Chemistry Reference
In-Depth Information
8
7
9
13
10
11
5
6
H
1
H
2
N
N
2
4
O
3
Huperzine A (
1
)
(5R, 9R, 11E)-5-amino-11-ethylidene-
5,6,9,10-tetrahydro-7-methyl-5,9-
methanocycloocta [
b
]pyridin-2[1
H
]-one
chapter represents a comprehensive documentation of the overview of studies on
HA up to January 2004.
4.1.2
Alzheimer's Disease
AD is a progressive, degenerative disease of the brain. The disease is the most com-
mon form of dementia affecting elderly people, with a mean duration of around
8.5 years between the onset of clinical symptoms and death. The incidence of
AD increases with age, even in the oldest age groups: from 0.5% at 65, it rises to
nearly 8% at 85 years of age. Some 12 million persons have AD, and by 2025,
that number is expected to increase to 22 million.
Neuropathologically, AD is characterized by (1) parenchymal amyloid deposits
or neuritic plaques; (2) intraneuronal deposits of neurofibrillary tangles; (3) cerebral
amyloid angiopathy, and (4) synaptic loss.
11
Current treatment for AD in
most countries consists in the administration of AChEIs to increase the amount
of acetylcholine (ACh) at the neuronal synaptic cleft by inhibiting AChE,
based on the finding that ACh is dramatically low in the brains of AD patients.
AChE is an enzyme that breaks down ACh, a neurotransmitter in the brain
that is required for normal brain activity and is critical in the process of forming
memories.
To date, four AChEIs, Cognex (tacrine), Aricept (donepezil or E2020), Exelon
(rivastigmine), and Reminyl (galanthamine hydrobromide) currently are approved
as prescription drugs by the United States to treat the symptoms of mild-to-moderate
AD. However, the clinical usefulness of AChEIs has been limited by their short
half-lives and excessive side effects caused by activation of peripheral cholinergic
systems, as well as by hepatotoxicity, which is the most frequent and important
side effect of tacrine therapy.
12-14
NH
2
O
MeO
Ph
N
MeO
N
Tacrine
Donepezil
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