Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from vitis
Reexamination Certificate
2001-04-20
2002-12-31
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from vitis
C424S400000, C424S725000
Reexamination Certificate
active
06500469
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to methods and compositions for reducing blood cholesterol levels in a subject.
According to recent information from the American Heart Association, an estimated 100,870,000 American adults have total cholesterol levels in the borderline-high risk range of 200 mg/dl to 239 mg/dl. There are 40,600,000 American adults living with high-risk cholesterol levels of 240 mg/dl or more. There are many risk factors that can indicate a propensity to have high levels of cholesterol, such as age, weight, health conditions such as diabetes, smoking, gender, race and ethnicity. Elevated blood cholesterol levels are associated with potentially deadly conditions of the heart and blood vessels, such as atherosclerosis, coronary artery insufficiency and stroke.
Atherosclerosis is the most common cause of death and serious morbidity in the Western world. Atherosclerosis is one of three morphologically distinct forms of arteriosclerosis. Arteriosclerosis is the hardening of the arteries due to their thickening and loss of elasticity. Atherosclerosis occurs when irregularly distributed lipid deposits form in the inner coating of the vessels of the elastic arteries, such as the aorta, carotid and iliac, or the large and medium-sized muscular arteries, such as the coronary and popliteal. These lipid deposits, called atheromatous plaques, cause fibrosis and calcification which leads to coronary heart disease and myocardial infarction. The plaques are comprised of cells, macrophages and other leukocytes, a connective tissue extra-cellular matrix and intracellular and extracellular lipid deposits. The progression of atherosclerosis can be slowed by reducing the plasma cholesterol and cholesterol LDL levels.
Hypercholesterolemia, or elevated blood cholesterol levels due to concentration of cholesterol in the cells and plasma, is also prevalent in the American population. Elevated total and LDL cholesterol levels are considered cardiovascular risk factors for coronary heart disease and myocardial infarction.
Cholesterol is the most abundant steroid in cell membranes and is essential to the growth and viability of cells. Cholesterol is classified as a lipid and forms lipoproteins, or complexes of cholesterol and protein. There are four major categories of lipoproteins: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). Chylomicrons transport some dietary cholesterol and mostly triglycerides from the intestines to the adipose tissue (also known as fat) and the liver. VLDLs transport cholesterol and triglycerides made by the liver to adipose and other tissues. LDL is a byproduct consisting of apolipoprotein and cholesterol that remains after the fat cells have removed the triglycerides from the VLDL. LDLs transport cholesterol to the peripheral tissues (cells outside the liver and intestine) and regulate the endogenous cholesterol levels therein. LDL is often referred to as the “bad cholesterol” because high levels increase the risk of developing arteriosclerosis and hypercholesterolemia. HDL, known as the “good cholesterol,” transports cholesterol from the peripheral tissues (and arterial walls) to the liver. HDLs operate as good cholesterol because they oppose LDLs. It is thought that high levels of HDL can reverse the negative effects of LDL activity. The primary site of cholesterol synthesis is in the liver, although some cholesterol is synthesized in the intestines. The liver's function in this pathway is to remove the cholesterol from the blood. Plasma LDL is the primary source of cholesterol in peripheral tissues, which do not synthesize cholesterol de novo. LDL is taken into these cells via endocytosis at LDL receptor cites. The molecular genetics and cellular biology of the LDL receptor has been characterized by Goldstein and Brown. The LDL receptor is essential to cholesterol metabolism. When cholesterol is abundant inside the cell, there is no synthesis of LDL receptors, and thus cholesterol uptake from plasma cholesterol is blocked. The absence of the LDL receptor leads to hypercholesterolemia and atherosclerosis.
Free radical activity produces oxidized LDL. When macrophages take up oxidized LDL, they form foam cells which form the atheromatous plaques, described above, in the larger blood vessels. As these plaques cause fibrosis and calcification which lead to coronary heart disease and myocardial infarction, oxidized LDL levels are important indicators of patients with a disease propensity. Yamakoshi et al., “Proanthocyanidin-Rich Extract From Grape Aortic Atherosclerosis in Cholesterol-Fed Rabbits,”
Atherosclerosis
, 142:139-149 (1999).
Wine has been shown to protect LDLs from lipid peroxidation. Specifically, red wine inhibits cell-mediated oxidation of LDL, whereas white wine does not seem to produce similar results. Rifici et al., “Red Wine Inhibits the Cell-Mediated Oxidation of LDL and HDL,”
J. Am. Coll. Nutr
., 18:137-143 (1999). This inhibition is believed to be caused by the antioxidant activity of proanthocyanidins responsible for the color of red wine. Nuttall et al., “An Evaluation of the Antioxidant Activity of a Standardized Grape Seed Extract,”
Leucoselect, J. Clin. Pharm. Ther
., 23:385-389 (1998); see also, Yanakoshi et al., “Proanthocyanidin-Rich Extract from Grape Seeds Attenuates the Development of Aortic Atherosclerosis in Cholesterol-Fed Rabbits,”
Atherosclerosis
, 142:139-149 (1999).
Proanthocyanidins comprise a group of polyphenolic bioflavonoids ubiquitously found in fruits and vegetables. They are the most common type of tannins found in fruits and vegetables, and are present in high amounts in the seeds and skins of grapes. Proanthocyanidins consist of polymers of the flavan-3-ol units (+)-catechin, (−)-epicatechin and (−)-epicatechin 3-O-gallate linked by C4-C8 or C4-C6 bonds. Some proanthocyanidins carry galloyl residues linked to the C-3 alcoholic function of the flavan-3-ol units. Proanthocyanidins have been the subject of considerable interest because of their broad pharmacologic activity and therapeutic potential. Chen et al., “Antioxidative Activity of Natural Flavonoids is Governed by Number and Location of Their Aromatic Hydroxyl Groups,”
Chem. Phys. Lipids
, 79:157-163 (1996). The biological and medicinal properties of the proanthocyanidins have been extensively reviewed, see, Rice-Evans et al., “Structure-Antioxidant Activity Relationships of Flavonoids and Phenolic Acids,”
Free Rad. Biol. Med
., 20:933-956 (1996). Purified proanthocyanidin compositions of this invention may be isolated or derived from a variety of plant sources according to known methods or may be produced synthetically. Proanthocyanidins are found in the fruit and seeds of a wide variety of fruit plants including but not limited to strawberry, blueberry and grapes. Proanthocyanidins are also present in large quantities in maritime pine bark, oak wood, black and green tea and in cocoa powder.
Chromium deficiency has also been linked to the development of atherosclerosis. Schroeder et al., “Chromium Deficiency as a Factor in Atherosclerosis,”
J. Chron. Dis
., 23:123-142 (1970); Newman et al., “Serum Chromium and Angiographically Determined Coronary Artery Disease,”
Clin. Chem
., 24:341-544 (1978); Simonoff, “Chromium Deficiency and Cardiovascular Risk,”
Cardiovas. Res
., 18:591-6 (1984); Simonoff et al., “Low Plasma Chromium in Patients with Coronary Artery and Heart Disease,”
Biol. Trace Elem. Res
., 6:431-439 (1984); Cote et al., “Hair Chromium Concentration and Coronary Artery Diseases in Canada, France, and Italy,”
Nutr. Res. Suppl. I
, 356-359 (1985). Chromium (Cr) is necessary for insulin function as it is the biologically active component of glucose tolerance factor (GTF). GTF also contains nicotinic acid and is responsible for insulin activity. Oral chromium supplementation can lower cholesterol and triglyceride levels and increase HDL levels. For example, a double-blind study of thirty-four male athletes examined the ef
Bagchi Debasis
Preuss Harry G.
Dry Creek Nutrition, Inc.
Marshall Gerstein & Borun
Tate Christopher R.
Winston Randall
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