(2R,6R)-Hydroxynorketamine Do Not Block NMDA Receptor Function

Total Page:16

File Type:pdf, Size:1020Kb

(2R,6R)-Hydroxynorketamine Do Not Block NMDA Receptor Function Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function Eric W. Lumsdena,1, Timothy A. Troppolib,1, Scott J. Myersc, Panos Zanosd, Yasco Aracavaa, Jan Kehre,f, Jacqueline Lovettg, Sukhan Kimc, Fu-Hua Wange,f, Staffan Schmidte,f, Carleigh E. Jenned, Peixiong Yuanh, Patrick J. Morrisi, Craig J. Thomasi, Carlos A. Zarate Jr.h, Ruin Moaddelg, Stephen F. Traynelisc,2, Edna F. R. Pereiraa,j,2, Scott M. Thompsonb,d,2, Edson X. Albuquerquea,j,k,2, and Todd D. Gouldd,j,l,m,2,3 aDepartment of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201; bDepartment of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201; cDepartment of Pharmacology, Emory University, Atlanta, GA 30329; dDepartment of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201; eDepartment of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden; fPronexus Analytical AB, SE-167 33 Bromma, Sweden; gBiomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224; hSection on the Neurobiology and Treatment of Mood Disorders, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; iDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892; jDepartment of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201; kDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; lDepartment of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201; and mVeterans Affairs Maryland Health Care System, Baltimore, MD 21201 Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 24, 2019 (received for review September 19, 2018) Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) Significance is a putative fast-acting antidepressant candidate. Although inhibi- tion of NMDA-type glutamate receptors (NMDARs) is one mecha- Standard antidepressant treatments require weeks to show effec- ’ nism proposed to underlie ketamine s antidepressant and adverse tiveness. A single subanesthetic dose of ketamine rapidly attenu- R R PHARMACOLOGY effects, the potency of (2 ,6 )-HNK to inhibit NMDARs has not been ates many clinical signs and symptoms of depression; however, established. We used a multidisciplinary approach to determine the ketamine treatment also has many adverse effects, including dis- R R effects of (2 ,6 )-HNK on NMDAR function. Antidepressant-relevant sociation and potential for abuse, which are mediated by NMDA R R behavioral responses and (2 ,6 )-HNK levels in the extracellular glutamate receptor (NMDAR) inhibition. Previous work has revealed compartment of the hippocampus were measured following sys- that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) R R temic (2 ,6 )-HNK administration in mice. The effects of ketamine, induces antidepressant-like responses in rodents while minimizing R R S S (2 ,6 )-HNK, and, in some cases, the (2 ,6 )-HNK stereoisomer were the adverse effects observed with ketamine. The results of this i ii evaluated on the following: ( ) NMDA-induced lethality in mice, ( ) study, using a multitude of experimental approaches, confirm that NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) antidepressant-relevant concentrations of (2R,6R)-HNK are not suf- iii in the CA1 field of mouse hippocampal slices, ( )NMDAR- ficient to block NMDARs. This provides a basis for work directed at mediated miniature excitatory postsynaptic currents (mEPSCs) and alternative molecular targets and toward novel drugs that exert NMDA-evoked currents in CA1 pyramidal neurons of rat hippocam- rapid antidepressant effects independent of NMDAR inhibition and iv Xenopus pal slices, and ( ) recombinant NMDARs expressed in oo- NMDAR-mediated adverse effects. cytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, Author contributions: E.W.L., T.A.T., S.J.M., P.Z., Y.A., J.K., S.F.T., E.F.R.P., S.M.T., E.X.A., the ED50 of (2R,6R)-HNK to prevent NMDA-induced lethality was and T.D.G. designed research; E.W.L., T.A.T., S.J.M., P.Z., Y.A., J.K., J.L., S.K., F.-H.W., S.S., found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. C.E.J., P.Y., P.J.M., C.J.T., C.A.Z., and R.M. performed research; E.W.L., T.A.T., S.J.M., P.Z., The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal Y.A., J.K., C.E.J., and S.F.T. analyzed data; and E.W.L., T.A.T., P.Z., E.F.R.P., S.M.T., E.X.A., and T.D.G. wrote the paper. extracellular concentrations of ∼8 μM, which were well below con- Conflict of interest statement: T.D.G. has received research funding from Janssen, Roche, and centrations required to inhibit synaptic and extrasynaptic NMDARs Allergan Pharmaceuticals, and served as a consultant for FSV7 LLC during the preceding in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less 3 years. The authors declare competing financial interests: T.D.G., P.Z., R.M., P.J.M., C.J.T., potent than ketamine at inhibiting NMDARs. These data demon- and C.A.Z. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxy- strate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)- norketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhe- donia, suicidal ideation, and post-traumatic stress disorders. C.A.Z. and R.M. are listed as co- HNK and support the conclusion that direct NMDAR inhibition does inventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, not contribute to antidepressant-relevant effects of (2R,6R)-HNK. and other stereoisomeric dehydro- and hydroxylated metabolites of ketamine metabolites in the treatment of depression and neuropathic pain. R.M., P.J.M., C.J.T., and C.A.Z. have as- depression | ketamine | hydroxynorketamine | antidepressant | signed patent rights to the US Government but will share a percentage of any royalties that may be received by the Government. P.Z. and T.D.G. have assigned their patent rights to the NMDA receptor University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland, Baltimore. S.F.T. received research support from ajor depressive disorder (MDD) occurs in about 16% of Janssen, is a consultant for Janssen, is a member of the Scientific Advisory Board for Sage Therapeutics, is a co-founder of NeurOp, Inc., and co-inventor on Emory-owned IP. S.J.M. owns Mthe population over the course of a lifetime (1). It is esti- stock in NeurOp, Inc., which is developing NMDAR inhibitors for use in treating neurological mated that MDD affected nearly 7% of all US adults in 2016, disease and disorders. All other authors declare no competing interests. and that one-half of those individuals were prescribed typical This article is a PNAS Direct Submission. antidepressant medications as part of their treatment regimen Published under the PNAS license. (2). Although such typical antidepressants, including selective 1E.W.L. and T.A.T. contributed equally to this work. serotonin and norepinephrine reuptake inhibitors, tricyclic an- 2S.F.T., E.F.R.P., S.M.T., E.X.A., and T.D.G. contributed equally to this work. tidepressants, and monoamine oxidase inhibitors, can sometimes 3To whom correspondence should be addressed. Email: [email protected]. mitigate clinical symptoms of MDD, the onset of action of these This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. drugs is very slow, requiring daily administration over weeks or 1073/pnas.1816071116/-/DCSupplemental. months for clinical improvement (3). In addition, ∼30% of pa- www.pnas.org/cgi/doi/10.1073/pnas.1816071116 PNAS Latest Articles | 1of10 Downloaded by guest on September 30, 2021 tients suffering from MDD fail to respond after attempting (14). Nevertheless, reports that at high concentrations (2R,6R)-HNK multiple treatments (3). The use of (R,S)-ketamine (ketamine) inhibits NMDAR function led to the suggestion that NMDAR in- for the treatment of MDD has generated much excitement be- hibition accounts for (2R,6R)-HNK’s antidepressant-relevant effects cause it reduces, and in some patients eliminates, many core (31, 32). symptoms of depression, including depressed mood, anhedonia, The present study systematically assessed the effects of (2R,6R)- and suicidal ideation, within hours following i.v. administration of HNK on NMDAR function. Tests exploring behavioral despair and ’ a single subanesthetic dose. Furthermore, ketamine is effective in hyponeophagia in mice were employed to confirm the metabolite s – antidepressant-relevant effects. Analytical assays were used to quantify patients who are refractory to typical antidepressants (4 9). R R Although ketamine is a promising alternative to standard clinically plasma, whole-brain, and extracellular hippocampal levels of (2 ,6 )- used antidepressants, it induces adverse effects at antidepressant doses, HNK following systemic treatment of mice with a dose that produces particularly dissociation (10). Furthermore, ketamine, a derivative of the antidepressant-relevant effects. A series of functional tests including in illicit drug phencyclidine, is widely abused (11). Ketamine is rapidly and vivo NMDA-induced lethality and ex vivo electrophysiological mea- stereoselectively metabolized in the liver to a number of metabolites, surements of NMDAR activity in hippocampal neurons and in oocytes including the norketamines, hydroxyketamines, dehydronorketamines, expressing distinct NMDAR subtypes (GluN1/GluN2A, GluN2B, and the hydroxynorketamines (HNKs) (12). Demethylation of the GluN2C, or GluN2D) were used to determine the potency for R R methyl amine on ketamine’s central cyclohexyl ring generates the nor- (2 ,6 )-HNK to inhibit NMDARs.
Recommended publications
  • PLGG1, a Plastidic Glycolate Glycerate Transporter, Is Required for Photorespiration and Defines a Unique Class of Metabolite Transporters
    PLGG1, a plastidic glycolate glycerate transporter, is required for photorespiration and defines a unique class of metabolite transporters Thea R. Picka,1, Andrea Bräutigama,1, Matthias A. Schulza, Toshihiro Obatab, Alisdair R. Fernieb, and Andreas P. M. Webera,2 aInstitute of Plant Biochemistry, Cluster of Excellence on Plant Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany; and bMax-Planck Institute for Molecular Plant Physiology, Department of Molecular Physiology, 14476 Potsdam-Golm, Germany Edited by Wolf B. Frommer, Carnegie Institution for Science, Stanford, CA, and accepted by the Editorial Board January 8, 2013 (received for review September 4, 2012) Photorespiratory carbon flux reaches up to a third of photosyn- (PGLP). Glycolate is exported from the chloroplasts to the per- thetic flux, thus contributes massively to the global carbon cycle. oxisomes, where it is oxidized to glyoxylate by glycolate oxidase The pathway recycles glycolate-2-phosphate, the most abundant (GOX) and transaminated to glycine by Ser:glyoxylate and Glu: byproduct of RubisCO reactions. This oxygenation reaction of glyoxylate aminotransferase (SGT and GGT, respectively). Glycine RubisCO and subsequent photorespiration significantly limit the leaves the peroxisomes and enters the mitochondria, where two biomass gains of many crop plants. Although photorespiration is molecules of glycine are deaminated and decarboxylated by the a compartmentalized process with enzymatic reactions in the glycine decarboxylase complex (GDC) and serine hydroxymethyl- chloroplast, the peroxisomes, the mitochondria, and the cytosol, transferase (SHMT) to form one molecule each of serine, ammo- nia, and carbon dioxide. Serine is exported from the mitochondria no transporter required for the core photorespiratory cycle has to the peroxisomes, where it is predominantly converted to glyc- been identified at the molecular level to date.
    [Show full text]
  • The Self-Inhibitory Nature of Metabolic Networks and Its Alleviation Through Compartmentalization
    ARTICLE Received 30 Oct 2016 | Accepted 23 May 2017 | Published 10 Jul 2017 DOI: 10.1038/ncomms16018 OPEN The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization Mohammad Tauqeer Alam1,2, Viridiana Olin-Sandoval1,3, Anna Stincone1,w, Markus A. Keller1,4, Aleksej Zelezniak1,5,6, Ben F. Luisi1 & Markus Ralser1,5 Metabolites can inhibit the enzymes that generate them. To explore the general nature of metabolic self-inhibition, we surveyed enzymological data accrued from a century of experimentation and generated a genome-scale enzyme-inhibition network. Enzyme inhibition is often driven by essential metabolites, affects the majority of biochemical processes, and is executed by a structured network whose topological organization is reflecting chemical similarities that exist between metabolites. Most inhibitory interactions are competitive, emerge in the close neighbourhood of the inhibited enzymes, and result from structural similarities between substrate and inhibitors. Structural constraints also explain one-third of allosteric inhibitors, a finding rationalized by crystallographic analysis of allosterically inhibited L-lactate dehydrogenase. Our findings suggest that the primary cause of metabolic enzyme inhibition is not the evolution of regulatory metabolite–enzyme interactions, but a finite structural diversity prevalent within the metabolome. In eukaryotes, compartmentalization minimizes inevitable enzyme inhibition and alleviates constraints that self-inhibition places on metabolism. 1 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. 2 Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. 3 Department of Food Science and Technology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Vasco de Quiroga 15, Tlalpan, 14080 Mexico City, Mexico.
    [Show full text]
  • The Effect of Morphine-Lidocaine-Ketamine
    THE EFFECT OF MORPHINE-LIDOCAINE-KETAMINE- DEXMEDETOMIDINE CO-INFUSION ON MINIMUM ALVEOLAR CONCENTRATION OF ISOFLURANE IN DOGS Thesis Presented in Partial Fulfillment of the Requirements for the Degree of Master of Science in the Graduate School of The Ohio State University By Lisa Michelle Sams, D.V.M. Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2011 Thesis Committee: Dr. Phillip Lerche, Advisor Dr. Richard M. Bednarski Dr. John A.E. Hubbell Copyright by Lisa Michelle Sams 2011 ABSTRACT The purpose of this study was to determine the effects of an infusion of dexmedetomidine, a co-infusion of morphine-lidocaine-ketamine (MLK), and a co- infusion of dexmedetomidine-morphine-lidocaine-ketamine (alpha-MLK) on minimum alveolar concentration (MAC) of isoflurane in dogs. The MAC of an inhalant anesthetic required to prohibit purposeful movement is a measure of anesthetic potency (Eger et al 1965). Isoflurane is the most commonly used inhalant anesthetic in veterinary practice (Lozano et al 2009), but has potent vasodilatory effects and causes a dose-dependent decrease in mean arterial pressure in anesthetized dogs (Steffey and Howland 1977). Additional drugs are used during anesthesia to decrease the inhalant anesthetic requirement, a concept referred to as balanced anesthesia. Each of the drugs we infused has a different central nervous system receptor mechanism of action. Co-infusion of MLK, as well as the infusion of each drug separately, has been shown to reduce MAC in isoflurane-anesthetized dogs (Muir et al 2003). Dexmedetomidine, an alpha-2 agonist, has been shown to reduce isoflurane MAC in dogs (Pascoe et al 2006).
    [Show full text]
  • Pharmacogenetics of Ketamine Metabolism And
    Pharmacogenetics of Ketamine Metabolism and Immunopharmacology of Ketamine Yibai Li B.HSc. (Hons) Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide September 2014 A thesis submitted for the Degree of PhD (Medicine) Table of contents TABLE OF CONTENTS .............................................................................................. I LIST OF FIGURES ....................................................................................................IV LIST OF TABLES ......................................................................................................IV ABSTRACT ............................................................................................................... V DECLARATION .......................................................................................................VIII ACKNOWLEDGEMENTS ..........................................................................................IX ABBREVIATIONS .....................................................................................................XI CHAPTER 1. INTRODUCTION .................................................................................. 1 1.1 A historical overview of ketamine ........................................................................................ 1 1.2 Structure and Chemistry ....................................................................................................... 3 1.3 Classical analgesic mechanisms of ketamine ...................................................................
    [Show full text]
  • Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice
    pharmaceutics Review Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice Malavika Deodhar 1, Sweilem B Al Rihani 1 , Meghan J. Arwood 1, Lucy Darakjian 1, Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (M.D.); [email protected] (S.B.A.R.); [email protected] (M.J.A.); [email protected] (L.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Received: 5 August 2020; Accepted: 31 August 2020; Published: 4 September 2020 Abstract: In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity.
    [Show full text]
  • Opioid Withdrawal ��������������������������������������������������������������������������������������������������� 15 Mark S
    Magdalena Anitescu Honorio T. Benzon Mark S. Wallace Editors Challenging Cases and Complication Management in Pain Medicine 123 Challenging Cases and Complication Management in Pain Medicine Magdalena Anitescu Honorio T. Benzon • Mark S. Wallace Editors Challenging Cases and Complication Management in Pain Medicine Editors Magdalena Anitescu Honorio T. Benzon Department of Anesthesia and Critical Care Department of Anesthesiology University of Chicago Medicine Northwestern University Chicago, IL Feinberg School of Medicine USA Chicago, IL USA Mark S. Wallace Division of Pain Medicine Department of Anesthesiology University of California San Diego School of Medicine La Jolla, CL USA ISBN 978-3-319-60070-3 ISBN 978-3-319-60072-7 (eBook) https://doi.org/10.1007/978-3-319-60072-7 Library of Congress Control Number: 2017960332 © Springer International Publishing AG 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication.
    [Show full text]
  • Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling
    H OH metabolites OH Article Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling Nhung Pham , Ruben G. A. van Heck † , Jesse C. J. van Dam , Peter J. Schaap , Edoardo Saccenti and Maria Suarez-Diez * Laboratory of Systems and Synthetic Biology; Wageningen University & Research, 6708 WE, Wageningen, The Netherlands; [email protected] (N.P.); [email protected] (R.G.A.v.H.); [email protected] (J.C.J.v.D.); [email protected] (P.J.S.); [email protected] (E.S.) * Correspondence: [email protected] † Current address: EDP Patent Attorneys, 6708 WH, Wageningen, The Netherlands. Received: 28 December 2018; Accepted: 31 January 2019; Published: 6 February 2019 Abstract: Genome-scale metabolic models (GEMs) are manually curated repositories describing the metabolic capabilities of an organism. GEMs have been successfully used in different research areas, ranging from systems medicine to biotechnology. However, the different naming conventions (namespaces) of databases used to build GEMs limit model reusability and prevent the integration of existing models. This problem is known in the GEM community, but its extent has not been analyzed in depth. In this study, we investigate the name ambiguity and the multiplicity of non-systematic identifiers and we highlight the (in)consistency in their use in 11 biochemical databases of biochemical reactions and the problems that arise when mapping between different namespaces and databases. We found that such inconsistencies can be as high as 83.1%, thus emphasizing the need for strategies to deal with these issues. Currently, manual verification of the mappings appears to be the only solution to remove inconsistencies when combining models.
    [Show full text]
  • Ranking Metabolite Sets by Their Activity Levels
    H OH metabolites OH Article Ranking Metabolite Sets by Their Activity Levels Karen McLuskey 1,† , Joe Wandy 1,† , Isabel Vincent 2 , Justin J. J. van der Hooft 3 , Simon Rogers 4 , Karl Burgess 5 and Rónán Daly 1,* 1 Glasgow Polyomics, University of Glasgow, Glasgow G61 1QH, UK; [email protected] (K.M.); [email protected] (J.W.) 2 IBioIC, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G1 1XQ, UK; [email protected] 3 Bioinformatics Group, Wageningen University, 6708 PB Wageningen, The Netherlands; [email protected] 4 School of Computing Science, University of Glasgow, Glasgow G12 8QQ, UK; [email protected] 5 Centre for Synthetic and Systems Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JG, UK; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Related metabolites can be grouped into sets in many ways, e.g., by their participation in series of chemical reactions (forming metabolic pathways), or based on fragmentation spectral similarities or shared chemical substructures. Understanding how such metabolite sets change in relation to experimental factors can be incredibly useful in the interpretation and understanding of complex metabolomics data sets. However, many of the available tools that are used to perform this analysis are not entirely suitable for the analysis of untargeted metabolomics measurements. Here, we present PALS (Pathway Activity Level Scoring), a Python library, command line tool, and Web application that performs the ranking of significantly changing metabolite sets over different experimental conditions.
    [Show full text]
  • Question of the Day Archives: Monday, December 5, 2016 Question: Calcium Oxalate Is a Widespread Toxin Found in Many Species of Plants
    Question Of the Day Archives: Monday, December 5, 2016 Question: Calcium oxalate is a widespread toxin found in many species of plants. What is the needle shaped crystal containing calcium oxalate called and what is the compilation of these structures known as? Answer: The needle shaped plant-based crystals containing calcium oxalate are known as raphides. A compilation of raphides forms the structure known as an idioblast. (Lim CS et al. Atlas of select poisonous plants and mushrooms. 2016 Disease-a-Month 62(3):37-66) Friday, December 2, 2016 Question: Which oral chelating agent has been reported to cause transient increases in plasma ALT activity in some patients as well as rare instances of mucocutaneous skin reactions? Answer: Orally administered dimercaptosuccinic acid (DMSA) has been reported to cause transient increases in ALT activity as well as rare instances of mucocutaneous skin reactions. (Bradberry S et al. Use of oral dimercaptosuccinic acid (succimer) in adult patients with inorganic lead poisoning. 2009 Q J Med 102:721-732) Thursday, December 1, 2016 Question: What is Clioquinol and why was it withdrawn from the market during the 1970s? Answer: According to the cited reference, “Between the 1950s and 1970s Clioquinol was used to treat and prevent intestinal parasitic disease [intestinal amebiasis].” “In the early 1970s Clioquinol was withdrawn from the market as an oral agent due to an association with sub-acute myelo-optic neuropathy (SMON) in Japanese patients. SMON is a syndrome that involves sensory and motor disturbances in the lower limbs as well as visual changes that are due to symmetrical demyelination of the lateral and posterior funiculi of the spinal cord, optic nerve, and peripheral nerves.
    [Show full text]
  • Ketamine Homogeneous Enzyme Immunoassay (HEIA™)
    Ketamine Homogeneous Enzyme Immunoassay (HEIA™) Exclusively from Immunalysis Formula: C13H16CINO Semi-Quantitative or Qualitative Testing Systematic Name: (RS)- 2- (2- chlorophenyl)- 2- (methylamino)cyclohexanone Accurate and reliable Brand Names: Ketanest®, Ketaset®, Ketalar® Ready to use About Ketamine: Ketamine is an anesthetic agent used in the United States since 1972 for veterinary and pediatric medicine. It is also used in the treatment of depression and postoperative pain management. However, in recent years it has gained popularity as a street drug used at clubs and raves due to its hallucinogenic effects. Administration: Oral; intravenous; intramuscular; insufflation Elimination: Ketamine metabolizes by N-demethylation to Norketamine and further dehydrogenates to Dehydronorketamine. After 72 hours of a single dose, 2.3% of Ketamine is unchanged, 1.6% is Norketamine, 16.2% is Dehydronorketamine, and 80% is hydroxylated derivatives of Ketamine.1,2 Abuse Potential: An overdose can cause unconsciousness and dangerously slowed breathing. 1) R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, Fourth Edition, p. 412-414. 2) K. Moore, J.Skerov, B.Levine, and A.Jacobs, Urine Concentrations of Ketamine and Norketamine Following Illegal Consumption, J.Anal, Toxicol. 25: 583-588 (2001). Ketanest® is a registered trademark of Pfizer, Inc., Ketaset® is a trademark of ZOETIS W LLC., Ketalar® is a trademark of PAR STERILE PRODUCTS, LLC. Tel 909.482.0840 | Toll Free 888.664.8378 | Fax 909.482.0850 ISO13485:2003 www.immunalysis.com CERTIFIED
    [Show full text]
  • Fundamentals of C.R.P.S
    FUNDAMENTALS OF C.R.P.S. PHILIP GETSON, D.O. SEPTEMBER 11, 2015 R.S.D. Association National Conference I DON’T KNOW ! Philip Getson, D.O. October 22, 1999 Third National RSD Association Conference Atlantic City N.J. HISTORY The first mention of CRPS dates back to the 17th Century when surgeon Ambrose Pare reported that King Charles IX suffered from persistent pain and contracture of his arm following a bloodletting procedure During the Civil War Mitchell described soldiers suffering from burning pain due to gunshot wounds. He termed this Causalgia In 1900 Sudek described complications of trauma to the limbs with swelling, limitation of motor function and resistance to treatment The term Reflex Sympathetic Dystrophy was first used by Evans in 1946 NOMENCLATURE Causalgia Sudek’s Atrophy Post traumatic Pain Syndrome Post traumatic Painful Arthrosis Sudek’s Dystrophy Post Traumatic Edema Reflex Dystrophy Shoulder Hand Syndrome Chronic Traumatic Edema Algodystrophy Peripheral Trophoneurosis Sympathalgia Reflex Sympathetic Dystrophy Reflex Neurovascular dystrophy DEFINITION Complex Regional Pain is a neuropathic/inflammatory pain disorder characterized by: 1. Severe pain that extends beyond the injured area and is disproportionate to the inciting event. 2. Autonomic dysregulation 3. Edema – usually neuropathic in nature 4. Movement disorders 5. Atrophy and/or dystrophy CAUSE There is no single cause of CRPS Some more common are: sprain, contusion, surgery, fracture, infections, myocardial infarctions, carpel tunnel syndrome,
    [Show full text]
  • Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events Christine Marie Emnett Washington University in St
    Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Winter 12-15-2014 Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events Christine Marie Emnett Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Part of the Biology Commons Recommended Citation Emnett, Christine Marie, "Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events" (2014). Arts & Sciences Electronic Theses and Dissertations. 347. https://openscholarship.wustl.edu/art_sci_etds/347 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology and Biomedical Sciences Neurosciences Dissertation Examination Committee: Steven Mennerick, Chair James Huettner Daniel Kerschensteiner Peter D. Lukasiewicz Joseph Henry Steinbach Modulation of NMDA Receptor Activity During Physiological and Pathophysiological Events by Christine Marie Emnett A dissertation presented to the Graduate School of Arts and Sciences of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2014
    [Show full text]