Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-04-27
2004-01-06
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S260100
Reexamination Certificate
active
06673831
ABSTRACT:
BACKGROUND OF THE INVENTION
The instant invention involves a combination therapy comprising the administration of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) and folic acid or a pharmaceutically acceptable salt or ester thereof for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events.
There is increasing evidence that high blood levels of homocysteine are associated with an increased risk of coronary heart disease (CHD) and stroke. The mechanism of the association is unknown, but it is well established that folic acid (a B complex vitamin) lowers plasma homocysteine by increasing its catabolism.
It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease, and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. Substantial reductions in LDL (low density lipoprotein) cholesterol accompanied by increases in HDL (high density lipoprotein) cholesterol could be achieved by the combination of a lipid-lowering diet and a bile acid sequestrant, with or without the addition of nicotinic acid. However, this therapy is not easy to administer or tolerate and was therefore often unsuccessful except in specialist lipid clinics. The fibrates produce a moderate reduction in LDL cholesterol accompanied by increased HDL cholesterol and a substantial reduction in triglycerides, and because they are well tolerated these drugs have been more widely used. Probucol produces only a small reduction in LDL cholesterol and also reduces HDL cholesterol, which, because of the strong inverse relationship between HDL cholesterol level and CHD risk, is generally considered undesirable. With the introduction of lovastatin, the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol with very few adverse effects.
Recent studies have unequivocally demonstrated that lovastatin, simvastatin and pravastatin, all members of the HMG-CoA reductase inhibitor class, slow the progression of atherosclerotic lesions in the coronary and carotid arteries. Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events, and in the case of simvastatin a highly significant reduction in the risk of coronary death and total mortality has been shown by the Scandinavian Simvastatin Survival Study. This study also provided some evidence for a reduction in cerebrovascular events.
Despite the substantial reduction in the risk of coronary morbidity and mortality achieved by simvastatin, the risk is still substantial in the treated patients. For example, in the Scandinavian Simvastatin Survival Study, the 42% reduction in the risk of coronary death still left 5% of the treated patients to die of their disease over the course of this 5 year study. Further reduction of risk is clearly needed.
The use of folic acid to reduce the risk of cardiovascular disease by reducing homocysteine levels is attractive as this therapy is believed to be almost risk-free (folic acid is a vitamin) and relatively inexpensive. In addition, as the dose of folic acid required to reduce homocysteine is small (typically 1-5 mg daily) and, like HMG-CoA reductase inhibitors, may be given once daily, the active agents can be readily combined in a single tablet, capsule or other dosage form having the same or similar size as the inhibitor of HMG-CoA reductase alone. This would provide patient convenience, an important consideration especially in patients who already have coronary heart disease, as such patients generally have several different drugs to take.
SUMMARY OF THE INVENTION
The instant invention involves a novel combination therapy comprised of a therapeutically effective amount of an HMG-CoA reductase inhibitor in combination with folic acid or a pharmaceutically acceptable salt or ester thereof.
One object of the instant invention is to administer the above-described combination therapy to people who do not yet show clinical signs of atherosclerosis, but who are at risk of developing atherosclerosis and associated diseases. Clinical manifestations of atherosclerosis include atherosclerotic cardiovascular disease such as coronary heart disease (also known as ischemic heart disease), cerebrovascular disease, and peripheral vessel disease. Toward this end, the instant invention provides methods for preventing or reducing the risk of developing atherosclerotic cardiovascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, by administering the above-described combination therapy to said at-risk persons.
A second object of the instant invention is to provide the above-described combination therapy to people who have clinical signs of atherosclerosis. Toward this end, the instant invention provides methods for halting or slowing the progression of atherosclerotic cardiovascular disease, coronary heart disease, ischemic heart disease, cerebrovascular disease and peripheral vessel disease, and preventing or reducing the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication, by administering the above-described combination therapy to said persons who have clinically manifest atherosclerotic disease.
A third object of the instant invention involves the above-described methods further comprising the administration of one or more additional active agents, for example, a bile acid sequestrant, cholesterol absorption inhibitor, squalene synthase inhibitor, and/or niacin, either in separate or combined dosage formulations. A fourth object is to provide pharmaceutical compositions which can be used in the above-described methods. Additional objects will be evident from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention provides methods for preventing or reducing the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a therapeutically effective amount of an HMG-CoA RI in combination with folic acid or a pharmaceutically acceptable salt or ester thereof to a person who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms “atherosclerosis” and “atherosclerotic disease.”
The combination comprised of an HMG-CoA RI and folic acid or folate may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication. Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermi
Criares Theodore J.
Merck & Co. , Inc.
Quagliato Carol S.
Winokur Melvin
LandOfFree
Combination therapy for reducing the risks associated with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Combination therapy for reducing the risks associated with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Combination therapy for reducing the risks associated with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3255200