Compositions and methods for the treatment, reduction and/or prevention of cardiovascular diseases and disorders are described. Individuals at high risk for developing or having cardiovascular disease or disorder may be treated with an effective dose of a polymethoxyflavone including limocitrin derivatives, quercetin derivatives, naturally occurring polymethoxyflavones, tocotrienols, and mixtures of these compounds.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases and disorders wherein an effective amount of a composition having at least one limocitrin and/or quercetin derivative is administered to reduce, prevent or treat a mammal at high risk for or suffering from a cardiovascular disease.

Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one flavonoid is administered to reduce, prevent or treat a mammal at high risk for or suffering from a cardiovascular disease.

A further object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin, quercetin derivative, tocotrienol, and mixtures thereof is administered to reduce, prevent or treat a mammal at high risk for or suffering from a cardiovascular disease.

A still further object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one naturally occurring polymethoxyaflavone is administered to reduce, prevent, or treat a mammal at high risk for or suffering from a cardiovascular disease.

Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one naturally occurring polymethoxyflavone, tocotrienols, and mixtures thereof, is administered to reduce, prevent or treat a mammal at high risk for or suffering from a cardiovascular disease.

A further object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one a tocotrienol, flavonoid, and mixtures thereof, is administered to reduce, prevent, or treat a mammal at high risk for or suffering from a cardiovascular disease.

A still further object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin derivative, quercetin derivative, naturally occurring polymethoxyaflavone, tocotrienol, and mixtures thereof, is administered to a mammal to lower serum cholesterol, apo-B, and/or LDL cholesterol.

Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin derivative, quercetin derivative, naturally occurring polymethoxyaflavone, tocotrienol, and mixtures thereof, in combination with a cholesterol-lowering drug, is administered to a mammal to lower serum cholesterol, apo-B, and/or LDL cholesterol.

Another object of the present invention is to provide compositions and methods for the reduction, prevention, and/or treatment of cardiovascular diseases or disorders wherein an effective amount of a composition having at least one limocitrin derivative, quercetin derivative, naturally occurring polymethoxyaflavone, tocotrienol, and mixtures thereof, in combination with a pharmaceutical drug including anti-platelets agents, beta-adrenergic blocking agents, nitrates or calcium channel blockers.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of at least one of limocitrin derivative, quercetin derivative, polymethoxyflavone, tocotrienol and mixtures thereof alone or in combination with at least one cholesterol-lowering drug for the treatment of cardiovascular diseases or disorders. Limocitrin occurs in the peel of lemon as limocitrin-3-O-glucoside, and can be produced from the 3-glycoside by enzymatic and acid hydrolysis (Horowitz et al., J. Org. Chem., Volume 25, 21885-21887, 1960) or by a chemical synthesis procedure such as reported by Dryer et al., Tetrahedron, Volume 20, 2977-2983, 1964. Two limocitrin analogues, limocitrin 3,7,4′-trimethylether and limocitrin-3,5,6-4′-tetramethylether, also occur in orange peel (Tatum et al., Phytochemistry, volume II, 2283-2288, 1972). Several polymethoxyflavones were tested and found to be active as inhibitors of apolipoprotein B (apoB) production and had negligible cytotoxicity in the human liver carcinoma cell line HepG2. It has been shown that humans with coronary heart disease (CAD) have higher levels of apoB in their blood. ApoB concentrations also reflect the number of LDL, and VLDL (very low density lipoprotein) particles in arteries. Administering polymethoxylatedflavone of the invention to a mammal results in a reduction in the amount of substances in the blood which contribute to CAD, such as for example apoB, LDL, cholesterol, etc; preferably reduction of the serum, plasma, or whole blood concentration or in vivo amounts of these substances. Preferably the concentration or in vivo amount of these substances is reduced to normal levels typically found in such a mammal. Also, preferably, the polymethoxylatedflavone of the present invention are administered in amounts which produce little or no cytotoxicity, more preferably where no cytotoxicity is produced.

By way of definition, a polymethoxylatedflavone is a flavone substituted with methoxy groups, preferably at least 2, more preferably at least 3, more preferably at least 4, more preferably 4-8, and most preferably 4-7 methoxy groups and optionally substituted by one or more hydroxy groups, preferably 1-3, and more preferably 1-2 hydroxy groups.

Four compounds of the present invention were synthesized from the lemon flavonoid limocitrin (3′,8-dimethoxy-3,5,7,4′-tetrahydroxyflavone) for use in the present invention: limocitrin-3,7,4′-trimethylether (5-hydroxy-3,7,8,3′,4′-pentamethoxyflavone); limocitrin-3,5,7,4′-tetramethylether (3,5,7,8,3′4′-hexamethoxyflavone); and limocitrin-3,7,4′-trimethylether-5-acetate.

A number of methoxylated flavones, most of which occur naturally in citrus, have been found to be useful in the present invention. Also included are substituted derivatives of quercetin. The compounds in these groups include 5-desmethylnobiletin (5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone); tetra-O-methylisoscutellarein (5,7,8,4′-tetramethoxyflavone); 3,5,6,7,8,3′,4′-heptamethoxyflavone; nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone); tangeretin (5,6,7,8,4′-pentamethoxyflavone); sinensetin (5,6,7,3′,4′-pentamethoxyflavone); 5-desmethylsinensetin (5-hydroxy-6,7,3′,4′-tetramethoxyflavone); quercetin tetramethylether (5-hydroxy-3,7,3′,4′-tetramethoxyflavone); quercetin 3,5-dimethylether-7,3′,4′-tribenzylether; quercetin pentamethyl ether (3,5,7,3′,4′-pentamethoxyflavone); quercetin-5,7,3′,4′-tetramethylether-3-acetate; quercetin-5,7,3′,4′-tetramethylether (3-hydroxy-5,7,3′,4′-tetramethoxyflavone).

Examples of tocotrienol compounds useful in the present invention include, but are not limited to, are alpha-tocotrienol, gamma-tocotrienol, delta-tocotrienol, and mixtures thereof.

Examples of cholesterol-lowering drugs for the treatment of cardiovascular diseases or disorders useful in the present invention include, but are not limited to, are cholestyramine, colestipol, clofibrate, gemfibrozil or lovastatin.

The methods of the present invention may be administered to any mammal. Most preferably, the polymethoxylatedflavone useful in the methods of the present invention are administered to humans.

In another aspect of the present invention, the polymethoxylatedflavone may be formulated into a pharmaceutical preparation by a conventional method usually employed in the art.

Dosages for the compositions of the present invention may be formulated into pharmaceutical preparations for administration to mammals for reduction, prevention, and treatment of cardiovascular diseases. Examples, not limited thereto, of cardiovascular disease treatable by the compositions of the present invention include hypercholesterolemia, hyperlipidemia, atherosclerosis, thrombosis, myocardial infarction, etc.

Many of the limocitrin derivatives, quercetin derivatives, naturally-occurring polymethoxyflavones, tocotrienol compounds and mixtures thereof may be provided as compounds with pharmaceutically compatible counterions, a form in which they may be soluble. Counterions for the purposes of this invention include, for example, hydrophilic and hydrophobic agents.

The polymethoxylatedflavone can be administered by a variety of routes, including oral, transdermal, rectal, intrarticular, intravenous, and intramuscular introduction. However, it should be understood that the amount of the polymethoxylatedflavone actually administered ought to be determined in light of various relavent factors including the condition to be treated, the chosen route of administration, the age and weight of the individual patient, and the severity of the patient's condition, and therefore, the doses given herein should not be construed to limit the scope of the invention in any way. The polymethoxylatedflavone useful in the present invention may be administered in a pharmaceutically or physiologically acceptable carrier. The pharmaceutically or physiologically acceptable carrier is any solvent with which the polymethoxylatedflavone is compatible and which is non-toxic to individuals treated at the amounts administered. A variety of delivery systems for pharmacological compositions may be employed including, but not limited to, liposomes and emulsions. The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Formulations suitable for oral administration include liquid solutions of the active compound or compounds dissolved in a diluent such as, for example, saline, water, PEG 400; solid preparations such as capsules or tablets, each containing a predetermined amount of the active agent as solids, granules, gelatins, suspensions, and/or emulsions.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions which contain buffers, antioxidants, and preservatives. The formulations may be in unit dose or multi-dose containers.

Dosages administered are any effective amount of a polymethoxylatedflavone which will, when given for the treatment, prophylactically or therapeutically, reduce or prevent cardiovascular diseases by reducing levels of substances which contribute to cardiovascular diseases to normal or near normal levels in the blood or in vivo. By way of definition substances which contribute to cardiovascular diseases, include but are not limited to apoprotein B, low density lipoproteins, very low density lipoproteins, cholesterol, etc.

Patient dosages for oral administration of flavonoids range from about 1-1000 mg/day, commonly 1-500 mg/day, and typically 1-100 mg/day. Stated in terms of patient with a 70 kg body weight, usual dosages range from about 0.01-15 mg/kg/day, commonly from about 0.01-7.0 mg/kg/day, and typically from about 0.01-2.0 mg/kg/day.

Patient dosages for oral administration of synthetic flavonoid analogues range from about 2000-5000 mg/day, commonly from about 1000-2000 mg/day, and typically from about 500-1500 mg/day.

Patient dosages for oral administration of limocitrin derivatives, quercetin derivatives, naturally-occurring polymethoxyflavones, and tocotrienols range from about 1-1000 mg/day, commonly about 1-500 mg/day, and typically from about 1-100 mg/day.

Patient dosages for oral administration of synthetic limocitrin derivatives range from about 200-500 mg/day, commonly about 1000-2000 mg/day, and typically from about 500-1500 mg/day.

Patient dosages for oral administration of naturally-occurring polymethoxyflavones range from about 1-1000 mg/day, commonly from about 1-500 mg/day, and typically from about 1-100 mg/day. Stated in terms of patient body weight, for about 70 kg body weight, usual dosages range from about 0.01-15 mg/kg/day, commonly from about 0.01-7.0 mg/kg/day, and typically from about 0.01-2.0 mg/kg/day.

Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the anti-proliferative and antioxidative effects of the disease being treated.

For local administration, the composition can be administered by injection directly into a tissue, often in a depot or sustained release formulation.
 

Claim 1 of 3 Claims

1. A composition for reducing apolipoprtein B production comprising an apolipoprotein B reducing amount of a polymethoxyflavone selected from the group consisting of limocitrin-3,5,7,4′-tetraethylether (8,3-dimethoxy-3,5,7,4′-tetraethoxyflavone), limocitrin-3,7,4′-trimethylether-5-acetate, and mixtures thereof.

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