Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1994-01-18
2002-04-09
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06369103
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for preventing or reducing the risk of or onset of cardiovascular events employing an HMG CoA reductase inhibitor, such as pravastatin.
BACKGROUND OF THE INVENTION
Despite significant progress in reducing mortality due to atherosclerotic coronary artery disease (CAD) over the last several years, cardiovascular disease remains the major cause of death in most developed countries. The relation between CAD and elevated concentrations of serum total cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is well documented.
It is well established that lipid disorders are important factors in the development of coronary heart disease (CHD), Schettler, G., “The role of diet and drugs in lowering serum cholesterol in the postmyocardial infarction patient,” Cardiovasc. Drugs Ther., 1989, 2/6 (795-799).
Glatter, T. R., “Hyperlipidemia. What is ‘normal’, who should be treated and how,” Postgrad. Med., 1984, 76/6 (49-59), states that “As the Coronary Primary Prevention Trial has recently shown, a 1% reduction in cholesterol level produces a 2% reduction in risk of myocardial infarction.”
Goldstein, J. L., et al, “The LDL receptor defect in familial hypercholesterolemia. Implications for pathogenesis and therapy,” Med. Clin. North Am., 1982, 66/2 (335-362) indicate that “familial hypercholesterolemia was the first genetic disorder recognized to cause myocardial infarction. To this day, it remains the outstanding example of a single gene mutation that causes both hypercholesterolemia and coronary atherosclerosis.”
Satler, L. F., et al, “Reduction in coronary heart disease: Clinical and anatomical considerations,” Clin. Cardiol., 1989, 12/8 (422-426) disclose that “the higher the total plasma cholesterol and low density lipoprotein cholesterol (LDL-C), the greater the risk that coronary artery disease will develop. Recently, clinical trials including the Coronary Drug Project, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), and the Helsinki Heart Study provided evidence that lowering cholesterol reduces the frequency of fatal and nonfatal coronary events.” In addition, Satler et al disclose that other studies “demonstrated that lowering of cholesterol was associated with a decreased incidence of progression of coronary disease, as well as with the potential for reduction in the atherosclerotic plaque.”
Wilhelmsen, L., “Practical guidelines for drug therapy after myocardial infarction,” Drugs, 1989, 38/6 (1000-1007) discloses that it is advisable to correct blood lipid disturbances in effective management of the postinfarction patient.
Yamamoto, A., et al, “Clinical features of familial hypercholesterolemia,” Arteriosclerosis, January-February 1989, 9 (1 Suppl.) p I66-74, disclose that “in addition to the low density lipoprotein (LDL) cholesterol level, higher triglyceride and lower high density lipoprotein (HDL) cholesterol levels correlate with an increased risk of ischemic heart disease.
Other references disclosing the relation between CAD and elevated concentrations of serum total cholesterol include
1. Canner P. L. et al, “Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin”, J. Am. Coll. Cardiol. 1986; 8:1245-1255.
2. Frick, M. H. et al, “Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease,” N. Engl. J. Med. 1987; 317:1237-1245.
3. Kannel, W. B. et al, “Serum cholesterol, lipoproteins, and the risk of coronary heart disease: the Framingham Study,” Ann. Intern. Med. 1971; 74:1-12.
4. “The Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease,” JAMA 1984; 251-351-364.
5. Martin, M. J. et al, “Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men,” Lancet 1986; 2:933-936.
Efforts to further reduce the mortality rate from CAD should benefit from appropriate screening for, and treatment of, hypercholesterolemia. Primary hypercholesterolemia is initially treated with a low-cholesterol low-fat diet and lifestyle modification. If these measures are inadequate, lipid lowering drugs are then added. Agents currently available for the treatment of hypercholesterolemia include bile acid-binding resins, nicotinic acid, probucol, fibrates, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Pravastatin, a member of the latter class, in doses up to 40 mg/day, reduces serum LDL cholesterol an average of 32 to 34% and total cholesterol an average of 24 to 26% in patients with primary hypercholesterolemia. Hunninghake, D. B. et al, “Efficacy and safety of pravastatin in patients with primary hypercholesterolemia, I: a dose-response study.” Atherosclerosis 1990; 85:81-89.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, surprisingly and unexpectedly, it has been found that patients with one or more risk factors for a coronary and/or cerebrovascular event such as hypercholesterolemia, who are treated an HMG CoA reductase inhibitor, such as pravastatin, experience a rapid marked and significant reduction in cardiovascular events. Thus, although a certain number of patients having one or more risk factors for coronary or cerebrovascular events are expected to suffer a cardiovascular incident, such as a myocardial infarction and/or unstable angina, it has unexpectedly been found that such patients when treated with an HMG CoA reductase inhibitor, such as pravastatin, have a rapid and sizable reduction in such cardiovascular events. What is even more remarkable is the fact that such reduction in cardiovascular events occur within one year and usually within 6 months of treatment and even sooner. This is especially significant inasmuch as until now it has been the generally held view that a treatment effect on cardiac event rates appears only after a lag phase of ≧2 years, as seen in the Coronary Primary Prevention Trial (JAMA 1984; 251:351-364) and the Helsinki Heart Study (N. Engl. J. Med. 1987; 317:1237-1245).
Thus, in accordance with the present invention, a method is provided for preventing onset of or reducing risk of a cardiovascular event in a patient having one or more risk factors for a coronary and/or cerebrovascular event wherein a therapeutically effective amount of an HMG CoA reductase inhibitor, preferably pravastatin, lovastatin, simvastatin and fluvastatin, more preferably pravastatin, is administered systemically, such as orally or parenterally.
The term “risk factors for a coronary and/or cerebrovascular event” as employed herein refers to risk factors such as hypercholesterolemia, coronary artery disease (CAD), family history of coronary artery disease, hypertension, diabetes, cigarette smoking, cerebrovascular disease and/or male gender.
The term “coronary artery disease” (CAD) as employed herein refers to diseases including atherosclerosis of the coronary arteries, previous myocardial infarction, angina pectoris and/or heart failure.
The term “cerebrovascular disease” as employed herein refers to diseases including atherosclerosis of the intracranial and/or extracranial arteries, stroke, and transient ischemic attacks.
The term “cardiovascular event(s)” or “serious cardiovascular adverse event(s)” as employed herein refers to coronary and/or cerebrovascular event(s) including primary myocardial infarction, secondary myocardial infarction, angina pectoris (including unstable angina), congestive heart failure, sudden cardiac death, cerebral infarction, syncope, transient ischemic attack and the like.
In accordance with the method of the invention, where the risk factor in patients to be treated is hypercholesterolemia, the serum total cholesterol concentrations will be at least 5.2 mmol/liter (at least 200 mg/dl). The patients may also have other risk factors for atherosclerotic coronary artery disease such as hypertension, previous myocardial infar
Behounek Bruce D.
McGovern Mark E.
Olukotun Adeoye Y.
Bristol--Myers Squibb Company
Criares Theodore J.
Rodney Burton
LandOfFree
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