Poster Session III, December 6, 2017
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RAP-MD-05 GLYX13-C-203 Protocol Amendment 3 Final-R
NCT02192099 Study ID: GLYX13‐C‐203 Title: Open Label Extension for Subjects with Inadequate/Partial Response to Antidepressants during the Current Episode of Major Depressive Disorder Previously Treated with Rapastinel (GLYX‐13) (Extension of GLYX13‐C‐202, NCT01684163) Protocol Amendment 3 Date: 23 Nov 2016 Clinical Study Protocol Protocol Number: GLYX13-C-203 Study Drug: Rapastinel (GLYX-13) Injection (rapastinel Injection) FDA ID: 107,974 Clinicaltrials.gov: Title: Open Label Extension for Subjects with Inadequate/Partial Response to Antidepressants during the Current Episode of Major Depressive Disorder Previously Treated with Rapastinel (GLYX-13) (Extension of GLYX13-C-202, NCT01684163) Study Phase: 2 Sponsor: Naurex, Inc, an affiliate of Allergan, plc. Date: Amendment 3 dated 23 November 2016 Replaces Amendment 2 dated 20 January 2015 This document is a confidential communication from Naurex, Inc, an affiliate of Allergan, plc.. Acceptance of this document constitutes an agreement by the recipient(s) that no information contained herein will be published or disclosed without prior written approval from Allergan, plc., except that this document may be disclosed to appropriate Institutional Review Boards (IRBs) under the condition that they are also required to maintain confidentiality. Naurex, Inc, an affiliate of Allergan, plc. Protocol GLYX13-C-203 INVESTIGATOR SIGNATURE PAGE The signature of the investigator below constitutes his/her approval of this protocol and provides the necessary assurances that this study will be conducted according to all stipulations of the protocol as specified in both the clinical and administrative sections, including all statements regarding confidentiality. This trial will be conducted in compliance with the protocol and all applicable regulatory requirements, in accordance with Good Clinical Practices (GCPs), including International Conference on Harmonization (ICH) Guidelines, and in general conformity with the most recent version of the Declaration of Helsinki. -
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. -
Rapastinel Flop Leaves Allergan in a Hole
March 06, 2019 Rapastinel flop leaves Allergan in a hole Madeleine Armstrong The failure of one of Allergan’s key pipeline projects puts the group’s chief executive under even more pressure. In the battle of the ketamine-like antidepressants Allergan had pitched rapastinel as an agent with a more benign safety profile than Johnson & Johnson’s just-approved Spravato. However, unlike Spravato, there is no sign that Allergan’s candidate actually works. The failure of three phase III trials of rapastinel yesterday might not be a disaster in itself, but it highlights the thinness of Allergan’s late-stage pipeline. The group’s chief executive, Brent Saunders, has faced criticism in recent weeks, and he could now come under more pressure to strike a big deal – or leave the company. Allergan's late-stage pipeline highlights 2024e Project Indication Note sales ($m) Acute Ubrogepant 425 FDA filing due Q1 2019 migraine Rapastinel Depression 359 Failed 3 ph III trials Migraine Ph III trial in chronic migraine to start Atogepant 297 prevention H1 2019 Bimatoprost Glaucoma 206 FDA filing due H2 2019 SR Ph III Maple trial of new formulation Abicipar Wet AMD 178 due H1 2019 Relamorelin Gastroparesis 86 Ph III Aurora trial due to complete Cenicriviroc Nash 28 2020 Source: EvaluatePharma. Activist shareholders have long been agitating for change at Allergan, and the latest failure will only provide more ammunition to those who want to split the roles of chairman and chief exec amid dissatisfaction with the group's acquisition strategy, and with its stock hovering around a five-year low. -
5-HT Receptor Agonist Befiradol Reduces Fentanyl-Induced
5-HT1A Receptor Agonist Befiradol Reduces Fentanyl-induced Respiratory Depression, Analgesia, and Sedation in Rats Jun Ren, Ph.D., Xiuqing Ding, B.Sc., John J. Greer, Ph.D. ABSTRACT Background: There is an unmet clinical need to develop a pharmacological therapy to counter opioid-induced respiratory depression without interfering with analgesia or behavior. Several studies have demonstrated that 5-HT1A receptor agonists alleviate opioid-induced respiratory depression in rodent models. However, there are conflicting reports regarding their effects on analgesia due in part to varied agonist receptor selectivity and presence of anesthesia. Therefore the authors performed a Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/122/2/424/267207/20150200_0-00031.pdf by guest on 27 September 2021 study in rats with befiradol (F13640 and NLX-112), a highly selective 5-HT1A receptor agonist without anesthesia. Methods: Respiratory neural discharge was measured using in vitro preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively. Results: Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 ± 5.7% of control minute ven- tilation 4 min after befiradol vs. saline 18.7 ± 2.2% of control, n = 9; P < 0.001), duration of analgesia (90.4 ± 11.6 min vs. saline 130.5 ± 7.8 min; P = 0.011), duration of sedation (39.8 ± 4 min vs. saline 58 ± 4.4 min; P = 0.013); and induced baseline hyperventilation, hyperalgesia, and “behavioral syndrome” in nonsedated rats. Further, the befiradol-induced alleviation of opioid-induced respiratory depression involves sites or mechanisms not functioning in vitro brainstem–spinal cord and medul- lary slice preparations. -
WO 2017/066590 Al 20 April 2017 (20.04.2017) P O P CT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/066590 Al 20 April 2017 (20.04.2017) P O P CT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 38/06 (2006.01) A61K 31/519 (2006.01) kind of national protection available): AE, AG, AL, AM, A61 38/07 (2006.0V) A61K 31/551 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/13 (2006.01) A61K 31/5513 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, A61K 31/135 (2006.01) A61P 25/24 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/496 (2006.01) A61P 25/18 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US20 16/057071 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 14 October 2016 (14.10.201 6) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, zw. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/242,633 16 October 2015 (16. -
Neuropharmacologic Studies on the Brain Serotonin1a Receptor Using
December 2013 Biol. Pharm. Bull. 36(12) 1871–1882 (2013) 1871 Review Neuropharmacologic Studies on the Brain Serotonin1A Receptor Using the Selective Agonist Osemozotan Toshio Matsudaa,b a Laboratory of Medicinal Pharmacology, Osaka University Graduate School of Pharmaceutical Sciences; 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan: and b Kanazawa University, Hamamatsu University School of Medicine, Chiba University, University of Fukui, Osaka Univeristy United Graduate School of Child Development; 2–2 Yamada-oka, Suita, Osaka 565–0871, Japan. Received August 13, 2013 Alterations in serotonin (5-HT) neurochemistry have been implicated in the etiology of major neuro- psychiatric disorders such as anxiety-spectrum disorders, depression, and schizophrenia. The neuromodula- tory effects of 5-HT are mediated through 14 receptor subtypes, and those receptors, including the 5-HT1A receptor, are considered to be potential targets for the treatment of psychiatric disorders. We developed the novel 5-HT1A receptor agonist MKC-242 (called osemozotan) and characterized its neurochemical and pharmacological profiles. 5-HT1A receptor agonists modulate the release of amine neurotransmitters through the activation of presynaptic or postsynaptic 5-HT1A receptors in the brain. The agonist has antianxiety and antidepressant effects and improves abnormal behaviors such as aggressive behavior and deficits of prepulse inhibition in isolation-reared mice. We also demonstrated that spinal 5-HT1A receptor activation is involved in isolation rearing-induced hypoalgesia. Concerning the mechanism for induction of isolation-induced ab- normal behaviors, we have recently found that the raphe-prefrontal 5-HT system plays a key role in encoun- ter stimulation-induced hyperactivity in isolation-reared mice. Furthermore, we showed that osemozotan at- tenuates psychostimulant-induced behavioral sensitization and that prefrontal dopamine release is enhanced by functional interaction between the 5-HT1A receptor and other receptors. -
Gottlieb's Shock Resignation Leaves Ripples in the Industry
15 March 2019 No. 3946 Scripscrip.pharmaintelligence.informa.com Pharma intelligence | informa time, which is difficult. He also used the office in a “forward-leaning way” not seen often. “He kind of drove the conversation through very good communication exter- nally,” Myers said. “He was able to use a lot of the ideas percolating in the agency, pack- age them and get them moved forward.” Gottlieb pushed FDA to the forefront of the drug pricing debate, a position the agency had not sought in the past. In his first speech to staff after confir- mation, he said that even though the agency cannot set drug prices, it can promote competition. Gottlieb was vocal in chastising the brand industry for blocking generic Credit: FDA Credit: competition, warning that Congress could make more drastic changes if it did not stop employing pay-for-delay and licensing tactics intended to pre- Gottlieb’s Shock Resignation vent patent challenges. (Also see “Got- tlieb: Real Risk Of Congressional Action If Leaves Ripples In The Industry Anti-Competitive Actions Continue” - Pink Sheet, 3 May, 2018.) DERRICK GINGERY [email protected] He also publicly released a list of com- panies thought to be using the Risk Evalu- S FDA Commissioner Scott Gott- being apart from my family for these past ation and Mitigation Strategy system to lieb, one of the most popular and two years and missing my wife and three prevent generic companies from purchas- Uvisible commissioners in decades, young children.” ing samples for testing, although it is not will end his tenure as head of FDA in about clear the move had much impact. -
Sustained Antidepressant Action of the N‑Methyl‑D‑Aspartate Receptor Antagonist MK‑801 in a Chronic Unpredictable Mild Stress Model
5376 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: 5376-5383, 2018 Sustained antidepressant action of the N‑methyl‑D‑aspartate receptor antagonist MK‑801 in a chronic unpredictable mild stress model BANG-KUN YANG1, JUN QIN2, YING NIE3 and JIN-CAO CHEN1 1Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071; Departments of 2Neurosurgery and 3Children's Medical Center, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442600, P.R. China Received December 29, 2016; Accepted November 29, 2017 DOI: 10.3892/etm.2018.6876 Abstract. (5S,10R)-5-methyl-10,11-dihydro-5H-dibenzo(A,D) mice. Therefore, the present study revealed the sustained cyclohepten-5,10-imine hydrogen maleate (MK-801) is antidepressant effects of MK-801 in the CUMS model. an N-methyl-D-aspartate non-competitive antagonist that Furthermore, synaptogenesis and neuronal regeneration in the possesses useful biological properties, including anticon- prelimbic regions of mPFC, DG and CA3 of the hippocampus vulsant and anesthetic activities. Studies have indicated the may be implicated as mechanisms that promote a sustained rapid antidepressant effects of MK-801 in animal models. antidepressant response. However, there are no reports concerning a sustained anti- depressant effect in the chronic unpredictable mild stress Introduction (CUMS) model. Furthermore, the antidepressant mechanism remains unclear. The aim of the present study was to examine In addition to being the most prevalent mental disorder, the effects of MK-801 (0.1 mg/kg) and rapastinel (10 mg/kg) depression is one of the leading causes of disability across on depression-like behavior in CUMS mice and measure the world (1). -
(12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday Et Al
US 20110245287A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday et al. (43) Pub. Date: Oct. 6, 2011 (54) HYBRD OPOD COMPOUNDS AND Publication Classification COMPOSITIONS (51) Int. Cl. A6II 3/4748 (2006.01) C07D 489/02 (2006.01) (76) Inventors: John W. Holaday, Bethesda, MD A6IP 25/04 (2006.01) (US); Philip Magistro, Randolph, (52) U.S. Cl. ........................................... 514/282:546/45 NJ (US) (57) ABSTRACT Disclosed are hybrid opioid compounds, mixed opioid salts, (21) Appl. No.: 13/024,298 compositions comprising the hybrid opioid compounds and mixed opioid salts, and methods of use thereof. More particu larly, in one aspect the hybrid opioid compound includes at (22) Filed: Feb. 9, 2011 least two opioid compounds that are covalently bonded to a linker moiety. In another aspect, the hybrid opioid compound relates to mixed opioid salts comprising at least two different Related U.S. Application Data opioid compounds or an opioid compound and a different active agent. Also disclosed are pharmaceutical composi (60) Provisional application No. 61/302,657, filed on Feb. tions, as well as to methods of treating pain in humans using 9, 2010. the hybrid compounds and mixed opioid salts. Patent Application Publication Oct. 6, 2011 Sheet 1 of 3 US 2011/0245287 A1 Oral antinociception of morphine, oxycodone and prodrug combinations in CD1 mice s Tigkg -- Morphine (2.80 mg/kg (1.95 - 4.02, 30' peak time -- (Oxycodone (1.93 mg/kg (1.33 - 2,65)) 30 peak time -- Oxy. Mor (1:1) (4.84 mg/kg (3.60 - 8.50) 60 peak tire --MLN 2-3 peak, effect at a hors 24% with closes at 2.5 art to rigg - D - MLN 2-45 (6.60 mg/kg (5.12 - 8.51)} 60 peak time Figure 1. -
GPCR/G Protein
Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33. -
Characterizing the Differential Roles of Striatal 5-HT1A Auto- and Hetero-Receptors in the Reduction of L-DOPA-Induced Dyskinesia
Experimental Neurology 292 (2017) 168–178 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr Research Paper Characterizing the differential roles of striatal 5-HT1A auto- and hetero-receptors in the reduction of L-DOPA-induced dyskinesia Samantha M. Meadows a, Nicole E. Chambers a, Melissa M. Conti a, Sharon C. Bossert a,CrystalTasbera, Eitan Sheena a, Mark Varney b, Adrian Newman-Tancredi b, Christopher Bishop a,⁎ a Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY 13902-6000, USA b Neurolixis Inc., Dana Point, CA 92629, USA article info abstract Article history: L-DOPA remains the benchmark treatment for Parkinson's disease (PD) motor symptoms, but chronic use leads to L- Received 6 September 2016 DOPA-induced dyskinesia (LID). The serotonin (5-HT) system has been established as a key modulator of LID and 5- Received in revised form 24 February 2017 HT receptors (5-HT R) stimulation has been shown to convey anti-dyskinetic effects. However, 5-HT Ragonists Accepted 22 March 2017 1A 1A 1A fi Available online 23 March 2017 often compromise clinical ef cacy or display intrinsic side effects and their site(s) of actions remain debatable. Re- cently, highly selective G-protein biased 5-HT1AR agonists, F13714 and F15599, were shown to potently target 5- Keywords: HT1A auto- or hetero-receptors, respectively. The current investigation sought to identify the signaling mechanisms LID and neuroanatomical substrates by which 5-HT1AR produce behavioral effects. In experiment 1, hemi-parkinsonian, Serotonin 1A receptor L-DOPA-primed rats received systemic injections of vehicle, F13714 (0.01 or 0.02 mg/kg), or F15599 (0.06 or Biased agonist 0.12 mg/kg) 5 min prior to L-DOPA (6 mg/kg), after which LID, motor performance and 5-HT syndrome were Serotonin syndrome rated. -
WO 2012/109445 Al 16 August 2012 (16.08.2012) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/109445 Al 16 August 2012 (16.08.2012) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/485 (2006.01) A61P 25/04 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US20 12/024482 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, ' February 2012 (09.02.2012) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 13/024,298 9 February 201 1 (09.02.201 1) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): QRX- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, PHARMA LTD.