Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-19
2002-12-17
Myers, Carla J. (Department: 1655)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S449000, C514S450000
Reexamination Certificate
active
06495593
ABSTRACT:
BACKGROUND OF THE INVENTION
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 Ca
2−
overloading, loss of sarcolemmal phospholipids and oxygen free radical generation (Bagchi et al., “Interrelationship 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., “Oxygen Free Radicals and Congestive Heart Failure,”
Brit. Heart J.,
65:245-248 (1991); Singal et al., “Role of Free Radicals in Catecholamine-Induced Cardiomyopathy,”
Can. J. Physiol. Pharmacol.,
60:1390-1397 (1982); Otani et al., “Enhanced prostaglandin synthesis due to phospholipase breakdown in ischemic-reperfused myocardium. Control of its production by a phospholipase inhibitor or free radical scavengers., ”
J. Mol. Cell Cardiol.,
18:953-961 (1986); Steinbrecher et al., “Role 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., “Protection Against Free Radical Injury in the Heart and Cardiac Performance,”
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., “Inverse Correlation Between Plasma Vitamin E and Mortality From Ischemic Heart Disease in Cross-Cultural Epidemiology,”
Am. J. Clin. Nutr.,
53:3265-3345 (1991)) and arteriosclerosis (Gey, “On the Antioxidant Hypothesis With Regard to Arteriosclerosis,”
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., “Cardiac Performance During Reperfusion Improved by Pretreatment With Oxygen Free Radical Scavengers,”
J. Thoracic Cardiovasc. Surg.,
91:290-295 (1986)) and free radical scavengers (Arroyo et al., “Identification 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 (OH—) and other reactive oxygen species has been demonstrated directly using ESR and High Pressure Liquid Chromatography (HPLC) techniques (Tosaki et al., “Comparisons 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., “Detection of Oxidative Stress in Heart by Estimating the Dinitrophenylhydrazine Derivative of Malonaldehyde,”
J. Mol. Cell. Cardiol.,
27:1645-1653 (1995)) and 8-hydroxydeoxyguanosine (Cordis et al., “Detection of Oxidative DNA Damage to Ischemic Reperfused Rat Hearts by 8-Hydroxydeoxyguanosine Formation,”
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., “Evaluation of Antioxidant Effectiveness in Ischemia Reperfusion Tissue Injury Methods,”
Methods Enzymol.,
233: 601-610 (1994); Jayakumari et al., “Antioxidant Status in Relation to Free Radical Production During Stable and Unstable Anginal Syndromes,”
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., “Antioxidative Activity of Natural Flavonoids is Governed by Number and Location of Their Aromatic hydroxyl Groups,
Chem. Phys. Lipids,
79:157-163 (1996)). The biologic
Bagchi Debasis
Das Dipak K.
Dry Creek Nutrition, Inc.
Marshall Gerstein & Borun
Myers Carla J.
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