group (LBABFG) makes recom- therapeutics, the topic of bioanalytical methods validation mendations for the development, validation, and implementation of was revisited in 2000 in 2 meetings, one focused on small ligand binding assays (LBAs) that are intended to support pharma- molecule analytes (7) and the other focused on macromol- cokinetic and toxicokinetic assessments of macromolecules. -
IJBCP International Journal of Basic & Clinical Pharmacology Antibiotic
Print ISSN: 2319-2003 | Online ISSN: 2279-0780 IJBCP International Journal of Basic & Clinical Pharmacology DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20191567 Original Research Article Antibiotic sensitivity profile and resistance of microorganisms isolated from south Indian population, a hospital based study at Velappanchavady, Chennai, India Brethis C. S.1*, Mahender G.2, Thamizharasan S.1, Suresh Kumar K.3, Sudharson T.3 1Department of Pharmacology, A.C.S Medical College and ABSTRACT Hospital, Velappanchavadi, Chennai, Tamil Nadu, India Background: Increasing rates of antibiotic drug resistance has been noted in 2Department of Forensic recent times and this adversely affects the prognosis and outcomes of patients. Medicine and Toxicology, There is a greater need for local resistance prevalence data in order to guide District Hospital Gajwel, empirical prescription and to identify areas in which medical need for newer Telangana, India antimicrobial agents is greater. 3Department of Forensic Methods: A prospective hospital based observational study was carried out to Medicine and Toxicology, determine antibiotic sensitivity profile and resistance pattern of microorganisms. A.C.S Medical College and Samples were collected from urinary tract infections, while cultures from blood Hospital, Velappanchavadi, stream infections, sputum samples and Serology. Antibiotic susceptibility was Chennai, Tamil Nadu, India determined by the standard disc diffusion method. Data interpretation was based on CLSI, 2017 guidelines for antimicrobial susceptibility testing. Received: 14 April 2019 Results: The predominant isolates from the samples were, Staphylococcus Accepted: 19 April 2019 aureus (16.7%) 67, K. pneumoniae (11.5%) 46, E. coli (29.4%) 118, P. aeruginosa (6%) 24. Escherichia coli, the most common causative organism *Correspondence to: showed high resistance to commonly used drugs such as Ampicillin (60.1%) 71, Dr. -
Simple, Rapid Ligand-Binding Assay Using Immobilized Cellular Membranes
Simple, Rapid Ligand-Binding Assay Using Immobilized Cellular Membranes Paula Denney Eason, Renée C. Benson, Jenny T. Ly, Rachel A. Saxer, James L. Wilbur, George B. Sigal, Eli N. Glezer, Hans A. Biebuyck, Jacob N. Wohlstadter, and Robert M. Umek TM TM A division of Meso Scale Diagnostics,TM LLC. Simple, Rapid Ligand-Binding Assay Using Immobilized Cellular Membranes Abstract This poster presents a robust, receptor-ligand binding assay based upon a novel assay platform developed by Meso Scale DiscoveryTM (MSDTM). MSD’s platform combines array technologies and electrochemiluminescence detection to achieve ultra-fast, highly sensitive assays in a homogeneous format. Cellular membranes containing the EGF receptor were passively adsorbed to MSD proprietary coated electrodes embedded in multi-well plates. Binding of EGF to the EGF receptor was detected by inducing and measuring electrochemi- luminescence from a labeled EGF ligand. Approximately 1000 cell equivalents per well yielded a signal to background ratio of 20. The observed KD agrees with that reported in the literature and demonstrates that immobilization of the membranes and modification of the ligand do not alter the binding affinity. Binding specificity was confirmed with two inhibitors. The assay can be readily adapted to facilitate analysis of a broad array of receptor-ligand interactions. TM TM A division of Meso Scale Diagnostics,TM LLC. Simple, Rapid Ligand-Binding Assay Using Immobilized Cellular Membranes TM Multi-Array TechnologyTM Multi-Array Technology Unified technology platform with instruments, plates and reagents for drug discovery for drug discovery. Combines the power of microarrays with the sensitivity of electrochemiluminescence Combines the power of microarrays with the sensitivity of electrochemiluminescence.96-, 384- and 1536 microplate formats 96-,Multi-Spot 384- TMand plates 1536 with microplate high density formats. -
Clinical Pharmacology and Pharmacogenomics Fellowship Research Training
CCPP COMMITTEE ON CLINICAL PHARMACOLOGY AND PHARMACOGENOMICS Clinical Pharmacology and Pharmacogenomics Fellowship Research Training The Committee on Clinical Pharmacology and Pharmacogenomics at the University of Chicago, chaired by M. Eileen Dolan, PhD, is seeking motivated trainees for our clinical pharmacology and pharmacogenomics fellowship training program. Candidates should have a PhD, MD, PharmD/PhD or PharmD degree and have successfully completed a clinical residency. Ability to demonstrate a commitment to research, including but not limited to evidence provided by a record of prior publication is encouraged. This program is open to those interested in personalized medicine, pharmacogenomics, new drug development, clinical pharmacology, clinical trial design, genome wide association studies, genetics of drug abuse and/or overcoming drug resistance. Our two-year American Board of Clinical Pharmacology (ABCP) accredited program is a multidisciplinary, comprehensive and collaborative initiative that emphasizes individual creativity in the context of an encouraging environment. The two-year fellowship provides salary support/benefits for protected research time dedicated to research efforts along with support to attend meetings. Trainees will have the opportunity to tailor their work to emphasize clinical, translational or basic science research spending protected time devoted to their research efforts with the remainder dedicated to core curriculum and clinical activities (as applicable). After successful completion, trainees are eligible to become board certified in Clinical Pharmacology. General information at: http://ccpp.uchicago.edu/ or contact the programs’ educational manager, Michelle Domecki at [email protected]. Candidates who are U.S. citizens or permanent residents will be considered for support via an institutional training grant. The University of Chicago is an Equal Opportunity/Affirmative Action Employer. -
Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: a Free Assay Disguised As Total
pharmaceutics Article Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total John Hood 1,*, Ignacio González-García 1 , Nicholas White 1, Leeron Marshall 1,2, Vincent F. S. Dubois 1 , Paolo Vicini 1,3 and Paul G. Baverel 1,4 1 Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Cambridge CB21 6GH, UK; [email protected] (I.G.-G.); [email protected] (N.W.); [email protected] (L.M.); [email protected] (V.F.S.D.); [email protected] (P.V.); [email protected] (P.G.B.) 2 Salford Royal Foundation Trust, Salford M6 8HD, UK 3 Confo Therapeutics, 9052 Ghent, Zwijnaarde, Belgium 4 Roche Pharma Research and Early Development, Clinical Pharmacology, Pharmaceutical Sciences, Roche Innovation Center Basel F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland * Correspondence: [email protected]; Tel.: +44-1223-749-6288 Abstract: A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, Citation: Hood, J.; González-García, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and function- I.; White, N.; Marshall, L.; Dubois, ally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation V.F.S.; Vicini, P.; Baverel, P.G. clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled Pharmacokinetic-Pharmacodynamic per cohort. Eight volunteers received placebo as control. -
Bioavailability and Bioequivalence Studies Submitted in Ndas Or Inds — General Considerations
Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact the CDER Office of Clinical Pharmacology at 301-796-5008 or [email protected]. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) March 2014 Biopharmaceutics Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs— General Considerations Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue, Silver Spring, MD 20993 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm Phone: 301-796-3400; Fax: 301-847-8714 [email protected] U.S. Department of Health and Human Services Food -
Real-Time Quantitative Measurement of Autocrine Ligand Binding Indicates That Autocrine Loops Are Spatially Localized
Proc. Natl. Acad. Sci. USA Vol. 95, pp. 15368–15373, December 1998 Cell Biology Real-time quantitative measurement of autocrine ligand binding indicates that autocrine loops are spatially localized DOUGLAS A. LAUFFENBURGER*†‡,GREGORY T. OEHRTMAN†,LAURA WALKER†, AND H. STEVEN WILEY§ *Division of Bioengineering & Environmental Health and Center for Biomedical Engineering and †Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; and §Department of Pathology, University of Utah Medical Center, Salt Lake City, UT 84132 Communicated by Edwin N. Lightfoot, Jr., University of Wisconsin, Madison, WI, October 15, 1998 (received for review July 21, 1998) ABSTRACT Autocrine ligands are important regulators rapid (,30 sec) and small (,0.1 unit) changes in solution pH of many normal tissues and have been implicated in a number in the cellular microenvironment in an '1 ml chamber above of disease states, including cancer. However, because by the sensor. These pH changes [termed ‘‘extracellular acidifi- definition autocrine ligands are synthesized, secreted, and cation rate’’ (ECAR)] can arise from both metabolic and bound to cell receptors within an intrinsically self-contained regulatory events and have been shown to be quantitatively ‘‘loop,’’ standard pharmacological approaches cannot be used related to specific activation of many types of cell receptors, to investigate relationships between ligandyreceptor binding including tyrosine kinase receptors, G protein receptors, and and consequent cellular responses. We demonstrate here a ion channel receptors (16) with EC50 values similar to those new approach for measurement of autocrine ligand binding to derived from direct-labeled ligand binding (17). Hence, for cells, using a microphysiometer assay originally developed for exogenous ligands the microphysiometer can be used to obtain investigating cell responses to exogenous ligands. -
BIOEQUIVALENCE and STATISTICS in CLINICAL PHARMACOLOGY
Interdisciplinary Statistics BIOEQUIVALENCE and STATISTICS in CLINICAL PHARMACOLOGY Scott Patterson GlaxoSmithKline Pharmaceuticals Pennsylvania, USA Byron Jones Pfizer Global Research & Development Kent, UK Chapman & Hall/CRC Taylor & Francis Croup Boca Raton London New York Contents Preface xi List of figures xiii List of tables xv 1 Drug Development and Clinical Pharmacology 1 1.1 Aims of This Book 2 1.2 Drug Development 3 1.3 Clinical Pharmacology 5 1.4 Statistics in Clinical Pharmacology 11 1.5 Structure of the Book 14 2 History and Regulation of Bioequivalence 17 2.1 When and How BE Studies Are Performed 19 2.2 Why Are BE Studies Performed? 27 2.3 Deciding When Formulations Are Bioequivalent 28 2.4 Potential Issues with TOST Bioequivalence 32 2.5 Current International Regulation 36 3 Testing for Average Bioequivalence 39 3.1 Background 39 3.2 Linear Model for 2 x 2 Data 44 3.3 Applying the TOST Procedure 49 3.4 Carry-over, Sequence, and Interaction Effects 52 3.5 Checking Assumptions Made about the Linear Model 56 3.6 Power and Sample Size for ABE in the 2x2 Design 58 3.7 Example Where Test and Reference Are Not ABE (il 3.8 Nonparametric Analysis 68 3.9 Some Practical Issues 76 4 BE Studies with More Than Two Periods 79 4.1 Background 80 4.2 Three-period Designs 81 viii CONTENTS 4.3 Within-subject Variability 87 4.4 Robust Analyses for Three Period Designs 90 4.5 Four-period Designs 92 4.6 Designs with More Than Two Treatments 96 4.7 Nonparametric Analyses of Tmax 102 4.8 Technical Appendix: Efficiency 116 4.9 Tables of Data 120 -
Action and Resistance Mechanisms of Antibiotics: a Guide for Clinicians
J Anaesthesiol Clin Pharmacol. 2017 Jul-Sep; 33(3): 300–305. PMCID: PMC5672523 doi: 10.4103/joacp.JOACP_349_15: 10.4103/joacp.JOACP_349_15 PMID: 29109626 Action and resistance mechanisms of antibiotics: A guide for clinicians Garima Kapoor, Saurabh Saigal,1 and Ashok Elongavan2 Department of Microbiology, Gandhi Medical College, Bhopal, Madhya Pradesh, India 1Department of Trauma and Emergency, AIIMS, Bhopal, Madhya Pradesh, India 2Department of Critical Care Medicine, Columbia Asia Hospital, Bengaluru, Karnataka, India Address for correspondence: Dr. Garima Kapoor, Department of Microbiology, Gandhi Medical College, Bhopal, Madhya Pradesh, India. E-mail: [email protected] Copyright : © 2017 Journal of Anaesthesiology Clinical Pharmacology This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. Abstract Infections account for a major cause of death throughout the developing world. This is mainly due to the emergence of newer infectious agents and more specifically due to the appearance of antimicrobial resistance. With time, the bacteria have become smarter and along with it, massive imprudent usage of antibiotics in clinical practice has resulted in resistance of bacteria to antimicrobial agents. The antimicrobial resistance is recognized as a major problem in the treatment of microbial infections. The biochemical resistance mechanisms used by bacteria include the following: antibiotic inactivation, target modification, altered permeability, and “bypass” of metabolic pathway. Determination of bacterial resistance to antibiotics of all classes (phenotypes) and mutations that are responsible for bacterial resistance to antibiotics (genetic analysis) are helpful.