Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
1999-11-04
2001-04-03
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S734000
Reexamination Certificate
active
06211247
ABSTRACT:
BACKGROUND
It has been noted that there are a number of biologically active phenolic compounds present in wine, particularly red wine. Such compounds include, for example, catechin, epicatechin, quercetin, rutin, trans-resveratrol, cis-resveratrol, cis-resveratrol glucoside and trans-resveratrol glucoside. See, e.g., Goldberg et al. (1996)
Anal. Chem.
68:1688-1694. These compounds have been shown to protect low-density lipoproteins against oxidation. The resveratrol isomers, in particular, have been found to promote vascular relaxation through the generation of nitric oxide by the endothelium, and to modulate eicosanoid synthesis in a manner that suggests use in preventing coronary heart disease. Id. at pp. 1688-89). This discovery appears to explain the studies demonstrating that moderate consumption of red wine tends to have a protective effect against heart disease. Bertelli et al. (1995)
Inst. J. Tiss. Reac.
XVII(1):1-3.
Resveratrol (3,5,4′-trihydroxystilbene) has been identified as a constituent not only of grape skins (Soleas et al. (1995)
Am. J. Enol. Vitic.
46(3):346-352) but has also been found to be present in ground nuts, eucalyptus, and other plant species. Goldberg et al. (1995),
Am. J. Enol. Vitic.
46(2):159-165. A great deal of interest has been focused on the compound's antifungal activity and its correlation with resistance to fungal infection. Id. at 159. Resveratrol may be obtained commercially (typically as the trans isomer, e.g. from the Sigma Chemical Company, St. Louis, Mo.), or it may be isolated from wine or grape skins, or it may be chemically synthesized. Synthesis is typically carried out by a Wittig reaction linking two substituted phenols through a styrene double bond, as described by Moreno-Manas et al. (1985)
Anal. Quim
81:157-61 and subsequently modified by others (Jeandet et al. (1991)
Am. J. Enol. Vitic.
42:41-46; Goldberg et al. (1994)
Anal. Chem.
66:3959-63).
There are more studies concerning trans-resveratrol than the cis isomer; however, the cis isomer also appears to be equally important from a biological standpoint. Numerous uses have been proposed and evaluated for the resveratrol isomers. Jang et al. (1997)
Science
275:218-220, show that resveratrol has cancer chemopreventive activity in assays representing three major stages of carcinogenesis. That is, the authors found that the compound: (1) acted as an antioxidant and antimutagen and induced phase II drug-metabolizing enzymes (“anti-initiation” activity); (2) mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase (“antipromotion” activity); and (3) induced human promyelocytic leukemia cell differentiation (“antipromotion” activity). In addition, as noted above, resveratrol has been extensively studied for its correlation to the cardiovascular utility of red wine. See, e.g., Bertelli et al., supra; Pace-Asciak et al. (1995),
Clinica Chimica Acta
235:207-2191; and Frankel et al. (Apr. 24, 1993),
The Lancet
341:1104. Neurologic uses have also been proposed (Lee et al. (1994),
Society for Neuroscience Abstracts
20(1-2): 1648).
The present invention is, however, premised on the discovery that cis- and trans-resveratrol are useful in preventing or treating restenosis and in preventing the progression or recurrence of coronary heart disease. “Restenosis” may be defined as the recurrence of stenosis or artery stricture after corrective surgery, and is viewed as an accelerated form of atherosclerosis. As explained in U.S. Pat. No. 5,616,608 to Kinsella et al., restenosis results from a complex series of fibroproliferative responses to vascular injury, and can occur after coronary artery bypass surgery, endarterectomy and heart transplantation, but is particularly likely to occur after heart balloon angioplasty, atherectomy, laser ablation or endovascular stenting. All of these procedures are generically referred to herein as “coronary intervention.” While certain pharmacologically active agents have been proposed for the prevention and treatment of restenosis (e.g., probucol and taxol), there remains a need for a safer, preferably natural active agent which avoids the side effects associated with the currently known and commercially available synthetic agents.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to address the above-described need in the art by providing a novel method for preventing or treating restenosis following coronary intervention and for preventing the progression or recurrence of coronary heart disease.
It is another object of the invention to provide such a method by administering a therapeutically effective amount of resveratrol to an individual in need of such treatment.
It is still another object of the invention to provide such a method by administering resveratrol orally.
It is a further object of the invention to provide such a method by administering resveratrol in stereoisomerically pure form, i.e., in either the cis or the trans form.
It is still a further object of the invention to provide a pharmaceutical composition for carrying out the aforementioned therapeutic method.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one embodiment, then, a method is provided for preventing or treating restenosis in an individual following coronary intervention, comprising treating the individual with a pharmaceutical composition comprising a therapeutically effective amount of an active agent selected from the group consisting of resveratrol and pharmacologically acceptable salts, esters, amides, prodrugs and analogs thereof. Generally, the active agent will be cis-resveratrol, trans-resveratrol, cis-resveratrol glucoside or trans-resveratrol glucoside, and administration will be either oral or parenteral. However, as will be appreciated by those skilled in the art, and as discussed in detail elsewhere herein, other forms of the active agents may also be used, as may a variety of composition types and modes of administration.
In another embodiment, pharmaceutical compositions are provided for carrying out the present therapeutic method. The compositions contain a therapeutically effective amount of an active agent as described above, and pharmacologically acceptable carrier. Preferably, although not necessarily, the compositions are oral dosage forms or liquid formulations suitable for parenteral administration, containing the active agent in unit dosage form.
REFERENCES:
patent: 0773020 A2 (1997-05-01), None
patent: 0773020 A3 (1997-05-01), None
patent: WO99/01148 (1999-01-01), None
Goldberg et al., “A Global Survey of Trans-Resveratrol Concentrations in Commercial Wines”, Am. J. Eno.. Vitic., 46(2):159-165, 1995.*
Bertelli et al. (1995) “Antiplatelet Activity of Synthetic and Natural Resveratrol in Red Wine,”Inst. J. Tiss. Reac. XVII(1):1-3.
Frankel et al. (1993) “Inhibition of Human LDL Oxidation by Resveratrol,”The Lancet 341:1104.
Goldberg et al. (1994) “Direct Injection Gas Chromatographic Mass Spectrometric Assay for trans-Resveratrol,”Anal. Chem. 66:3959-3963.
Goldberg et al. (1995) “A Global Survey of Trans-Resveratrol Concentrations in Commercial Wines,”Am. J. Enol. Vitic. 46(2):159-165.
Goldberg et al. (1996) “Method to Assay the Concentrations of Phenolic Constituents of Biological Interest in Wines,”Anal. Chem. 68:1688-1694.
Jang et al. (1997) “Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes,”Science 275:218-220.
Jeandet et al. (1991) “The Production of Resveratrol (3,5,4′-trihydroxystilbene) by Grape Berries in Different Development Stages,”Am. J. Enol. Vitic. 42(1):41-46.
Lee et al. (1994),Society for Neuroscience Abstracts 20(1-2):1648.
Moreno-Manas et al. (1985) “Dehydroacetic Acid Chemistry, A New Synthesis of Resveratrole, A Phytoalexine ofVitis Vinifera,” Anal. Quim 81:157-61.
Pace-Asciak et al
Jones Dwayne C.
Pharmascience Inc
Reed Dianne E.
Reed & Associates
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