WO2000016759A2 - Genistein for the treatment of coronary heart disease and for the prevention of restenosis after percutaneous transluminal coronary angioplasty - Google Patents

Genistein for the treatment of coronary heart disease and for the prevention of restenosis after percutaneous transluminal coronary angioplasty Download PDF

Info

Publication number
WO2000016759A2
WO2000016759A2 PCT/IB1999/001545 IB9901545W WO0016759A2 WO 2000016759 A2 WO2000016759 A2 WO 2000016759A2 IB 9901545 W IB9901545 W IB 9901545W WO 0016759 A2 WO0016759 A2 WO 0016759A2
Authority
WO
WIPO (PCT)
Prior art keywords
genistein
treatment
restenosis
prevention
arteries
Prior art date
Application number
PCT/IB1999/001545
Other languages
French (fr)
Other versions
WO2000016759A3 (en
Inventor
Guido Schnyder
Original Assignee
Guido Schnyder
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guido Schnyder filed Critical Guido Schnyder
Priority to AU54407/99A priority Critical patent/AU5440799A/en
Publication of WO2000016759A2 publication Critical patent/WO2000016759A2/en
Publication of WO2000016759A3 publication Critical patent/WO2000016759A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to a method and to a drug, dietary product, dietary supplement or food supplement for the primary and secondary treatment of any stenotic artery as well as for the prevention of restenosis after treating narrowed, stenosed or stenotic arteries, in particular by percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
  • Coronary heart disease or atherosclerotic artery disease in general is usually the result of an injured endothelium allowing an accumulation of oxidised low density lipoprotein (LDL) in the arterial wall, which consequently leads to the formation of foam cells.
  • LDL oxidised low density lipoprotein
  • foam cells generate atherosclerotic plaques with reactive proliferation of arterial smooth muscle cells and fibroblasts.
  • atherosclerotic plaques narrow the coronary artery lumen which causes silent or symptomatic myocardial ischemia, or lead to myocardial infarction when occluded by a thrombus.
  • Stenotic arteries in particular coronary arteries can be efficiently treated by percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
  • the major drawback of these techniques is a frequent restenosis of the treated site within 6 months .
  • restenosis rates of 20% to 50% (depending upon the definition used) have been observed (see Colombo A et al . J Am Coll Cardiol 1996;28:830-6, Berger PB et al . J Am Coll Cardiol 1996;27:1-7, Hotie H et al . Circulation 1997;96:166-73) .
  • the restenosis mechanism appears to be a multifactorial phenomenon combining plaque persistence, elastic recoil of arterial walls, platelet deposition, thrombus formation, cellular proliferation, vascular remodeling and release of platelet derived growth factor.
  • new pharmacological interventions such as treatments with calcium antagonists, ACE-inhibitors, heparin, low molecular weight heparin, lipid lowering drugs, antioxidants , as well as new procedures such as intravascular irradiation and rotablator, the rate of restenosis following percutaneous transluminal angioplasty is still very high.
  • Another object of the invention is to provide a method and a pharmaceutical composition for the secondary treatment of stenotic arteries, in particular coronary heart disease, by the stabilisation or reduction of the atherosclerotic plaques.
  • a major object of the invention is to provide a primary treatment of stenotic arteries, in particular coronary heart disease, by inhibiting the formation of atherosclerotic plaques.
  • a further object of the invention is to provide a method and a pharmaceutical composition for the prevention of restenosis after PTCA, for the primary or secondary treatment of stenotic arteries, in particular coronary heart disease, which is inexpensive, safe and has substantially no side effect.
  • Yet another object of the invention is to provide a method and a pharmaceutical composition for the prevention of restenosis after percutaneous transluminal angioplasty, for the primary or secondary treatment of stenotic arteries, in particular coronary heart disease, which can be carried out respectively administered without medical supervision.
  • the invention is based on a series of observations and studies of the effect of genistein on humans in respect to its antineoplastic properties, particularly in relation to prostate and breast cancers .
  • Genistein affects oxidation of LDL.
  • Genistein has been found to reduce the generation of superoxide (O 2 -) (see Wei H et al. Proc Soc Exp Biol Med 1995; 208: 124-30) and to enhance the activation of antioxidant enzymes, in particular catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase (see Cai Q and Wei H. Nutr. Cancer 1996; 25: 1-7).
  • Genistein also enhances the LDL (see Ruiz-Larrea MB et al .
  • Genistein has been found to reduce the peripheral blood mononuclear cell proliferation by inhibiting interleukin-2 and leukotriene B4 production (see Altluru D et al . Clin Immunol Immunopathol 1991; 59: 379-87). Genistein also significantly reduces monocyte adherence on the vascular endothelium by inhibiting TNF alpha-stimulated adherence (see McGregor PE et al . Biochem Biophys Res Commun 1994; 198: 359-65), which is likely to reduce the amount of subendothelial macrophages scavenging oxidized LDL, thereby reducing the formation of foam cell production.
  • genistein inhibits platelet activation and aggregation by suppressing GPIIb-IIIa activation (see Furman MI et al . Circ Rese 1994; 75: 172-80), by antagonising the thromboxane receptor and by inhibiting the thrombin-induced release of arachidonic acid and prostacyclin .
  • Liu C. Y. and Sturek M. genistein inhibits significantly the magnitude of vascular smooth muscle contractions induced by phorbol ester, endothelin, angiotensin, and serotonin by attenuating the calcium response (see Liu C. Y. and Sturek M. Am J Physiol 1996; 270: 1825-33). In addition, genistein also inhibits the sustained phase of contractions induced by serotonin. Genistein induces an oestrogen-like relaxant effect on vascular smooth muscles by enhancing the dilator response to acetylcholine of normal (see Babaei H et al . Biochem Soc Trans 1997; 25:
  • the proliferation of endothelial cells and fibroblasts which are stimulated by bFGF can be reduced by 95% by maintaining a genistein concentration in the plasma of 15 to 50 micromol/1.
  • This effect on the proliferation of vascular endothelial cells has a 6-7 days time course for reversibility.
  • Genistein is cytostatic up to concentrations of 100 micromol/1 and becomes cytotoxic above this level.
  • quiescent endothelial cells do not show any sign of toxicity even at a genistein concentration of up to 200 micromol/1, which clearly indicates that genistein targets only proliferating cells and that quiescent, nondividing cells remain unaffected. This indicates that side effects are unlikely to be expected (see Fotsis T et al . J Nutr 1995; 125: 790-797).
  • genistein inhibits the bFGF-induced migration of endothelial cells, the half-maximal effect being at a genistein plasma concentration of 150 micromol/1.
  • the endothelial cell proliferation and the migration inhibition interferes with important early events of restenosis as described above.
  • Genistein blocks the platelet derived growth factor receptor which stimulates not only the proliferation and migration of arterial smooth muscle cells, but also the transcription, translation and posttranslational processing of versican, a large chondroitin sulfate proteoglycan present in the extracellular matrix of blood vessels (see Schonherr E et al . Arch Biochem Biophys 1997; 339: 353-61, Munoz R et al . Oncogene 1997; 15: 525-36). Most of the properties of genistein are triggered by deactivating the "tyrosine kinase" enzyme (see Akiyama T et al. Journal of Biological Chemistry 1987; 262: 5592- 5595) .
  • genistein can be advantageously used for the treatment of coronary heart disease.
  • the present invention is based on the following property of genistein which has so far never been identified, namely the ability to inhibit the formation and to reduce the size of atherosclerotic plaques and to prevent restenosis after percutaneous transluminal angioplasty or related procedures .
  • the invention relates to a method for the primary and the secondary treatment of stenotic (or narrowed or stenosed) arteries, in particular coronary heart disease, as well as for the prevention of restenosis after treating stenotic arteries, such as coronary arteries, in particular after percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
  • the method comprises administering to humans or animals an effective amount of genistein to inhibit, stabilize or reduce the formation of atherosclerotic plaques or scar tissue and prevent restenosis after percutaneous transluminal angioplasty.
  • Another aspect of the invention is a drug, dietary product, dietary supplement or food supplement for the primary and the secondary treatment of stenotic (or narrowed or stenosed) arteries, in particular coronary heart disease, as well as for the prevention of restenosis after a treatment of stenotic arteries, such as coronary arteries, in particular after percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
  • the drug, dietary product, dietary supplement or food supplement comprises an effective amount of genistein to inhibit, stabilize or reduce the formation of atherosclerotic plaques or scar tissue and prevent restenosis after percutaneous transluminal angioplasty.
  • the invention also relates to the use of concentrated genistein or genistein with a pharmaceutically acceptable carrier for the prepartion of a pharmaceutical composition for the primary and the secondary treatment of stenotic (or narrowed or stenosed) arteries, in particular coronary arteries, as well as for the prevention of restenosis after a treatment of stenotic arteries, such as coronary arteries, in particular after a treatment consisting of percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy, whereby the genistein inhibits, stabilises or reduces the formation of atherosclerotic plaques or scar tissue and prevents restenosis after percutaneous transluminal angioplasty.
  • Genistein refers to the isoflavone compound as defined in the Merck Index (7 th Edition, 1960, p474) , or a derivative or analogue thereof.
  • the present invention encompasses the use of any genistein derivative having the same effect on humans or animals as described above.
  • Genistein is a dietary factor which is the cause of a significant difference in incidence of coronary heart disease between Asians and Anglo-Americans. Genistein is found in high concentration (up to 100 mg/100 g) in soy products which is reflected in the different plasma levels of Genistein in Japanese (74,7 ng/ml) and Fins (1,7 ng/ml) (see Adlercreutz H et al . Lancet 1993b, 342: 1209-1210).
  • Genistein is a member of the isoflavonoid family and a naturally occurring substance, found primarily in soy beans but also in lower concentrations in many other plants . Genistein can thus be administered to a patient by placing the patient on a diet containing high levels of soy-based food products or other plant products rich in genistein.
  • genistein can be extracted from soy or other plants, or otherwise synthesized, as described in US Patents 5,726,034 and 5,506,211 and incorporated into any carrier.
  • Genistein can be administered in a substantially concentrated pure form. Alternatively, genistein can be incorporated in almost any food carrier or supplement with suitable flavoring to please all tastes.
  • the dietary product may be any type of food product, such as cereals, confectionery bars, beverages, yoghurt, ice cream, chocolate, biscuits etc.
  • the dietary product contains at least 40mg/serving of genistein and is consumed at least once a day, preferably 2 to 3 times a day depending upon the indication (primary / secondary treatment of stenotic arteries, in particular coronary heart disease, or prevention of restenosis after angioplasty) and may be taken in an amount of up to 1000 mg/day and in some cases in an even greater amount, such as 2000 mg/day. In most cases, a sufficient therapeutic effect can be obtained with a daily consumption of about 200 mg to 300 mg of genistein which corresponds to a plasma concentration of 5-7 micromol/1.
  • Genistein can also be administered, preferably in similar dosages, as a drug, usually mixed with a pharmaceutically acceptable carrier to form a tablet, powder, syrup, transdermal patch, oral/nasal spray, intravenous solution or any other kind of carrier.
  • a pharmaceutically acceptable carrier may consist of any molecular entities and compositions that do not produce an adverse, allergic or other undesirable reaction when administred to a human or an animal.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

A method, and a drug, dietary product, dietary supplement or food supplement are provided for the primary and secondary treatment of stenotic arteries, such as coronary heart disease, as well as prevention of restenosis after percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy of stenotic arteries, such as coronary heart disease. The method comprises administering to humans or animals the drug, dietary product, dietary supplement or food supplement which contains an effective amount of genistein.

Description

METHOD AND DRUG FOR THE TREATMENT OF CORONARY HEART
DISEASE AND FOR THE PREVENTION OF RESTENOSIS AFTER
PERCUTANEOUS TRANSLUMINA CORONARY ANGIOPLASTY
Field of the Invention
This invention relates to a method and to a drug, dietary product, dietary supplement or food supplement for the primary and secondary treatment of any stenotic artery as well as for the prevention of restenosis after treating narrowed, stenosed or stenotic arteries, in particular by percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
Background Art
Coronary heart disease or atherosclerotic artery disease in general is usually the result of an injured endothelium allowing an accumulation of oxidised low density lipoprotein (LDL) in the arterial wall, which consequently leads to the formation of foam cells. These foam cells generate atherosclerotic plaques with reactive proliferation of arterial smooth muscle cells and fibroblasts. These atherosclerotic plaques narrow the coronary artery lumen which causes silent or symptomatic myocardial ischemia, or lead to myocardial infarction when occluded by a thrombus.
Stenotic arteries, in particular coronary arteries can be efficiently treated by percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy. However, the major drawback of these techniques is a frequent restenosis of the treated site within 6 months . Despite technical progress and new adjunctive therapies, restenosis rates of 20% to 50% (depending upon the definition used) have been observed (see Colombo A et al . J Am Coll Cardiol 1996;28:830-6, Berger PB et al . J Am Coll Cardiol 1996;27:1-7, Hotie H et al . Circulation 1997;96:166-73) .
The restenosis mechanism appears to be a multifactorial phenomenon combining plaque persistence, elastic recoil of arterial walls, platelet deposition, thrombus formation, cellular proliferation, vascular remodeling and release of platelet derived growth factor. Despite an ever growing body of studies about new pharmacological interventions, such as treatments with calcium antagonists, ACE-inhibitors, heparin, low molecular weight heparin, lipid lowering drugs, antioxidants , as well as new procedures such as intravascular irradiation and rotablator, the rate of restenosis following percutaneous transluminal angioplasty is still very high.
So far, only two treatments preventing restenosis have shown benefits in large scale clinical trials: the administration of a platelet glycoprotein lib / Ilia receptors antagonist and the use of intracoronary metallic stents. However, in about 20% of the cases these treatments still lead to no or insufficient results.
Objects of the Invention
It is therefore an object of the invention to provide a method and a pharmaceutical composition for the prevention of restenosis after the treatment of stenotic (or narrowed or stenosed) arteries, in particular coronary arteries .
Another object of the invention is to provide a method and a pharmaceutical composition for the secondary treatment of stenotic arteries, in particular coronary heart disease, by the stabilisation or reduction of the atherosclerotic plaques.
A major object of the invention is to provide a primary treatment of stenotic arteries, in particular coronary heart disease, by inhibiting the formation of atherosclerotic plaques.
A further object of the invention is to provide a method and a pharmaceutical composition for the prevention of restenosis after PTCA, for the primary or secondary treatment of stenotic arteries, in particular coronary heart disease, which is inexpensive, safe and has substantially no side effect.
Yet another object of the invention is to provide a method and a pharmaceutical composition for the prevention of restenosis after percutaneous transluminal angioplasty, for the primary or secondary treatment of stenotic arteries, in particular coronary heart disease, which can be carried out respectively administered without medical supervision.
It is a further object of the invention to provide a method and a pharmaceutical composition for the prevention of restenosis after percutaneous transluminal angioplasty, for the primary or secondary treatment of stenotic arteries, in particular coronary heart disease, which can be carried out by taking respectively administered a dietary product, dietary supplement, food supplement or a drug containing said pharmaceutical composition.
Summary of the Invention
The invention is based on a series of observations and studies of the effect of genistein on humans in respect to its antineoplastic properties, particularly in relation to prostate and breast cancers .
Several oncological studies have shown how Genistein affects oxidation of LDL. Genistein has been found to reduce the generation of superoxide (O2-) (see Wei H et al. Proc Soc Exp Biol Med 1995; 208: 124-30) and to enhance the activation of antioxidant enzymes, in particular catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase (see Cai Q and Wei H. Nutr. Cancer 1996; 25: 1-7). Genistein also enhances the LDL (see Ruiz-Larrea MB et al . Free Radic Res 1997; 26: 63-70) and tissue resistance to free radicals and lipid peroxidation (see Tzeng SH et al . Thrombosis Research 1991; 64: 91-100). Therefore genistein reduces the generation of oxidized LDL.
Further oncological studies have shown how genistein affects the generation of foam cells. Genistein has been found to reduce the peripheral blood mononuclear cell proliferation by inhibiting interleukin-2 and leukotriene B4 production (see Altluru D et al . Clin Immunol Immunopathol 1991; 59: 379-87). Genistein also significantly reduces monocyte adherence on the vascular endothelium by inhibiting TNF alpha-stimulated adherence (see McGregor PE et al . Biochem Biophys Res Commun 1994; 198: 359-65), which is likely to reduce the amount of subendothelial macrophages scavenging oxidized LDL, thereby reducing the formation of foam cell production.
Additionally, genistein inhibits platelet activation and aggregation by suppressing GPIIb-IIIa activation (see Furman MI et al . Circ Rese 1994; 75: 172-80), by antagonising the thromboxane receptor and by inhibiting the thrombin-induced release of arachidonic acid and prostacyclin .
Another group of oncological studies has shown how genistein affects smooth muscle contractions. According to
Liu C. Y. and Sturek M. genistein inhibits significantly the magnitude of vascular smooth muscle contractions induced by phorbol ester, endothelin, angiotensin, and serotonin by attenuating the calcium response (see Liu C. Y. and Sturek M. Am J Physiol 1996; 270: 1825-33). In addition, genistein also inhibits the sustained phase of contractions induced by serotonin. Genistein induces an oestrogen-like relaxant effect on vascular smooth muscles by enhancing the dilator response to acetylcholine of normal (see Babaei H et al . Biochem Soc Trans 1997; 25:
111S) and atherosclerotic arteries (see Honore EK et al .
Fertil Steril 1997; 67: 148-54).
The proliferation of endothelial cells and fibroblasts which are stimulated by bFGF can be reduced by 95% by maintaining a genistein concentration in the plasma of 15 to 50 micromol/1. This effect on the proliferation of vascular endothelial cells has a 6-7 days time course for reversibility. Genistein is cytostatic up to concentrations of 100 micromol/1 and becomes cytotoxic above this level. In contrast, quiescent endothelial cells do not show any sign of toxicity even at a genistein concentration of up to 200 micromol/1, which clearly indicates that genistein targets only proliferating cells and that quiescent, nondividing cells remain unaffected. This indicates that side effects are unlikely to be expected (see Fotsis T et al . J Nutr 1995; 125: 790-797).
Furthermore, genistein inhibits the bFGF-induced migration of endothelial cells, the half-maximal effect being at a genistein plasma concentration of 150 micromol/1. The endothelial cell proliferation and the migration inhibition interferes with important early events of restenosis as described above.
Genistein blocks the platelet derived growth factor receptor which stimulates not only the proliferation and migration of arterial smooth muscle cells, but also the transcription, translation and posttranslational processing of versican, a large chondroitin sulfate proteoglycan present in the extracellular matrix of blood vessels (see Schonherr E et al . Arch Biochem Biophys 1997; 339: 353-61, Munoz R et al . Oncogene 1997; 15: 525-36). Most of the properties of genistein are triggered by deactivating the "tyrosine kinase" enzyme (see Akiyama T et al. Journal of Biological Chemistry 1987; 262: 5592- 5595) .
Surprisingly, the results of the abovementioned separate studies identifying different useful properties of genistein for the treatment of prostate and breast cancers can also be used in the cardiovascular field. In particular, by providing a combined antioxidant, antiproliferative and antithrombotic effect, genistein can be advantageously used for the treatment of coronary heart disease. Thus the present invention is based on the following property of genistein which has so far never been identified, namely the ability to inhibit the formation and to reduce the size of atherosclerotic plaques and to prevent restenosis after percutaneous transluminal angioplasty or related procedures .
Method and Pharmaceutical Composition
The invention relates to a method for the primary and the secondary treatment of stenotic (or narrowed or stenosed) arteries, in particular coronary heart disease, as well as for the prevention of restenosis after treating stenotic arteries, such as coronary arteries, in particular after percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy. The method comprises administering to humans or animals an effective amount of genistein to inhibit, stabilize or reduce the formation of atherosclerotic plaques or scar tissue and prevent restenosis after percutaneous transluminal angioplasty.
Another aspect of the invention is a drug, dietary product, dietary supplement or food supplement for the primary and the secondary treatment of stenotic (or narrowed or stenosed) arteries, in particular coronary heart disease, as well as for the prevention of restenosis after a treatment of stenotic arteries, such as coronary arteries, in particular after percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy. The drug, dietary product, dietary supplement or food supplement comprises an effective amount of genistein to inhibit, stabilize or reduce the formation of atherosclerotic plaques or scar tissue and prevent restenosis after percutaneous transluminal angioplasty. The invention also relates to the use of concentrated genistein or genistein with a pharmaceutically acceptable carrier for the prepartion of a pharmaceutical composition for the primary and the secondary treatment of stenotic (or narrowed or stenosed) arteries, in particular coronary arteries, as well as for the prevention of restenosis after a treatment of stenotic arteries, such as coronary arteries, in particular after a treatment consisting of percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy, whereby the genistein inhibits, stabilises or reduces the formation of atherosclerotic plaques or scar tissue and prevents restenosis after percutaneous transluminal angioplasty.
As mentioned above, genistein has already been described in relation to different medical application including the inhibition of osteoclasts (US Patent
5,506,211), the treatment of alcohol dependence or alcohol abuse (US Patent 5,624,910), methods and compositions for inhibiting cell proliferative disorders, such as cancers (US Patents 5,773,476, 5,760,066, 5,721,277 and
5,712,305), the treatment of cancer which depend on the platelet derived growth factor (US Patent 5,700,822), the treatment of baldness and gray hair using isoflavonoid derivatives (US Patent 5,639,785), the use as antibacterial compound (US Patent 5,399,558), as well as the treatment of menopausal and premenstrual symptoms (US
Patent 5,498,631) .
Genistein refers to the isoflavone compound as defined in the Merck Index (7th Edition, 1960, p474) , or a derivative or analogue thereof. The present invention encompasses the use of any genistein derivative having the same effect on humans or animals as described above. Genistein is a dietary factor which is the cause of a significant difference in incidence of coronary heart disease between Asians and Anglo-Americans. Genistein is found in high concentration (up to 100 mg/100 g) in soy products which is reflected in the different plasma levels of Genistein in Japanese (74,7 ng/ml) and Fins (1,7 ng/ml) (see Adlercreutz H et al . Lancet 1993b, 342: 1209-1210).
Detailed Description
Genistein is a member of the isoflavonoid family and a naturally occurring substance, found primarily in soy beans but also in lower concentrations in many other plants . Genistein can thus be administered to a patient by placing the patient on a diet containing high levels of soy-based food products or other plant products rich in genistein.
These soy-based food products are not readily available in all geographic regions but are predominantly found in Japan and other Asian countries. In addition, these products may not correspond to Western food expectations.
However, genistein can be extracted from soy or other plants, or otherwise synthesized, as described in US Patents 5,726,034 and 5,506,211 and incorporated into any carrier.
Genistein can be administered in a substantially concentrated pure form. Alternatively, genistein can be incorporated in almost any food carrier or supplement with suitable flavoring to please all tastes. The dietary product may be any type of food product, such as cereals, confectionery bars, beverages, yoghurt, ice cream, chocolate, biscuits etc... Usually, the dietary product contains at least 40mg/serving of genistein and is consumed at least once a day, preferably 2 to 3 times a day depending upon the indication (primary / secondary treatment of stenotic arteries, in particular coronary heart disease, or prevention of restenosis after angioplasty) and may be taken in an amount of up to 1000 mg/day and in some cases in an even greater amount, such as 2000 mg/day. In most cases, a sufficient therapeutic effect can be obtained with a daily consumption of about 200 mg to 300 mg of genistein which corresponds to a plasma concentration of 5-7 micromol/1.
Genistein can also be administered, preferably in similar dosages, as a drug, usually mixed with a pharmaceutically acceptable carrier to form a tablet, powder, syrup, transdermal patch, oral/nasal spray, intravenous solution or any other kind of carrier. A pharmaceutically acceptable carrier may consist of any molecular entities and compositions that do not produce an adverse, allergic or other undesirable reaction when administred to a human or an animal.

Claims

1. A method for the primary and the secondary treatment of stenotic arteries as well as for the prevention of restenosis after a treatment of stenotic arteries, said method comprising administering to humans or animals, an effective amount of concentrated genistein or genistein with a pharmaceutically acceptable carrier to inhibit, stabilize or reduce the formation of atherosclerotic plaques or scar tissue.
2. The method of claim 1, for the primary and secondary treatment of coronary heart disease as well as for the prevention of restenosis after a treatment of stenotic coronary arteries .
3. The method of claim 1, for the primary and secondary treatment of stenotic arteries as well as for the prevention of restenosis after a treatment consisting of percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
4. The method of claim 1 wherein the genistein is administered in an amount of 40 mg/day to 2000 mg/day.
5. The method of claim 4, wherein the genistein is administered in an amount of 200 mg/day to 300 mg/day.
6. The method of claim 1, comprising administering a dietary product, dietary supplement or food supplement which contains said effective amount of genistein.
7. The method of claim 1, comprising administering a drug in the form of a tablet, powder, syrup, transdermal patch, oral/nasal spray or intravenous solution which contains said effective amount of genistein.
8. A drug, dietary product, dietary supplement or food supplement for the primary and the secondary treatment of stenotic arteries as well as for the prevention of restenosis after a treatment of stenotic arteries, said drug, dietary product, dietary supplement or food supplement comprising an effective amount of genistein to inhibit, stabilize or reduce the formation of atherosclerotic plaques or scar tissue.
9. The drug, dietary product, dietary supplement or food supplement of claim 8, for the primary and secondary treatment of coronary heart disease as well as for the prevention of restenosis after a treatment of stenotic coronary arteries .
10. The drug, dietary product, dietary supplement or food supplement of claim 8, for the primary and secondary treatment of stenotic arteries as well as for the prevention of restenosis after a treatment consisting of percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
11. Use of concentrated genistein or genistein with a pharmaceutically acceptable carrier for the preparation of a pharmaceutical composistion for the primary and the secondary treatment of stenotic arteries as well as for the prevention of restenosis after a treatment of stenotic arteries, said genistein inhibiting, stabilizing or reducing the formation of atherosclerotic plaques or scar tissue .
12. The use of genistein according to claim 11, for the primary and secondary treatment of coronary heart disease as well as for the prevention of restenosis after a treatment of stenotic coronary arteries.
13. The use of genistein according to claim 11 or 12, for the primary and secondary treatment of stenotic arteries as well as for the prevention of restenosis after a treatment consisting of percutaneous transluminal angioplasty, laser angioplasty or rotablator atherectomy.
14. The use of genistein as defined in claim 11, 12 or 13, for the preparation of a dietary product, dietary supplement or food supplement containing said pharmaceutical composition.
15. The use of genistein as defined in claim 14, for the preparation of cereals, confectionery bars, beverages, yoghurt, ice cream, chocolate or biscuits.
16. The use of genistein as defined in claim 11, 12 or 13, for the preparation of a tablet, powder, syrup, transdermal patch, oral/nasal spray or intravenous solution.
17. The use of genistein for the preparation of a pharmaceutical composition according to any one of claims 11 to 16, which contains an amount of 40 mg to 2000 mg of genistein, preferably between 200 mg and 300 mg of genistein for a daily administration.
PCT/IB1999/001545 1998-09-17 1999-09-14 Genistein for the treatment of coronary heart disease and for the prevention of restenosis after percutaneous transluminal coronary angioplasty WO2000016759A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54407/99A AU5440799A (en) 1998-09-17 1999-09-14 Method and drug for the treatment of coronary heart disease and for the prevention of restenosis after percutaneous transluminal coronary angioplasty

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB98/01444 1998-09-17
IB9801444 1998-09-17

Publications (2)

Publication Number Publication Date
WO2000016759A2 true WO2000016759A2 (en) 2000-03-30
WO2000016759A3 WO2000016759A3 (en) 2000-05-25

Family

ID=11004753

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB1999/001545 WO2000016759A2 (en) 1998-09-17 1999-09-14 Genistein for the treatment of coronary heart disease and for the prevention of restenosis after percutaneous transluminal coronary angioplasty

Country Status (2)

Country Link
AU (1) AU5440799A (en)
WO (1) WO2000016759A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074307A1 (en) * 2001-03-16 2002-09-26 Novogen Research Pty Ltd Treatment of restenosis
AU2006200292B2 (en) * 2001-03-16 2007-11-22 Novogen Research Pty Ltd Treatment of restenosis
AU2008200518B2 (en) * 2001-03-16 2010-04-01 Novogen Research Pty Ltd Treatment of restenosis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023069A1 (en) * 1992-05-19 1993-11-25 Graham Edmund Kelly Health supplements containing phyto-oestrogens, analogues or metabolites thereof
WO1996021403A1 (en) * 1995-01-13 1996-07-18 Wake Forest University Dietary phytoestrogen in estrogen replacement therapy
WO1998008503A1 (en) * 1996-08-30 1998-03-05 Novogen Research Pty. Ltd. Therapeutic methods and compositions involving isoflavones
WO2000001716A2 (en) * 1998-07-06 2000-01-13 Karo Bio Ab Vasculoprotector

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3476604B2 (en) * 1995-08-22 2003-12-10 鐘淵化学工業株式会社 Method for manufacturing stent with drug attached / coated

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023069A1 (en) * 1992-05-19 1993-11-25 Graham Edmund Kelly Health supplements containing phyto-oestrogens, analogues or metabolites thereof
WO1996021403A1 (en) * 1995-01-13 1996-07-18 Wake Forest University Dietary phytoestrogen in estrogen replacement therapy
WO1998008503A1 (en) * 1996-08-30 1998-03-05 Novogen Research Pty. Ltd. Therapeutic methods and compositions involving isoflavones
WO2000001716A2 (en) * 1998-07-06 2000-01-13 Karo Bio Ab Vasculoprotector

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
ANTHONY M.S. ET AL: "Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys." ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, (1997) 17/11 (2524-2531). , XP000892357 *
DATABASE WPI Section Ch, Week 199720 Derwent Publications Ltd., London, GB; Class A96, AN 1997-215838 XP002133366 & JP 09 056807 A (KANEBUCHI KAGAKU KOGYO KK), 4 March 1997 (1997-03-04) *
E.C. TSAI ET AL.: "Inhibition of low density lipoprotein oxidation by genistein" JOURNAL OF INVESTIGATIVE MEDICINE, vol. 43, 1995, page 245a XP000889947 *
HONORE E.K. ET AL: "Soy isoflavones enhance coronary vascular reactivity in atherosclerotic female macaques." FERTILITY AND STERILITY, (1997) 67/1 (148-154). , XP002126539 *
KAPIOTIS S. ET AL: "Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells from damage by atherogenic LDL." ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, (1997) 17/11 (2868-2874). , XP002126537 *
KIRK E A ET AL: "Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor-deficient mice." JOURNAL OF NUTRITION, (1998 JUN) 128 (6) 954-9. , XP000889840 *
M S ANTHONY ET AL: "Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys" JOURNAL OF NUTRITION,XX,XX, vol. 126, no. 1, 1 January 1996 (1996-01-01), pages 43-50, XP002095625 ISSN: 0022-3166 *
PEIFLEY K A ET AL: "Angiotensin II and endothelin-1 increase fibroblast growth factor-2 mRNA expression in vascular smooth muscle cells." BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, (1998 JAN 6) 242 (1) 202-8. , XP000877352 *
RAINES E W ET AL: "Biology of atherosclerotic plaque formation: possible role of growth factors in lesion development and the potential impact of soy." JOURNAL OF NUTRITION, (1995 MAR) 125 (3 SUPPL) 624S-630S. REF: 51 , XP000889935 *
ST CLAIR R.W.: "Estrogens and atherosclerosis: Phytoestrogens and selective estrogen receptor modulators." CURRENT OPINION IN LIPIDOLOGY, (1998) 9/5 (457-463). , XP002126541 *
WILCOX, JOSIAH N. ET AL: "Thrombotic mechanisms in atherosclerosis: potential impact of soy proteins" J. NUTR. (1995), 125(3S), 631S-8S , XP000889934 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074307A1 (en) * 2001-03-16 2002-09-26 Novogen Research Pty Ltd Treatment of restenosis
AU2006200292B2 (en) * 2001-03-16 2007-11-22 Novogen Research Pty Ltd Treatment of restenosis
JP2009143908A (en) * 2001-03-16 2009-07-02 Novogen Research Pty Ltd Treatment of restenosis
AU2008200518B2 (en) * 2001-03-16 2010-04-01 Novogen Research Pty Ltd Treatment of restenosis

Also Published As

Publication number Publication date
AU5440799A (en) 2000-04-10
WO2000016759A3 (en) 2000-05-25

Similar Documents

Publication Publication Date Title
EP1014968B1 (en) NARINGIN AND NARINGENIN AS 3-HYDROXY-3-METHYLGLUTARYL CoA(HMG-CoA) REDUCTASE INHIBITOR
CA2331393C (en) Fatty acid analogues for the treatment of primary and secondary restenosis
JP4256679B2 (en) How to treat restenosis
WO1999025336A1 (en) Methods for preventing restenosis using tocotrienols
US20080021083A1 (en) 4-Methylpyrazole Formulations for Inhibiting Ethanol Intolerance
JP2001526658A (en) Use of a pharmaceutical composition in treating and / or preventing ischemia
US20030187055A1 (en) Synergistic pharmaceutical combinations for treating obesity
US20030104077A1 (en) Relieving symptoms of erectile dysfunction with proanthocyanidins
CA2370553A1 (en) Cardiovascular and bone treatment using isoflavones
US20040072765A1 (en) Cardiovascular and bone treatment using isoflavones
JPH08503451A (en) Use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors as a modality for cancer treatment
WO2000016759A2 (en) Genistein for the treatment of coronary heart disease and for the prevention of restenosis after percutaneous transluminal coronary angioplasty
US20030162725A1 (en) Synergistic pharmaceutical combinations for treating obesity with EGCG
US4997852A (en) Method and composition for achieving cancer chemopreventive and chemotherapeutic activity
EP1569635B1 (en) Use of carnitines for the prevention and/or treatment of disorders caused by the andropause
KR19990071183A (en) Honggyeongcheon Extract with Efficacy and Prevention of Circulatory Diseases
US7776913B2 (en) Carnitines for treating or preventing disorders caused by andropause
US6998397B2 (en) Method for decreasing cholesterol level in blood
KR100291143B1 (en) Acyl coa: cholesterol-o-acyltransferase inhibitory composition comprising naringin or naringenin
CN1723019B (en) Compounds having anti-proliferative properties
AU4092300A (en) Cardiovascular and bone treatment using isoflavones
JPH04342526A (en) Peripheral circulation improver of extremity and inhibitor of blood vessel contracture
AU2152800A (en) Phenylacetic acid compositions for treating or preventing atherosclerosis and restenosis
KR20000023557A (en) Acyl coa: cholesterol-o-acyltransferase inhibitory composition comprising hesperidin or hesperetin
MXPA01000491A (en) Synergetic compositions comprising ascorbate and lysine for the states related to the extracellular matrix degradation.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase