Alzheimer Disease: Therapeutic Strategies

497 Pages·1994·12.82 MB·English

by  Ezio Giacobini

ALZHEIMER DISEASE
THERAPEUTIC STRATEGIES
Advances in Alzheimer Disease Therapy
Series Editors:
Ezio Giacobini
Robert Becker
This series periodically brings up-to-date advances in basic and clinical
sciences that are relevant to understanding the etiology, pathogenesis,
diagnosis, and treatment of Alzheimer disease. Experts from the vari
ous fields relevant to understanding Alzheimer disease report their new
research findings and discuss the newest developments in possible
Alzheimer disease therapies.
Books in the Series
Cholinergic Basis for Alzheimer Therapy
Edited by Robert Becker and Ezio Giacobini
ISBN 0-8176-3566-1
Alzheimer Disease: Therapeutic Strategies
Edited by Ezio Giacobini and Robert Becker
ISBN 0-8176-3757-5
ALZHEIMER DISEASE
THERAPEUTIC STRATEGIES
Ezio Giacobini
Robert Becker
Editors
with the editorial assistance of
Diana L. Smith & Joyce M. Barton
Birkhiiuser
Ezio Giacobini Robert E. Becker
Chairman of Pharmacology Chairman of Psychiatry
Southern Illinois University Southern Illinois University
School of Medicine School of Medicine
P.O. Box 19230 P.O. Box 19230
Springfield, IL 62794-9230 Springfield, IL 62794-9230
USA USA
Library of Congress Cataloging-in-Publication Data
Alzheimer disease: therapeutic strategies 1 Ezio Giacobini, Robert
Becker, editors, with the editorial assistance of Diana L. Smith and
Joyce M. Barton.
p. cm. - (Advances in Alzheimer disease therapy)
Includes bibliographical references and index.
ISBN 978-1-4615-8151-2 ISBN 978-1-4615-8149-9 (eBook)
DOI 10.1007/978-1-4615-8149-9
I. Alzheimer's disease-Chemotherapy. 2. Alzheimer's disease
Pathophysiology. 3. Alzheimer's disease-Treatment.
I. Giacobini, Ezio. II. Becker, Robert E. III. Series.
[DNLM: I. Alzheimer's Disease-therapy. WM 220 A4755 1994]
RC523.A39757 1994
616.8'31-dc20
DNLMlDLC
for Library of Congress 94-34494
CIP
Printed on acid-free paper. ~®
Birkhiiuser a(J?)
© 1994 Birkhauser Boston
Softcover reprint of the hardcover 1s t edition 1994
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ISBN 978-1-4615-8151-2
Camera-ready text prepared by the editors using WordPerfect 6.0 on an IBM PS2
987654321
CONTENTS
Introductions
Development of Drugs for Alzheimer Therapy: A Decade of Progress ... 1
Ezio Giacobini and Robert Becker
Epidemiology of AD: Impact on the Treatment ................. 8
Luigi Amaducci and Laura Fratiglioni
Part I. Neuropathologic and Genetic Basis of AD Treatment
Neuropathological Bases of Alzheimer Disease,
Implications for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Henryk M. Wisniewski and Jerzy Wegiel
Amyloid Deposition as the Central Event in the
Etiology and Pathogenesis of Alzheimer's Disease ............... 23
John Hardy and Karen Duff
Role of Abnormal Phosphorylation of Tau in Neurofibrillary
Degeneration: Implications for Alzheimer Therapy . . . . . . . . . . . . . . . 28
Khalid Iqbal and Inge Grundke-Iqbal
Olfactory Bulb Involvement in AD: An Early Change? ............ 34
Robert G. Struble, Mona Ghobrial and Larry F. Hughes
Alzheimer Disease-A Spirochetosis? . . . . . . . . . . . . . . . . . . . . . . . 41
Judit Miklossy
Part II. Therapeutical Strategies to Arrest Production
and Processing of Amyloid
Beta Amyloid (Afj) as a Therapeutic Target in Alzheimer's Disease .... 49
Ivan Lieberburg
Regulation of APP Processing by First Messengers .............. 54
Roger M. Nitsch, John H. Growdon, Steven A. Farber,
Meihua Deng and Richard J. Wurtman
vi Contents
In Vitro Production of Amyloid (J-Protein: A Route to the
Mechanism and Treatment of Alzheimer's Disease ............... 62
Dennis J. Selkoe
Apolipoprotein E and Alzheimer's Disease: Therapeutic Implications . ... 65
Warren J. Strittmatter, David Y. Huang, Ann Saunders,
Donald Schmechel, Margaret Pericak-Vance,
Allen D. Roses, Karl H. Weisgraber and Michel Goedert
Apolipoprotein E4 and Cholinergic Dysfunction
in Alzheimer's Disease ................................ 72
Judes Poirier, Isabelle Aubert, Philippe Bertrand, Remi Quirion,
Serge Gauthier and Josephine Nalbantoglu
m.
Part The Cholinergic System of Human Brain
Butyrylcholinesterase in Alzheimer's Disease .................. 79
M.-Marsel Mesulam
Modulating Cholinergic Neurotransmission Through Transgenic
Overexpression of Human Cholinesterases . . . . . . . . . . . . . . . . . . . . 84
Hermona Soreq, Rachel Beeri, Shlomo Seidman, Rina Timberg,
Yael Loewenstein, Meira Sternfeld, Christian Andres
and Moshe Shani
Structure-Function Relationships in the Binding of Reversible
Inhibitors in the Active-Site Gorge of Acetylcholinesterase .......... 88
I. Silman, M. Harel, J. Eichler, J.L. Sussman,
A. Anselmet and J. Massoulie
Cholinergic Changes and Synaptic Alterations
in Alzheimer's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Steven T. DeKosky, Scot D. Styren and Mark E. O'Malley
Part IV. Cholinesterase Inhibitors in AD Treatment
Introduction to Cholinesterase Inhibitors Used
in Alzheimer's Disease Therapy .......................... 99
Vinod Kumar
Contents vii
A Pharmacodynamic Strategy to Optimize the Clinical Response to
Eptastigmine (MF-20J) ............................... 103
Bruno P. Imbimbo and Paolo E. Lucchelli
Eptastigmine (MF-20J). A Double-Blind, Placebo-Controlled,
Clinical Trial in Alzheimer Disease Patients . . . . . . . . . . . . . . . . . . 108
Nicola Canal, Massimo Franceschi
and the Italian Eptastigmine Investigators
Cognition Improvement by Oral Hupenine A:
A Novel Acetylcholinesterase Inhibitor ..................... 113
Xi Can Tang, Zhi Qi Xiong, Bo Chu Qian,
Zhi Fang Zhou and Ci Lu Zhang
In Vitro and In Vivo Effects of a Dual Inhibitor of
Acetylcholinesterase and Muscarinic Receptors, CI-JOO2 .......... 120
Mark R. Emmerling, Vlad E. Gregor, Roy D. Schwarz,
Jeff D. Scholten, Michael J. Callahan, Chitase Lee,
Catherine J. Moore, Charlotte Raby, William J. Lipinski,
Juan Jaen and Robert E. Davis
Effects of Novel Cholinesterase Inhibitors Based on
the Mechanism of Enzyme Inhibition ...................... 125
Albert Enz, Dieter Meier and Rene Spiegel
Biochemistry, Pharmacokinetics and Pharmacodynamics of MDL 73,745:
A Potent and Selective Inhibitor of Acetylcholinesterase . .......... 131
Jean-Marie Homsperger, Jean-Noel Collard, Daniel Schirlin,
James Dow, Jean-Georges Heydt and Bertrand Dulery
Clinical Experience with MDL 73,745; Pharmacokinetics,
Pharmacodynamics, and Clinical Tolerance in Normal Volunteers .... 137
Margo M. Schleman, Stephen S. Songer, 010 J. Szylleyko,
Randall D. Seifert and Neal R. Cutler
Galanthamine in Alzheimer's Disease . ..................... 140
Helmut Kewitz, Gordon Wilcock and Bonnie Davis
Tacrine: An Overview of Efficacy in Two Parallel Group Studies . .... 145
Stephen I. Gracon and Margaret J. Knapp
Clinical Update of Velnacrine Research 150
Klaudius Siegfried and Rich Civil
viii Contents
Second and Third Generation Cholinesterase Inhibitors:
From Preclinical Studies to Clinical Efficacy ................. 155
Ezio Giacobini and Gabriel Cuadra
Second and Third Generation Cholinesterase Inhibitors:
Clinical Aspects ................................... 172
Robert E. Becker, Pamela Moriearty, Rita Surbeck, Latha Unni,
Andrew Varney and Sandra K. Vicari
Part V. Nicotinic Agonists as Drugs for AD Treatment
Nicotinic Receptors in Human Brain ...................... 181
Hannsjorg SchrOder, Andrea Wevers, Christina Birtsch,
Mona Ghobrial, Ezio Giacobini and Alfred Maelicke
Development of Nicotinic Agonists for the Treatment
of Alzheimer's Disease ............................... 186
Patrick M. Lippiello, William S. Caldwell, Michael J. Marks
and Allan C. Collins
The Role of Nicotinic Systems in the Cognitive Disorder of
Alzheimer's Disease . ................................ 191
Paul A. Newhouse, Alexandra Potter, June Corwin and Robert Lenox
ABT-418: A Novel Cholinergic Channel Activator (ChCA)
for the Potential Treatment of Alzheimer's Disease . ............. 196
Stephen P. Americ, James P. Sullivan, Michael W. Decker,
Jorge D. Brioni, Clark A. Briggs, Diana Donnelly-Roberts,
Kennan C. Marsh, A. David Rodrigues, David S. Garvey,
Michael Williams and Jerry J. Buccafusco
Nicotine, Catecholamines and Cognitive Enhancement ........... 201
Jeffrey A. Gray, Grigory A. Grigoryan, Chuly Lee,
Stephen N. Mitchell and Helen Hodges
The Subunit Specific Effects of Novel Anabaseine-Derived
Nicotinic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Roger L. Papke, Christopher M. de Fiebre,
William Kem and Edwin M. Meyer
Serotonin Depletion Decreases Therapeutic Effect of
THA and Nicotine ................................. 212
Paavo J. Riekkinen, Jr., Minna K. Riekkinen and Jouni S. Sirvio
Contents ix
Part VI. Muscarinic Agonists: Preclinical and
Clinical Approaches
Selective Signaling Via Novel Muscarinic Agonists:
Implications for Alzheimer'S Disease Treatments
and Clinical Update ................................ 219
Abraham Fisher, Eliahu Heldman, David Gurwitz, Rachel Haring,
Yishai Karton, Haim Meshulam, Zippora Pittel, Daniele Marciano,
Itzhak Marcovitch, Rachel Brandeis, Terese A. Treves,
Ruth Verchovsky, Sonia Klimowsky and Amos D. Korczyn
Selective Muscarinic Agonists for Alzheimer Disease Treatment . . . . . . 224
Roy D. Schwarz, Michael J. Callahan, Robert E. Davis,
Juan C. Jaen, William Lipinski, Charlotte Raby,
Carolyn J. Spencer and Haile Teele
Xanomeline: An Efficacious and Specific MI Receptor
Agonist-Preclinical Update ........................... 229
Harlan E. Shannon, Frank P. Bymaster, David O. Calligaro,
Beverley Greenwood, Charles H. Mitch, John S. Ward,
Per Sauerberg, Preben Olesen, Malcolm Sheardown,
Michael D.B. Swedberg and Peter D. Suzdak
Xanomeline, A Specific MI Agonist: Early Clinical Studies. . . . . . . . . 234
N.C. Bodick, A.F. DeLong, P.L. Bonate, T. Gillespie,
D.P. Henry, J.H. Satterwhite, R.A. Lucas, J. Heaton,
G.V. Carter, L. Farde, N.R. Cutler, J.J. Sramek,
R.D. Seifert, J.J. Conrad and T.S. Wardle
CI-979/RU 35926: A Novel Muscarinic Agonist for the
Treatment of Alzheimer'S Disease ........................ 239
Toni M. Hoover
Part Vll. Drugs to Enhance Acetylcholine Synthesis and Release
Choline Metabolism, Membrane Phospholipids,
and Alzheimer's Disease . ............................. 247
Steven A. Farber, Barbara E. Slack, Enrico DeMicheli,
Richard J. Wurtman, Roger M. Nitsch, John H. Growdon,
Bruce M. Cohen, Andrew L. Stoll and Perry F. Renshaw
x Contents
Neurotransmitter Release Enhancement as a Possible Therapy for
Neurodegenerative Diseases: Update on Linopirdine (DUP996) ..... 252
Robert Zaczek, Robert J. Chorvat, Richard A. Earl and S. William Tam
Part vm. Nootropic Drugs in AD Treatment
Nootropic Drugs: The Gap Between Preclinical and Clinical Results . .. 259
Giancarlo Pepeu, Maria Grazia Giovannini,
neana Marconcini Pepeu and Luciano Bartolini
Nootropic Drugs in Allheimer Disease Treatment.
New Pharmacological Strategies . . . . . . . . . . . . . . . . . . . . . . . . . 265
Tatiana A. Voronina
Therapeutic Efficacy of Nootropic Drugs in Alzheimer's
Disease and Age Related Cognitive Dysfunction ............... 270
Julian A. Gray, Jennifer A. Nagel, Roman Amrein,
Giorgio Marini and Umberto Senin
Part IX. Neurotrophins, Growth Factors, and Neuroprotection
in the Treatment or Alzheimer's Disease
Toward the Repair of Cortical Synapses in Alzheimer's Disease . . . . . . 277
A. Claudio Cuello
Gangliosides in Allheimer's Disease:
Experimental and Clinical Data ......................... 284
Lars Svennerholm and Gino Toffano
Part X. Excitatory Amino Acids, Ca + + Cellular Homeostasis,
Nitric Oxide, and AD Treatment
Excitatory Transmitter Neurotoxicity and Allheimer's Disease . . . . . . . 293
John W. Olney and Nuri B. Farber
Free Intracellular Calcium in Aging and Allheimer's Disease ....... 299
Walter Muller, Anne Eckert, Henrike Hartmann and Hans Forstl
Nitric Oxide Synthase in a Lesion Model of Alzheimer'S Disease ..... 304
Kiminobu Sugaya and Michael McKinney