DOCSLIB.ORG

Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose 1521-0103/371/2/409–415$35.00 https://doi.org/10.1124/jpet.118.256115 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 371:409–415, November 2019 U.S. Government work not protected by U.S. copyright Special Section on The Opioid Crisis Fighting Fire with Fire: Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose Philip Krieter, Shwe Gyaw, Roger Crystal, and Phil Skolnick National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (P.K., S.G.) and Opiant Pharmaceuticals, Santa Monica, California (R.C., P.S.) Downloaded from Received January 2, 2019; accepted March 27, 2019 ABSTRACT The dramatic rise in overdose deaths linked to synthetic opioids Encinitas, CA) reduced Tmax to 0.25 hour and increased Cmax by (e.g., fentanyl, carfentanil) may require more potent, longer- ∼2.2-fold. The pharmacokinetic properties of IN nalmefene jpet.aspetjournals.org duration opiate antagonists than naloxone. Both the high affinity (3 mg) formulated with dodecyl maltoside has characteristics of nalmefene at m opiate receptors and its long half-life led us to consistent with an effective rescue medication: its onset of examine the feasibility of developing an intranasal (IN) formula- action is comparable to an i.m. injection of nalmefene (1.5 mg) tion as a rescue medication that could be especially useful in previously approved to treat opioid overdose. Furthermore, treating synthetic opioid overdose. In this study, the pharmaco- the Cmax following IN administration was ∼3-fold higher than kinetic properties of IN nalmefene were compared with an following i.m. dosing, comparable to previously reported plasma intramuscular (i.m.) injection in a cohort of healthy volunteers. concentrations of nalmefene observed 5 minutes following a Nalmefene was absorbed slowly following IN administration, 1-mg i.v. dose. The high affinity, very rapid onset, and long half-life at ASPET Journals on September 25, 2021 with a median time to reach Cmax (Tmax) of 2 hours. Addition of the (.7 hours) of IN nalmefene present distinct advantages as a rescue absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., medication, particularly against longer-lived synthetic opioids. Introduction and prescription opioids [reviewed by Skolnick (2018)]. Fur- thermore, the piperidine-based structure of fentanyl is highly A Government Accountability Office report released in mutable. More than 1400 fentanyl analogs have been de- October 2018 declared the opioid crisis a public health scribed in the patent and scientific literature, and a dozen or emergency (https://www.gao.gov/products/GAO-18-685R). more are available on the illicit market (Misailidi et al., 2018), The most visible manifestation of this crisis is the rising adding another layer of complexity for both detection and number of opioid overdose deaths and the dramatic spike in interdiction by law enforcement. fatalities linked to fentanyl and related synthetic opioids. Naloxone is currently the only Food and Drug Administra- Thus, based on 2017 estimates (https://www.drugabuse.gov/ tion (FDA)–approved treatment for suspected or confirmed related-topics/trends-statistics/overdose-death-rates), syn- opioid overdose. The efficacy of naloxone at reversing the thetic opioids (“synthetics”) were linked to more than half of pharmacological actions of opioids, including synthetics such the estimated 49,000 opioid-related deaths, far surpassing as fentanyl, has been well established in both the emergency fatalities attributed to either heroin or prescription opioids. department and operating room [Glass et al., 1994; Kaplan et al., There are multiple factors responsible for the dangers posed 1999; reviewed by Boyer (2012)]. There are two FDA-approved by synthetics, including very high potencies, rapid onset of naloxone products (an autoinjector and a nasal spray) that are action, long half-lives, and ease of synthesis; this latter primarily used by first responders (e.g., police, emergency property translates to a low cost of goods relative to heroin medical service technicians, bystanders) to treat overdose victims (Skolnick, 2018). However, both anecdotal reports (https://www.bloomberg.com/news/articles/2017-08-16/heroin- P.S. and R.C. are employees of Opiant Pharmaceuticals, Inc. P.K. and S.G. are employees of the National Institutes of Health. era-antidotes-can-t-handle-overdoses-in-age-of-synthetics; The work was conducted under a Clinical Trial Agreement supported in part https://www.washingtonpost.com/amphtml/news/post-nation/ by Opiant Pharmaceuticals and National Institute on Drug Abuse contracts N01DA-12-8905, N01DA-13-8920, and N01DA-14-8914. wp/2018/04/10/study-despite-decline-in-prescriptions-opioid- https://doi.org/10.1124/jpet.118.256115. deaths-skyrocketing-due-to-heroin-and-synthetic-drugs/) and ABBREVIATIONS: AE, adverse event; AUC0–t, area under the concentration time curve from time zero to the last measurable concentration; CI, confidence interval; DDM, dodecyl maltoside; FDA, Food and Drug Administration; IN, intranasal; LC-MS/MS, liquid chromatography–tandem mass spectrometry; Tmax, time to reach Cmax;t1/2, elimination phase half-life. 409 410 Krieter et al. clinical case studies (Sutter et al., 2017; Uddayasankar, et al., alcohol from admission to the end of the last blood draw of the study, 2018) indicate overdose with synthetics such as fentanyl and from nicotine and from caffeine-containing products and food for at least carfentanil often requires more naloxone than the standard 1 hour prior to and 2 hours after dose administration, and from caffeine- unit doses [2 mg i.m./4 mg intranasal (IN)] generally available containing products and food from midnight the day prior to and 4 hours ’ to first responders. Some authors (Li et al., 2018) have recom- after nalmefene dosing. On days of dosing, a subject s vital signs were required to be within the normal range before receiving nalmefene mended parenteral naloxone doses of up to 12–15 mg to (systolic blood pressure .90 and #140 mm Hg, diastolic blood pressure .55 successfully reverse a synthetic overdose. While each overdose and #90 mm Hg, resting heart rate .40 and #100 beats per minute, situation is unique (Skolnick, 2018), the current National and respiratory rate .8 and #20 respirations per minute). Institute on Drug Abuse position states that “Overdoses of Study Design. The study was an inpatient, double-blind (for fentanyl should be treated immediately with naloxone and IN administration), randomized, four-period, four-treatment, six- may require higher doses to successfully reverse the overdose” sequence crossover. Subjects were randomly assigned to one of six (https://www.drugabuse.gov/publications/drugfacts/fentanyl). sequences to ensure at least two subjects in each sequence. On the day Moreover, the short half-life of naloxone (t1/2 1.3–2.4 hours) after clinic admission, participants were administered the study drug (Ryan and Dunne, 2018) can complicate the management of in randomized order with a 4-day washout period between doses. overdose with long-lived synthetics, including fentanyl (Ahonen Subjects remained at the clinic for 17 days until all four treatments – et al., 2000; Kharasch, 2015). were administered. They were contacted 3 5 days after discharge by a follow-up telephone call. Subjects fasted overnight before each dosing In response to the increasing number of overdose deaths day and received one of the following four treatments: Downloaded from linked to synthetics, National Institutes of Health leadership recently called for the development of “…stronger, longer- Treatment A: 3 mg IN (one 0.1-ml spray of a 30-mg/ml acting formulations of antagonists” (Volkow and Collins, nalmefene solution in one nostril). 2017). At face value, the opiate antagonist nalmefene fulfills Treatment B: 3 mg plus 0.25% dodecyl maltoside (DDM; Intravail) IN (one 0.1-ml spray of a 30-mg/ml nalmefene these criteria. Thus, multiple studies (Emmerson et al., 1994; solution containing 0.25% DDM in one nostril). Toll et al., 1998; Cassel et al., 2005) have demonstrated that Treatment C: 1.5 mg IN (one 0.1-ml spray of a 15-mg/ml the affinity of nalmefene is ∼5Â higher than naloxone at both nalmefene solution in one nostril). jpet.aspetjournals.org native and recombinant m opioid receptors. The half-life (t1/2) Treatment D: 1.5 mg i.m. (1.5 ml of a 1.0-mg/ml nalmefene solution). of parenterally administered nalmefene is ∼8.2–8.9 hours The IN treatments were randomized while the intramuscular dose (Dixon et al., 1986), comparable to the half-lives of synthetics was the last treatment of all subjects. The high dose (3 mg) of – such as fentanyl (7 to 8 hours) and sufentanil (6 9 hours) nalmefene was selected based on the relative bioavailability (∼50%) (Ahonen et al., 2000; Kharasch, 2015). In addition, the efficacy of the structurally related molecule, naloxone (Krieter et al., 2016), of nalmefene in treating opioid overdose has been established. and the FDA guidance on parenteral dosing of nalmefene that Thus, parenteral nalmefene was FDA approved (1995) to treat produces a maximum reversal of a suspected opioid overdose (https:// at ASPET Journals on September 25, 2021 opioid overdose was but withdrawn from the market in 2008 www.accessdata.fda.gov/drugsatfda_docs/label/2006/020459s006lbl.pdf). due to low sales, with no significant safety issues (https:// In phase I studies, intravenous doses of up to 24 mg have been well www.federalregister.gov/documents/2017/11/03/2017-23952/ tolerated in normal volunteers (Dixon et al., 1986). determination-that-revex-nalmefene-hydrochloride-injection-01- Study Details. IN devices were coded so neither the staff nor the milligram-basemilliliter-and-10). Here, we describe a pilot study subjects knew the treatment administered. IN nalmefene was admin- istered in the supine position, and subjects remained in this position in healthy volunteers demonstrating the feasibility of developing for approximately 1 hour after dosing.
Load more

Recommended publications
  • BMC Pharmacology Biomed Central
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Springer - Publisher Connector BMC Pharmacology BioMed Central Research article Open Access Pharmacological Properties of DOV 315,090, an ocinaplon metabolite Dmytro Berezhnoy†1, Maria C Gravielle†1, Scott Downing1, Emmanuel Kostakis1, Anthony S Basile2, Phil Skolnick2, Terrell T Gibbs1 and David H Farb*1 Address: 1Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, USA and 2DOV Pharmaceutical, Inc, 150 Pierce St., Somerset, NJ 08873-4185, USA Email: Dmytro Berezhnoy - [email protected]; Maria C Gravielle - [email protected]; Scott Downing - [email protected]; Emmanuel Kostakis - [email protected]; Anthony S Basile - [email protected]; Phil Skolnick - [email protected]; Terrell T Gibbs - [email protected]; David H Farb* - [email protected] * Corresponding author †Equal contributors Published: 13 June 2008 Received: 20 December 2007 Accepted: 13 June 2008 BMC Pharmacology 2008, 8:11 doi:10.1186/1471-2210-8-11 This article is available from: http://www.biomedcentral.com/1471-2210/8/11 © 2008 Berezhnoy et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Compounds targeting the benzodiazepine binding site of the GABAA-R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for pre- anesthetic sedation and muscle relaxation. It has been hypothesized that these various pharmacological effects are mediated by different GABAA-R subtypes.
    [Show full text]
  • Failed Trials for Central Nervous System Disorders Do Not Necessarily
    CORRESPONDENCE LINK TO ORIGINAL ARTICLE funding often outweighs the efforts required to rigorously challenge the novel findings; Failed trials for central nervous system thus, verification in an independent laboratory is unlikely. disorders do not necessarily invalidate As the costs of clinical studies are so much higher than those of preclinical development, preclinical models and drug targets one might assume that pharmaceutical com- panies would conduct robust replications of key findings. This is indeed the case during Anton Bespalov, Thomas Steckler, Bruce Altevogt, Elena Koustova, Phil Skolnick, lead optimization, candidate selection, test- Daniel Deaver, Mark J. Millan, Jesper F. Bastlund, Dario Doller, Jeffrey Witkin, ing different administration routes and the Paul Moser, Patricio O’Donnell, Ulrich Ebert, Mark A. Geyer, Eric Prinssen, use of primary preclinical disease models. Theresa Ballard and Malcolm Macleod However, this is far less common for stud- ies in the more complex disease models that are used in late stages of development and A recent article identified five key technical modest effects on survival. Numerous other are potentially more relevant for predicting determinants that make substantial contribu- drug candidates have reported efficacy in a clinical efficacy. tions to the outcome of drug R&D projects superoxide dismutase 1 (SOD1) mouse model In general, the rigorousness with which (Lessons learned from the fate of AstraZeneca’s of ALS (one of the common animal models preclinical data is obtained — and the result- drug pipeline: a five-dimensional framework. for this disease), but none of these candidates ing robustness of the data — is quite low; Nat. Rev. Drug Discov. 13, 419–431 (2014))1.
    [Show full text]
  • The Opioid Epidemic: Crisis and Solutions
    PA58CH09-Skolnick ARI 18 November 2017 9:40 Annual Review of Pharmacology and Toxicology The Opioid Epidemic: Crisis and Solutions Phil Skolnick Opiant Pharmaceuticals, Santa Monica, California 09401, USA; email: [email protected] Annu. Rev. Pharmacol. Toxicol. 2018. 58:143–59 Keywords First published as a Review in Advance on heroin, overdose, naloxone, vaccines, medication-assisted therapies, pain October 2, 2017 The Annual Review of Pharmacology and Toxicology Abstract by [email protected] on 01/16/18. For personal use only. is online at pharmtox.annualreviews.org The widespread abuse of prescription opioids and a dramatic increase in https://doi.org/10.1146/annurev-pharmtox- the availability of illicit opioids have created what is commonly referred to 010617-052534 as the opioid epidemic. The magnitude of this epidemic is startling: About Copyright c 2018 by Annual Reviews. 4% of the adult US population misuses prescription opioids, and in 2015, Annu. Rev. Pharmacol. Toxicol. 2018.58:143-159. Downloaded from www.annualreviews.org All rights reserved more than 33,000 deaths were attributable to overdose with licit and illicit opioids. Increasing the availability of medication-assisted treatments (such as buprenorphine and naltrexone), the use of abuse-deterrent formulations, and ANNUAL REVIEWS Further the adoption of US Centers for Disease Control and Prevention prescribing Click here to view this article's guidelines all constitute short-term approaches to quell this epidemic. How- online features: • Download figures as PPT slides ever, with more than 125 million Americans suffering from either acute or • Navigate linked references • Download citations chronic pain, the development of effective alternatives to opioids, enabled at • Explore related articles • Search keywords least in part by a fuller understanding of the neurobiological bases of pain, offers the best long-term solution for controlling and ultimately eradicating this epidemic.
    [Show full text]
  • Bfm:978-3-0348-8470-9/1.Pdf
    Milestones in Drug Therapy MDT Series Editors Prof. Dr. Michael J. Pamham Prof. Dr. J. Bruinvels PLIVA INFARM Research Institute Sweelincklaan 75 Prilaz baruna Filipovica 25 NL-3723 JC Bilthoven 10000 Zagreb The Netherlands Croatia Anxiolytics Edited by M. Briley and D. Nutt Springer Basel AG Editors Dr. Mike Briley Professor David Nutt Institut de Recherche Pierre Fabre University of Bristol Parc Industriei de la Chartreuse Psychophannacology Unit 8 I 100 Castres School of Medical Science France University Walk Bristol BS8 ITD UK Library of Congress Cataloging-in-Publication Data Anxiolytics / edited by M. Briley and D. NuU, p. cm - Milestones in drug therapy) lncludes bibliographical references and index. ISBN 978-3-0348-9581-1 ISBN 978-3-0348-8470-9 (eBook) DOI 10.1007/978-3-0348-8470-9 1. Tranquilizing drugs. 1. Briley, M. II. Nutt, David J., 1951- III. Series. RM333 A582 2000 615'.7882--{jc2I 00-033748 Deutsche Bibliothek Cataloging-in-Publication Data Anxiolytics / ed. by M. Briley and D. Nutt. - Basel ; Boston; Berlin: Birkhiiuser, 2000 (Milestones in drug therapy) ISBN 978-3-0348-9581-1 ISBN 978-3-0348-9581-1 The publisher and editor can give no guarantee for the infonnation an drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws aud regulations or free for general use. This work is subject to copyright.
    [Show full text]
  • Beyond Monoamine-Based Therapies: Clues to New Approaches
    Beyond Monoamine-Based Therapies: New Approaches Beyond Monoamine-Based Therapies: Clues to New Approaches Phil Skolnick, Ph.D. Advances in antidepressant therapy have resulted in agents with fewer serious side effects than, for example, nonselective monoamine oxidase inhibitors and tricyclic antidepressants. Nonetheless, these © Copyrightnewer agents are far from 2002 the ideal. Physicians Many of the drawbacks Postgraduate associated with these newer Press, agents—slow Inc. onset, low rate of response, and low rate of remission—are likely to be mechanism related. In order to overcome these problems, researchers must either improve upon these traditional, biogenic amine– based mechanisms or explore nontraditional mechanisms. Strategies for improving biogenic amine– based antidepressants include the so-called serotonin augmentation strategy and the broad spectrum agent that simultaneously blocks reuptake at the serotonin, norepinephrine, and dopamine transport- ers. Two nontraditional approaches employ modulation of glutamate receptor function. At face value, these glutamate-based approaches (N-methyl-D-aspartate [NMDA] antagonists and α-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA] receptor potentiators) appear diametrically opposed. However, these 2 mechanisms may ultimately impact similar cellular endpoints. (J Clin Psychiatry 2002;63[suppl 2]:19–23) One personal copy may be printed dvances in antidepressant treatment have resulted in generally termed serotonin augmentation. This strategy is Aagents that are safer and easier to use than, for based on the hypothesis that the delayed onset of seroto- example, nonselective irreversible monoamine oxidase in- nin-based agents (including selective serotonin reuptake hibitors (MAOIs) and tricyclics (TCAs). These newer inhibitors [SSRIs] and TCAs such as imipramine) is agents are far from ideal.
    [Show full text]
  • Virginia Drug Discovery Consortium Virginiabrainrx: a Symposium on Drug Discovery for the Brain
    Virginia Drug Discovery Consortium VirginiaBrainRx: A Symposium on Drug Discovery for the Brain May 23 - 24, 2016 Omni Richmond Hotel Richmond, Virginia Welcome letter May 23, 2016 Dear Symposium Participants: On behalf of the Organizing Committee, it is my great pleasure to welcome you to Richmond and to the VirginiaBrainRx Symposium. This Symposium includes five keynote lectures and several invited lectures from distinguished scientists, and also features poster presentations by scientists from around the Commonwealth. One of the major purposes of this Symposium is to provide networking opportunities that could foster new inter-university and public-private collaborative projects in brain drug-discovery. The NIH Roadmap for Research states “The scale and complexity of today’s … research problems increasingly demand that scientists move beyond the confines of their own discipline and explore new organizational models for team science….…”, and this Symposium has the goal of furthering such collaborations, especially when it comes to the discovery, development, and delivery of drugs to treat brain illness. The organizers hope that everyone will take advantage of the poster sessions and social times to meet new colleagues and to explore new collaborations. This Symposium is the first major public project of the fledgling irginia“V Drug Discovery Consortium.” This Consortium has the aim of fostering collaborative drug discovery research in all disease areas between Virginia’s universities and the pharmaceutical and biotech industries, and it plans to sponsor regular Symposia on different aspects of drug discovery, with the next one tentatively scheduled for Spring 2017. A short questionnaire is included in your registration materials, and I hope that you will take the time to complete this on Tuesday so as to guide the organizers in planning future Symposia.
    [Show full text]
  • Milestones in Drug Therapy
    Milestones in Drug Therapy Series Editors Michael J. Parnham, Director of Science & Technology, MediMlijeko d.o.o., Zagreb, Croatia Jacques Bruinvels, Bilthoven, The Netherlands Advisory Board J.C. Buckingham, Imperial College School of Medicine, London, UK R.J. Flower, The William Harvey Research Institute, London, UK A.G. Herman, Universiteit Antwerpen, Antwerp, Belgium P. Skolnick, National Institute on Drug Abuse, Bethesda, MD, USA For further volumes: http.//www.springer.com/series/4991 . Phil Skolnick Editor Glutamate-based Therapies for Psychiatric Disorders Volume Editor Phil Skolnick, Ph.D., D.Sc. (hon.) Director, Division of Pharmacotherapies & Medical Consequences of Drug Abuse National Institute on Drug Abuse 6001 Executive Boulevard Bethesda, MD 20892 USA [email protected] Series Editors Prof. Dr. Michael J. Parnham Director of Science & Technology MediMlijeko d.o.o. Pozarinje 7 HR-10000 Zagreb Croatia Prof. Dr. Jaques Bruinvels Sweelincklaan 75 NL-3723 JC Bilthoven The Netherlands ISBN 978-3-0346-0240-2 e-ISBN 978-3-0346-0241-9 DOI 10.1007/978-3-0346-0241-9 Library of Congress Control Number: 2010935790 # Springer Basel AG 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcast- ing, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protec- tive laws and regulations and therefore free for general use.
    [Show full text]
  • ASPET Preliminary Program for Experimental Biology 2003
    ASPET Preliminary Program for Experimental Biology 2003 Symposia Saturday Morning Inverse agonism: translation to in vivo function Chairs: James H. Woods and Richard Neubig Current status of inverse agonism as a pharmacological and therapeutic tool. Graeme Milligan, Univ. of Glasgow, Scotland Delta-opioid inverse agonists. Chris J. Evans, UCLA Inverse agonists in chemokine receptors. M.R. Brann, Acadia Pharmaceut. Inverse agonists and competitive antagonists in benzodiazepine dependent monkeys. Charles P. France, Univ. of Texas Hlth. Sci. Ctr., San Antonio Actions of hallucinogens and atypical antipsychotic drugs at serotonin receptors Chairs: Bryan L. Roth and David R. Sibley Atomic and molecular mechanisms of 5-HT2A receptor activation, targeting and trafficking. Bryan L. Roth, Case Western Reserve Univ. Med. Sch. RNA editing and genomic polymorphisms: relevance for schizophrenia, atypical antipsychotics and hallucinogens. Elaine Sanders-Bush, Vanderbilt Univ. Med. Sch. Functional roles of 5-HT2A receptors in the prefrontal cortex. Rodrigo Andrade, Wayne State Univ. Med. Sch. 5-HT2A receptors in psychosis and antipsychotic treatments: insights from knockout mice. Jay Gingrich, Columbia Univ. Serotonin 2C receptor distribution in the ventral tegmental area. Marcy J. Bubar, Univ. of Texas Med. Br. at Galveston (Abstract 3105) A pharmacology core curriculum: to be or not to be Chairs: Patricia B. Williams and Gregory D. Fink Introduction: More than facts: knowledge, skills and attitudes. Patricia B. Williams, Eastern Virginia Med. Sch. The knowledge objectives and essential drug list. Gary Rosenfeld, Univ. of Texas-Houston Med. Sch. A view from the top: a chairman speaks. Kenneth E. Moore, Michigan State Univ. Teaching medical school pharmacology in the 21st Century – can a core knowledge base be defined? Eric P.
    [Show full text]
  • Resource List
    National Institute of OPIOIDS AND THE WORKPLACE: Environmental Health Sciences Worker Training Program PREVENTION AND RESPONSE RESOURCE LIST Agency, Industry, Labor Union Information Federal Agency ■ National Institute of Environmental Health Sciences (NIEHS), National Clearinghouse for Worker Safety and Health Training. Illicit Drug Exposure. This page has links to the NIEHS “Prevention of Occupational Exposure to Fentanyl and Other Opioids” awareness-level training tool. https://tools.niehs.nih.gov/wetp/index.cfm?id=2562 ■ National Institute for Occupational Safety and Health (NIOSH). Opioids in the Workplace. This page has links to NIOSH field studies, guidelines, research, and data. https://www.cdc.gov/niosh/topics/opioids/default.html ■ National Institutes of Health (NIH), U.S. National Library of Medicine (NLM). Opioid Addiction and Treatment Health Information Resources. This page contains comprehensive and organized links to government information. https://envirotoxinfo.nlm.nih.gov/opiate-addiction-and-human-health.html#a2 Industry ■ 3M. Beyond Responding to Drug Overdoses: Keeping You Safe from Fentanyl. https://multimedia.3m.com/mws/media/1383737O/fentanyl-3m-whitepaper.pdf ■ Construction Industry Alliance for Suicide Prevention. http://www.cfma.org/news/content.cfm?ItemNumber=4570 ■ Dupont. Fentanyl and Other Opioids. http://www.dupont.com/products-and-services/personal-protective-equipment/chemical-protective- garments/articles/protection-against-fentanyl-opiods.html ■ Harris P. 2017. The opioid crisis and workplace safety. Cremation Association of North America Blog, 14 September. http://www.cremationassociation.org/blogpost/776820/284743/The-Opioid-Crisis-and-Workplace- Safety 1 Opioids and the Workplace National Institute of OPIOIDS AND THE WORKPLACE: Environmental Health Sciences Worker Training Program PREVENTION AND RESPONSE Labor Union ■ Association of Union Contractors.
    [Show full text]
  • Pharmacology of Ibogaine and Ibogaine-Related Alkaloids
    The Ibogaine Dossier. Pharmacology of Ibogaine https://ibogainedossier.com/alkaloids.html The Ibogaine Dossier Main | Search | Science | Opinion | Literature | Links | Treatment | Bookshop | Feedback Pharmacology of Ibogaine and Ibogaine-Related Alkaloids Piotr Popik , Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, NYU Conference on Ibogaine Poland Nov 5-6, 1999 and Phil Skolnick , Neuroscience Discovery, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA Appeared as Chapter #3, in "THE ALKALOIDS", Vol.52, pp. 197-231. 1998, San Diego, USA. ISBN 0-12-469552-3. Edited by G.A. Cordell. © 1998 by Academic Press Order The Alkaloids, Vol. 52 T. iboga roots Ibogaine is extracted from the bark of the root CONTENT I. INTRODUCTION II. HISTORICAL OVERVIEW. III. CHEMICAL STRUCTURE AND PROPERTIES. IV. PHARMACOKINETICS. V. GENERAL PHARMACOLOGICAL ACTIONS. A. Animal Studies 1. Locomotor activity. a. Effects on locomotor activity induced by other drugs 2. Tremor. 3. Anxiety and fear. 4. Effects on self-administration of other drugs. 5. Effects on drug dependence. 6. Pain and analgesia. 7. Aggression. 8. Interoceptive properties. 9. Reinforcing effects. 10. Effects on learning and memory. 11. Cardiovascular actions. B. Human Studies. VI. LETHALITY AND NEUROTOXIC EFFECTS. VII. EFFECTS ON SPECIFIC NEUROTRANSMITTER SYSTEMS A. Ibogaine Effects on Dopaminergic Systems. 1. Dopaminergic effects: Pharmacological Specificity. 2. Ibogaine alters the effects of abused drugs on dopaminergic systems. B. Opioid Systems C. Serotonergic Systems. D. Calcium Regulation. 1 of 30 1/20/2019 6:13 AM The Ibogaine Dossier. Pharmacology of Ibogaine https://ibogainedossier.com/alkaloids.html E. Cholinergic Systems. F. Gamma-Aminobutyric Acidergic [GABAergic] Systems. G.
    [Show full text]
  • Elsevier Editorial System(Tm) for Trends in Pharmacological Sciences Manuscript Draft
    Elsevier Editorial System(tm) for Trends in Pharmacological Sciences Manuscript Draft Manuscript Number: TIPS-D-09-00098R1 Title: Glutamate Based Antidepressants: 20 Years On Article Type: Opinion Keywords: N-methyl-D-aspartate receptors; NMDA antagonists; depression; antidepressants; glutamate; ionotropic glutamate receptors; metabotropic glutamate receptors Corresponding Author: Dr Phil Skolnick, Corresponding Author's Institution: New York University Langone Medical Center First Author: Phil Skolnick Order of Authors: Phil Skolnick; Piotr Popik, M.D., Ph.D.; Ramon Trullas, Ph.D. Abstract: Depression is a chronic, recurring illness that affects more than 120 million people worldwide. Drugs increasing the synaptic availability of serotonin and norepinephrine (biogenic amine-based agents) have been used to treat depression for more than 50 years. However, significant symptom improvement requires ≥2-4 weeks of treatment, and a first course of therapy provides symptom relief to only 60-65% of patients. Roche and Evotec recently announced plans to develop N- methyl-D-aspartate (NMDA) receptor antagonists targeting the NR2B subtype for treatment resistant depression. This announcement closely follows a report that another NR2B antagonist, traxoprodil (CP 101,606), is antidepressant in patients unresponsive to a serotonin selective reuptake inhibitor (SSRI) as well as reports of rapid and sustained antidepressant effects following a single injection of the NMDA antagonist, ketamine. Here we describe evidence that glutamate-based therapies may represent an effective alternative to biogenic-amine based agents for depression, and provide perspectives on developing these agents. Cover letter Department of Behavioral Neuroscience and Drug Development tel: (+48+12) 6623375, fax: (+48+12) 6374500, e-mail: [email protected] Kraków, August 30, 2009 Dr.
    [Show full text]
  • Ketamine for Treatment-Resistant Depression Sanjay J
    Ketamine for Treatment-Resistant Depression Sanjay J. Mathew • Carlos A. Zarate Jr. Editors Ketamine for Treatment- Resistant Depression The First Decade of Progress Editors Sanjay J. Mathew Carlos A. Zarate Jr. Psychiatry and Behavioral Sciences Experimental Therapeutics and Baylor College of Medicine Pathophysiology Branch Michael E. Debakey VA Medical Center National Institute of Mental Health Houston , Texas National Institutes of Health USA Bethesda , Maryland USA ISBN 978-3-319-42923-6 ISBN 978-3-319-42925-0 (eBook) DOI 10.1007/978-3-319-42925-0 Library of Congress Control Number: 2016960037 © Springer International Publishing Switzerland (outside the USA) 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms 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 specifi c 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. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.
    [Show full text]