Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-15
2003-09-16
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212010, C514S217080, C514S315000, C514S317000, C514S323000, C514S307000, C514S345000, C514S428000, C514S213010, C514S582000, C514S585000, C514S648000, C514S331000, C514S414000, C514S415000
Reexamination Certificate
active
06620806
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods and kits for improving vascular health, including preventing myocardial infarction or stroke; maintaining or improving vascular reactivity; treating acute or chronic renal failure, peripheral arterial occlusive disease, coronary artery disease, or Raynaud's phenomenon; or lowering plasma levels of Lp(a) using an estrogen agonist/antagonist.
BACKGROUND OF THE INVENTION
The hormone estrogen has a profound effect in the vascular system of both male and female subjects, 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.”
In premenopausal women, 17&bgr;-estradiol produced by the ovaries is the chief circulating estrogen. Serum estradiol concentrations are low in preadolescent girls and increase at menarche. In women, they range from about 100 pg per milliliter (367 pmol per liter) in the follicular phase to about 600 pg per milliliter (2200 pmol per liter) at the time of ovulation. They may rise to nearly 20,000 pg per milliliter (70,000 pmol per liter) during pregnancy. After menopause, serum estradiol concentrations fall to values similar to or lower than those in men of similar age (5 to 20 pg per milliliter [18 to 74 pmol per liter]) (Yen, S. S. C. and Jaffe, R. B., eds.
Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management,
3rd ed. Philadelphia: W. B. Saunders, (1991)).
The ovaries are the principle source of estrogen in premenopausal women. The major secretory product is estradiol, synthesized by granulosa cells from androgenic precursors provided by thecal cells. Secreted estradiol is oxidized reversibly to estrone, and both of these estrogens can be converted to estriol. These transformations take place mainly in the liver, where interconversion between estrone and estradiol is catalyzed by 17-hydroxysteroid dehydrogenase.
In men and postmenopausal women, the principle source of estrogen is adipose tissue. In this and in other peripheral tissues, estrone is synthesized from dehydroepiandrosterone, which is secreted by the adrenal cortex. Thus, the contribution of adipose tissue estrogens is regulated, in part by the availability of androgenic precursors (Mendelson, C.R. and Simpson, E.R.,
Mol. Cell Endocrinol.,
52:169-176, (1987)).
There are two estrogen receptors, estrogen receptor a 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 NadAcad 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 receptor &agr; has been identified in both types of vascular cells in women and men, (Karas, R. H., et al.,
Circulation
1994;89:1943-50; Losordo, D. W., et al.,
Circulation
1994;89:1501-10; Venkov, C. D., et al.,
Circulation
1996;94:727-33; Kim-Schulze, S., et al.,
Circulation
1996;94:1402-7; Caulin-Glaser, T., et al.,
J Clin Invest
1996;98:36-42) as well as in myocardial cells (Grohe, C., et al., FEBS Lett 1997;416:107-12).
Estrogen receptor &agr; activates specific target genes in vascular smooth-muscle and endothelial cells (Table 1) (Karas, R. H., et al.,
Circulation
1994;89:1943-50, Venkov, C. D., et al.,
Circulation
1996;94:727-33; Kim-Schulze, S., et al,
Circulation
1996;94:1402-7; Caulin-Glaser, T., et al., J Clin Invest 1996;98:36-42; Koike, H., etal.,
J Vasc Surg
1996;23:477-82). Estrogen receptor &bgr; is structurally and functionally distinct from estrogen receptor &agr;. Functional estrogen receptor &bgr; is also present in myocardial cells, in which it regulates the expression of nitric oxide synthases.
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 result largely from estrogen-receptor-mediated effects on the hepatic expression of apoprotein genes (Table 1). 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. Increased Lp(a) levels have been associated with increased risk of recurrent coronary heart disease events after menopause (Shlipak, M. G., et al.,
JAMA
2000;283: 1845-1852). Hepatic expression of the genes for several coagulation and fibrinolytic proteins is also regulated by estrogen through estrogen receptors (Table 1).
Estrogen directly regulates vasomotor tone through both short-term and long-term effects on the vasculature. Long-term administration of estrogen is associated with decreased plasma concentrations of renin (Schunkert, H., et al.,
Circulation
1997;95:39-45), angiotensin-converting enzyme (Proudler, A., et al.,
Lancet
1995;346:89-90) and endothelin-1 (Ylikorkala, O., et al., J Clin Endocrinol Metab 1995;80:3384-7) and decreased vascular expression of the gene for angiotensin II receptor type 1 (Nickenig, G., et al.,
Circulation
1998;97:2197-201) as well as an increased ratio of nitric oxide to endothelin-1 in plasma (Best, P. J. M., et al.,
Ann Intem Med
1998;128:285-8). The net effect of these changes is to promote vasodilatation.
Estrogens can cause short-term vasodilatation by both endothelium-dependent and endothelium-independent pathways. These rapid effects do not appear to involve changes in gene expression. Two mechanisms for the rapid vasodilatory effects of estrogens have been explored in some depth: effects on ion-channel function and effects on nitric oxide. At physiologic concentrations, estrogen stimulates the opening of calcium-activated potassium channels through a nitric oxide- and cyclic guanosine monophosphate-dependent pathway (White, R. E., et al.,
Circ Res
1995;77:936-42; Wellman, G. C., et al.,
Circ Res
1996;79:1024-30) thus relaxing smooth muscle and promoting vasodilatation. These rapid effects of estrogen on vascular cells could be mediated by a known estrogen receptor, perhaps located in the plasma membrane (Pappas, T. C., et al.,
FASEB J
1995;9:404-10) that is able to activate nitric oxide synthase rapidly in a nongenomic manner. This suggestion is consistent with the observations that estrogen-induced stimulation of nitric oxide synthase ac
Day Wesley W.
Lee Andrew G.
Thompson David D.
Benson Gregg C.
Crissey Todd M.
Pfizer Inc.
Reamer James H.
Richardson Peter C.
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