Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-10-11
2003-04-29
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S439000, C424S464000, C424S484000, C424S725000, C424S754000
Reexamination Certificate
active
06555134
ABSTRACT:
BACKGROUND OF THE INVENTION
Atherosclerosis is the cause of death in more than 50% of people in Western Societies (Davies MJ and Woolf N.
Atherosclerosis: what is it and why does it occur? Br Heart J
69:S3, 1993). In addition, it results in significant cardiac morbidity, such as anginal syndromes, myocardial infarctions, ischemic cardiomyopathy, sudden cardiac death, cerebrovascular accidents, and peripheral vascular disease. Indisputable evidence for an association between coronary heart disease (CHD) and risk factors, such as arterial hypertension, cigarette smoking and hyperlipidemia, has been derived from a variety of epidemiological studies. Of all the risk factors established thus far, lipid disorders play a key role in the pathogenesis of atherosclerotic vascular disease, especially of CHD. Many epidemiological and clinical trials have demonstrated the powerful association between hyperlipidemia and the widespread incidence of CHD. The Framingham Heart Study (Castell WP, Anderson K, Wilson PW., Levy D.
Lipids aid risk of coronary heart disease. The Framingham Study. Ann Epidemiol
2(1-2): 23-28, 1992), which has been continuous since 1984, showed that hypercholesterolemia is a major contributor to the development of CHD. The link between atherosclerosis and cholesterol has been confirmed by a number of clinical trials.
Fats are insoluble in the aqueous medium of the blood. Thus, transport of the lipids triglycerides, phospholipids and cholesterol occurs exclusively by way of lipid-protein complexes, the lipoproteins. The lipoproteins are classified into 4 broad classes-chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL), which differ in their composition, size, and potential atherogenicity.
Measurement of total cholesterol level in plasma reflects the sum of cholesterol being transported in each individual lipoprotein. However, LDL and HDL are the main cholesterol carriers in plasma and only a small fraction of cholesterol is carried in VLDL or in the chylomicrons.
Atherosclerosis is a gradual pathological process, which is characterized by an accumulation of lipid filled macrophages (foam cells), and smooth muscle cells resulting in lesions that thicken and harden the arterial wall. The main source for the cholesterol accumulating in the foam cells is the circulating LDL. There is evidence from numerous epidemiological and clinical studies that LDL, as the carrier of ca. 70% of the total cholesterol in plasma, are the most potent atherogenic lipoproteins. Their elevation carries a particular risk, and reduction in LDL cholesterol constitutes a diminished atherosclerotic risk. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) had for the first time presented firm proof that in man, a lowering of LDL cholesterol level reduces the rate of myocardial infarcton and infarction mortality.
Nearly all cells, including macrophages, take up exogenous cholesterol via LDL-receptors. Increase in cell cholesterol content, however, result in down-regulation of LDL receptor number, thereby protecting cells from excessive accumulation of cholesterol by way of this pathway. It was shown that chemical or biological modification, including oxidation of LDL, results in increased uptake of the modified lipoprotein by way of other cell surface receptors, termed scavenger receptors. These receptors are present on macrophages and endothelial cells.
Oxidative modification of LDL is thought to play a causal role in atherosclerosis: (see e.g. Steinberg D, Parthasarathy S., Carew T. E., Khoo J. C. and Witztum J. L, “Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity”, N. Engl. J. Med. 1989, 320: 915-924, Haberland M. E. and Fogelman A. M., “The role of altered lipoproteins in the pathogenesis of atherosclerosis”, Am. Heart. J. 1987; 113: 573-577, and Witztun J. L., “The oxidation hypothesis of atherosclerosis”, Lancet. 1994; 344, 793). It is believed, accordingly, that prevention of LDL oxidation by antioxidants may arrest the progression of atherosclerosis. (see e.g., Aviram M. Beyond cholesterol: Modification of lipoproteins and increased pitherogenicity. In Atherosclerosis, Inflammation and and Thrombosis (GG Neri Serneri, GF Geusini, R. Abbate and D. Prisco eds) Scientific Press-Florence, Italy, pp: 15-36, 1993, Aviram M. Oxidized low density lipoprotein (OX-LDL) interaction with macrophages in atherosclerosis and the ocutioctberogenicity of antioxidants. Europ. J. Clin. Chem. Clin. Biochem. 34: 599-608, 1996).
The ability to prevent the development of atherosclerotic lesions would have major implications for the public health. Thus using therapeutic agents with plural effects, such as lowering cholesterol and inhibiting oxidative modification, might have beneficial effects over other individual agent.
Carotenoids are colored pigments with lipophilic properties, widely distributed in fruits and vegetables, (e.g. &bgr;-carotene in carrots and lycopene in tomatoes) and possess some antioxidant properties: (see e.g. Burton G. W., “Antioxidant action of carotenoids,” 1989; J. Nutr. 119:109-111 and Krinsky N. I., “antioxidant functions of carotenoids”, Free Rad. Biol. Med. 1989, 7: 617-635 (9-13)). Carotenoids are transported within circulating lipoproteins, and it was postulated that they participate in the protection of LDL from oxidative modification.
Carotenoids consumption was shown in previous epidemiological studies to be associated with reduced cardiovascular mortality (see e.g.: Kohlmeier L. and Hasting S. B., “Epidemiologic evidence of a role of carotenoids in cardiovascular disease prevention”, Am. J. Clin. Nutr. 1995; 62: 137S-146S), although recent data did not demonstrate similar beneficial effect (see e.g., Hennekens C. H., Buring J. E., Manson J. E., Stampfer M, Rosier B., Cook N. R., Belanger C., LaMotte F., Gaziano J. M., Ridker P. M., Willett W. and Peto R, “Lack of effect of long-term supplementation with &bgr; carotene on the incidence of malignant neoplasms and cardiovascular disease”, N. Engl. J. Med. 1996; 334: 1145-1149).
Reduced plasma lipid peroxidation was recently shown to be associated with increased consumption of tomatoes. Low levels of plasma carotenoids were shown to be associated with an increased risk of myocardial infarction, and recently it was demonstrated that the association between &bgr;-carotene and acute myocardial infarction depends on the polyunsaturated fatty acids status, and that feeding the all-trans isomer of &bgr;-carotene to cholesterol-fed rabbits attenuated the extent of their atherosclerosis, with no effect on LDL oxidizability ex vivo. Data on the ability of &bgr;-carotene supplementation in vitro or in vivo to protect LDL from oxidation are conflicting: some studies found an inhibitory effect of &bgr;-carotene supplementation on LDL oxidation, whereas several other did not find such effect.
Lycopene, the open chain analog of &bgr;-carotene, shares with it similar structure with an extended conjugated double bonds. In human plasma, lycopene and &bgr;-carotene are quantitatively the major carotenoids. Lycopene was shown to possess the greatest quenching ability of singlet oxygen among the various carotenoids (DiMascio P., Kaiser S. & Sies H., “Lycopene as the most efficient biological carotenoid singlet oxygen quencher,” Arch. Biochem. Biophys., 1989, 274: 532-538) and it was shown to be at least twice as effective antioxidant as &bgr;-carotene in protecting blood lymphocytes form NO
2
radical damage (Bohrn F., Tinkler J. H., and Truscott T. G., “Carotenoids protect against cell membrane damage by the nitrogen dioxide radical”, Nature Medicine, 1995, 2: 98-99).
We have recently demonstrated a protective effect of tomatoes lycopene against oxidative modification of LDL. This protection of LDL by lycopene exceeded the protection exhibited by &bgr;-carotene, was selective only to LDL's with high vitamin E content and was shown when the carotene was present in combination with vitamin E. (see e.g., Fuhrna
Aviram Michael
Fuhrman Bianca
Gruenwald Jeorg
Nir Zohar
Browdy and Neimark , P.L.L.C.
Lycored Natural Products Industries Ltd.
Spear James M.
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