Drug Discovery and Development for Alzheimer s Disease

297 Pages·2005·15.86 MB·English

by  Howard M. Fillit MD

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DRUG DISCOVERY AND .
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DEVELOPMENT FOR d
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ALZHEIMER'S DISEA/SE
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Howard Martin Fillit, MD is the founding Executive Director of the Institute for
the Study of Aging, Inc., a private venture philanthropy based in New York City.
The Institute's mission is to catalyze and fund research on drug discovery and
drug development for cognitive aging and Alzheimer's disease. The Institute sup-
ports research nationally and internationally, in both academia and in the biotech-
nology industry. In addition, Dr. Fillit serves as a consultant in gerontology and
geriatric medicine to individuals, managed care organizations, health care sys-
tems, pharmaceutical and biotechnology companies. He is also a clinical professor
of geriatrics and medicine and a professor of neurobiology at The Mount Sinai-
NYU Medical Center.
Dr. Fillit previously served as Corporate Medical Director for Medicare for
New York Life's managed health plans (NYLCare), now a subsidiary of Aetnap US
Healthcare. During his tenure, NYLCare served more than 100,000 elderlyh indi-
viduals in several regional Medicare managed care programs and a total pof more
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than 2.5 million individuals in 50 states. He received a BA cum laude fxrom Cornell
University and earned his Medical Degree at the State University eof New York-
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Upstate Medical Center at Syracuse. From 1976 to 1987, he received postgraduate
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training and held academic positions at The Rockefeller University and The New
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York Hospital-Cornell Medical Center. s
Dr. Fillit has received numerous awards and honmors, including the Rita
Hayworth Award for lifetime achievement in researchu and practice in Alzheimer's
disease from the Alzheimer's Association (1999). Her is also a fellow of the American
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Geriatrics Society, the American College of Physicians, the Gerontological Society of
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America, and the New York Academy of Mnedicine. He has published more than
200 scientific and clinical articles, abstractsv, and books and is an editor of the lead-
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ing international Textbook of Geriatric Mledicine and Gerontology.
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Alan O'Connell, PhD is Scientific Affairs Officer at the Institute for the Study of
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Aging, Inc. He is a neuroscientist by training and has extensive professional expe-
rience primarily in the bioteechnology and pharmaceutical industries. During his
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career, Dr. O'Connell has held positions in pharmaceutical product development,
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licensing and technology evaluation. Before joining the institute, Dr. O'Connell
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was Manager of Nweurobiology Product Development at American Biogenetic
Sciences, Inc., a Nwew York-based biotechnology company. Dr. O'Connell completed
his undergraduwate studies at the University of London and subsequently obtained
a PhD in ne/urobiology from the National University of Ireland. He then complet-
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ed a two-:year postdoctoral fellowship in aging and Alzheimer's disease research at
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Univetrsity College, Dublin, before joining Elan Corporation Plc., as Manager of
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Prehclinical Pharmacology within the Pharmaceutical Technology Division. Dr.
O'Connell has also worked as a Scientific Officer with the Medicines Control
Agency (MCA) in London. During his time at the MCA he coordinated contacts
between the Pharmacoviligance Section of the agency and the U.K. pharmaceutical
industry. Dr. O'Connell has published numerous scientific abstracts and papers.
INSTITUTE FOR THE STUDY OF AGING
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DRUG DISCOVERY ANDh
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DEVELOPMENT FORe
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Howward M. Fillit, MD
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Aplan W. O'Connell, PhD
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Editors
Springer Publishing Company
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Copyright © 2002 by Springer Publishing Company, Inc.
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All rights reserved e
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No part of this publication may be reproduced, stored in a retrieval
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system, or transmitted in any form or by any means, electronic, m/echanical,
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photocopying, recording, or otherwise, without the prior pemrmission of
Springer Publishing Company, Inc.
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Springer Publishing Company, Inc. o
536 Broadway f
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New York, NY 10012-3955 n
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Acquisitions Editor: Sheri W. Sussman l.
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Production Editor: Sara Yoo a
Cover design by Susan Hauley 4
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02 03 04 05 06 / 5 4 3 2 e1
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Library of Congresws .Cataloging-in-Publication Data
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Drug discovery and development for Alzheimer's disease 2000 / Howard
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Fillit, Alan O'Connell, editors.
p./; cm.
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pIn:cludes bibliographical references and index.
tISBN 0-8261 -1542-X
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h 1. Alzheimer's disease—Chemotherapy—Congresses. 2. Alzheimer's
disease—Chemotherapy—Evaluation—Congresses. 3. Drugs—Testing—
Congresses. I. Fillit, Howard. II. O'Connell, Alan. III. Institute for the
Study of Aging.
[DNLM: 1. Alzheimer Disease—diagnosis—Congresses.
2. Alzheimer Disease—drug therapy—Congresses. 3. Dementia—drug
therapy—Congresses. WT 155 A24383 2002]
RC523 .A329 2002
616.831061—dc21
2001049760
Printed in the United States of America by Sheridan Books.
Contents
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Contributors ix
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Acknowledgments xvi
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1 The Challenges of Drug Discovery and Drug Development 1
for Cognitive Aging and Alzheimer's Diseuase
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Howard Fillit and Alan O'Connell o
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Part I. Earl.y Detection
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2 Genetic Correlates of Succ4essful Cognitive Aging 7
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Thomas Perls
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3 Genetic and Envirhonmental Risk Factors for Alzheimer's 13
Disease in Arabsc Residing in Israel
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Robert P. Frwiedland, Amos Korczyn, and Lindsay Farrer
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4 Telephonic Screening of Mental Status: A Feasibility 17
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Study in a Managed Care Clinic
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D/avid Knopman, Thomas Vonsternberg, and Jim Haefemeyer
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5 tUse of Brain MRI Volumetric Analysis in a Mild 24
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h Cognitive Impairment Trial to Delay the Diagnosis
of Alzheimer's Disease
Michael Grundman, Drahomira Sencakova, Clifford R. Jack, Jr.,
Ronald C. Petersen, Hyun T. Kim, Arlan Schultz,
Ronald G. Thomas, Leon J. Thal, for the Alzheimer's
Disease Cooperative Study
6 Hippocampal Volume Assessment in Mild Cognitive 33
Impairment
Michael S. Mega, Paul M. Thompson, Arthur W. Toga,
and Jeffrey L. Cummings
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vi Contents
7 Brain Imaging Surrogate Markers for Detection and 42
Prevention of Cognitive Aging and Alzheimer's Disease
Gary W. Small
8 Novel -Amyloid Probes 50
Mei-Ping Kung, Zhi-Ping Zhuang, Catherine Hou, Daniel
Skovronsky, Tamar Gur, Sumalee Chumpradit, Virginia M.-Y. Lee,
John Q. Trojanowski, and Hank F. Kung
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9 Early Clinical and Biological Manifestations of Alzheimer's 57
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Disease: Implications for Screening and Treatment p
Richard C. Mohs, Deborah Marin, and Vahram Haroutunian.
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Part II. Drug Discovery
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10 Identification of Brain-Expressed ABC Transporters That May 67
Mediate Detachment of ß-Amyloid From uBiological Membranes
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Peter B. Reiner and Stephane Le Bihano
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11 Targeting an RNA Structure in the nAmyloid Precursor 74
Protein Gene as a New Therapeuvtic Strategy for
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Alzheimer's Disease l
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Principal Investigator: Jack T. Rogers
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12 Novel Tricyclic Pyrone Compounds Prevent Intracellular 89
APP C99-Induced Ceell Death
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Lee-Way Jin, Duy H. Hua, Feng-Shiun Shie, Izumi Maezawa,
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Bryce Sopher., and George M. Martin
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13 Novel Glywcosaminoglycans as Antiamyloid Agents 98
Roberwt Kisilevsky and Walter A. Szarek
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14 Strate/gies for Inhibiting Alzheimer's y-Secretase 106
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Michael S. Wolfe
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15 h Phosphorylations of Tau and APP as Targets for Drug 116
Discovery
John DeBernardis, Dan Kerkman, Cintia Vianna, and Peter Davies
16 Estrogen and ApoE: Drug Discovery Implications 129
Jonathan D. Smith and Justine A. Levin
17 Structure-Based Functional Design of Agonists and 137
Antagonists for AMPA-Subtype Glutamate Receptors
Ming-Ming Zhou, Harel Weinstein, Diomedes E. Logothetis,
and Eric Gouaux
Contents vii
18 Alzheimer's Therapeutics: Neurotrophin Small 147
Molecule Mimetics
Stephen M. Massa, You-Mei Xie, and Frank M. Longo
Part HI. Drug Development—Preclinical
19 Antioxidants in the Treatment of Alzheimer's Disease: 159
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Breakthrough Potential of Indole-3-Propionic Acid
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Daniel G. Chain, Douglas Galasko, Eyal Neria, Miguel Pappollpa,
Paul E. Bendheim, and Burkhard Poeggeler .
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20 AF150(S) and AF267B: Ml Muscarinic Agonists for 171
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Treatment and as Disease-Modifying Agents in Alznheimer's
and Related Diseases /i
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A. Fisher, Z. Pittel, R. Bmndeis, N. Bar-Ner, H. Sonego,
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I. Marcovitch, N. Natan, and R. Haring
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21 ABS-205: Effects on Cognition in Maturoe and Aged Rats 184
Ciaran M. Regan f
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22 Calpain Inhibitors: A Treatment ovf Alzheimer's Disease 194
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Ottavio Arancio l
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23 Femtomolar-Acting Neuro4protective Peptides: 204
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Application for Inhibition of Alzheimer's Disease
Illana Gozes, Sharoen Furman, Ruth A. Steingart,
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Albert Pinhasov, Inna Vulih, Jacob Romano, Roy Zaltzman,
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Rachel Zamo.stiano, Eliezer Giladi, Sara Rubinraut,
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Mati Fridkin, Janet Hauser, and Douglas E. Brenneman
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24 tA Phase I Clinical Study of Ex Vivo Nerve Growth Factor 217
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Gene Therapy for Alzheimer's Disease
Mark H. Tuszynski
25 Lowering Homocysteine Levels in Patients 225
With Alzheimer's Disease
Paul Aisen, Mary Sano, Ramon Diaz-Arrastia,
and William Jagust
26 Therapeutic Potential of Positive AMPA Receptor Modulators 234
in Mild Cognitive Impairment and Alzheimer's Disease
Steven A. Johnson, Gary Lynch, Gary A. Rogers, and Ursula V. Staubli
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27 The Alzheimer's Disease Atorvastatin Treatment Trial: 244
Scientific Basis and Position on the Use of HMG-CoA
Reductase Inhibitors (Statins) That Do or Do Not Cross
the Blood-Brain Barrier
D. Larry Sparks, Donald J. Connor, Patrick J. Browne,
Dawn R. Wasser, Jean E. Lopez, and Marwan N. Sabbagh
28 A Double-Blind, Randomized Investigation of the Effects 253
of Testosterone or Placebo in Male Patients With p
Mild-to-Moderate Alzheimer's Disease h
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Bruce Miller
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29 Estrogen and Cognitive Functioning in Men With Mild e 263
Cognitive Impairment d
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Barbara B. Sherwin and Howard Chertkow
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Index m 271
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Contributors
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Paul Aisen, MD Daniel G. Chain, PhD
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Department of Psychiatry President and Chiief Scientist
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Georgetown University Medical Mindset BioPhsarmaceuticals
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College Jerusalem, Israel
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Washington, DC
Howardr Chertkow, MD
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Ottavio Arancio, MD, PhD Ladyf Davis Institute
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Nathan Kline Institute Jewnish General Hospital
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Orangeburg, NY Bloomfield Center for Research
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N. Bar-Ner, PhD a
4 Montreal, Canada
Israel Institute for Biological
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Research Sumalee Chumpradit, PhD
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Ness-Ziona, Israel Department of Radiology
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c University of Pennsylvania
Paul E. Bendheim, MD
. Philadelphia, PA
Mindset BioPharmwaceuticals
Jerusalem, Israewl Donald J. Connor, PhD
w Sun Health Center for Clinical
R. Brandeis, PhD
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Israel In:s/titute for Biological
p Sun Health Research Institute
Research
tt Sun City, AZ
Nehss-Ziona, Israel
Jeffrey L. Cummings, MD
Douglas E. Brenneman, PhD
Director
Laboratory of Developmental
UCLA School of Medicine
Neurobiology
Los Angeles, CA
National Institutes of Health
Bethesda, MD
Peter Davies, PhD
Patrick J. Browne, MD Professor
Department of Cardiology Albert Einstein College of
Boswell Hospital Medicine
Baltimore, MD Bronx, NY
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