The invention relates generally to a method and composition for preventing and/or treating adverse physiological effects associated with cardiac disease.
Heart disease is one of the most common forms of disease in many parts of the world. and is a leading cause of mortality and morbidity. Heart disease may be characterized as either chronic or acute. Chronic cardiac disease includes cardiomyopathies, congestive heart failure and conditions such as chronic pericardial disease. Cardiomyopathies are characterized hemodynamically into dilated, hypertrophic, restrictive and obliterative cardiomyopathy and can be of known or idiopathic etiology. Among the etiologies of dilated cardiomyopathy are pregnancy, drugs and toxins, such as alcohol, cocaine and chemotherapeutic agents and infectious and autoimmune processes. Hypertrophic cardiomyopathy is hereditary in more than 50% of cases and has a distinctive pattern of myocardial hypertrophy (thickening of muscle). Restrictive cardiomyopathies are usually the product of an infiltrative disease of the myocardium, such as amyloidosis, hemochromatosis or a glycogen storage disease, and may also be seen in certain diabetic patients. Obliterative cardiomyopathy can be caused by endomyocardial fibrosis and hypereosinophilis syndrome.
Congestive heart failure is characterized by the inability of the heart to deliver a supply of oxygenated blood sufficient to meet the metabolic needs of peripheral tissues at normal filling pressures and is a common complication of cardiomyopathies and is also a complication of other conditions such as diabetes mellitus, coronary artery disease, myocarditis, aortic stenosis, pericarditis, neoplastic pericardial effusion and numerous other conditions.
Acute cardiac diseases include acute pericarditis as well as complications of myocardial infarction and the ischemia resulting therefrom. One such complication is the injury resulting from the physiological effects resulting from reperfusion of the ischemic tissue. Ischemia is defined as a condition in which a tissue or organ does not receive a sufficient supply of blood, usually due to obstruction of the arterial blood supply. Ischemic reperfusion injury describes functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion of oxygenated blood to the ischemic areas. These changes can be fatal to muscle cells, and can include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage can include hemorrhage and ventricular arrhythmias.
Myocardial cellular injury associated with the reperfusion of ischemic myocardium has been attributed to many interrelated factors, including intracellular Ca2xe2x88x92 overloading, loss of sarcolemmal phospholipids and oxygen free radical generation (Bagchi et al., xe2x80x9cInterrelationship Between Cellular Calcium Homeostasis and Free Radical Generation in Mycocardial Reperfusion Injury, Chem. Biol. Int., 104:65-85 (1997)). In particular, such injury can occur when a person is provided with certain compounds, such as an artificial blood substitute. One possible mechanism of damage for ischemic reperfusion injury is via oxygen free radicals. Reactive oxygen species have been implicated in pathogenesis of diverse degenerative diseases including ischemic heart disease (Belch et al., xe2x80x9cOxygen Free Radicals and Congestive Heart Failure,xe2x80x9d Brit. Heart J., 65:245-248 (1991); Singal et al., xe2x80x9cRole of Free Radicals in Catecholamine-Induced Cardiomyopathy,xe2x80x9d Can. J. Physiol. Pharmacol., 60:1390-1397 (1982); Otani et al., xe2x80x9cEnhanced prostaglandin synthesis due to phospholipase breakdown in ischemic-reperfused myocardium. Control of its production by a phospholipase inhibitor or free radical scavengers., xe2x80x9d J. Mol. Cell Cardiol., 18:953-961 (1986); Steinbrecher et al., xe2x80x9cRole of Oxidatively Modified LDL in Atherosclerosis, Free Rad. Biol. Med., 9:155-168 (1990)). Evidence exists that oxidative stress resulting from increased production of free radicals associated with decreased amount of antioxidants in the myocardium plays a crucial role in ischemic heart disease, as well as atherosclerosis, congestive heart failure, cardiomyopathy, hypertrophy and arrhythmias (Das et al., xe2x80x9cProtection Against Free Radical Injury in the Heart and Cardiac Performance,xe2x80x9d Exercise and Oxygen Toxicity, (C. K. Sen, L. Packer, O. Hanninen, eds.) Elsevier Science, Amsterdam (1995). Epidemiological relationships also exist between oxidative stress and occurrence of cardiovascular diseases that include ischemic heart disease (Gey et al., xe2x80x9cInverse Correlation Between Plasma Vitamin E and Mortality From Ischemic Heart Disease in Cross-Cultural Epidemiology,xe2x80x9d Am. J. Clin. Nutr., 53:3265-3345 (1991)) and arteriosclerosis (Gey, xe2x80x9cOn the Antioxidant Hypothesis With Regard to Arteriosclerosis,xe2x80x9d Bibl. Nutr. Dieta., 37:53-91 (1986)). The anticipation of free radicals has been demonstrated by the beneficial effects of antioxidants and antioxidant enzymes (Otani et al., xe2x80x9cCardiac Performance During Reperfusion Improved by Pretreatment With Oxygen Free Radical Scavengers,xe2x80x9d J. Thoracic Cardiovasc. Surg., 91:290-295 (1986)) and free radical scavengers (Arroyo et al., xe2x80x9cIdentification of Free Radicals in Myocardial Ischemia/Reperfusion by Spin Trapping With Nitrone DMPO, FEBS Lett., 221:101 -104 (1987)). The role of oxygen free radicals in myocardial ischemic reperfusion injury is well documented. The presence of hydroxyl (OHxe2x80x94) and other reactive oxygen species has been demonstrated directly using ESR and High Pressure Liquid Chromatography (HPLC) techniques (Tosaki et al., xe2x80x9cComparisons of ESR and HPLC methods for the detection of hydroxyl radicals in ischemic/reperfused hearts. A relationship between the genesis of oxygen-free radicals and reperfusion-induced arrhythmias, Biochem. Pharmacol., 45:961-969 (1993)) and indirectly by identifying the formation of malonaldehyde (Cordis et al., xe2x80x9cDetection of Oxidative Stress in Heart by Estimating the Dinitrophenylhydrazine Derivative of Malonaldehyde,xe2x80x9d J. Mol. Cell. Cardiol., 27:1645-1653 (1995)) and 8-hydroxydeoxyguanosine (Cordis et al., xe2x80x9cDetection of Oxidative DNA Damage to Ischemic Reperfused Rat Hearts by 8-Hydroxydeoxyguanosine Formation,xe2x80x9d Mol. Cell. Cardiol., 30:1939-1944 (1998)) in the heart as well as in the coronary effluents.
Ischemic reperfusion injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. Additionally, pretreatment of hearts with antioxidants or antioxidant enzymes can ameliorate ischemic reperfusion injury, presumably by reducing the formation of detrimental free radicals (Das et al., xe2x80x9cEvaluation of Antioxidant Effectiveness in Ischemia Reperfusion Tissue Injury Methods,xe2x80x9d Methods Enzymol., 233: 601-610 (1994); Jayakumari et al., xe2x80x9cAntioxidant Status in Relation to Free Radical Production During Stable and Unstable Anginal Syndromes,xe2x80x9d Atherosclerosis, 94:183-190 (1992)). Nevertheless, the administration of traditional antioxidant compositions has not necessarily proved to be completely effective in the prevention or treatment of the adverse physiological effects associated with cardiac disease generally or ischemic reperfusion injury in particular. There thus remains a need for an effective method to prevent and/or treat ischemic reperfusion injury in persons who have or are at risk for ischemic reperfusion injury.
Proanthocyanidins comprise a group of polyphenolic bioflavonoids ubiquitously found in fruits and vegetables. They are the most common type of tannins found in fruits and vegetables, and are present in high amounts in the seeds and skins of grapes. Proanthocyanidins have been the subject of considerable interest because of their broad pharmacologic activity and therapeutic potential (Chen et al., xe2x80x9cAntioxidative Activity of Natural Flavonoids is Governed by Number and Location of Their Aromatic hydroxyl Groups, Chem. Phys. Lipids, 79:157-163 (1996)). The biological and medicinal properties of the proanthocyanidins have been extensively reviewed (Rice-Evans et al., xe2x80x9cStructure-Antioxidant Activity Relationships of Flavonoids and Phenolic Acids,xe2x80x9d Free Rad. Biol. Med., 20:933-956 (1996)). For example, the epidemiological evidence indicates that the consumption of red wine is beneficial in the prevention of coronary heart disease (Rimm et al., xe2x80x9cProspective Study of Alcohol Consumption and Risk of Coronary Disease in Men,xe2x80x9d Lancet, 338:464-86 (1991); St. Leger et al., xe2x80x9cFactors Associated With Cardiac Mortality in Developed Countries With Particular Reference to the Consumption of Wine,xe2x80x9d Lancet, 1:1017-1020 (1979)). This beneficial effect has been attributed to the antioxidants present in the polyphenol fraction of red wine (Hertog et al., xe2x80x9cAntioxidant Flavonols and Coronary Heart Disease Risk,xe2x80x9d Lancet, 349:699 (1997)), such as the proanthocyanidins present in grape seeds. Also, a Dutch epidemiological study showed that incidence of coronary heart disease in elderly males is inversely correlated with their intake of flavonoids (Hertog et al., xe2x80x9cDietary Antioxidant Flavonoids and Risk of Coronary Heart Disease: The Zutphen Elderly Study,xe2x80x9d Lancet, 342:1007-1011 (1993)), further supporting cardioprotective effects of polyphenolic compounds.
Proanthocyanidins and other polyphenolic bioflavonoids have demonstrated potential antioxidant and free radical scavenging ability, and have demonstrated a broad spectrum of biological, pharmacological and medicinal properties. Proanthocyanidins consist of polymers of the flavan-3-ol units (+)-catechin, (xe2x88x92)-epicatechin and (xe2x88x92)-epicatechin 3-O-gallate linked by C4-C8 or C4-C6 bonds. Some proanthocyanidins carry galloyl residues linked to the C-3 alcoholic function of the flavan-3-ol units.
Proanthocyanidins are present in a number of natural plant sources and are particulary plentiful in the tissue and seeds of various fruits. The skins and seeds of grapes (Vitis vinifera) are particulary rich sources of proanthocyanidins with red wine and grape juice having high contents of proanthocyanidins. (See U.S. Pat. Nos. 5,484,594 and 5,912,363 describing methods for extraction of purified proanthocyanidin compositions.) A purified proanthocyanidin composition derived from grape seeds according to such methods contains monomeric, dimeric, trimeric, tetrameric and higher oligomeric and polymeric proanthocyanidins, as well as tannin. According to U.S. Pat. No. 4,698,360 the bark of certain species of maritime pine has also proved to be a rich source of proanthocyanidins.
Proanthocyanidins are known to be potent free radical scavengers and metal chelators and reduce free radicals, a by-product of metabolism and block their propagation. The proanthocyanidins are also thought to protect cells from lipid peroxidation, resulting in the protection of target organs"" membranes. One example, is the protection of low density lipoproteins (LDL) from oxidation. While the oxidation of LDL has been identified as a contributing factor to atherosclerosis and cardiovascular disease, the ability of proanthocyanidin compositions to prevent or treat specific adverse physiological effects of cardiac disease has not been demonstrated.
The present invention provides methods for preventing and treating the adverse physiological effects associated with cardiac disease by the administration of purified proanthocyanidin compositions. Specifically, the invention provides a method of preventing or treating adverse physiological effects associated with cardiac disease in a person at risk for such adverse physiological effects, the method comprising: identifying a person at risk for such adverse physiological effects; and administering a purified proanthocyanidin composition to the person in an amount effective to prevent or reduce the adverse physiological effects.
Cardiac disease susceptible to treatment according to the present method includes both chronic and acute cardiac disease. Chronic cardiac diseases, having physiological effects susceptible to treatment according to the invention include but are not limited to cardiomyopathies, congestive heart failure and conditions such as chronic pericardial disease. Acute cardiac diseases susceptible to treatment according to the present method include, but are not limited to, ischemia reperfusion injury resulting from myocardial infarction, administration of blood substitutes, circulatory collapse from hemorrhage and the like as well as conditions such as acute peritonitis and other acute cardiac conditions.
The present invention is based upon the discovery that administration of sufficient dosages of purified proanthocyanidin compositions to a human or mammalian subject alleviates adverse physiological effects associated with cardiac disease including decreased cardiac pressure, decreased aortic flow, decreased systolic aortic pressure, and enhancement of the proapoptotic factors, c-Jun and JNK 1 in the heart tissue. In particular, it is believed that the enhancement of the proapoptotic factors c-Jun and JNK-1 associated with apoptosis (programmed cell death) may be one mechanism by which various adverse physiological effects of cardiac disease are mediated. The decreased enhancement of these proapoptotic factors upon administration of the purified proanthocyanidin compositions of the invention may thus be the mechanism by which ischemia reperfusion injury and other cardiac diseases are prevented and treated by administration of purified proanthocyanidin compositions.
The compositions of the invention may be administered prophylactically or therapeutically in treatment of chronic cardiac disease conditions. Alternatively, they may be administered prophylactically in anticipation of a acute cardiac event such as in preparation for cardiac surgery such as angioplasty and the like or other surgery having potential hemodynamic effects upon the heart. Further, the purified proanthocyanidin compositions of the invention may be administered in response to acute cardiac events such as myocardial infarction and events resulting therefrom such as ischemia reperfusion of the heart muscle.
The present invention also provides a composition comprising purified proanthocyanidin composition and another compound, the introduction of which into a person""s body can lead to such injury, such as an artificial blood substitute. Artificial blood substitutes to which purified proanthocyanidin compositions of the invention may be usefully applied according to this aspect of the invention include perfluorocarbon emulsions available commercially as FLUOSOL(copyright) (Green Cross Corporation, Japan) and OXYGENT(copyright) (Alliance Pharmaceutical Corp., San Diego Calif.).
Also provided by the invention is use of a purified proanthocyanidin composition in preparation of a medicament for prevention or treatment of adverse physiological effects associated with cardiac disease.
Purified proanthocyanidin compositions of the invention may be isolated or derived from a variety of plant sources according to known methods or may be produced synthetically. Proanthocyanidins are found in the fruit and seeds of a wide variety of fruit plants including but not limited to strawberry, blueberry and grapes. Proanthocyanidins are also present in large quantities in maritime pine bark, oak wood, black and green tea and in cocoa powder. A preferred source for proanthocyanidins is grapes with grape skin and particularly grape seeds being preferred sources. Purified proanthocyanidin compositions may be obtained by practice of methods such as those described in Nasfi-Movaghar et al., U.S. Pat. No. 5,912,363 the disclosure of which is hereby incorporated by reference. A particularly preferred purified proanthocyanidin composition available as a standardized water-ethanol extract from red grape seeds for use according to the invention is available as a grape seed proanthocyanidin extract (GSPE) known as ActiVin(copyright) available from InterHealth Nutraceuticals Inc., Concord, Calif. A compositional analysis of the ActiVin(copyright) grape seed proanthocyanidin extract shows a content comprising (by weight) 54% proanthocyanidin dimer, 13% proanthocyanidin trimer, 7% proanthocyanidin tetramer, and 6% monomer and other flavonoids. Because it is believed that the prophylactic and therapeutic activities of the purified proanthocyanidin compositions of the invention are primarily associated with the low molecular weight (DP2 to DP4) oligomeric content of the purified proanthocyanidin compositions preferred purified proanthocyanidin compositions comprise at least 50% and more preferably greater than 70% by weight DP2 to DP4 oligomeric proanthocyanidins.
While it is contemplated that daily dosages of the purified proanthocyanidin compositions of the invention can range up to 1000 mg/day and higher, it is recognized that the ability of the human body to absorb and retain large quantities of proanthocyanidins may be limited. Nevertheless, it may be desirable in cases of acute cardiac disease to administer dosages of 1000 mg/day and larger intravenously and otherwise by injection (intramuscularly) to maximize the immediate therapeutic or prophylactic effect of the proanthocyanidins. More conventionally, and particularly in cases of administration for prophylactic uses the invention contemplates administering dosages ranging from 50 to 200 mg/day for adult persons. According to one preferred method of the invention, the purified proanthocyanidin composition is administered twice daily orally soon after the person has eaten a meal.
Other features and advantages of the present invention should become apparent from the following detailed description of the invention, taken with the illustrative drawings, which illustrate the principles of the invention.