DOCSLIB.ORG

Predictive Value of Parkinsonian Primates in Pharmacological Studies, a Comparison Between the Macaque, Marmoset and Squirrel Monkey I

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Predictive Value of Parkinsonian Primates in Pharmacological Studies, a Comparison Between the Macaque, Marmoset and Squirrel Monkey I JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version. JPET #247171 Title: Predictive value of parkinsonian primates in pharmacological studies, a comparison between the macaque, marmoset and squirrel monkey i Authors: Nicolas Veyres, Adjia Hamadjida, Philippe Huot Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada NV Montreal Neurological Institute, Montreal, QC, Canada HA,PH Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada PH Downloaded from jpet.aspetjournals.org at ASPET Journals on September 25, 2021 1 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version. JPET #247171 Running title: Predictive value of parkinsonian primates in drug research Text pages: 11 Word count abstract: 253 Word count introduction: 290 Word count discussion: 534 Word count manuscript: 2808 Number of figures: 9 Number of tables: 4 Number of references: 364 Number of supplementary tables: 3 Number of supplementary references: 231 Downloaded from Corresponding Author: Philippe Huot: Montreal Neurological Institute, 3801 University St, BT 209, Montreal, QC, Canada, H3A 2B4, Tel: +1-514-398-5957; Fax: +1-514-398-6644; Email: [email protected] List of non-standard abbreviations jpet.aspetjournals.org AADC: L-aromatic amino acid decarboxylase L-DOPA: L-3,4-dihydroxyphenylalanine MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Financial disclosure: There are no conflicts of interest. at ASPET Journals on September 25, 2021 2 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version. JPET #247171 Abstract The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold- standard animal model of Parkinson’s disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism and psychosis. Three species have been used in the majority of studies, the macaque, marmoset and squirrel monkey, the latter much less so than the first 2 species. However, the predictive value of each species at forecasting clinical efficacy, or lack thereof, is poorly documented. Here, we have reviewed all the published literature detailing Downloaded from pharmacological studies that assessed the effects of experimental drugs on dyskinesia, parkinsonism and psychosis in each of these species and have calculated their predictive value of jpet.aspetjournals.org success and failure at the clinical level. We found that, for dyskinesia, the macaque has a positive predictive value of 87.5% and a false positive rate of 38.1%, while the marmoset has a positive predictive value of 76.9% and a false positive rate of 15.6%. For parkinsonism, the macaque has a at ASPET Journals on September 25, 2021 positive predictive value of 68.2% and a false positive rate of 44.4%, while the marmoset has a positive predictive value of 86.9% and a false positive rate of 41.7%. No drug that alleviates psychosis in the clinic has shown efficacy at doing so in the macaque, while the marmoset has 100% positive predictive value. The small number of studies conducted in the squirrel monkey precluded us from calculating its predictive efficacy. We hope that our results will help in the design of pharmacological experiments and will facilitate the drug discovery and development process in PD. 3 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version. JPET #247171 Introduction Since its accidental discovery (Davis et al., 1979; Langston et al., 1983), 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used extensively to model Parkinson’s disease (PD) in a breadth of non-human primates, enabling the investigation of anatomical (Jan et al., 2000; Zeng et al., 2008), behavioural (Pessiglione et al., 2004a; Pessiglione et al., 2004b), neuro-chemical (Soghomonian et al., 1994; Huot et al., 2008), etc. aspects of the disease. The MPTP-lesioned primate has also been invaluable in the search of effective anti-dyskinetic and anti-parkinsonian Downloaded from agents. A review article previously examined the translational predictive value of the MPTP- lesioned primate for the development of anti-dyskinetic drugs, but it was published over a decade jpet.aspetjournals.org ago (Fox et al., 2006a), and many drug have since then been tested both in the primate and in clinical settings. This previous review did not examine the translational predictive value of the MPTP-lesioned primate when it relates to the effect of drugs on parkinsonian disability or at ASPET Journals on September 25, 2021 dopaminergic psychosis, nor did it look at differences between different primate species when it comes to predict the clinical effectiveness of an experimental molecule. We have therefore conducted a thorough and unbiased review of the literature in order to compare the predictive effectiveness of different MPTP-lesioned primate species on the clinical effectiveness of potential anti-dyskinetic, anti-parkinsonian and anti-psychotic agents. We believe that this Review comes at a critical time, given that it has recently been suggested that some primate species might be more suited than other to conduct behavioural pharmacological research (Porras et al., 2012), and that there have been several failures of high- profile drugs in clinical trials (Cook et al., 2014; Bespalov et al., 2016), emphasising the need to use the best animal model possible in pre-clinical settings, to maximise chances of success when translating to the clinic. 4 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version. JPET #247171 Methods Three non-human primate species have been used in the majority of experiments to determine the anti-dyskinetic, anti-parkinsonian and anti-psychotic effect of experimental drugs: the macaque (both cynomolgus (Di Paolo et al., 1986) and rhesus (Burns et al., 1983), Macaca fascicularis and Macaca mulatta, respectively), common marmoset (Jenner et al., 1984) (Callithrix jacchus) and common squirrel monkey (Langston et al., 1984) (Saimiri sciureus). For each of these 3 primate species, we have reviewed all the studies that reported their effect, or lack thereof, on Downloaded from each of dyskinesia, parkinsonism and psychosis. We then sought which of these drugs tested in the non-human primate underwent clinical testing and compared their pre-clinical and clinical effects jpet.aspetjournals.org and calculated different predictive values (see “Endpoints” below). Inclusion criteria at ASPET Journals on September 25, 2021 The literature search spans from 1983, time at which the first MPTP-lesioned non-human primate was engineered (Burns et al., 1983), until 10th December 2017. Studies published after this date, either online or in print format, are not included. Only drugs whose pre-clinical and clinical efficacy, or lack thereof, was reported in peer- reviewed articles are included in this article. Results disseminated solely through abstracts or conference proceedings are therefore not reported in this article. We are aware that not all studies conducted on parkinsonian primates have been published, and that results of some clinical trials have not been disseminated through peer-reviewed journals; by choosing to include only studies and reports that were published in peer-reviewed journals, we may be introducing a selection bias in our analysis. For instance, whereas it has been studied in human (NCT00034814, NCT00108667), the clinical effectiveness of talampanel will not be discussed here, as the results of the clinical trials where it was assessed were not published in peer-reviewed scientific journals. 5 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted. The final version may differ from this version. JPET #247171 In addition, we have excluded L-3,4-dihydroxyphenylalanine (L-DOPA) and inhibitors of L- aromatic amino acid decarboxylase (AADC, e.g. benserazide (Rinne et al., 1975) and carbidopa (Marsden et al., 1973)) from our analysis, as these were used in almost all studies cited here, to reverse parkinsonism and induce dyskinesia. Research methodology Literature review was conducted primarily through the United States National Library of Downloaded from Medicine (NLM) database, accessed via PubMed. The search engine Google was used to complete the literature review and to access articles not indexed in the NLM database. The following terms jpet.aspetjournals.org were used to perform the literature search: abnormal involuntary movements, chorea, cynomolgus, dyskinesia, dyskinetic, dystonia, hallucinations, hyperactivity, hyperkinesia, L-DOPA, levodopa, macaque, marmoset, monkey, at ASPET Journals on September 25, 2021 MPTP, non-human primate, Parkinson’s disease, parkinsonian, parkinsonism, primate, psychosis, rhesus, squirrel monkey, visual hallucinations. Definition of “efficacy” Throughout our literature search, a reduction of dyskinesia/psychosis was considered such only if statistical significance was reached; trends were not considered. A drug was deemed to have anti-parkinsonian benefit if it alleviated parkinsonism as monotherapy or as adjunct to L-DOPA. Impulse-control disorders (Weintraub et al., 2010) were not considered as a psychotic manifestation. Several studies, especially in the macaque, were performed that administered drugs, e.g. cabergoline, to reduce the development of dyskinesia and then conducted post-mortem experiments; we have included these studies in our analysis, even if their primary end-point was 6 JPET Fast Forward. Published on March 9, 2018 as DOI: 10.1124/jpet.117.247171 This article has not been copyedited and formatted.
Load more

Recommended publications
  • Sustained Release Tablet Comprising Pramipexole
    (19) & (11) EP 2 172 199 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 07.04.2010 Bulletin 2010/14 A61K 31/428 (2006.01) A61K 9/20 (2006.01) A61K 9/28 (2006.01) (21) Application number: 09178277.1 (22) Date of filing: 25.07.2003 (84) Designated Contracting States: • Lee, Ernest, J. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Kalamazoo, MI 49009 (US) HU IE IT LI LU MC NL PT RO SE SI SK TR • Martino, Alice, C. Kalamazoo, MI 49009 (US) (30) Priority: 25.07.2002 US 398427 P • Noack, Robert, M. 25.07.2002 US 398447 P Grand Rapids, MI 49506 (US) 28.08.2002 US 406609 P • Reo, Joseph, P. 18.06.2003 US 479387 P Kalamazoo, MI 49009 (US) • Skoug, Connie, J. (62) Document number(s) of the earlier application(s) in Portage, MI 49024 (US) accordance with Art. 76 EPC: 03771898.8 / 1 536 791 (74) Representative: Summers, Victoria Clare Pfizer Limited (71) Applicant: Pharmacia Corporation European Patent Department Peapack, NJ 07977 (US) Ramsgate Road Sandwich, Kent CT13 9NJ (GB) (72) Inventors: • Amidon, Gregory, E. Remarks: Portage, MI 49024 (US) This application was filed on 08-12-2009 as a • Ganorkar, Loksidh, D. divisional application to the application mentioned Kalamazoo, MI 49009 (US) under INID code 62. • Heimlich, John, M. Portage, MI 49002 (US) (54) Sustained release tablet comprising pramipexole (57) A sustained - release pharmaceutical composi- hydrophilic polymer and astarch having a tensile strength tion in a form of an orally deliverable tablet comprising of at least about 0.15kNcm -2 at a solid fraction represent- an active pharmaceutical agent having solubility not less ative of the tablet.
    [Show full text]
  • Evidence for the Involvement of Spinal Cord 1 Adrenoceptors in Nitrous
    Anesthesiology 2002; 97:1458–65 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Evidence for the Involvement of Spinal Cord ␣ 1 Adrenoceptors in Nitrous Oxide–induced Antinociceptive Effects in Fischer Rats Ryo Orii, M.D., D.M.Sc.,* Yoko Ohashi, M.D.,* Tianzhi Guo, M.D.,† Laura E. Nelson, B.A.,‡ Toshikazu Hashimoto, M.D.,* Mervyn Maze, M.B., Ch.B.,§ Masahiko Fujinaga, M.D.ʈ Background: In a previous study, the authors found that ni- opioid peptide release in the brain stem, leading to the trous oxide (N O) exposure induces c-Fos (an immunohisto- 2 activation of the descending noradrenergic inhibitory chemical marker of neuronal activation) in spinal cord ␥-ami- nobutyric acid–mediated (GABAergic) neurons in Fischer rats. neurons, which results in modulation of the pain–noci- 1 In this study, the authors sought evidence for the involvement ceptive processing in the spinal cord. Available evi- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/6/1458/337059/0000542-200212000-00018.pdf by guest on 01 October 2021 ␣ of 1 adrenoceptors in the antinociceptive effect of N2O and in dence suggests that at the level of the spinal cord, there activation of GABAergic neurons in the spinal cord. appear to be at least two neuronal systems that are Methods: Adult male Fischer rats were injected intraperitone- involved (fig. 1). In one of the pathways, activation of ally with ␣ adrenoceptor antagonist, ␣ adrenoceptor antago- 1 2 ␣ nist, opioid receptor antagonist, or serotonin receptor antago- the 2 adrenoceptors produces either direct presynaptic nist and, 15 min later, were exposed to either air (control) or inhibition of neurotransmitter release from primary af- 75% N2O.
    [Show full text]
  • Lysergic Acid on the Heart of Venus Mercenaria By
    Brit. J. Pharmacol. (1962), 18, 440-450. ACTIONS OF DERIVATIVES OF -LYSERGIC ACID ON THE HEART OF VENUS MERCENARIA BY ANNE McCOY WRIGHT, MERILYN MOORHEAD AND J. H. WELSH From the Biological Laboratories, Harvard University, Cambridge, Massachusetts, U.S.A. (Received February 5, 1962) 5-Hydroxytryptamine and a number of (+ )-lysergic acid derivatives have been tested on the heart of Venus mercenaria. One group of derivatives was found to increase the amplitude and frequency of heart beat in a manner much like 5-hydroxy- tryptamine. It included the monoethylamide, diethylamide, propanolamide (ergometrine), butanolamide (methylergometrine) and certain peptide derivatives of lysergic acid without substituents in positions 1 or 2. Of these, lysergic acid diethyl- amide was the most active. Given sufficient time (up to 4 hr), as little as 10 ml. of 10"6 M lysergic acid diethylamide produced a maximum increase in amplitude and frequency in about one-half of the 80 hearts on which it was tested. Its action was very slowly reversed by washing, as was true of all lysergic acid derivatives. A second group of lysergic acid derivatives, substituted in positions 1 or 2, had weak excitor action, if any, and specific 5-hydroxytryptamine blocking action. This group consisted of 1-methyl-, I-acetyl-, and 2-bromo-lysergic acid diethylamide and 1-methyl- lysergic acid butanolamide (methysergide). Of these, the last showed least signs of excitor action, usually none up to 10' M, and it blocked 5-hydroxytryptamine in a molar ratio of about one to one. During the early studies on the pharmacology of the heart of the mollusc, Venus mercenaria, certain of the ergot alkaloids were observed to have a remarkable excitatory action that was only very slowly reversed by washing (Welsh & Taub, 1948).
    [Show full text]
  • Xenoport Hurt by Solzira NDA Withdrawal
    November 11, 2008 Xenoport hurt by Solzira NDA withdrawal Evaluate Vantage News that Xenoport and partner GlaxoSmithKline’s recent application for restless legs syndrome (RLS) drug Solzira will have to be withdrawn, with the FDA requesting that data from a single trial be re-formatted, caused Xenoport’s shares to fall 13% yesterday to a new 18-month low of $34.44. With a potential 4-6 month delay to approval and the postponement of a $23m milestone that Xenoport was due to receive from Glaxo on the FDA’s acceptance of Solzira’s NDA, senior executives at the specialty US company could be forgiven for feeling somewhat aggrieved with Glaxo for this apparent oversight, given the pharma giant’s supposed experience and expertise in regulatory filings. The setback to Solzira and resulting slump in Xenoport’s share price suggests that shareholders who have not fled the stock will be even more desperate for positive phase IIb data for GERD treatment, XP19986 (Event - XenoPort looking for end of year trial lift, October 10, 2008). Formatting issues Avoiding these kinds of regulatory pitfalls, after all the cost and hard work involved in taking a drug through clinical development, is becoming an increasingly important factor behind a company’s decision to sign up a big pharma partner in today’s tougher regulatory environment. Both companies were naturally keen to stress that the NDA withdrawal has nothing to do with the content of the filing, which probably makes the rejection on a technicality all the more frustrating for Xenoport. Whilst the FDA requested the data from one particular study to be re-formatted, Glaxo has decided to review the formatting of other data sets in the application, presumably to ensure there can be no further grounds for rejection.
    [Show full text]
  • Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission
    The Journal of Neuroscience, October 14, 2015 • 35(41):14057–14069 • 14057 Neurobiology of Disease Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission Alexandra Alvarsson,1* Xiaoqun Zhang,1* Tiberiu L Stan,1 Nicoletta Schintu,1 Banafsheh Kadkhodaei,2 Mark J. Millan,3 Thomas Perlmann,2,4 and Per Svenningsson1 1Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden, 2Ludwig Institute for Cancer Research, SE-17177 Stockholm, Sweden, 3Pole of Innovation in Neuropsychiatry, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris 87290, France, and 4Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden Parkinson’s disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by L-DOPA relieves symptoms of PD but causes dyskinesia. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in experimental Parkinsonism and L-DOPA responses has been neglected. Here, we report that TAAR1 knock-out (KO) mice show a reduced loss of dopaminergic markers in response to intrastriatal 6-OHDA administra- tion compared with wild-type (WT) littermates. In contrast, the TAAR1 agonist RO5166017 aggravated degeneration induced by intra- striatal6-OHDAinWTmice.Subchronic L-DOPAtreatmentofTAAR1KOmiceunilaterallylesionedwith6-OHDAinthemedialforebrain bundle resulted in more pronounced rotational behavior and dyskinesia than in their WT counterparts. The enhanced behavioral sensitization to L-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted both L-DOPA-induced rotation and dyskinesia as well as AMPA receptor phosphorylation.
    [Show full text]
  • The Serotonergic System in Migraine Andrea Rigamonti Domenico D’Amico Licia Grazzi Susanna Usai Gennaro Bussone
    J Headache Pain (2001) 2:S43–S46 © Springer-Verlag 2001 MIGRAINE AND PATHOPHYSIOLOGY Massimo Leone The serotonergic system in migraine Andrea Rigamonti Domenico D’Amico Licia Grazzi Susanna Usai Gennaro Bussone Abstract Serotonin (5-HT) and induce migraine attacks. Moreover serotonin receptors play an impor- different pharmacological preventive tant role in migraine pathophysiolo- therapies (pizotifen, cyproheptadine gy. Changes in platelet 5-HT content and methysergide) are antagonist of are not casually related, but they the same receptor class. On the other may reflect similar changes at a neu- side the activation of 5-HT1B-1D ronal level. Seven different classes receptors (triptans and ergotamines) of serotoninergic receptors are induce a vasocostriction, a block of known, nevertheless only 5-HT2B-2C neurogenic inflammation and pain M. Leone • A. Rigamonti • D. D’Amico and 5HT1B-1D are related to migraine transmission. L. Grazzi • S. Usai • G. Bussone (౧) syndrome. Pharmacological evi- C. Besta National Neurological Institute, Via Celoria 11, I-20133 Milan, Italy dences suggest that migraine is due Key words Serotonin • Migraine • e-mail: [email protected] to an hypersensitivity of 5-HT2B-2C Triptans • m-Chlorophenylpiperazine • Tel.: +39-02-2394264 receptors. m-Chlorophenylpiperazine Pathogenesis Fax: +39-02-70638067 (mCPP), a 5-HT2B-2C agonist, may The 5-HT receptor family is distinguished from all other 5- Introduction 1 HT receptors by the absence of introns in the genes; in addi- tion all are inhibitors of adenylate cyclase [1]. Serotonin (5-HT) and serotonin receptors play an important The 5-HT1A receptor has a high selective affinity for 8- role in migraine pathophysiology.
    [Show full text]
  • The Use of Illicit Drugs As Self-Medication in the Treatment of Cluster Headache: Results from an Italian Online Survey
    XML Template (2015) [21.4.2015–2:34pm] [1–5] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/150048/APPFile/SG-CEPJ150048.3d (CEP) [PREPRINTER stage] Original Article Cephalalgia 0(0) 1–5 ! International Headache Society 2015 The use of illicit drugs as self-medication Reprints and permissions: sagepub.co.uk/journalsPermissions.nav in the treatment of cluster headache: DOI: 10.1177/0333102415583145 Results from an Italian online survey cep.sagepub.com C Di Lorenzo1, G Coppola2, G Di Lorenzo3, M Bracaglia4, P Rossi5 and F Pierelli4,6 Abstract Background: Cluster headache (CH) patients often receive unsatisfactory treatment and may explore illicit substances as alternatives. We aimed to explore this use of illicit drugs for CH treatment. Methods: We invited CH patients from an Internet-based self-help group to complete a questionnaire regarding their therapeutic use of illicit substances. Results: Of the 54 respondents, 29 were classified as chronic and 39 were drug-resistant cases. Fifty patients had previously tried subcutaneous sumatriptan, 40 had tried O2, and 48 had tried at least one prophylactic treatment. All 54 patients specified that they were dissatisfied with conventional treatments. Thirty-four patients had used cannabin- oids, 13 cocaine, 8 heroin, 18 psilocybin, 12 lysergic acid amide (LSA), and 4 lysergic acid diethylamide (LSD). Discussion: Some patients with intractable CH decided to try illicit drugs concomitantly with cessation of medical care. Most of these patients found suggestions for illicit drug use on the Internet. Many patients seemed to underestimate the judicial consequences of, and had an overestimated confidence in the safety of, such illicit treatments.
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Pharmacology and Toxicology of Amphetamine and Related Designer Drugs
    Pharmacology and Toxicology of Amphetamine and Related Designer Drugs U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol Drug Abuse and Mental Health Administration Pharmacology and Toxicology of Amphetamine and Related Designer Drugs Editors: Khursheed Asghar, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Errol De Souza, Ph.D. Addiction Research Center National Institute on Drug Abuse NIDA Research Monograph 94 1989 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 Pharmacology and Toxicology of Amphetamine and Related Designer Drugs ACKNOWLEDGMENT This monograph is based upon papers and discussion from a technical review on pharmacology and toxicology of amphetamine and related designer drugs that took place on August 2 through 4, 1988, in Bethesda, MD. The review meeting was sponsored by the Biomedical Branch, Division of Preclinical Research, and the Addiction Research Center, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other matieral in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors.
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • Endogenous Metabolites in Drug Discovery: from Plants to Humans
    Endogenous Metabolites in Drug Discovery: from Plants to Humans Joaquim Olivés Farrés TESI DOCTORAL UPF / ANY 201 6 DIRECTOR DE LA TESI: Dr. Jordi Mestres CEXS Department The research in this T hesis has been carried out at the Systems Pharmacolo gy Group , within the Research Programme on Biomedical Informatics (GRIB) at the Parc de Recerca Biomèdica de Barcelona (PRBB). The research presented in this T hesis has been supported by Ministerio de Ciencia e Innovación project BIO2014 - 54404 - R and BIO2011 - 26669 . Printing funded by the Fundació IMIM’s program “Convocatòria d'ajuts 2016 per a la finalització de tesis doctorals de la Fundació IMIM.” Agraïments Voldria donar les gràcies a tanta gent que em fa por deixar - me ningú. Però per c omençar haig agrair en especial al meu director la tesi, Jordi Mestres, per donar - me la oportunitat de formar part del seu laboratori i poder desenvolupar aquí el treball que aquí es presenta. A més d’oferir l’ajuda necessària sempre que ha calgut. També haig de donar les gràcies a tots els companys del grup de Farmacologia de Sistemes que he anat coneguent durants tots aquests anys en què he estat aquí, en especial en Xavi, a qui li he preguntat mil coses, en Nikita, pels sdfs que m’ha anat llençant a CTL ink, i la Irene i la Cristina, que els seus treballs també m’ajuden a completar la tesis. I cal agrair també a la resta de companys del laboratori, l’Albert, la Viktoria, la Mari Carmen, l’Andreas, en George, l’Eric i l’Andreu; de Chemotargets, en Ricard i en David; i altres membres del GRIB, com són l’Alfons, en Miguel, en Pau, l’Oriol i la Carina.
    [Show full text]
  • Compositions and Methods for Selective Delivery of Oligonucleotide Molecules to Specific Neuron Types
    (19) TZZ ¥Z_T (11) EP 2 380 595 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 26.10.2011 Bulletin 2011/43 A61K 47/48 (2006.01) C12N 15/11 (2006.01) A61P 25/00 (2006.01) A61K 49/00 (2006.01) (2006.01) (21) Application number: 10382087.4 A61K 51/00 (22) Date of filing: 19.04.2010 (84) Designated Contracting States: • Alvarado Urbina, Gabriel AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Nepean Ontario K2G 4Z1 (CA) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Bortolozzi Biassoni, Analia Alejandra PT RO SE SI SK SM TR E-08036, Barcelona (ES) Designated Extension States: • Artigas Perez, Francesc AL BA ME RS E-08036, Barcelona (ES) • Vila Bover, Miquel (71) Applicant: Nlife Therapeutics S.L. 15006 La Coruna (ES) E-08035, Barcelona (ES) (72) Inventors: (74) Representative: ABG Patentes, S.L. • Montefeltro, Andrés Pablo Avenida de Burgos 16D E-08014, Barcelon (ES) Edificio Euromor 28036 Madrid (ES) (54) Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types (57) The invention provides a conjugate comprising nucleuc acid toi cell of interests and thus, for the treat- (i) a nucleic acid which is complementary to a target nu- ment of diseases which require a down-regulation of the cleic acid sequence and which expression prevents or protein encoded by the target nucleic acid as well as for reduces expression of the target nucleic acid and (ii) a the delivery of contrast agents to the cells for diagnostic selectivity agent which is capable of binding with high purposes.
    [Show full text]