Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-03-01
2002-11-05
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S458000, C514S556000, C514S725000
Reexamination Certificate
active
06476010
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for increasing the intestinal absorption, cellular concentration, biliary secretion, hepatic storage, and/or liver concentration of a fat soluble vitamin in a post-menopausal woman or a lower animal by orally administering L-carnitine and a fat soluble vitamin.
BACKGROUND OF THE INVENTION
L-carnitine plays a crucial role in the energy supply of tissues by modulating the entry of long-chain fatty acids into the mitochondrial matrix and their subsequent oxidation. Consistent with such a metabolic role, L-carnitine has been shown to be effective in lowering the serum levels of cholesterol, triglyceride, and free fatty acids, while increasing high density lipoprotein (HDL) cholesterol which is antiatherogenic. See Pola, P. et al., “Carnitine in the theraphy of dyslipemic patients”,
Curr Ther Res
27:208-16 (1980); Lacour, B. et al., “Carnitine improves lipid abnormalies in haemodialysis patients”,
Lancet
12:763-4 (1980); Avogaro, P., “Acute effect of L-carnitine on FFA and beta-hydroxy-butyrate in man”,
Pharmacol Res Commun
13:433-50 (1981); and Vacha, G. M. et al. “Favourable effects of L-carnitine treatment on hypertriglyceridemia in hemodialysis patients: Decisive role of low levels of high density lipoprotein cholesterol”,
Am J Clin Nutr
38:532-40 (1983). Existing evidence indicates that L-carnitine and its esters enhance the stability and integrity of erythrocyte membranes by participating in the reacylation (repair) of membrane phospholipids subjected to oxidative damage. See Arduini, A. et al., “Effect of propionyl-L-carnitine treatment on membrane phospholipid fatty acid turnover in diabetic rat erythrocytes”,
Mol Cell Biochem
152:31-7 (1995); Arduini, A. et al., “Carnitine palmitoyltransferase and acyl-CoA binding protein: two more players in the membrane phospholipid fatty acid turnover of human red cells?”,
Biochem J
325:811-4 (1997); and Arduini, A. et al., “Addition of L-carnitine to additive solution-suspended red cells stored at 4° C. reduces in vitro hemolysis and improves in vivo viability”,
Trandfusion
37:166-74 (1997). It is of interest to note that such an action of L-carnitine and its esters is shown in the erythrocyte devoid of mitochondrial. L-carnitine supplementation to old rats has been shown to reverse the age-related decline in mitochondrial function, which may be linked to the membrane-stabilizing effect of L-carnitine. See Hagen, T. M. et al., “Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity”,
Proc Natl Acad Sci USA
95:9562-6 (1998). This finding is of particular significance in that oxidative damage to mitochondrial DNA increases markedly with age, leading to impaired cellular metabolism and function. See Hagen, T. M. et al., “Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase”,
Proc Natl Acad Sci USA
94:3064-9 (1997).
Postmenopausal women make up over 15% of the total population in industrialized countries. By 2030, the proportion of postmenopausal women is predicted to increase to 23% of the total population. See Hill, K., “The demography of menopause”,
Maturitas
23:113-127 (1996). In addition, numerous epidemiological studies have shown that depletion of estrogen at the menopause influences cause-specific morbidity and mortality in later life. From the nutritional standpoint, the menopause is the time when the body's ability to absorb, assimilate, and metabolize nutrients begins to deteriorate. Consequently, the body status of nutrients is compromised at and after menopause, with the manifestations of specific nutrient deficiency symptoms with time.
It is well documented that postmenopausal women are substantially more susceptible to coronary heart disease, age-related macular degeneration, osteoporosis, cancer, and Alzheimer's disease. See Hill, K., “The demography of menopause”,
Maturitas
23:113-127 (1996). Although this is partly associated with the process of aging and deterioration of bodily functions and the immune systems, epidemiological evidence suggests that a significant association exists between the risks (or incidence) of certain chronic diseases and the inadequacies or deficiencies of specific nutrients in postmenopausal women. Current evidence strongly suggests that the compromised body status of lipid-soluble vitamins, such as vitamins A, D, and E, is a key factor influencing or contributing to the onset or development of the diseases. For example, the risk of coronary heart disease rises dramatically in postmenopausal and ovariectomized women, compared with women in their child-bearing years. Supplemental vitamin E has been shown to reduce significantly the risk of coronary heart disease by retarding the oxidation of serum lipoproteins and inhibiting the proliferation of vascular smooth muscle cells. See Chan, A. C., “Vitamin E and atherosclerosis”,
J Nutr
128:1593-6 (1998); Motoyama, T. et al., “Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spasmic angina”,
J Am Coll Cardiol
32:1672-9 (1998); and Meydani, M. et al., “The effect of long-term dietary supplementation with antioxidants”,
Ann NY Acad Sci
854:352-60 (1998). Also, it is well established that vitamin D deficiency is prevalent in postmenopausal women with increased risk for bone loss and osteoporosis. See WHO Scientific Group, “Research on the menopause in the 1990s”, WHO Technical Report, Series 866, 1996, WHO, Geneva, Switzerland. Also, studies have shown that the incidence of age-related macular degeneration in postmenopausal women is inversely correlated with intakes of provitamin A (carotenoids) and vitamin E. See Seddon, J. M. et al., “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye disease case-control study group”,
JAMA
272:1413-20 (1994); West, S. et al., “Are antioxidants or supplements protective for age-related macular degeneration?”,
Arch Opthalmol
112:222-7 (1994); Van der Hagen, A. M., et al., “Free radicals and antioxidant supplementation: a review of their roles in age-related macular degeneration”,
J Am Optom Assoc
64:871-8 (1993); and Golberg, J. et al., “Factors associated with age-related macular degeneration. An analysis of data from first National Health and Nutrition Examination Survey”,
Am J Epidemiol
128:700-10 (1988). Furthermore, recent evidence suggests that oxidative stress may play an important role in the pathogenesis of Alzheimer's disease and that supplemental vitamin E may lower the risk of the disease. See Sinclair, A. J. et al., “Altered plasma antioxidant status in subjects with Alzheimer's disease and vascular dementia”,
Int J Geriatr Psychiatry
13:840-5 (1998); Morris, M. C., et al., “Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease”,
Alzheimer Dis Assoc Disord
12:121-6 (1998); Subramaniam, R. et al., “The free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid beta-peptide (25-35) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimer's disease”,
Neurochem Res
23:1403-10 (1998).
It has also been shown that cancer accounts for 47% of disease-related deaths in dogs followed by heart diseases (12%) and kidney diseases (7%). In cats, top ranking diseases include cancer (32%), kidney/urinary diseases (23%), and heart diseases (9%). See Morris Animal Foundation Animal Health Survey 1997. It is thought that these diseases in animals are associated with inadequate levels of certain vitamins, especially antioxidant vitamins like vitamin E and vitamin C, as well as vitamin A.
Therefore, there is a need for improving the nutritional status of the fat-soluble vitamins in postmenopausal women, particularly, considering the decreased efficiency of nutrient absorption and deterioration of the intestinal absorptive function with aging in general. There is also a need for improving the
Gross Kathy Lynn
Koo Sung I.
Owen Kevin
Barancik Martin B.
Henley III Raymond
Hill's Pet Nutrition
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