Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-23
2004-06-29
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...
C514S461000, C514S473000
Reexamination Certificate
active
06756401
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions containing combinations of estrogen agonists/antagonists and statins, and pharmaceutically acceptable salts thereof, kits containing such combinations and methods of using such combinations to prevent bone loss and/or promote bone formation and to lower blood lipid levels. The compositions and methods are useful for treating subjects suffering from osteoporosis, bone fracture or deficiency, primary or secondary hyparathyroidism, periodontal disease, metastatic bone disease, osteolytic bone disease, or undergoing orthopedic or oral surgery and treating cardiovascular disease, atherosclerosis and hyperlipidemia, or presenting with symptoms of cardiac risk.
BACKGROUND OF THE INVENTION
Estrogen alters serum lipid concentrations, coagulation and fibrinolytic systems, antioxidant systems, and the production of other vasoactive molecules, such as nitric oxide and prostaglandins, all of which can influence the development of vascular disease.
The effects of estrogen therapy on serum lipid concentrations may result largely from estrogen-receptor-mediated effects on the hepatic expression of apoprotein genes. Many studies, including one large, randomized, controlled trial (The Writing Group for the PEPI Trial,
JAMA
1995;273:199-208. [Erratum, JAMA 1995;274:1676.]) have documented that estrogen therapy in post-menopausal women decreases serum total cholesterol and low density lipoprotein (LDL) cholesterol concentrations, increases serum high-density lipoprotein (HDL) cholesterol and triglyceride concentrations, and decreases serum Lp(a) lipoprotein concentrations. Hepatic expression of the genes for several coagulation and fibrinolytic proteins is also regulated by estrogen through estrogen receptors.
Statins inhibit the enzyme HMG-CoA reductase that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate in an early and rate-limiting step in the cholesterol biosynthetic pathway. It is believed that this effect is responsible for statins being considered as potent lipid lowering agents. The bone-forming effect of statins may be due to their ability to increase bone formation rate possibly through the stimulation of growth factors such as bone morphogenic protein-2 (BMP-2) (Mundy, G., et al.,
Science
, 1999;286:1946-1949).
Statins include such compounds as simvastatin, disclosed in U.S. Pat. No. 4,444,784; pravastatin, disclosed in U.S. Pat. No. 4,346,227; cerivastatin, disclosed in U.S. Pat. No. 5,502,199; mevastatin, disclosed in U.S. Pat. No. 3,983,140; velostatin, disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171; fluvastatin, disclosed in U.S. Pat. No. 4,739,073; compactin, disclosed in U.S. Pat. No. 4,804,770; lovastatin, disclosed in U.S. Pat. No. 4,231,938; dalvastatin, disclosed in European Patent Application Publication No. 738510 A2; fluindostatin, disclosed in European Patent Application Publication No. 363934 A1; atorvastatin, disclosed in U.S. Pat. No. 4,681,893; atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995; dihydrocompactin, disclosed in U.S. Pat. No. 4,450,171; ZD-4522, disclosed in U.S. Pat. No. 5,260,440; bervastatin, disclosed in U.S. Pat. No. 5,082,859; and NK-104, disclosed in U.S. Pat. No. 5,102,888.
High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C), in man (Brown and Goldstein,
N Engl J Med
, 1981;305:515-517). It has now been established that lowering LDL-C levels affords protection from coronary heart disease (see, e.g., The Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S),
Lancet
, 1994;344:1383-89; and Shepherd, J. et al., Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia,
N Engl J Med
, 1995;333:1301-07).
Coronary heart disease is a multifactorial disease in which the incidence and severity are affected by the lipid profile, the presence of diabetes and the sex of the subject. Incidence is also affected by smoking and left ventricular hypertrophy, which is secondary to hypertension. To meaningfully reduce the risk of coronary heart disease, it is important to manage the entire risk spectrum. For example, hypertension intervention trials have failed to demonstrate full normalization in cardiovascular mortality due to coronary heart disease. Treatment with cholesterol synthesis inhibitors in patients with and without coronary artery disease reduces the incidence of cardiovascular morbidity and the risk of mortality.
The incidence of cardiovascular disease differs significantly between men and women, in part because of differences in risk factors and hormones (Barrett-Connor E.
Circulation
1997;95:252-64). The incidence of atherosclerotic diseases is low in premenopausal women, rises in post-menopausal women, and is reduced to premenopausal levels in post-menopausal women who receive estrogen therapy. (Barrett-Connor E.,
Circulation
1997;95:252-64; Stampfer M. J., et al.,
N Enql J Med
1991;325:756-62.; Grady D., et al.,
Ann Intern Med
1992;117:1016-37) Until recently, the atheroprotective effects of estrogen were attributed principally to the hormone's effects on serum lipid concentrations. However, estrogen-induced alterations in serum lipids account for only approximately one third of the observed clinical benefits of estrogen (Grady D., et al.,
Ann Intern Med
1992;117:1016-37; Mendelsohn M. E., Karas R. H.
Curr Opin Cardiol
1994;9:619-26; Bush T. L., et al.,
Circulation
1987;75:1102-9). The results, however, can be nonetheless significant. It is now also believed that the direct actions of estrogen on blood vessels contribute substantially to the cardiovascular protective effects of estrogen (Mendelsohn M. E.,
Curr Opin Cardiol
1994;9:619-26; Farhat M. Y. et al.,
FASEB J
1996;10:615-24).
The hormone estrogen has a profound effect in the vascular system of both men and women although its administration is associated with other effects that can be undesirable. Estrogen increases vasodilatation and inhibits the response of blood vessels to injury and the development of atherosclerosis. Estrogen-induced vasodilatation occurs 5 to 20 minutes after estrogen has been administered and is not dependent on changes in gene expression; this action of estrogen is sometimes referred to as “nongenomic.” The estrogen-induced inhibition of the response to vascular injury and the preventive effect of estrogen against atherosclerosis occur over a period of hours or days after estrogen treatment and are dependent on changes in gene expression in the vascular tissues; these actions are sometimes referred to as “genomic.”
There are two estrogen receptors, estrogen receptor &agr; and estrogen receptor &bgr;, both of which are members of the superfamily of steroid hormone receptors. (Walter P., et al.,
Proc Nad Acad Sci USA
1985;82:7889-93; Kuiper G. G. J. M., et al;
Proc Nad Acad Sci USA
1996;93:5925-30) Estrogen receptors &agr; and &bgr; have considerable homology and, like all steroid hormone receptors, are transcription factors that alter gene expression when they are activated. (Walter P., et al.
Proc Nad Acad Sci USA
1985;82:7889-93; Kuiper G. G. J. M., et al.;
Proc Nad Acad Sci USA
1996;93:5925-30; Shibata H., et al.
Recent Prog Horm Res
1997;52:141-65; Evans R. M.,
Science
1988;240:889-95; Brown M.,
Hematol Oncol Clin North Am
1994;8:101-12). Blood vessels are complex structures, with walls containing smooth-muscle cells and an endothelial cell lining. Vascular endothelial and smooth muscle cells bind estrogen with high affinity (Mendelsohn M. E., et al.,
Curr Opin Cardiol
1994;9:619-26; Farhat M. Y., et al.,
FASEB J
1996;10:615-24) and estrogen recept
Day Wesley W.
Lee Andrew G.
Thompson David D.
Benson Gregg C.
Criares Theodore J.
Pfizer Inc.
Richardson Peter C.
Wichtowski John A.
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