Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-08
2001-02-06
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S733000, C514S734000
Reexamination Certificate
active
06184248
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for the treatment of various neurological diseases and neurodegenerative disorders, particularly those affected by an overabundance of Amyloid Precursor Protein (APP). In particular, it has been discovered that APP synthesis is stimulated by activation of cell surface receptors coupled to the formation of cyclic adenosine monophosphate (cAMP). Moreover, it has been found that certain substances can inhibit APP synthesis, either directly or by antagonizing receptors coupled to cAMP formation.
BACKGROUND OF THE INVENTION
Alzheimer's Disease (AD) is the most common neurodegenerative disorder of aging, and is characterized by progressive dementia and personality dysfunction. The abnormal accumulation of amyloid plaques in the vicinity of degenerating neurons and reactive astrocytes is a pathological characteristic of AD.
As the fourth leading cause of death in industrialized societies, surpassed only by heart disease, stroke and cancer, AD affects 5-11% of the population over the age of 65 and 30% of those over the age of 85. The estimated cost of caring for the approximate 2.5-4.0 million AD cases in the USA exceeded $60 billion in 1991 alone. Considering the estimated 17-25 million existing AD cases worldwide, AD will no doubt become an escalating healthcare problem of unparalleled proportions as the world's geriatric population grows. Much work remains in the quest to find an effective treatment for AD.
APP processing is regulated by neurotransmitters and synaptic activity. Amyloid plaques in AD accumulate near dystrophic neurons and reactive astrocytes. B. Cordell,
Annu. Rev. Pharmacol. Toxicol.
34, 69 (1994); D. J. Selkoe,
Annu. Rev. Neurosci.
17, 489 (1994). The activation of neurotransmitter receptors, which are coupled to phosphotidylinositol (PI) hydrolysis or to protein kinase C (PKC) activation, can promote APP metabolism and decrease amyloid formation. R. M. Nitsch, B. E. Slack, R. J. Wurtman, J. H. Growdon,
Science
258, 304 (1992); B. A. Wolf et al.,
J. Biol. Chem.
270, 4916 (1995); J. D. Buxbaum, A. A. Ruefli, C. A. Parker, A. M. Cypess, P. Greengard,
Proc. Natl. Acad. Sci. U.S.A.
91, 4489 (1994); R. K. K. Lee, R. J. Wurtman, A. J. Cox, R. M. Nitsch,
Ibid.,
92, 8083 (1995); Ulus and Wurtman,
J. Pharm. Exp. Ther.,
281,149 (1997); Lee et al.,
PNAS USA,
92, 8083 (1995). Activation of neurotransmitters coupled to cAMP production suppresses both constitutive and PKC/PI-stimulated APPs secretion in astroglioma cells and in primary astrocytes. Eftimiopoulos et al.,
J. Neurochem.,
67, 872 (1996); Lee et al.,
J. Neurochem.,
68,1830 (1997). Cyclic AMP and PK activators also increase A production, Marambaud et al.,
Br. J. Pharmacol.
126, 1186 (1999). The drastic alterations in neurotransmitter levels and second messenger signalling created by neurodegeneration and synapse loss in AD may disrupt APP processing in ways that promote the accumulation of amyloidogenic or neurotoxic APP fragments. In contrast, the loss of various neurotransmitters in AD may increase cellular levels of APP holoprotein containing amyloidogenic or neurotoxic peptides due to a decrease in proper APP metabolism. B. A. Yankner et al.,
Science,
245, 417 (1989); M. R. Kozlowski, A. Spanoyannnis, S. P. Manly, S. A. Fidel, R. L. Neve,
J. Neurosci.
12, 1679 (1992).
Increased APP production in Down's syndrome/Trisomy 21 is associated with a high incidence of AD at an early age due to the extra copy of the APP gene. Overexpression of APP in cell cultures and in transgenic mice is also associated with neurodegeneration and with age-related cognitive deficits, suggesting that overexpression of APP could contribute to the neuropathology of AD. K. Maruyama, K. Terakado, M. Usami, K. Yoshikawa,
Nature,
347, 566 (1990); K. K. Hsiao et al.,
Neuron
15, 1203-1218 (1995); P. M. Moran, L. S. Higgins, B. Cordell, P. C. Moser,
Proc. Natl. Acad. Sci. U.S.A.
92, 5341 (1995).
Several APP isoforms, ranging in size from 695-770 amino acids, are derived by differential splicing of a primary transcript. Of the three major APP isoforms, APP695 is predominantly expressed in neurons; APP751 and APP770, which harbor an additional Kunitz-type protease inhibitor (KPI) insert at the N-terminus, are predominantly expressed in astrocytes and appear to be increased in AD brain. T. E. Golde, S. Estes, M. Usiak, L. H. Younkin, S. G. Younkin,
Neuron
4, 253 (1990); R. L. Neve, E. A. Finch, L. R. Dawes,
Ibid.,
1, 669 (1990); J. P. Anderson et al.,
EMBO J.
8, 3627 (1989); C. Nordstedt et al. ,
Proc. Natl. Acad. Sci. U.S.A.
88, 8910 (1991). The decreased amounts of APP695 in postmortem AD brains may be due to neuronal loss. The increase in KPI-containing APP isoforms in AD and in regions surrounding senile plaques raises the possibility that transcriptional activation of APP synthesis in astrocytes contributes to AD neuropathology.
Prior AD Studies
Aging, neurodegeneration and synapse loss in AD are associated with astrocyte proliferation and an upregulation of KPI-containing APP isoforms. See, e.g., A. Brun, X. Liu, C. Erikson,
Neurodegeneration
4, 171 (1995); R. Schechter, S. H. C. Yen, R. D. Terry, J.
Neuropathol. Exp. Neurol.
40, 95 (1981); L. A. Hansen, D. N. Armstrong, R. D. Terry,
Neurobiol. Aging
8, 1 (1987); K. Iverfeldt, S. I. Walaas, P. Greengard,
Proc. Natl. Acad. Sci. U.S.A.
90, 4146 (1993).
McGeer, P. L. et al., in
The Lancet,
335, 1037 (1990), present the results of a retrospective study that revealed an apparently low incidence of Alzheimer's Disease in rheumatoid arthritis patients. These authors propose the possibility that anti-inflammatory therapy confers some protection against AD. While provocative, the authors' proposal is based solely on circumstantial evidence. This fact is not lost on the authors, who note three alternative explanations for their observations, in addition to the possible protective role of anti-inflammatory therapy.
Andersen, K. et al., in
Neurology
(August 1995) 45:1441, describe the results of their retrospective study. This article, perhaps, illustrates the care that one should take in conducting studies “in hindsight” because of the danger of over-interpretation or over-manipulation of the data in an effort to enhance any perceived differences. To their credit, the authors tempered their conclusions, stating that their findings are “compatible” with a possible protecting effect of NSAIDs (non-steroidal anti-inflammatory drugs) on the risk of AD. The authors fairly point out that important issues remain, including whether the presence of complement leads to neurodegeneration or whether the activation of complement is brought about by the cell's need to phagocytose damaged neurons, how long one has to be exposed to NSAIDs to obtain clinically detectable results, and the need for studies that are better designed. The article adds that no relationship between NSAIDs exposure and cognitive function is found.
In contrast, an earlier article by Rich, J. B. et al., which appeared in
Neurology
(January 1995) 45:51, reported on the results of their review of the records of 210 Alzheimer's patients. These authors concluded that patients on NSAIDs performed better on certain tests, including Mini-Mental State Examination, Boston Naming Test, delayed Benton Visual Retention Test, among others, versus non-NSAID patients. However, no significant difference is found in an even greater number of other tests performed, including Block Design, Immediate Benton Visual Retention Test, Gollin Incomplete Figures Test, to name a few. Recognizing the inherent limitations of their study, the authors state that “[m]ethodologic limitations inherent in retrospective studies such as this one preclude us from addressing the specificity of the protective effects of NSAIDs.” Indeed, the patients examined are likely to be on several types of medication at once.
In fact, in an earlier study by Lindsay, J. and co-workers reported in
Neurology
(November 1994)
Lee Robert K. K.
Wurtman Richard J.
Pepper Hamilton LLP
Reamer James H.
Villacorta Gilberto M.
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