Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2001-06-18
2004-04-06
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
Reexamination Certificate
active
06716883
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a composition useful to treat periodontal disease. In particular, the present invention relates to a composition comprising resveratrol, and its use to treat periodontal disease. It is particularly useful in the treatment of individuals at high risk for developing periodontal disease, for example, those exposed to high levels of aryl hydrocarbons such as individuals that smoke tobacco products, individuals exposed to second-hand tobacco smoke and individuals exposed to environmental pollutant AhR ligands.
BACKGROUND OF THE INVENTION
Periodontal disease is characterized by gingival inflammation, bone loss and loss of teeth. It is believed to be the most common cause of tooth loss resulting in significant dental morbidity.
Smokers are 2.5-6 times more likely to develop periodontal disease than non-smokers, and there is evidence for a direct correlation between the number of cigarettes smoked and the risk of developing the disease (Barbour et al, 1977
, Crit Rev Oral Biol Med
8(4): 437-60). Smokers also tend to exhibit increased severity of periodontal disease compared to non-smokers with direct correlations between smoking and increased attachment loss, increased pocket depth, and reduced bone crest height (Barbour et al, supra). In addition, there is a strong association between smoking and both attachment loss and gum recession in young smokers (Linden et al, 1994
, J Periodontol
65(7): 718-23) and even in subjects who have minimal or no periodontal disease (Gunsolley et al, 1998
, J Periodontol
69(2): 165-70).
At the present time, it is not known how cigarette smoke exerts its negative effects on bone formation or bone-related diseases such as osteoporosis and periodontitis (Genco et al. J Int Acad Periodontol. 1999 1(1):21-33).
Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-&agr;) and interleukin 1&bgr; (IL-1&bgr;) possess bone-resorptive properties, and are generally considered to play a role in the pathogenesis of periodontal disease (Hou et al, 1995
, J Clin Periodontol
22(2): 162-7; Liu et al, 1996
, Cytokine
8(2): 161-7; Galbraith et al, 1997
, J Periodontol
68(9): 832-8). Pathogenic oral bacteria have been shown to cleave active IL-1&bgr; from pro-IL-1&bgr; (Beausejour et al, 1997
, Infect Immun
65(8): 3199-202). Blocking antibodies, which inhibit IL-1/TNF, reduce both inflammatory cell recruitment and bone loss in patients with periodontal disease (Assuma et al, 1998
, J Immunol
160(1): 403-9).
It has been demonstrated previously that aryl hydrocarbon receptor (AhR) ligands such as dioxin and benzo[a]pyrene, which are present in high concentrations in cigarette smoke, are powerful stimulators of IL-1&bgr; and TNF-&agr; and, thus, may be significant in the pathogenesis of periodontal disease in smokers. In this regard, AhR antagonists may be useful to block stimulation of IL-1&bgr; and TNF-&agr;, thereby minimizing some symptoms of periodontal disease.
Resveratrol, the parent compound of a family of molecules including glucosides and polymers, is a potent AhR antagonist as described in French Patent Application No. 9805673 filed May 5, 1998. It is an anti-fungal agent or phytoalexin produced by plants classified as spermatophytes of which vines, peanuts and pines are prime representatives (Soleas et al., 1997, Clin Biochemistry, 30:91-113). As an AhR antagonist, resveratrol, the chemical name of which is 3,5,4′-trihydroxystilbene, is useful generally to prevent the toxic effects of environmental exposure to AhR ligands, including, for example, halogenated and polycyclic aryl hydrocarbons, polyaromatic hydrocarbons and polychlorinated biphenyls. In addition, resveratrol has been demonstrated to prevent the induction of the proinflammatory cytokine, IL-1 Beta, by AhR ligands (Casper et al. 1999. Molecular Pharmacology, 56:784-790).
Although there are many treatments for various aspects of periodontal disease, there remains a need to develop a method which focuses more directly on prevention of bone loss and loss of tooth attachment, particularly among patients who smoke tobacco products.
SUMMARY OF THE INVENTION
Accordingly, in one aspect, the present invention provides a composition for treating periodontal disease comprising resveratrol and a pharmaceutically acceptable carrier.
A method for treating periodontal disease in a patient is also provided comprising the step of administering a composition comprising resveratrol as described to the oral cavity of the patient.
In a further aspect of the present invention, there is provided an article of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein the composition comprises resveratrol in combination with at least one pharmaceutically acceptable carrier and is effective to treat periodontal disease, and the packaging material comprises a label which indicates that the composition is for use to treat periodontal disease.
Other aspects of the invention include the use of resveratrol for treating periodontal disease and for the manufacture of pharmaceutical compositions for treating periodontal disease.
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Aryl Hydrocarbon-Mediated Inhibition of Osteogenesis: Reversal by Resveratrol, A Novel Aryl Hydrocarbon Receptor Antagonist—Sacha U.N. Singh, 1999.
Resveratrol Has Antagonist Activity on the Aryl Hydrocarbon Receptor: Implications for Prevention of Dioxin Toxicity—Robert F. Casper, Monique Quesne, Ian M. Rogers, Takuhiko Shirota, Andre Jolivet, Edwin Milgrom, Jean-Francois Savouret—The American Society for Pharmacology and Experimental Therapeutics, 1999.
Ciolino et al: “Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor”, Cancer Research, US, American Association for Cancer Research, Vol 28, No. 24, Dec. 15, 1998 pp. 5707-5712; XP002090260 ISSN: 0008-5472, p. 5707.
Database WPI, Week 199729, Derwent Publications Ltd., London, GB; An 1997-311392; XP002140688 & CN 1 104 896 A (Chen), Jul. 12, 1995.
EPODOC abstract of CN1154850 (fang genfa), Jul. 23, 1997, XP002140687 abstract.
Subbaramaiah, Kotha et al: “Resveratrol inhibits the expresson of cyclooxygenase-2 in human mammary and oral apithelial cells”; Pharmaceutical Biology, (Dec. 1998) vol. 36, No. Suppl, pp. 35-43, XP000910993 whole document.
Casper Robert F.
Tenenbaum Howard Charles
1333366 Ontario Inc.
Rose Shep K.
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