Practical Pharmacology for Alzheimer’s Disease

144 Pages·2016·3.26 MB·English

by  Takashi Kudo

Practical
Pharmacology for
Alzheimer’s Disease
Takashi Kudo
Kenneth L. Davis
Rafael Blesa Gonzalez
David George Wilkinson
123
Practical Pharmacology
for Alzheimer’s Disease

Takashi Kudo (cid:129) Kenneth L. Davis
Rafael Blesa Gonzalez
David George Wilkinson
Practical Pharmacology
for Alzheimer’s Disease
Takashi Kudo Rafael Blesa Gonzalez
Toyonaka Barcelona
Japan Spain
Kenneth L. Davis David George Wilkinson
New York Southhampton
New York United Kingdom
USA
ISBN 978-3-319-26204-8 ISBN 978-3-319-26206-2 (eBook)
DOI 10.1007/978-3-319-26206-2
Library of Congress Control Number: 2015958779
Springer Cham Heidelberg New York Dordrecht London
© Springer International Publishing Switzerland 2016
T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfi lms 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.
T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
T he 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.
Printed on acid-free paper
Springer International Publishing AG Switzerland is part of Springer Science+Business Media
(www.springer.com)
Contents
1 Basic Theory of Pharmacology for Alzheimer’s Disease . . . . . . . . . . . 1
Takashi Kudo
1.1 From the First Report of Alzheimer’s Disease
to Its Establishment as a Concept. . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Elucidating the Formation of Neurofi brillary Changes . . . . . . . . . . 4
1.3 The Acetylcholine Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.4 The Amyloid Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.5 Development of Disease-Modifying Drugs (DMDs)
Based on the Amyloid Hypothesis. . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.5.1 Amyloid Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.5.2 γ-/β-Secretase Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.6 Paradigm Shift of the Dementia Pathology Hypothesis. . . . . . . . . . 13
1.6.1 The Pathology of Abnormal Protein
Accumulation Commonly Seen in Dementia. . . . . . . . . . . . 13
1.6.2 Endoplasmic Reticulum (ER) Stress and Dementia. . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2 The Practical Pharmacology of Donepezil. . . . . . . . . . . . . . . . . . . . . . . 27
Takashi Kudo
2.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.1.1 ACh and Donepezil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.2 Effects Against AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2.1 Effects on Cardinal Symptoms in Mild to Moderate AD. . . 29
2.2.2 Effects on Cardinal Symptoms in Advanced AD. . . . . . . . . 29
2.2.3 Effects on the Biological and Psychological Symptoms
of Dementia (BPSD) and on Caretaker Burden . . . . . . . . . . 29
2.2.4 Effects on Slowing Disease Progression. . . . . . . . . . . . . . . . 30
2.3 Effects Against Vascular Dementia . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.4 Effects Against Dementia with Lewy Bodies. . . . . . . . . . . . . . . . . . 31
2.4.1 Intracerebral ACh Nerves. . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.4.2 Donepezil Effects Against DLB. . . . . . . . . . . . . . . . . . . . . . 31
2.5 Clinical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
v
vi Contents
3 Galantamine for Alzheimer’s Disease and Alzheimer’s
Disease with Cerebrovascular Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 35
Kenneth L. Davis
3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.2 Nicotinic Enhancement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.2.1 Peripheral Cholinergic Effects . . . . . . . . . . . . . . . . . . . . . . . 36
3.2.2 Cognitive Profi le. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.2.3 Neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.2.4 Aβ Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.3 Human Clinical Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.3.1 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.3.2 Mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.3.3 Cognitive and Functional Outcomes. . . . . . . . . . . . . . . . . . . 45
3.3.4 Galantamine and Memantine . . . . . . . . . . . . . . . . . . . . . . . . 47
3.3.5 Sleep Disturbance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.3.6 Cholinesterase Inhibitor Withdrawal . . . . . . . . . . . . . . . . . . 50
3.3.7 Tau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.3.8 Long-Term Outcomes in MCI . . . . . . . . . . . . . . . . . . . . . . . 54
3.3.9 Switch Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4 Practical Pharmacology of Rivastigmine. . . . . . . . . . . . . . . . . . . . . . . . 63
Rafael Blesa Gonzalez , Ignacio Flores , and Roser Ribosa-Nogué
4.1 Alzheimer’s Defi nition and Treatment Lines . . . . . . . . . . . . . . . . . . 63
4.2 Biochemical and Physiological Aspects of Acetylcholine. . . . . . . . 64
4.2.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.2.2 Acetylcholine Synthesis and Mechanism of Action. . . . . . . 64
4.2.3 Acetylcholine Receptors and Actions. . . . . . . . . . . . . . . . . . 64
4.2.4 Central Nervous System Cholinergic Pathways. . . . . . . . . . 65
4.2.5 Functions of Acetylcholine in the Central
Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.2.6 Cholinergic Susceptibility in Aging Brain . . . . . . . . . . . . . . 67
4.3 Cholinergic Hypothesis in Alzheimer’s Disease . . . . . . . . . . . . . . . 67
4.3.1 Loss of Cholinergic Activity. . . . . . . . . . . . . . . . . . . . . . . . . 67
4.3.2 Role of Acetylcholine in Learning and Memory . . . . . . . . . 68
4.3.3 Questioning the Cholinergic Hypothesis . . . . . . . . . . . . . . . 69
4.3.4 Corroborating the Cholinergic Hypothesis. . . . . . . . . . . . . . 70
4.3.5 Reformulating the Cholinergic Hypothesis . . . . . . . . . . . . . 71
4.4 The Interplay of Cholinergic Function
and Alzheimer’s Pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.4.1 Cholinergic Agonists and Amyloid Precursor
Protein Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.4.2 Acetylcholinesterase and Butyrylcholinesterase
Relationship with Beta-Amyloid . . . . . . . . . . . . . . . . . . . . . 72
4.4.3 Cholinergic Agonists and Tau Protein . . . . . . . . . . . . . . . . . 72
4.4.4 Beta-Amyloid and Cholinergic Function . . . . . . . . . . . . . . . 73
Contents vii
4.5 Enhancing Cholinergic Transmission as a Therapy
of Alzheimer’s Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.6 Acetylcholinesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.7 Pharmacodynamic Properties of Rivastigmine. . . . . . . . . . . . . . . . . 75
4.8 Pharmacokinetic Properties of Rivastigmine . . . . . . . . . . . . . . . . . . 77
4.8.1 Absorption and Distribution. . . . . . . . . . . . . . . . . . . . . . . . . 77
4.8.2 Metabolism and Elimination. . . . . . . . . . . . . . . . . . . . . . . . . 78
4.8.3 Special Populations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4.9 Clinical Evidence Supporting the Use of Rivastigmine. . . . . . . . . . 79
4.9.1 Cognitive Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.9.2 Behavioral Symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.9.3 Activities of Daily Living. . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.9.4 Quality of Life of Patients and Carers . . . . . . . . . . . . . . . . . 83
4.9.5 Physician-Rated Overall Impression Tests. . . . . . . . . . . . . . 84
4.9.6 Incidence of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 84
4.10 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
4.10.1 Risk of Overdose and Death. . . . . . . . . . . . . . . . . . . . . . . . . 90
4.11 Rivastigmine Effi cacy Compared with Other
Cholinesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4.12 Rivastigmine in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
4.13 Present and Future of Rivastigmine . . . . . . . . . . . . . . . . . . . . . . . . . 92
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
5 Practical Pharmacology of Memantine . . . . . . . . . . . . . . . . . . . . . . . . . 105
David G. Wilkinson
5.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.1.1 Glutamate and Memantine . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.1.2 Effects of Memantine on Neurodegeneration. . . . . . . . . . . . 106
5.2 Memantine in Vascular Dementia. . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.3 Memantine in AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5.3.1 Clinical Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5.3.2 Moderately Severe AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5.3.3 Mild to Moderate AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.3.4 Responder Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.3.5 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.4 Effects of Memantine in Combination with ChEIs . . . . . . . . . . . . . 113
5.5 Clinical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
6 How Do We Use Symptomatic Drugs to Treat Dementia?. . . . . . . . . . 119
Takashi Kudo
6.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
6.2 Characteristics of Symptomatic Drugs. . . . . . . . . . . . . . . . . . . . . . . 119
6.2.1 Donepezil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
6.2.2 Galantamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
6.2.3 Rivastigmine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
6.2.4 Memantine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
viii Contents
6.3 WFSBP Guidelines for the Treatment of Dementia. . . . . . . . . . . . . 125
6.3.1 The Preventive Effects of Symptomatic Drugs. . . . . . . . . . . 125
6.3.2 Indications for Symptomatic Drugs . . . . . . . . . . . . . . . . . . . 125
6.3.3 Selection of Drugs and Their Dosage. . . . . . . . . . . . . . . . . . 126
6.3.4 Start and End of Drug Administration and Monitoring . . . . 126
6.3.5 Concomitant Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.4 Use of Different Symptomatic Drugs to Suit Different
Situations Based on the Guidelines Released by Japan’s
Six Relevant Academic Societies. . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.4.1 Guidelines Issued by Japan’ Six Relevant
Academic Societies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.4.2 Policies on Using Symptomatic Drugs. . . . . . . . . . . . . . . . . 127
6.4.3 Selection of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
6.5 The Overviews of Symptomatic Drugs
in AD Drug Guidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
6.5.1 Use of Anti-dementia Drugs to Treat
Diseases Other Than AD . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
6.5.2 Future Tasks and Challenges . . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
1
Basic Theory of Pharmacology
for Alzheimer’s Disease
Takashi Kudo
1.1 From the First Report of Alzheimer’s Disease to Its
Establishment as a Concept
A n illness, later to be named Alzheimer’s disease (AD), was fi rst reported by the
German psychiatrist Alois Alzheimer about 100 years ago (Fig. 1 .1 ). On November
25, 1901, a 51-year-old woman named Auguste Deter (Fig. 1 .2) was admitted to a
municipal mental institution in Frankfurt am Main, where Alzheimer served as the
department head. The letter of referral said, “The patient has suffered loss of mem-
ory, paranoia, insomnia, and a feeling of anxiety for a considerably long time. The
patient is believed to be unable to deal with any kind of physical or mental labor.” It
all began after Mrs. Deter strongly suspected her husband of having an extramarital
affair. Her memory rapidly deteriorated thereafter. When she had to carry things,
she could not remember where to carry them; therefore, she wandered back and
forth in her apartment. In the end, she could not remember where to put things away,
so she hid them in other places. She also had the delusion that someone was trying
to kill her, so she would scream for hours. Alzheimer, who was exploring the ana-
tomical basis of mental illnesses, felt that a “specifi c disease” was concealed behind
the woman’s amnesia and pathological jealousy. He therefore examined her almost
every day. However, she continued to become increasingly refractory to treatment;
therefore, further treatment and examination became impossible. Alzheimer’s writ-
ings in the medical record ended in June 1902 with “When I try to examine Auguste
Deter, she refuses, as before. She cries, shouts, and even hits me. She abruptly
begins crying and often continues for several hours. So I sometimes must forcibly
hold her down on the bed. She can no longer eat the meals provided to her. She has
developed furuncles on her back.” Several months later, Alzheimer left the mental
institution in Frankfurt. In April 1906, he received a phone call from the Munich
Royal Psychiatric Hospital and learned that Auguste had died. He asked that her
medical records and brain be sent to him. After suffering the disease for 4.5 years,
she became bedridden and incontinent during the fi nal days of her life. Auguste
© Springer International Publishing Switzerland 2016 1
T. Kudo et al., Practical Pharmacology for Alzheimer’s Disease,
DOI 10.1007/978-3-319-26206-2_1