Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1999-09-02
2001-04-24
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C514S027000, C514S032000, C514S456000, C536S008000
Reexamination Certificate
active
06221357
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for inhibiting a collagen-induced platelet aggregation in a mammal, which comprises administering an effective amount of a flavonoid derived from citrus peels thereto. The flavonoids can be administered to the mammal in the form of a pharmaceutical composition or a food composition.
BACKGROUND OF THE INVENTION
Platelet aggregation on a blood vessel is induced by several factors, e.g., collagen, adenosine diphosphate (ADP), thrombin, epinephrine, ristocetin and arachidonic acid. For instance, when epithelial cells of a blood vessel are damaged, collagen underneath the epithelial cells is exposed to blood stream and activates platelets. The activation of platelets triggers a cascade of reactions resulting in a thrombogenesis and platelet aggregation on the blood vessel, which may cause serious circulatory diseases, e.g., thrombosis, atherosclerosis, cerebral stroke and coronary artery thromboembolism.
Hitherto, various drugs, e.g., thromboxane A2 inhibitor, PGG/H synthase inhibitor, thromoxane synthase inhibitor, thromboxane A2 receptor antagonist, ticlopidine, GP Hb-IHa inhibitor and serotonin antagonist, have been developed in order to prevent such platelet aggregation. However, these drugs have shown various undesirable side effects on the internal organs, and hemorrhagenic properties.
Ticlopidine and analogues thereof, e.g., clopidogrel, selectively inhibit the ADP-induced platelet aggregation in vivo and are known to be effective in the treatment of a transient ischemic cerebral stroke and peripheral arterial or ischemic heart disease(Hass, W. K. et al.,
N. Engl. J. Med.,
21, 501(1989); and Easton, J. D.,
Drugs,
42, 39(1991)). However, these drugs have been reported to have such undesirable side effects as myelosuppression, increase of total cholesterol level, diarrhea, eruption and neutropenia((McTavish, E. et al., 2
Drugs,
40, 238(1990)); Hass, W. K. et al., supra; and Dunn C. D. R., Scrip. Reports,
Stroke: Trends, Treatments and Markets,
PJB Publications Ltd. pp133-139(1995)).
Accordingly, there has continued to exist a need to develop a platelet aggregation inhibitor having a highly selective inhibitory activity on the collagen-induced platelet aggregation and yet without incurring adverse side effects.
It is known that the flavonoids extracted from citrus peel, e.g., naringin, naringenin, hesperidin and hesperetin, have activities in improving lipid metabolism to prevent cardio-circulatory diseases, as well as anticancer and antiviral activities. In particular, it has been reported that both hesperidin and hesperetin have capillary-enhancing, permeability-reducing, anti-inflammation, anti-viral, and blood pressure- and cholesterol-lowering activities(Meyer, O. C.,
Angiology,
45, 579-584(1994); Struckmann, J. R. et al.,
Angiol.,
45, 419-428(1994); Matsubara, Y. et al.,
Japan Organic Synthesis Chem. Association Journal,
52, 318-327(1994. March); Galati, E. M. et al.,
Farmaco.,
51(3), 219-221(1996, March); Monforte, M. T. et al.,
Farmaco.,
50(9), 595-599(1995, September); JP 95-86929; JP 95-86930; Galati, E. M. et al.,
Farmaco.,
40(11), 709-712(1994, November); and Emim, J. A. et al.,
J. Pharm. Pharmacol.,
46(2), 118-122(1994)). Further, it has been reported that both naringin and naringenin have anti-cancer, anti-ulcer, and cholesterol-lowering activities(Monforte, M. T. et al.,
Farmaco.,
50(9), 595-599(1995, September); JP 95-86929; JP 95-86930; Felicia, V. et al.,
Nutr. Cancer,
26, 167-181(1996); EP 0352147 A2(1990.1.24); and Martin, M. J. et al.,
Parmacol.,
49, 144-150(1994)).
Recently, it has also been reported that naringenin inhibits an arachidonic acid-induced platelet aggregation(Corcazier, E. et al.,
Biochimica Biophysica Acta,
835, 315-321(1985)).
However, there has been no report on the selective inhibitory activity of flavonoids derived from citrus peels on a collagen-induced platelet aggregation.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a method for inhibiting a collagen-induced platelet aggregation.
In accordance with the present invention, there is provided a method for inhibiting a collagen-induced platelet aggregation in a mammal which comprises administering a flavonoid derived from citrus peels thereto.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, flavonoids derived from citrus peels can be administered to a mammal in the form of a pharmaceutical composition or a food composition.
The citrus may be a tangerine, orange, lemon, grapefruit or
Poncirus trifoliata.
The flavonoids obtainable from citrus peels include naringin, naringenin, hesperidin and hesperetin. These flavonoids may also be synthesized according to the processes described by Zemplen, Bognar,
Ber.,
75, 1043(1943) and Seka, Prosche,
Monatsh.,
69, 284(1936). Further, naringenin and hesperetin can be prepared by the hydrolysis of naringin and hesperidin, respectively.
The flavonoids exert a selective inhibitory effect on a collagen-induced platelet aggregation as well as thrombogenesis.
Moreover, in spite of their potent efficacy, the flavonoids show little toxicity or mitogenicity in animal tests. More specifically, the flavonoids exhibit no toxicity when they are orally administered to a mouse at a dosage of 1,000 mg/kg, which corresponds to an oral administration dose of 3 to 10 g per kg of body weight. Further, the flavonoids exert no adverse effects on the liver function.
The present invention also provides a pharmaceutical composition for inhibiting a collagen-induced platelet aggregation, which comprises an effective amount of a flavonoid derived from citrus peels as an active ingredient together with pharmaceutically acceptable excipients, carriers or diluents.
The pharmaceutical formulation may be prepared by using any of the conventional procedures. In preparing the formulation, the active ingredient is preferably admixed or diluted with a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material acting as a vehicle, excipient or medium for the active ingredient. Thus, the formulation may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder and the like.
Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoates, propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations may additionally include fillers, anti-agglutinating agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a mammal by employing any of the procedures well known in the art.
The pharmaceutical formulation of the present invention can be administered via various routes including oral, transdermal, subcutaneous, intravenous and intramuscular introduction. In case of human, a typical daily dose of flavonoid may range from about 0.5 to 100 mg/kg body weight, preferably 2 to 10 mg/kg body weight, and can be administered in a single dose or in divided doses. However, it should be understood that the amount of the active ingredient actually administered ought to be determined in light of various relevant factors including the condition to be treated, the chosen route of administration, the age, sex and body weight of the individual patient, and the severity of the patient's symptom; and, therefore, the above dose should not be intended to limit the scope of the invention in any way.
Moreover, the flavono
Bok Song-Hae
Cho Han-Ik
Jeong Tae-Sook
Lee Dong-Soon
Anderson Kill & Olick PC
Korea Research Institute of Bioscience and Biotechnology
Tate Christopher R.
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