Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-11-13
2002-10-29
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S455000, C514S510000, C514S543000
Reexamination Certificate
active
06472421
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of treating, preventing, and reducing the risk of Alzheimer's disease by administering a 3 beta-hydroxy-3 beta-methyl glutaryl CoA reductase inhibitor (“HMG CoA reductase inhibitor”) to a patient in need of treatment.
BACKGROUND OF THE INVENTION
Alzheimer's disease (“AD”) is a major cause of dementia among the elderly throughout the world. Beginning at age 65, the incidence of the disease rises steadily until by age 85, where conservative estimates place its rate of incidence at some 30% of that population. It is generally believed that the disease begins a number of years before it manifests itself in the mild cognitive changes that are the early signs of AD. Thus, the at risk population is believed to be 60 years or older.
The consequences of this disease are devastating, both to the patient and his or her family and care givers. The disease typically results in an inexorable decline in cognitive functions often coupled with gross behavioral changes, leading to the patient's inability to care for his or herself in the community and increased burdens on care givers and home care and nursing home providers. As the baby-boom generation enters the age of risk for Alzheimer's disease, the social and economic consequences of this disease loom even larger.
HMG CoA Reductase Inhibitors
HMG CoA reductase is the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, i.e., conversion of HMG-CoA to mevalonate. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. These complexes can be separated by density ultracentrifugation into high (HDL), intermediate (IDL), low (LDL), and very low (VLDL) density lipoprotein fractions. Triglycerides (TG) and cholesterol synthesized in the liver are incorporated into VLDLs and released into the plasma for delivery to pheripheral tissues. In a series of subsequent steps, VLDLs are transformed into IDLs and cholesterol-rich LDLs. HDLs, containing apolipoprotein A, are hypothesized to participate in the reverse transport of cholesterol from tissues back to the liver.
Clinical and pathological studies have shown that elevated levels of total cholesterol, low LDL-cholesterol (LDL-C), and apolipoprotein B (a membrane transport protein for LDL) promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total cholesterol and LDL-C, and inversely with the level of HDL-C. Thus, HDLs have been characterized as “good” lipoproteins, while cholesterol-rich LDLs have been characterized as being less favorable.
Elevated serum total cholesterol is closely related to the development of cardiovascular, cerebrovascular, and peripheral vascular disorders. Hypercholesterolemia has been linked to increased risk of coronary heart disease. Many studies have found that a reduction of elevated serum cholesterol levels leads to a decreased incidence of coronary disease.
HMG CoA reductase inhibitors have been shown to reduce total serum cholesterol levels, LDL-C, and apolipoprotein B, most likely by increasing the fractional catabolic rate of LDL and the liver's extraction of LDL precursors, blocking enzymes that synthesize cholesterol, and simultaneously increasing the levels of HDL. Lipid lowering drugs, such as HMG CoA reductase inhibitors, have been used successfully to lower serum cholesterol levels when diet and lifestyle changes have proven inadequate and have been shown to reduce the incidence of both cardiovascular and cerebrovascular events.
Many references teach the use of HMG CoA reductase inhibitors for treating coronary disease. For example, U.S. Pat. No. 5,831,115, for “Inhibitors of squalene synthase and protein farnesyltransferase,” describes lipid-lowering compositions comprising an HMG CoA reductase inhibitor; U.S. Pat. No. 5,807,834, for “Combination of a cholesterol absorption inhibitor and a cholesterol synthesis inhibitor,” teaches that HMG CoA reductase inhibitors are known to be useful for the treatment of hypercholesterolemia; U.S. Pat. No. 5,801,143, for “Cyclic depsipeptides useful for treatment of hyperlipemia,” teaches that HMG CoA reductase inhibitors are known to exhibit a remarkable lowering of cholesterol and are useful in treating hypercholesterolemia; U.S. Pat. No. 5,798,375, for “Treatment of arteriosclerosis and xanthoma,” teaches the use of HMG CoA reductase inhibitors for treating arteriosclerosis and xanthoma; and U.S. Pat. No. 5,786,485, for “Optically active beta-aminoalkoxyborane complex,” notes that HMG CoA reductase inhibitors are known to be antihyperlipemia agents.
Relationship Between Alzheimer's Disease and Cholesterol Levels
While Alzheimer's disease is typically characterized pathologically by the presence of senile plaques and neurofibrillary tangles found at autopsy in the brains of patients afflicted with the disease, vascular components of the disease have also been noted. These include lesions in the cerebral microcirculation and vascular deposits of A&bgr; protein, which is also a major constituent of the senile plaques found in AD.
In addition to a relationship with coronary disease, it is known that there is a relationship between serum cholesterol levels and the incidence and the pathophysiology of AD. Epidemiological studies show that patients with elevated cholesterol have an increased risk of AD. (Notkola et al., “Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease,”
Neuroepidemiology;
17(1): 14-20 (1998); Jarvik et al., “Interactions of apolipoprotein E genotype, total cholesterol level, age and sex in prediction of Alzheimer's disease: a case-control study,”
Neurology,
45(6):1092-6 (1995).) Other studies have established that patients possessing the apolipoprotein &egr;4 genotype (“apoE4”) that codes for a variant of apolipoprotein, a cholesterol transport protein, have an increased risk for AD, as well as for elevated levels of cholesterol and for heart disease. (Mahley R, “Cholesterol transport protein with expanding role in cell biology,”
Science,
240:622-630 (1988); Saunders et al., “Association of apolipoprotein E allele &egr;4 with late-onset familial and sporadic Alzheimer's disease,”
Neurology,
43:1467-1472 (1993); Corder et al., “Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late-onset families,”
Science,
261:921-923 (1993); Jarvik et al., “Coronary artery disease, hypertension, ApoE and cholesterol: a link to Alzheimer's disease?”
Annals of the New York Academy of Sciences,
826:128-146 (1997).) Both apoE4 and a second putative risk factor for AD, &agr;-2-macroglobulin, bind to a receptor, the lipoprotein receptor related protein, which is important for cellular uptake of cholesterol. (Narita et al., “Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein,”
Journal of Neurochemistry;
69(5):1904-11 (1997); and Blacker et al., “Alpha-2 macroglobulin is genetically associated with Alzheimer's disease,”
Nat. Gen.,
19:357-60 (1998).) Other studies have shown that cholesterol increases the production of A&bgr; protein, which accumulates in the brains of patients with AD and is thought by many researchers to cause the neurodegeneration underlying the disease. (Selkoe D J, “Cell biology of the beta-amyloid precursor protein and the genetics of Alzheimer's disease,”
Cold Spring Harbor Symposia on Quantitative Biology,
61:587-96 (1996); and Simons et al., “Cholesterol depletion inhibits the generation of &bgr;-amyloid in hippocampal neurons,”
Proc. Natl. Acad. Sci., USA,
95:6460-4 (1998).)
While it was known that there is a connection between serum cholesterol levels and the incidence and the p
Criares Theodore J.
Foley & Lardner
Nymox Corporation
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