Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing
Reexamination Certificate
2000-08-14
2004-11-30
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C514S002600, C514S04400A, C800S003000, C530S387100
Reexamination Certificate
active
06825164
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced by number. Full citations for these publications may be found listed at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
The pain of Alzheimer's disease results directly from the memory loss and cognitive deficits suffered by the patient. These eventually result in the patient's loss of identity, autonomy, and freedom. As a step toward curing this disease, alleviating its symptoms, or retarding its progression, it would be desirable to develop a transgenic animal model exhibiting the main debilitating phenotype of Alzheimer's disease, that is, memory loss, expressed concomitantly with the neuropathological correlates of Alzheimer's disease, for example, beta-amyloid accumulation, increased glial reactivity, and hippocampal cell loss.
It is estimated that over 5% of the U.S. population over 65 and over 15% of the U.S. population over 85 are beset with some form of Alzheimer's disease (Cross, A. J., Eur J Pharmacol (1982) 82:77-80; Terry, R. D., et al., Ann Neurol (1983) 14:497506). It is believed that the principal cause for confinement of the elderly in long term care facilities is due to this disease, and approximately 65% of those dying in skilled nursing facilities suffer from it.
Certain facts about the biochemical and metabolic phenomena associated with the presence of Alzheimer's disease are known. Two morphological and histopathological changes noted in Alzheimer's disease brains are neurofibrillary tangles (NFT) and amyloid deposits. Intraneuronal neurofibrillary tangles are present in other degenerative diseases as well, but the presence of amyloid deposits both in the interneuronal spaces (neuritic plaques) and in the surrounding microvasculature (vascular plaques) seems to be characteristic of Alzheimer's. Of these, the neuritic plaques seem to be the most prevalent (Price, D. L., et al., Drug Development Research (1985) 5:59-68). Plaques are also seen in the brains of aged Down's Syndrome patients who develop Alzheimer's disease.
SUMMARY OF THE INVENTION
The present invention provides a method for decreasing cerebral vasoconstriction in a subject suffering from chronic or acute cerebral amyloid angiopathy which comprises administering to the subject an inhibitor of receptor for advanced glycation endproduct (RAGE) in an effective amount to inhibit transcytosis of amyloid &bgr; peptides across the blood-brain barrier in the subject, thereby decreasing cerebral vasoconstriction in the subject. The invention further provides for a method for ameliorating neurovascular stress in a subject which comprises administering to the subject an effective amount of an inhibitor of receptor for advanced glycation endproduct (RAGE), so as to increase cerebral blood flow in the subject, thereby ameliorating neurovascular stress in the subject.
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Ghersi-Egea JF, Gorevic PD, Ghiso J, Frangione BF, Patlak CS, Fenstermacher JD. Fate of cerebrospinal fluid-borne amyloid &bgr;-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries J Neurochem 1996; 67:880-83.
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999;97:889-901.
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Mackic JB, Stins M, McComb JG, Calero M, Ghiso J, Kim KS, Yan SD, Stern D, Schmidt AM, Frangione B, Zlokovic BV. Human blood-brain barrier receptors for Alzheimer's amyloid-&bgr;1-40: asymmetrical binding, endocytosis and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J Clin Invest 1998; 102:734-743.
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Schmidt AM, Hasu M, Popov D, Zhang JH, Chen J, Yan SD, Brett J, Cao R, Kuwabara K, Gostache G, Simionescu N, Simionecu M, Stern D. Receptor for advanced glycation end products (AGE) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins. Proc Natl Acad Sci USA 1994;91:8807-11.
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Yan SD, Zhu H, Zhu A, Golabek A, Du H, Roher A, Yu J, Soto C, Schmidt AM, Stern D, Kindy M. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med 2000;6:643-51.
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Schmidt Ann Marie
Stern David M.
Yan Shi Du
Zlokovic Berislav
Cooper & Dunham LLP
Crouch Deborah
The Trustees of Columbia University in the City of New York
Ton Thai-an N.
White John P.
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