Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-14
2001-06-05
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S458000
Reexamination Certificate
active
06242479
ABSTRACT:
II. FIELD OF INVENTION
The present invention is generally related to the discovery of the therapeutic benefit of administering &ggr;-tocopherol and &ggr;-tocopherol derivatives. More specifically, the use of &ggr;-tocopherol and racemic LLU-&agr;, (S)-LLU-&agr;, or other &ggr;-tocopherol derivatives as antioxidants and nitrogen oxide scavengers which treat and prevent high blood pressure, thromboembolic disease, cardiovascular disease, cancer, natriuretic disease, the formation of neuropathological lesions, and a reduced immune system response are disclosed.
III. BACKGROUND OF THE INVENTION
Vitamin E, an essential fat-soluble vitamin, encompasses eight naturally occurring compounds in two classes. The first class, tocopherols, have four members designated alpha, beta, gamma and delta. The two major forms, &agr;-tocopherol and &ggr;-tocopherol, differ structurally only by a methyl group substitution at the 5-position. The second class, tocotrienols, are molecules related to the tocopherols and also consist of four members designated alpha, beta, gamma and delta. The tocotrienol structure differs from the tocopherols by possessing three double bonds in their side chain rather than being saturated.
One of the important chemical features of the tocopherols is that they are redox agents which act under certain circumstances as antioxidants. In acting as an antioxidant, tocopherols presumably prevent the formation of toxic oxidation products, such as perioxidation products formed from unsaturated fatty acids. Early on, investigators attributed most if not all of the biological activity of the tocopherols to their ability to act as antioxidants. More recently, however, other biological activities have been associated with tocopherols including the modulation of signal transduction, modulation of phospholipid metabolism, inhibition of protein kinase C, inhibition of phospholipase A and inhibition of prostaglandin production. (Meydani and Mosen,
The Lancet
345(8943):170-175 (1995)).
Further, it has recently been discovered that individual members in the class of tocopherols may exhibit different biological properties from one another despite their structural similarity. Some investigators, for example, believe that &ggr;-tocopherol, unlike &agr;-tocopherol, acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens. (Christen et al.
Proc. Natl. Acad. Sci.
94: 3217-3222 (1997)). In contrast, others report that &agr;-tocopherol is a more powerful antioxidant and has ten times the biological activity of &ggr;-tocopherol. (Meydani and Mosen,
The Lancet
345(8943):170-175 (1995)). Alpha-tocopherol is also thought to be retained in the body longer than &ggr;-tocopherol and has been shown to preferentially reincorporate into nascent very low-density lipoproteins (LDL). (Christen et al.
Proc. Natl. Acad. Sci.
94: 3217-3222 (1997)). At present, an understanding of the differences in biological activity of the four tocopherols and their effect on the body is in its infancy.
Alpha tocopherol is largely considered the most important member of the class of tocopherols because it constitutes about 90% of the tocopherols found in animal tissues and displays the greatest biological activity in the commonly used bioassay systems. In consequence, vitamin E supplements are almost exclusively made of &agr;-tocopherol and little investigation into the efficacy of supplementation with &ggr;-tocopherol has been conducted.
The therapeutic benefits of vitamin E supplementation remains a subject of considerable debate. Several studies have proposed that vitamin E supplementation may prevent a plethora of ills but many of these studies fail to provide causal connections between vitamer supplementation and therapeutic benefit; they merely indicate that a high dietary or plasma concentration and supplemental intake of vitamin E is associated with a reduced risk of disease. In fact, some studies have failed to demonstrate that tocopherol supplementation provides any protection from disease. (Meydani and Mosen,
The Lancet
345(8943):170-175 (1995) and (Christen et al.
Proc. Natl. Acad. Sci.
94: 3217-3222 (1997)). A reliable method to treat and prevent diseases associated with oxidative stress and vitamin E deficiency is highly desirable.
IV. SUMMARY OF THE INVENTION
The present invention reveals the discovery of the therapeutic benefit of administering &ggr;-tocopherol and &ggr;-tocopherol derivatives such as LLU-&agr;. The novel use of &ggr;-tocopherol and &ggr;-tocopherol derivatives as antioxidants and nitrogen oxide scavengers which treat and prevent high blood pressure, thromboembolic disease, cardiovascular disease, cancer, natriuretic disease, the formation of neuropathological lesions, and a reduced immune system response are disclosed.
One embodiment of the present invention is a medicament comprising &ggr;-tocopherol and LLU-&agr; with and without additional active ingredients that are effective in producing a natriuretic effect. Another embodiment is a medicament comprising &ggr;-tocopherol, &agr;-tocopherol, and LLU-&agr; with and without additional active ingredients that are effective in producing a natriuretic effect. A further embodiment is a medicament comprising &ggr;-tocopherol, &bgr;-tocopherol, and LLU-&agr;, with and without additional active ingredients that are effective in producing a natriuretic effect. Still further, an embodiment comprising &agr;-tocopherol, &ggr;-tocopherol, &bgr;-tocopherol, and LLU-&agr;, with and without additional active ingredients that are effective in producing a natriuretic effect, is disclosed. In the alternative, the embodiments described above may include (S)-LLU-&agr; or other &ggr;-tocopherol derivatives instead of LLU-&agr;.
According to the methods of treatment and prevention disclosed, the medicaments described above are administered to subjects suffering from high blood pressure, thromboembolic disease, atherosclerosis, cardiovascular disease, cancer, natriuretic disease, the formation of neuropathological lesions, and a reduced immune system response. One method involves the administration of a therapeutically beneficial amount of &ggr;-tocopherol, with or without supplementation of LLU-&agr;, to subjects suffering from a high blood pressure so as to treat and prevent this condition. By another method, a therapeutically beneficial amount of &ggr;-tocopherol, with or without supplementation of LLU-&agr;, is administered to treat and prevent thromboembolic disease. A related method to treat and prevent the aggregation of platelets and/or binding of platelets to adhesive proteins is also disclosed.
Another method contemplated by the present inventor involves the administration of a therapeutically beneficial amount of &ggr;-tocopherol, with or without supplementation of LLU-&agr;, to treat and prevent cardiovascular diseases, such as ischemia, angina, edematous conditions, artherosclerosis, LDL oxidation, adhesion of monocytes to endothelial cells, foam-cell formation, fatty-streak development, platelet adherence, platelet aggregation, smooth muscle cell proliferation, and reperfusion injury. Further, a method to treat and prevent cancers, such as lung cancer, prostate cancer, breast cancer, and colon cancer by administering a therapeutically beneficial amount of &ggr;-tocopherol, with or without supplementation of LLU-&agr; are presented.
Methods of treatment and prevention of natriuretic diseases, such as hypertension, high blood pressure, ischemia, angina pectoris, congestive heart failure, cirrhosis of the liver, nephrotic syndrome, ineffective renal perfusion, or ineffective glomerular filtration, by administering a therapeutically beneficial amount of &ggr;-tocopherol, with or without supplementation of LLU-&agr; are also provided. Additionally, methods of treating and preventing neurological diseases including hyporeflexia, opthalmoplegia, and axonal dystrophy using a therapeutically beneficial amount of &ggr;-tocopherol, with or without supplementation of LLU-&agr;, are described. Finally,
Henley III Raymond
Knobbe Martens Olson & Bear LLP
Loma Linda University Medical Center
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