Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-20
2002-07-23
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S337000
Reexamination Certificate
active
06423847
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The fields of the invention reside in biochemistry and in pharmacology. This invention relates to the synthesis and the therapeutic uses of various dosage forms comprised of D,&agr;-tocopherol nicotinate and their uses as nutritional supplements and therapeutic agents.
2. Description of the Prior Art
D,&agr;-tocopherol (Vitamin E, DAT)
Dextro and levo stereoisomeric forms of a-tocopherol exist, but the dextro form is the most physiologically active and the most nutritionally useful.
The lipid soluble, free oxygen radical scavenger (DAT) or vitamin E has a variety of antioxidant activities which include among others: promotion of the Ach/cAMP synthesis of nitric oxide (NO), decomposition of fatty acid hydroperoxides and hydrogen peroxides, maintenance of cell membrane stability, prevention of DNA strand breakage, improvement in the uptake of glutamate by synaptosomes at neural junctions and the suppression of oxidative conversion of low density lipids. These pluralistic activities have been demonstrated in several ways and confirm its preventive role in the development of some human diseases:
1. Vascular oxidative stress brought about by superoxide radicals and oxidized low-density lipoproteins (oxLDL) are major factors contributing to decreased NO-dependent vasodilator functions in hypercholesterolemia and atherosclerosis. DAT antagonizes the oxLDL-related events in atherogenesis. DAT is generally regarded as the most important lipid-soluble, chain-breaking antioxidant in human plasma.
2. There is epidemiological evidence that suggests that the incidence of human cardiovascular disease is lowered in populations having a high level of antioxidants, such as vitamin E, in their diet, or who have enhanced their level of intake of this vitamin by taking dietary supplements. The antioxidant defense of elderly patients is improved even with low doses of supplemental vitamin E.
3. The addition of vitamin E in doses of 400 mg once a day, orally for 4 weeks significantly reduces malonyldialdehyde and superoxide anion levels and produces an elevation of antioxidant enzymes. After vitamin E supplementation, there is a normalization of the indices of oxidative stress following heart failure; this is especially true for catalase, glutathione reductase and superoxide dismutase. Following supplementation with DAT, glutathione peroxidase (GSHPx) activities (necessary for the decomposition of fatty acid hydroperoxides) increase as much as twofold.
4. In patients with active variant angina who continue to have anginal attacks in spite of receiving calcium channel blockers, the addition of vitamin E significantly elevates plasma alpha-tocopherol levels and inhibits the further occurrence of angina. Plasma vitamin E levels are significantly lower in patients with active variant angina than in subjects without coronary spasm, suggesting an association between vitamin E deficiency and persistent coronary artery spasm.
5. Reactive oxygen species (ROS) produced by cells of the arterial wall may cause oxidative damage to cellular components altering endothelial cell function. Changes in endothelial cell function play a key role in the pathogenesis of atherosclerosis. However, human aortic endothelial cells pre-incubated with vitamin E demonstrate a dose-dependent increase in resistance to oxidative stress and increased cell viability from 37% to 85%.
6. Vitamin E has an inhibitory effect on the oxLDL-induced production of vascular endothelial adhesion molecules and upon the adhesion of monocytes to vascular endothelium; this functional alteration may take place via DAT's antioxidant abilities and/or its direct regulatory effect on sICAM- 1 expression. The rheological properties of blood and red cell deformability may be improved by DAT. This can be attributed to reduced lipid peroxidation stress on the membrane envelop of red blood cells. Supplementation with vitamin E may be useful in slowing the clinical deteriorations associated with microangiopathic conditions in diabetes mellitus Type 2. All of these activities reduce the development of conditions of risk associated with vasoconstriction.
7. Tobacco-specific nitrosamines are common metabolites of nicotine and are major carcinogens in cigarette smoke. Conditions of chronic inflammation may enhance or promote the carcinogenic effect of these nitrosamines through the generation of toxic oxygen radicals, which cause a significant increase in DNA strand breakage. In vitro pre-treatment of these cells with vitamin E provides significant protection against the induction of DNA damage.
8. More alpha-tocopherol derived from the synaptosomes of older rats is oxidized than that derived from the synaptosomes younger rats. These older animals may be more susceptible to conditions of neural glutamate excitotoxicity because: a) synaptosomal reuptake of glutamate is less efficient and, b) oxidative stress induced by various agents including glutamate may be higher in older animals. Improving synaptosomal levels of alpha-tocopherol in the elderly provides protection from neural excitotoxicity; this may be particularly important in conditions of cardiac ischemia and irregularities.
Nicotinamide, Niacin, Nicotinate (NIC)
The water-soluble vitamin nicotinamide, or niacin, has established itself as a supplement appropriate for reducing plasma oxLDL in patients at risk of atherosclerosis or vasoconstriction and their attendant clinical diseases. It also has the additional functional benefit of decreasing plasma fibrinogen levels and stimulating fibrinolysis, thus reducing the risk of thrombosis and embolism. An additional plus for these patients is the apparent improvement in cardiac glucose utilization that occurs with nicotinic acid supplementation and the suggestion that there is a concurrent improvement in zinc (Zn
+2
) uptake. However, when nicotinamide is used simultaneously with pharmacological levels of lipid-reducing statins, there is concern for hepatic health.
1. Niacin supplementation decreases plasma fibrinogen and LDL cholesterol in subjects with peripheral vascular disease: in general, changes in fibrinogen levels seem to be quite closely correlated with niacin-induced reductions in LDL cholesterol.
2. Nicotinic acid in gram doses decreases cholesterol and triglyceride concentrations in plasma. At the same time it is lowering the triglyceride levels it is also reducing the fibrinogen concentration in plasma and stimulates fibrinolysis.
3. As measured by uptake of 18F-fluorodeoxyglucose and PET imaging, niacin treatment of normal volunteers is associated with a two- to three-fold increase in exogenous glucose utilization by the heart; a significant decrease in fatty acid levels is associated with these increases in myocardial glucose utilization rates.
4. Nicotinic acid and nicotinamide (at 1000 mg/kg) cause elevations in liver NAD
+
; poly(ADP-ribose) is a homopolymer of ADP-ribose units synthesized from NAD
−
on nuclear acceptor proteins and is known to be involved in DNA repair. Nicotinamide treatment significantly elevates liver polyADP-ribose above control groups.
5. Nicotinic acid supplementation given to laboratory mice significantly increases Zn
+2
absorption—by 38.9% in fasting states and by 70.9% in postprandial conditions. Because of the important role of Zn
+2
in many nutritional functions, nicotinic acid supplementation, especially in the aged, is advisable.
SUMMARY OF THE INVENTION
Synthesis of D, alpha-tocopherol Nicotinate
The present invention comprises the compound of D,&agr;-tocopherol nicotinate (C
35
H
53
NO
3
). The present invention also includes the pharmaceutically acceptable salts of this compound such as the hydrochloride, hydrobromide and nitrate salts. This compound has been described as a racemic mixture in Japanese Patent 24,968 (1964) to Eisai Company. It was prepared by treating D,L,&agr;-tocopherol with nicotinic acid chloride in pyridine. In the present invention, optically pure D,&agr;-tocopherol is employed as the starting material
Pearson Don C.
Richardson Kenneth T.
Chronorx LLC
Robinson Binta
Rotman Alan L.
Townsend and Townsend / and Crew LLP
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