Anti-hypercholesterolemic drug combination

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai

Reexamination Certificate

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C514S563000, C514S619000, C514S459000, C549S416000, C560S043000, C560S167000, C560S070000

Reexamination Certificate

active

06680340

ABSTRACT:

FIELD OF THE INVENTION
The instant invention involves a drug combination comprising a thyroid hormone receptor beta agonist in combination with a fibrate.
BACKGROUND OF THE INVENTION
Cholesterol concentrations are increased in plasma in hypothyroidism and diminished in hyperthyroidism; treatment of thyroid disease normalizes cholesterol (Aviram et al. Clin. Biochem. 15, pp. 62-66 (1982)). In man (Hansson et al., Horm. Metab. Res. 15, pp. 449-452 (1983)), and animal models (Boyd et al., J. Endocrinol. 21, 25-32 (1960) and Engleken et al., Atherosclerosis 38, pp. 177-188 (1981)), with normal thyroid function, relatively low levels of thyroid hormones reduce circulating cholesterol. But L-3,5,3′-triiodothyronine (T3) and L-thyroxine cannot be used therapeutically to treat hypercholesterolaemia because of adverse consequences of some of their other actions, notably related to the heart. The cardiac effects could either be a direct consequence of the interaction of the hormones with their cardiac receptors, or a result of the characteristic increase in metabolic rate, leading, indirectly, to increased cardiac output. Several workers have attempted to design analogs that retain hypercholesteroleamic activity but lack cardiac and metabolic effects. However, despite claimed selectivity in animals for certain compounds (Boyd et al., J. Endocrinol. 21, pp. 25-32 (1960) and Cuthbertson et al. J. Endocrin. 21, pp. 45-63 (1960)), all agents that mimic the thyroid hormones (Boyd et al., J. Endocrin. 20, pp. 33-43 (1960) and The Coronary Drug Project Research Group J. Am. Med. Ass. 220, pp. 996-1008 (1972)), including D-T4 (The Coronary Drug Project Research Group J. Am. Med. Ass. 220, pp. 996-1008 (1972)), have shown unacceptable cardiac side effects when tested in man.
Thyroid hormone exerts its effects by interacting with specific nuclear thyroid hormone receptors that exist as three main isoforms: thyroid hormone receptor-alpha1, thyroid hormone receptor-beta1 and thyroid hormone receptor-beta2.
Wikstrom et al., The EMBO Journal (1998) Vol. 17, No. 2, pp. 455461, describe specific roles for thyroid hormone receptor-alpha1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarization and control of body temperature. Weiss et al., Endocrinology (1998) Vol. 139 No. 12, pp. 4945-4952 explain that serum levels of cholesterol seem to be mainly regulated by thyroid hormone action on the liver, and that liver alkaline phosphatase appears to be regulated by thyroid hormone receptor beta.
Fibrates such as fibric acid derivatives are known to lower the levels of triglyceride-rich lipoproteins, such as VLDL, raise HDL levels, and have variable effects on LDL levels. The effects on VLDL levels appear to result primarily from an increase in lipoprotein lipase activity, especially in muscle. This leads to enhanced hydrolysis of VLDL triglyceride content and enhanced VLDL catabolism.
WO 00/37078 describes the combination of an HMG-CoA inhibitor with fibrates in the prophylaxis and treatment of disorders and diseases of lipid metabolism and of illnesses caused by such disorders and diseases.
The present invention involves the combined administration of a thyroid hormone receptor beta agonist with a fibrate to obtain reductions in cholesterol levels which are greater than the reductions that would be predicted based on lowering obtained with independent administration of thyroid hormone receptor beta agonist and independent administration of fibrate. The amount of cholesterol lowering obtaions by the combination is greater than lowering that is obtained with a two-fold greater amount of fibrate administered alone.
SUMMARY OF THE INVENTION
The instant invention provides a drug combination comprised of a therapeutically effective amount of a thyroid hormone receptor beta agonist in combination with a therapeutically effective amount of a fibrate, which is useful for lowering plasma triglyceride levels.
The instant invention further provides the drug combination comprised of a therapeutically effective amount of a thyroid hormone receptor beta agonist in combination with a therapeutically effective amount of a fibrate, which is useful for reducing cholesterol synthesis, lowering plasma cholesterol levels and lowering plasma triglyceride levels.
The drug combination is also useful for treating, preventing, and/or reducing the risk of developing atherosclerosis and atherosclerotic disease events. Another 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. 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 a first or subsequent occurrence 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.
Another object of the instant invention is to provide the above-described combination therapy to people who have clinical signs of atherosclerosis. 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 a first or subsequent occurrence 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 further object of the instant invention involves the above-described methods further comprising the administration of one or more additional active agents either in separate or combined dosage formulations. A still further object is to provide pharmaceutical compositions that 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 reducing cholesterol synthesis, lowering plasma cholesterol, lowering plasma triglycerides, and 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 a thyroid hormone receptor beta agonist in combination with a therapeutically effective amount of a fibrate to a mammal in need of such treatment, and particularly to a mammal 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 a thyroid hormone receptor beta agonist and a fibrate 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

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