Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-30
2003-08-19
Kim, Vickie (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06608105
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a TNF-&agr; production inhibitor containing a kavalactone as an active ingredient, and to a preventive, ameliorating, or therapeutic agent for diseases caused by abnormal production of TNF-&agr;.
2. Background Art
TNF (Tumor Necrosis Factor) was discovered as an antitumor cytokine, and has been elucidated to have carcinostatic activity (i.e., the effect of inhibiting cancer cell growth or necrotizing cancer cells), and to participate in a series of inflammatory responses or immunoreactions, as well as in differentiation or maturation of cells.
Recent studies have shown that excessive production of TNF-&agr; induces onset of a variety of diseases, including cachexia attributed to cancer or infectious diseases (
Nature
, 316: 552, 1985), septic shock (
J. Immunol
., 145: 4185, 1990
; Science
, 229: 869, 1985
; Shock
, 30: 1990), chronic rheumatoid arthritis (
Ann. Rheum. Dis
., 49: 665, 1990
; Lancet
, 344: 1105, 1994
; Lancet
, 344: 1125, 1994
; British J. Rheum
., 34: 334, 1995), inflammatory diseases such: as ulcerative colitis and Crohn disease (
Arch. Dis. Child
, 66: 561, 1991
; Gastroenterology
), osteoarthritis (
Arthritis Rheum
., 36: 819, 1993), Kawasaki's disease (
Clin. Immunol. Immunopathol
., 56: 29, 1990), multiple sclerosis (
N. Engl. J. Med
., 325(7): 467, 1991), Behchet's disease (
J. Rheumatol
., 17: 1107, 1990), systemic lupus erythematosus (SLE) (
Arthritis Rheum
., 32: 146, 1989), rejection during bone marrow transplantation (
J. Exp. Med
., 175: 405, 1992), multiple organ failure (
Rinshoi
, 17(20), 2006, 1991), malaria (
Science
, 237: 1210, 1987), AIDS (
J. Acquir. Immune Defic. Syndr
., 5: 1099, 1992), meningitis (
Lancet
, 1: 355,1987), hepatitis (Kozo Kanno,
Kanzo
, 33: 213, 1992), and type-II diabetes (
Science
, 259: 87, 1993).
The aforementioned diseases caused by excessive production of TNF-&agr; have hitherto been treated from a mere palliative approach by use of steroid agents, anti-inflammatory agents, antibiotics, etc., and drugs for fundamentally treating the diseases have not yet been developed.
Kava is a plant found in Fiji and belongs to Piperaceae, Piper L. (nomenclature:
Piper Methysticum Forst
., alias: Yangona). Since anesthetic beverages are obtained from the kava root, in Oceania, kava is widely cultivated by privileged people and is used in traditional ceremonies or events (
Chem. Australia
. Oct 377-378 (1987)).
It has been reported that an extract obtained from the dried kava root through extraction with water contains a class of &agr;-pyrone derivatives called kavalactones which induce numbness of the lips or tongue or exert sedative effect, such as methysticin (
Chem. Australia
. Oct 377-378 (1987),
Planta Med
. 64 504-506 (1998)).
Studies performed in the University of New South Wales have elucidated that kavalactones exert a sedative effect through a mechanism different from those of other sedative drugs which exert sedative effects when being bound to receptors present in the brain (
Planta Med
. 64 507-510 (1998)). It has also been reported that kavalactones exert an analgesic effect in a manner different from that of a formulated analgesic drug such as aspirin, and that, unlike morphine, kavalactones are not bound to receptors in the brain (e.g., European Patent Application Laid-Open Nos. 664131 and 523591, and Japanese Kdhyo (PCT) Patent Publication No.
5-502457
).
It has also been reported that kava extract exerts an antibacterial effect and is useful for treating Helicobacter pylori infection (German Patent Application Laid-Open No. 19716660), and that the kava extract exerts a neuroprotective effect and is useful for treating brain dysfunction, Alzheimer's disease, brain injury, etc. (e.g., European Patent Application Laid-Open No. 523591, and Japanese Kohyo (PCT) Patent Publication No.
5-502457
).
However, until the present invention was attained, kavalactones and kava extract have not been known to exert the effect of inhibiting TNF-&agr; production.
SUMMARY OF THE INVENTION
In view of the foregoing, the present inventors have performed studies on naturally occurring substances which inhibit production of TNF-&agr;, and have found that kavalactones contained in kava extract exert an excellent effect of inhibiting TNF-&agr; production, and that the kavalactones are useful as TNF-&agr; production inhibitors and as preventive, ameliorating, or therapeutic agents for a variety of diseases caused by abnormal production of TNF-&agr;. The present invention has been accomplished on the basis of this finding.
Thus, an object of the present invention is to provide a drug which is endowed with high safety, inhibits TNF-&agr; production, and is useful as a preventive or therapeutic agent for the aforementioned diseases.
Accordingly, the present invention provides a TNF-&agr; production inhibitor comprising a kavalactone as an active ingredient.
The present invention also provides a preventive, ameliorating, or therapeutic agent comprising a kavalactone as an active ingredient for diseases caused by abnormal production of TNF-&agr;.
The present invention further provides a method for the treatment of diseases caused by abnormal production of TNF-&agr;, which method comprises administering an effective amount of a kavalactone.
The present invention further provides use of a kavalactone for the manufacture of a TNF-&agr; production inhibitor.
Still, the present invention provides use of a kavalactone for the manufacture of a medicament for preventing, ameliorating, or treating diseases caused by abnormal production of TNF-&agr;.
Preferably, the kavalactone is one or more species selected from the group consisting of desmethoxyyangonin, dihydrokavain, kavain, yangonin, methysticin, dihydromethysticin, and 7,8-epoxyyangonin.
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patent: 6288109 (2001-09-01), Chatterjee et al.
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patent: 0 664 131 (1995-07-01), None
patent: 5-502457 (1993-04-01), None
Fujiki, H., Two stages of cancer prevention . . . , Database CAplus, AN 1999:670294, abstract, J. Cancer Res. oncol., 1999, vol. 125(11), pp. 589-597.*
Archives of Disease in Childhood, vol. 66, pp. 561-562, 1991.
B. Beutler, et al., Nature, vol. 316, pp. 552-554, “Identity of Tumour Necrosis Factor and the Macrophage-Secreted Factor Cachectin”, Aug. 8, 1985.
B. Beutler, et al., Science, vol. 229, pp. 869-871, “Passive Immunization Against Cachectin/Tumor Necrosis Factor Protects Mice From Lethal Effect of Endotoxin”, Aug. 30, 1985.
G. Boonen et al., Planta Medica, vol. 64, pp. 504-506, “Influence of Genuine Kavapyrone Enantiomers on the GABAABinding Site”, 1998.
G. Boonen, et al., Planta Medeca, vol. 64, pp. 507-510, “In Vivo Effects of the Kavapyrones (+)-Dihydromethysticin and (±)-Kavain on Dopamine, 3,4-Dihydroxyphenylacetic Acid, Serotonin and 5-Hydroxyindoleacetic Acid Levels in Striatal and Cortical Brain Regions”, 1998.
B. J. DeZube, et al., Journal of Acquired Immune Deficiency Syndromes, vol. 5, No. 11, pp. 1099-1104, “Cytokine Dysregulation in Aids: In Vivo Overexpression of mRNA of Tumor Necrosis Factor-&agr; and its Correlation With That of the Inflammatory Cytokine Gro”, 1992.
M. J. Elliott, et al., The Lancet, vol. 344, pp. 1105-1110, “Randomised Double-Blind Comparison of Chimeric Monoclonal Antibody to Tumour Necrosis Factor &agr; (cA2) Versus Placebo in Rheumatoid Arthritis”, Oct. 22, 1994.
M. J. Elliott, et al., The Lancet, vol. 344, pp. 1125-1127, “Repeated Therapy With Monoclonal Antibody to Tumour Necrosis Factor &agr; (cA2) in Patients With Rheumatoid Arthritis”, Oct. 22, 1994.
H. Fujiki, et al., Proceedings of the Fifty-Eighth Annual Meeting of the Japanese Cancer Association, S11-3, vol. 90, “Cancer Prevention With Drinking Green Tea”, Sep. 29 to Oct. 1, 1999.
G. E. Grau, et al., Science,
Asakawa Yoshinori
Murata Natsuko
Okabe Sachiko
Suma Yukie
Suzuki Hiroto
Kim Vickie
Meiji Dairies Corporation
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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