Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-06-23
2003-02-25
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S757000
Reexamination Certificate
active
06524616
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compositions and methods for supplementing or complementing natural central nervous system hormonal and neurotransmitter activity to optimize global brain function, particularly in disorders associated with memory impairment. More specifically, the present invention relates to a composition comprising phytoestrogens and an acetylcholinesterase inhibitor for use in treating, retarding, or preventing neurodegeneration and cognitive decline and dysfunction associated with Alzheimer's disease (AD), aging, other related dementia disorders, and menopause.
The physiologic impact of estrogen deprivation, preceding and following the menopause, has a significant effect on the brain function and, hence, the quality of life for numerous women. A side variety of disorders may occur including, but not limited to, vasomotor instability with resulting hot flashes, disturbances in mood and affect, depression and irritability, spatial disorientation, and difficulty with verbal memory recall. Estrogen deprivation may also be an initiator or promotor of a series of biochemical abnormalities associated with the pathogenesis of Alzheimer's disease, senile dementia, and related conditions, including central nervous system (CNS) arteriosclerotic disease (also known as stroke). Impairment of balance involving cerebellar dysfunction and other postural mechanisms predisposes older postmenopausal women to falls, resulting in hip fractures and its consequences.
An individual's response to the menopausal transition depends on a number of variables, for example, genetic background, life-style factors (i.e., substance abuse, smoking), physical activity, response to chronologic aging, as well as the individual's brain “set-point” for estrogen. This, in turn, could depend on the distribution of beta and: alpha receptors in the brain and their affinity for either endogenous or exogenous estrogen.
A further manageable determinant of CNS dysfunction is the availability and reserve of the various CNS neurotransmitters. Senile dementia, especially Alzheimer's disease is a major disease associated with aging. Although the exact mechanisms responsible for senile dementia and Alzheimer's disease have not been elucidated, a growing body of evidence suggests that cholinergic neurons are essential for learning and memory processes [Bartus et al.,
Science
217:408 (1982); and Singh et al.,
Brain Research
644: 305 (1994)]. Alzheimer's disease is strongly associated with decreased choline acetyltransferase (ChAT) activity and (loss of cholinergic neurons [New England Journal of medicine 313:7 (Jul. 4, 1985); and Kosik,
Science
256:780 (1992)]. The number of patients suffering with Alzheimer's disease and the costs associated with this disease are increasing dramatically with the increasing population of the elderly. About four million Americans (10% of the elderly at the age of 65 and 47% of the elderly at the age of 85 or higher) suffer with Alzheimer's disease [Evans et al.,
JAMA
262:2251 (1989)]. The incidence of dementia and Alzheimer's disease is reported to double every 5 years after the age of 65 [Jorm et al.,
Acta Psychiatr. Scand
. 76:465 (1987)].
Currently, there is no cure for this devastating disease. Tremendous efforts have been undertaken to develop treatments for this disease. Treatment approaches which have been tested extensively include precursors for acetylcholine synthesis, cholinergic agonists, release enhancers and acetylcholinesterase (AChE) inhibitors. Various treatment approaches are shown below in Table 1.
TABLE 1
Cholinergic Treatment Strategies for Cognitive
Decline in Alzheimer's Disease
1
Type
Effects on Cognitive Function
Precursors
Choline
Unchanged/Slight Improvement
Lecithin
Unchanged/Slight Improvement
Cholinergic Agonists
Pilocarpine
Unchanged
Arecoline
Unchanged/Slight Improvement
Oxotremorine
Unchanged
Bethanecol
Unchanged/Slight Improvement
Nicotine
Slight Improvement
CEE/Estradiol
2
Improvement
Soy Phytoestrogens
3
Improvement
Release Enhancers
Phosphatidylserine
Slight Improvement
4-aminopyridine
Unchanged/Slight Improvement
AChE Inhibitors
Physostigmine
Unchanged to Significant Improvement
Tacrine
Unchanged to Significant Improvement
HupA
4
Significant Improvement
1
From Messamore et al, Acta Neurol Scand 149:4 1993
2
From Sherwin et al, Ann NY Acad Sci 743:213 1994
3
From Pan et al, Proc Soc Exp Biol Med 221(2):118 1999; Neurosci Lett 261(1-2):17 1999
4
From Skolnick, JAMA 278:1053 1997
Of these treatments, only AChE inhibitors like tacrine and physostigmine appear to be mildly effective in improving symptoms of Alzheimer's disease. For example, in some patients, these inhibitors increased the levels of acetylcholine in the brain. However, the major limitation of AChE inhibitor treatment is that cognitive function is improved only in patients whose brains still have a sufficient number of cholinergic neurons to synthesize acetylcholine. This treatment approach is totally ineffective in patients whose brains have suffered a serious loss of cholinergic neurons. Moreover, this treatment is not able to retard the loss of cholinergic neurons. In addition, tacrine has also been shown to be toxic to the liver [Watkins et al.,
JAMA
271:992 (1994)], and produces other undesirable side effects as well (see Table 2 below).
TABLE 2
Side Effects of Tacrine
(100 mg/day)
Side Effect
Per Cent of Patients
Abdominal Cramps
38
Nausea
25
Polyuria
25
Diarrhea
23
Vomitin
15
Dizziness
12
Ptyalsim
10
Excessive Sweating
4
From Beermann, Acta Neurologica Scandinavica 149:53 (1993)
The AChE inhibitor, physostigmine, has been found to exert mild beneficial effects on cognitive function in patients with Alzheimer's disease. Unfortunately, the short half-life of physostigmine renders this compound ineffective for use in treating Alzheimer's disease [Whitehouse,
Acta Neurol. Scand
. 149:42 (1993)].
STRUCTURE, SOURCE, AND ANTI-AChE PROPERTY OF HUPERZINE A
Recently, a novel AChE inhibitor, Huperzine A, has been reported to have selective and long-term inhibition of brain AChE with few side effects, and appears to be an effective treatment for improving cognitive function associated with cholinergic deficiency in patients with Alzheimer's disease [Tang,
Acta Pharmacol. Sinica
. 17:481(1996)].
Huperzine A (Hup A) was first isolated from Huperzia Serrata Trev and Chinese folk herb Qian Cheng Ta [Liu et al.,
Can J. Chem
. 64:837 (1986)]. Hup A is a novel Lycopodium alkaloid [(5R, 9R, 11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta(b)pyridin2(1H)-one] as shown in FIG.
1
. Hup A appears to be a much more potent and selective inhibitor of brain AChE than the other AChE inhibitors tested, and has few side effects [Tang,
Acta Pharmacol. Sinica
. 17:481 (1996)]. As shown below, Table 3 illustrates the in vivo anti-acetylcholinesterase activity of various AChE inhibitors in the blood and brain.
TABLE 3
Anti-acetylcholinesterase Activity (in vitro)
Blood (BuChE) vs Brain (AChE)
IC
50
(nmol/L
−1
)
Ratio of IC
50
BuChE
AChE
(BuChE/AChE)
Huperzine A
58,894
58.4
1,008.5
Tacrine
74.6
93.0
0.8
Physostigmine
1259
251
5.0
In vivo animal studies indicated that Hup A can exert inhibition of brain AChE much longer than physostigmine (360 min vs 60 min) [Tang, supra, (1996)]. In fact, Hup A is very specific against AChE as indicated by the IC
50
values shown above in Table 3. In contrast, tacrine has a lower specificity for AChE, and also inhibits butyrylcholinesterase (BuChE) at an IC
50
value comparable to AChE. Studies further revealed that Hup A inhibits AChE in the cerebral cortex and, more importantly, in the hippocampus where acetylcholine synthesis was markedly reduced in Alzheimer's patients [Hallak and Giacobine,
Neurochem. Res
. 11:1037 (1986); and Tang, J.,
Neurosci. Res
. 24:276 (1989)]. These results are ill
Anthony Mary S.
Clarkson Thomas B.
Notelivitz Morris
Pan Yuanlong
Dees Jose′ G.
George Konata M
Kilpatrick & Stockton LLP
Wake Forest University Health Services
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