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Appendix 1: STOPP/START criteria version 2 applied to the TRUST dataset Physiological system Criteria Criteria included Number (%) (The relevant () criteria for each participant were applied to the dataset and recorded in of Microsoft Office Excel ® (2013)) criteria included out of total criteria STOPP criteria Indication of medication A1. Any drug prescribed without an evidence-based clinical indication. X 1/3 (33.3) A2. Any drug prescribed beyond the recommended duration, where treatment duration is X well defined. A3. Any duplicate drug class prescription e.g. two concurrent NSAIDs, SSRIs, loop diuretics, ACE inhibitors, anticoagulants (optimisation of monotherapy within a single drug class should be observed prior to considering a new agent). Cardiovascular system B1. Digoxin for heart failure with preserved systolic ventricular function (no clear evidence X 7/13 (53.8) of benefit). B2. Verapamil or diltiazem with NYHA Class III or IV heart failure (may worsen heart failure). B3. Beta-blocker in combination with verapamil or diltiazem (risk of heart block). B4. Beta blocker with symptomatic bradycardia (< 50/min), type II heart block or complete heart block (risk of profound hypotension, asystole). B5. Amiodarone as first-line antiarrhythmic therapy in supraventricular tachyarrhythmias X (higher risk of side-effects than beta-blockers, digoxin, verapamil or diltiazem). B6. Loop diuretic as first-line treatment for hypertension (safer, more effective alternatives available). B7. Loop diuretic for dependent ankle oedema without clinical, biochemical evidence or radiological evidence of heart failure, liver failure, nephrotic syndrome or renal failure (leg elevation and /or compression hosiery usually more appropriate). B8. Thiazide diuretic with current significant hypokalaemia (i.e. -
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CURRENT THERAPEUTIC RESEARCH VOL. 56, NO. 5, MAY 1995 EFFECTS OF CEREBRAL METABOLIC ENHANCERS ON BRAIN FUNCTION IN RODENTS KOICHIRO TAKAHASHI,l MINORU YAMAMOTO,’ MASANORI SUZUKI,’ YUKIKO OZAWA,’ TAKASHI YAMAGUCHI,l HIROFUMI ANDOH, AND KOUICHI ISHIKAWA2 ‘Department of Pharmacology, Clinical Pharmacology Research Laboratory, Yamunouchi Pharmaceutical Co. Ltd., and ‘Department of Pharmacology, School of Medicine, Nihon University, Tokyo, Japan AFWI’RACT The effects of cerebral metabolic enhancers (indeloxazine, bi- femelane, idebenone, and nicergoline) on reserpine-induced hypother- mia, the immobility period in forced swimming tests, and passive avoidance learning behavior were compared with the effects of ami- triptyline in rodents. Indeloxazine, bifemelane, and amitriptyline antagonized hypothermia in mice given reserpine. Indeloxaxine and amitriptyline decreased the immobility period in mice in the forced swimming test in a dose-dependent manner. The latency of step- through in the passive avoidance test in rats was prolonged by ad- ministration of indeloxazine but shortened by administration of amitriptyline. Neither idebenone nor nicergoline displayed any phar- macologic action in these tests. The results suggest that indeloxaxine possesses an antidepressant activity similar to that of amitriptyline but differs from amitriptyline in its anticholinergic properties and its ability to ameliorate impaired brain function such as that of learning behavior. In addition, indeloxazine exhibited broader effects on brain functions than either bifemelane, idebenone, or nicergoline. INTRODUCTION Cerebral metabolic enhancers (drugs that enhance energy metabolism) including brain glucose and ATP levels such as indeloxazine,1*2 bi- femelane, 3*4idebenone?6 and nicergoline,7>8 are currently used for the treatment of patients with various psychiatric symptoms. These symptoms include reduced spontaneity and emotional disturbance in patients with cerebral vascular disease. -
Local Product Document Pfizer Venezuela, S.A
LOCAL PRODUCT DOCUMENT PFIZER VENEZUELA, S.A. 1. MEDICINAL PRODUCT BRAND NAME ® SERMION 2. CUALITATIVE AND CUANTITATIVE COMPOSITION Every coated tablet contains 10 and 30 mg of Nicergoline. 3. PHARMACEUTICAL FORM Coated tablets. 4. CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS 1. Cerebrovascular insufficiency of senile source. 2. Peripheral Vasodilator. 3. Treatment of Senile dementia from light to medium level of vascular type and Alzheimer. 4.2 DOSAGE 1. 30 mg/day and Cerebrovascular insufficiency of senile source. 2. 30 mg twice per day, as Peripheral Vasodilator and on treatment of Senile dementia from light to medium level of vascular type and Alzheimer. 4.3 CONTRAINDICATIONS Hypersensitivity to Nicergoline. 4.4 WARNINGS AND PRECAUTIONS Nicergoline, as other adrenergic blocking agents, may significantly reduce blood pressure (arterial hypotension) in some patients. Likewise, as other sympatholytic agents, it has been associated to different degrees of sexual impotence and libido reduction. Do not administer this product if pregnant, if pregnancy is suspected or during breast-feeding. 4.5 ADVERSE EFFECTS Drowsiness, cephalea, tiredness, constipation, pyrosis, vomiting, diarrhea, facial flushing, sexual impotence and libido reduction, uric acid and L.H increment. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacokinetics Properties A) Onset and Duration - Benign prostatic hypertrophy, intramuscular: 2 hours. - Two hours after a single 4-mg intramuscular injection, average peak and mean urinary flow rates increased by 50% and 77%, respectively. B) Drug Concentration Levels - ORAL: 1 to 1.5 hours. - Maximal blood levels are reached 1 to 1.5 hours after oral dosing. - The mean maximum plasma concentrations after daily administration of a 30-mg film-coated tablet and a 30-mg effervescent tablet solution are 88 ng/mL and 41 ng/mL, respectively). -
Sciatica and Chronic Pain
Sciatica and Chronic Pain Past, Present and Future Robert W. Baloh 123 Sciatica and Chronic Pain Robert W. Baloh Sciatica and Chronic Pain Past, Present and Future Robert W. Baloh, MD Department of Neurology University of California, Los Angeles Los Angeles, CA, USA ISBN 978-3-319-93903-2 ISBN 978-3-319-93904-9 (eBook) https://doi.org/10.1007/978-3-319-93904-9 Library of Congress Control Number: 2018952076 © Springer International Publishing AG, part of Springer Nature 2019 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. 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. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. -
(12) United States Patent (10) Patent No.: US 7.803,838 B2 Davis Et Al
USOO7803838B2 (12) United States Patent (10) Patent No.: US 7.803,838 B2 Davis et al. (45) Date of Patent: Sep. 28, 2010 (54) COMPOSITIONS COMPRISING NEBIVOLOL 2002fO169134 A1 11/2002 Davis 2002/0177586 A1 11/2002 Egan et al. (75) Inventors: Eric Davis, Morgantown, WV (US); 2002/0183305 A1 12/2002 Davis et al. John O'Donnell, Morgantown, WV 2002/0183317 A1 12/2002 Wagle et al. (US); Peter Bottini, Morgantown, WV 2002/0183365 A1 12/2002 Wagle et al. (US) 2002/0192203 A1 12, 2002 Cho 2003, OOO4194 A1 1, 2003 Gall (73) Assignee: Forest Laboratories Holdings Limited 2003, OO13699 A1 1/2003 Davis et al. (BM) 2003/0027820 A1 2, 2003 Gall (*) Notice: Subject to any disclaimer, the term of this 2003.0053981 A1 3/2003 Davis et al. patent is extended or adjusted under 35 2003, OO60489 A1 3/2003 Buckingham U.S.C. 154(b) by 455 days. 2003, OO69221 A1 4/2003 Kosoglou et al. 2003/0078190 A1* 4/2003 Weinberg ...................... 514f1 (21) Appl. No.: 11/141,235 2003/0078517 A1 4/2003 Kensey 2003/01 19428 A1 6/2003 Davis et al. (22) Filed: May 31, 2005 2003/01 19757 A1 6/2003 Davis 2003/01 19796 A1 6/2003 Strony (65) Prior Publication Data 2003.01.19808 A1 6/2003 LeBeaut et al. US 2005/027281.0 A1 Dec. 8, 2005 2003.01.19809 A1 6/2003 Davis 2003,0162824 A1 8, 2003 Krul Related U.S. Application Data 2003/0175344 A1 9, 2003 Waldet al. (60) Provisional application No. 60/577,423, filed on Jun. -
(12) United States Patent (10) Patent No.: US 8.598,119 B2 Mates Et Al
US008598119B2 (12) United States Patent (10) Patent No.: US 8.598,119 B2 Mates et al. (45) Date of Patent: Dec. 3, 2013 (54) METHODS AND COMPOSITIONS FOR AOIN 43/00 (2006.01) SLEEP DSORDERS AND OTHER AOIN 43/46 (2006.01) DSORDERS AOIN 43/62 (2006.01) AOIN 43/58 (2006.01) (75) Inventors: Sharon Mates, New York, NY (US); AOIN 43/60 (2006.01) Allen Fienberg, New York, NY (US); (52) U.S. Cl. Lawrence Wennogle, New York, NY USPC .......... 514/114: 514/171; 514/217: 514/220; (US) 514/229.5: 514/250 (58) Field of Classification Search (73) Assignee: Intra-Cellular Therapies, Inc. NY (US) None See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (56) References Cited U.S.C. 154(b) by 215 days. U.S. PATENT DOCUMENTS (21) Appl. No.: 12/994,560 6,552,017 B1 4/2003 Robichaud et al. 2007/0203120 A1 8, 2007 McDevitt et al. (22) PCT Filed: May 27, 2009 FOREIGN PATENT DOCUMENTS (86). PCT No.: PCT/US2O09/OO3261 S371 (c)(1), WO WOOOf77OO2 * 6, 2000 (2), (4) Date: Nov. 24, 2010 OTHER PUBLICATIONS (87) PCT Pub. No.: WO2009/145900 Rye (Sleep Disorders and Parkinson's Disease, 2000, accessed online http://www.waparkinsons.org/edu research/articles/Sleep PCT Pub. Date: Dec. 3, 2009 Disorders.html), 2 pages.* Alvir et al. Clozapine-Induced Agranulocytosis. The New England (65) Prior Publication Data Journal of Medicine, 1993, vol. 329, No. 3, pp. 162-167.* US 2011/0071080 A1 Mar. -
Non-Antibiotics, Efflux Pumps and Drug Resistance of Gram-Negative Rods
Polish Journal of Microbiology MINIREVIEW 2018, Vol. 67, No 2, 129–135 DOI: 10.21307/pjm-2018-017 Non-antibiotics, Efflux Pumps and Drug Resistance of Gram-negative Rods AGNIESZKA EWA LAUDY* Department of Pharmaceutical Microbiology, Medical University of Warsaw, Warsaw, Poland Submitted 24 March 2018, revised 29 March 2018, accepted 04 April 2018 Abstract Non-antibiotic medicinal products consist of drugs with diverse activity against bacteria. Many non-antibiotics demonstrate direct anti- bacterial activity against Gram-positive cocci. The activity observed against Gram-negative rods is much lower and non-antibiotics primarily from the following groups: non-steroidal anti-inflammatory drugs, cardiovascular and antidepressant medicinal products demonstrate this activity. It has been shown that the low activity of some non-antibiotics or the absence of activity against Gram-negative rods is related, among other things, to the extrusion of these compounds from bacterial cells by multi-drug resistance efflux pumps. Substrates for the resistance-nodulation-division efflux systems include the following non-antibiotics: salicylate, diclofenac, ibuprofen, mefenamic acid, naproxen, amitriptyline, alendronate sodium, nicergoline, and ticlopidine. In addition, interactions between non-antibiotics and multi-drug resistance efflux pumps have been observed. It has also been revealed that depending on the concentration, salicylate induces expression of multi-drug resistance efflux pumps in Escherichia coli, Salmonella enterica subsp. enterica serotype Typhimurium, and Burkholderia cenoce pacia. However, salicylate does not affect the expression of the resistance-nodulation-division efflux systems Stenotrophomonasin maltophilia and Acinetobacter baumannii. Most importantly, there were no effects of medicinal products containing some non-antibiotic active substances, except salicylate, as substrates of multi-drug resistance efflux pumps, on the induction of Gram-negative rod resistance to quinolones. -
4 Supplementary File
Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation. -
A Human Stem Cell-Derived Test System for Agents Modifying Neuronal N
Archives of Toxicology (2021) 95:1703–1722 https://doi.org/10.1007/s00204-021-03024-0 IN VITRO SYSTEMS A human stem cell‑derived test system for agents modifying neuronal 2+ N‑methyl‑D‑aspartate‑type glutamate receptor Ca ‑signalling Stefanie Klima1,2 · Markus Brüll1 · Anna‑Sophie Spreng1,3 · Ilinca Suciu1,3 · Tjalda Falt1 · Jens C. Schwamborn4 · Tanja Waldmann1 · Christiaan Karreman1 · Marcel Leist1,5 Received: 28 October 2020 / Accepted: 4 March 2021 / Published online: 13 March 2021 © The Author(s) 2021 Abstract Methods to assess neuronal receptor functions are needed in toxicology and for drug development. Human-based test systems that allow studies on glutamate signalling are still scarce. To address this issue, we developed and characterized pluripotent stem cell (PSC)-based neural cultures capable of forming a functional network. Starting from a stably proliferating neu- roepithelial stem cell (NESC) population, we generate “mixed cortical cultures” (MCC) within 24 days. Characterization by immunocytochemistry, gene expression profling and functional tests (multi-electrode arrays) showed that MCC contain various functional neurotransmitter receptors, and in particular, the N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDA-R). As this important receptor is found neither on conventional neural cell lines nor on most stem cell- derived neurons, we focused here on the characterization of rapid glutamate-triggered Ca2+ signalling. Changes of the intra- 2+ cellular free calcium ion concentration ([Ca ]i) were measured by fuorescent imaging as the main endpoint, and a method to evaluate and quantify signals in hundreds of cells at the same time was developed. We observed responses to glutamate in the low µM range. -
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. -
Advances in Non-Dopaminergic Treatments for Parkinson's Disease
REVIEW ARTICLE published: 22 May 2014 doi: 10.3389/fnins.2014.00113 Advances in non-dopaminergic treatments for Parkinson’s disease Sandy Stayte 1,2 and Bryce Vissel 1,2* 1 Neuroscience Department, Neurodegenerative Disorders Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia 2 Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia Edited by: Since the 1960’s treatments for Parkinson’s disease (PD) have traditionally been directed Eero Vasar, University of Tartu, to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic Estonia L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has Reviewed by: resulted in extensive efforts to develop new therapies that work in ways other than Andrew Harkin, Trinity College Dublin, Ireland restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic Sulev Kõks, University of Tartu, therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, Estonia and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron Pille Taba, Universoty of Tartu, chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a Estonia Pekka T. Männistö, University of detailed account of their success in animal models and their translation to human clinical Helsinki, Finland trials. We then consider how advances in understanding the mechanisms of PD, genetics, *Correspondence: the possibility that PD may consist of multiple disease states, understanding of the Bryce Vissel, Neuroscience etiology of PD in non-dopaminergic regions as well as advances in clinical trial design Department, Neurodegenerative will be essential for ongoing advances. We conclude that despite the challenges ahead, Disorders Laboratory, Garvan Institute of Medical Research, patients have much cause for optimism that novel therapeutics that offer better disease 384 Victoria Street, Darlinghurst, management and/or which slow disease progression are inevitable. -
Therapy Focus – J&J Confirms Hope for New Mechanism in Depression
May 09, 2018 Therapy focus – J&J confirms hope for new mechanism in depression Amy Brown The first look at late-stage data on Johnson & Johnson’s hotly-tipped novel antidepressant esketamine came at a medical conference last weekend, and the results were not quite as strong as many were hoping to see. Encouraging signals could be certainly be found, however, and J&J seems undeterred from trying to seek regulatory approval. Others pursing NMDA modulation in depression are also likely to draw comfort in the results, which provide the first phase III validation of this mechanism, and a clear bar to beat (see table below). Hopes for esketamine and other products like it lie in their similarity to ketamine, which at low doses displays antidepressant effects that kick in very quickly. Traditional antidepressants which act via the serotonergic system – selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) – can take weeks to have an effect; a large proportion of patients fail to respond at all. Hence the need for both faster acting agents – for example in suicidal patients – and novel mechanisms to treat those who need different options. A new target NMDA receptor modulation is a novel mechanism in depression. Over the last decade researchers have become increasingly convinced that dysregulation of glutamate, a neurotransmitter which signals through NMDA, plays an important role in the condition. This system is already known to be a factor in cognitive function and neurodegeneration and Namenda, the NMDA antagonist mematine, has been available as a treatment for Alzheimer’s dementia for several years.