Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-01
2003-08-19
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S453000, C514S455000, C514S032000
Reexamination Certificate
active
06608103
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to an inhibitor for neovasculation, cell multiplication, lumen formation and fibroblast growth factor (FGF), wherein the active component is a tocotrienol, and a food and a food additive containing tocotrienol.
Neovasculation is the formation of a new blood vessel from an existing blood vessel, and is composed of the following steps. (1) Neovasculation factor transfers a neovasculation signal to an endothelial cell, and the endothelial cell digests basement lamina and extracellular substrate in the neighborhood. (2) The hemoendothelial cell wanders while it multiplies. (3) The hemoendothelial cell forms lumen (neovasculation), and forms capillaries reticularly. It is observed that the neovasculation occurs on the onset and progress of diseases, such as a solid tumor, diabetic retinopathy, rheumatoid arthritis, hemangioma, periodontal disease, scleroderma, glaucoma, psoriasis and age-related macular degeneration, and it is considered to advance the progress of each disease. Various neovasculation inhibitors have been developed, but none of them have been put to practical use. Accordingly, it is still desired to develop a compound having safe neovasculation-inhibitory activity without side effects.
By the way, an inhibitor for the synthesis of heat-shock proteins having a molecular weight of 47 kilo daltons is known comprising tocopherol or a derivative thereof as an active component (JA09 040556A). The derivative includes the homologs of tocotrienol, i.e. &agr;-, &bgr;-, &ggr;- and &dgr;-tocotrienols. The invention intends the treatment of diseases which produce extracellular matrices, such as cirrhosis of the liver and scleroderma, and discloses that the fibrosis accompanied with these diseases is caused by the increase of collagen synthesis, and that collagen synthesis increases with increasing the development of the above heat-shock proteins. Furthermore, it is pointed out that collagen synthesis in basement lamina exhibits an important role in neovasculation, and the inhibitor for the synthesis of heat-shock proteins is effective for the diseases based on the abnormal growth of neovasculation, i.e. diabetic retinopathy, glaucoma, rheumatic arthritis, etc. However, it is also taught that &agr;-tocopherol, which is vitamin E, is the most preferred, and only &agr;-tocopherol is shown in the Examples. Tocotrienols are only listed in the derivatives of tocopherol.
On the other hand, it is said that tocophenols have no action to inhibit neovasculation, the inventors also confirmed this matter in the following comparative examples.
SUMMARY OF THE INVENTION
An object of the invention is to provide an inhibitor exhibiting inhibitory action against neovasculation, cell multiplication, lumen formation and fibroblast growth factor (FGF), which has no problem in safety and is far superior to &agr;-tocopherol, and to contribute to the treatment of diseases caused by abnormal growth of neovasculation.
The inventors investigated eagerly in order to achieve the above object, and as a result, they found that tocotrienols, especially &bgr;-, &ggr;-, &dgr;-tocotrienols, have a much greater inhibitory action against neovasculation, cell multiplication (cell growth), lumen formation and FGF than &agr;-tocopherol to complete the invention.
Thus, the present invention provides;
A neovasculation inhibitor which comprises &bgr;-, &ggr;-, &dgr;-tocotrienol as an active component,
A cell multiplication inhibitor which comprises &bgr;-, &ggr;-, &dgr;-tocotrienol as an active component,
A lumen formation inhibitor which comprises &bgr;-, &ggr;-, &dgr;-tocotrienol as an active component,
A fibroblast growth factor inhibitor which comprises &bgr;-, &ggr;-, &dgr;-tocotrienol as an active component.=,
A food containing a tocotrienol selected from the group consisting of &agr;-tocotrienol, &bgr;-tocotrienol, &ggr;-tocotrienol and &dgr;-tocotrienol, and
A food additive comprising a tocotrienol selected from the group consisting of &agr;-tocotrienol, &bgr;-tocotrienol, &ggr;-tocotrienol and &dgr;-tocotrienol.
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Antitumor and Antioxidant Activity of Tocotrienols, by K. Komiyama et al, Lipid-Soluble Antioxidants: Biochemistry and Clinical Applications, 1992, 152-159.
Tocotrienols inhibit growth of ZR-75-1 breast cancer cells, by Kalanithi Nesarethnam et al, International Journal of Food Sciences and Nutrition (2000), 51 S95-S103.
Vitamin E Inhibits Experimental Carcinogenesis and Tumour Angiogenesis, by G. Shklar et al, Oral Oncol. Eur. J. Cancer., vol. 32B, No. 2, 1996, pp. 114-119.
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The Merck Manual of Diagnosis and Therapy, by M.H. Beers, et al, p. 731.
Ikushima Heiji
Miyazawa Teruo
Flynn ,Thiel, Boutell & Tanis, P.C.
Fuji Chemical Industry Co., Ltd.
Jagoe Donna
Jarvis William R. A.
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