Cholesterol-lowering therapy

Details Cholesterol-lowering therapy Cholesterol-lowering therapy

1998-05-13

2001-01-30

Jordan, Kimberly (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S460000, C514S824000

Reexamination Certificate

active

06180660

ABSTRACT:

FIELD OF THE INVENTION
The instant invention involves a method of using a cholesterol reducing agent such as a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (or HMG-CoA RI) alone or in combination with other lipid altering agents for preventing or reducing the risk of first occurrence of a cardiovascular event.
BACKGROUND OF THE INVENTION
It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), 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. 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 comparatively large reductions in plasma cholesterol with very few adverse effects.
Recent studies have unequivocally demonstrated that lovastatin, simvastatin, and pravastatin, which are 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 in patients with hypercholesterolemia and/or CHD, 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 evidence for a reduction in cerebrovascular events. Additional studies have shown that HMG CoA RI's may have an effect on platelet aggregation.
SUMMARY OF THE INVENTION
One object of the instant invention is to provide a novel method for preventing or reducing the risk of a first occurrence of a cardiovascular event in a subject having an average to mildly elevated level of LDL cholesterol, and below average high-density lipoprotein (HDL) cholesterol, with no clinical evidence of coronary heart disease, comprising administering a prophylactically effective amount of a lipid altering agent such as an HMG-CoA reductase inhibitor either alone or in combination with another lipid altering agent such as a fibrate, or niacin to the subject. Additional objects will be evident from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938), simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin (PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin (LESCOL®; see U.S. Pat. No. 5,354,772), atorvastatin (LIPITOR®; see U.S. Pat. No. 5,273,995) and cerivastatin (also known as rivastatin; see U.S. Pat. No. 5,177,080), and the pharmaceutically acceptable salt, ester and lactone forms thereof. The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,
Chemistry & Industry,
pp. 85-89 (Feb. 5, 1996). The HMG-CoA RI is selected from lovastatin, cerivastatin, atorvastatin, pravastatin and simvastatin, a sub-class comprises simvastatin and lovastatin. Examples of fibrates that may be used in combination with the HMG-CoA RI include, but are not limited to benzofibrate, ciprofibrate, fenofibrate, gemfibrazol and clofibrate.
The term HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester and lactone forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters and lactone forms is included within the scope of this invention.
Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat. Nos. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33.
Ester derivatives of the described compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
Herein, the term “pharmaceutically acceptable salts” shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate.
Prophylactically effective amounts of the HMG-CoA reductase inhibitors are suitable for use in the compositions and methods of the present invention. The term “prophylactically effective amount” is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The dosage regimen utilizing an HMG-CoA RI is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the subject; and the particular compound or salt or ester thereof employed. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the prophylactically effective amounts of the drug needed to prevent or reduce the risk of occurrence of the condition sought to be prevented. In one embodiment, the prophylactically effective amount to be used in the methods of this invention is that amount of drug sufficient to lower the human subject's LDL cholesterol to a target level of 130 mg/dl or less; in a sub-embodiment to a target level of 115 mg/dl or less; and in a further sub-embodiment to a target level of 110 mg/dl or less. The ordinarily skilled clinician will be able to titrate the subject to the appropriate amount of lipid altering agent such as an HMG-CoA RI which, when taken on a daily basis, will allow the patient to reach this goal.
The term “patient” or “subject” includes mammals, especially humans, who take a lipid altering agent for any of the uses described herein. Administration of the lipid altering agent to the subject includes both self-administration and administration to the subject by another person.
Dosage information for HMG-CoA RI's is well known in the art, since several are marketed in the U.S. In particular, the daily dosage amounts of the HMG-CoA reductase inhibitor may be the same or similar to those amounts which are employed for anti-hypercholesterolemic treatment and which are described in the
Physicians' Desk Reference
(PDR). For example, see the 50
th
Ed. of the PDR, 1996 (Medical Economics Co); in particular, see at page 216 the heading “Hypolipidemics,” sub-heading “HMG-CoA Reductase Inhibitors,” and the reference pages cited therein. Preferably, the oral dosage amount of HMG-CoA RI is from about 1 to 200

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