Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-08-22
2001-12-04
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S456000
Reexamination Certificate
active
06326366
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a composition and a method for reducing the risk of coronary heart disease, osteoporosis, loss of cognitive function, urinary incontinence, weight and fat mass gain, and vasomotor symptoms in women having a reduced level of endogenous estrogen. In particular, a combination of a mammalian estrogen and an isoflavone are used in a hormone replacement therapy regimen, where the isoflavone is incapable of being metabolized to equol by a human.
BACKGROUND OF THE INVENTION
Estrogen plays an important role in protecting the health of women. It has been implicated as a significant factor in protecting and maintaining cardiovascular health, bone mass, and mental cognition. The health protective effects of estrogen for women have been proposed as one of the reasons that women in the United States live an average of 7½ years longer than men. Women form 59% of the U.S. population over age 65 and 72% of the population over age 85.
A woman's endogenous level of estrogen is significantly reduced upon entering menopause or upon premature surgical menopause induced by removal of the uterus and/or ovaries. The amount of a woman's endogenous estrogen is typically reduced to less than 10% of premenopausal levels following natural or surgical menopause. This reduction of endogenous estrogen levels results in the loss of estrogen's health protective effects, particularly with respect to cardiovascular health, bone health, and mental cognition.
Cardiovascular disease is the leading cause of death in women. Compared to men, premenopausal women are relatively protected from cardiovascular disease by estrogen, but gradually lose this protection following menopause as estrogen levels decline. Patterns in Coronary Heart Disease—Morbidity and Mortality in the Sexes: A 26-Year Follow-Up of the Framingham Population, Lerner & Kannel,
Amer. Heart J.,
111: 383-90 (1986). The onset of cardiovascular disease is hastened in women by prematurely induced surgical menopause and its attendent reduction in endogenous estrogen levels. Time Interval from Castration in Premenopausal Women to Development of Excessive Coronary Atherosclerosis, Parrish, H. M. et al.,
Amer. J. Obst. Gynecol.,
99: 155-62 (1967).
Osteoporosis, while not a leading cause of mortality in post-menopausal women, is a substantial contributor to morbidity in such women. Osteoporosis is present in approximately one in four women over the age of 65, and typically develops after post-menopausal reduction of endogenous estrogen. Loss of bone mineral density, the key indicator of osteoporosis, is also hastened by prematurely induced surgical menopause and its attendent reduction in endogenous estrogen levels. Relative Contributions of Aging and Estrogen Deficiency to Postmenopausal Bone Loss, Richeson, L. S. et al., N.
Eng. J. Med.,
311: 1273-75 (1984).
Loss of cognitive function is also significantly more likely to occur in postmenopausal women as a result of the loss of the protective effects of estrogen. Loss of cognitive function is associated with decreased choline acetyltransferase (“ChAT”) and the loss of cholinergic neurons. Estrogen has been identified as an agent which upregulates ChAT production, thereby inhibiting the loss of cognitive function associated with decreased ChAT. Ovarian Steroid Deprivation Results in a Reversible Learning Impairment and Compromised Cholinergic Function in Female Sprague-Dawley Rats, Singh et al.,
Brain Research,
644: 305-12 (1994).
The reduction of endogenous estrogen as a result of natural or surgical menopause also has other deleterious health effects. Reduced estrogen levels have been implicated in the development of urinary incontinence as a result of the effect of the loss of estrogen on the smooth muscle cells of the urethra. Reduced estrogen levels are also implicated in significant weight and fat mass gain in postmenopausal women. Impact of Hormone Replacement Therapy on the Body Mass and Fat Compositions of Menopausal Women: A Cross-Sectional Study, Sayegh, R. et al.,
Menopause,
Vol. 6, No. 4, 312-15 (1999).
Hormone replacement therapy is currently utilized as a treatment to increase the level of estrogen in women having reduced levels of endogenous estrogen resulting from natural or surgical menopause. Supplemental estrogen is provided to the women in order to inhibit, ameliorate, or prevent diseases or conditions which result from the reduction of endogenous estrogen.
The estrogen provided in hormone replacement therapy is particularly useful to ameliorate the diseases and conditions noted above-cardiovascular disease and coronary heart disease, osteoporosis, declining mental cognition, urinary incontinence, and weight and fat mass gain in postmenopausal women, as well as inhibiting vasomotor symptoms resulting from a reduction in endogenous estrogen such as hot flush. Administration of unopposed conjugated estrogen has been found to reduce the relative risk of coronary disease in postmenopausal women to a level of 0.41 to 0.56 that of untreated postmenopausal women. Estrogen Replacement Therapy and Coronary Disease: A Quantitative Assessment of the Epidemiological Evidence, Stampfer & Colditz,
Prev. Med,
20: 47-63 (1991). Unopposed estrogen has been shown to prevent menopausal bone loss at a number of skeletal sites, and tends to maintain bone mass at the level present when administration is initiated. Long Term Prevention of Post-Menopausal Osteoporosis by Estrogen, R. Lindsay et al.,
Lancet,
1: 1038-41 (1976); HRT and Osteoporosis, J. Compston,
Brit. Med Bull.,
48: 304-44 (1992). As a result, estrogen is regarded as a first-line therapy for postmenopausal women having reduced bone mineral density. Treatment of postmenopausal women with unopposed estrogen has also been shown to have beneficial effects on cognitive function by maintaining short term memory and ameliorating clinical symptoms of Alzheimer's disease. The Influence of Estrogens On the Psyche In Climacteric and Post-Menopausal Women, Furuhjelm & Fedor-Freybergh,
Consesus on Menopause Research,
Van Keep, Greenblatt, & Albeaux-Fernet (eds.), University Park Press, Baltimore, 84-93 (1976); Estrogen and/or Androgen Replacement Therapy and Cognitive Functioning in Surgically Menopausal Women, B. Sherwin,
Psychoneuroendocrinology,
13: 345-47 (1988); Estrogen and Memory in Postmenopausal Women; B. Sherwin, Third Annual Meeting, North American Menopause Society, 50 (1992); Senile Dementia-Alzheimer's Type and Estrogen, Honjo et al.,
Hormone Metab. Res.,
27: 204-07 (1995). Hormone replacement therapy is also indicated to treat vasomotor symptoms such as hot flush, which are associated with a decrease in endogenous estrogen levels in women. Determining the Role of Long-Term Hormone Therapy After Menopause in the Context of Primary Preventive Health Care for Women, Wolf H. Utian,
Menopause,
Vol. 3, No.2, 65-70 (1996).
Unfortunately, administration of unopposed estrogen to postmenopausal women presents serious health risks. Estrogen has a stimulatory effect on the growth of uterine and breast tissues, and treatment of postmenopausal women with estrogen is associated with significant increases in uterine and breast cancer. Unopposed estrogen users are 3-6 times more likely than non-users to develop endometrial cancer after 3-10 years of use, and are 10 times more likely to develop endometrial cancer after 10 years of use. Hormone Replacement and Cancer, E. Barrett-Conner,
Brit. Med. Bull.,
48:345-55 (1992). Administration of estrogen over a long period of time, e.g. 10-15 years, is associated with a 30-50% increase in the risk of breast cancer, although short term administration of estrogen, e.g. less than 5 years, appears to have no adverse effects. Selective Estrogen Receptor Modulators, Kauffman & Bryant,
DN&P,
8(9): 531-539 (November 1995).
Currently prescribed hormone replacement therapies utilize a progestin which is co-administered with estrogen to limit the estrogen's uterine stimulatory effects, thereby reducing the risk of
Henley Edna C.
Potter Susan M.
Taylor Richard B.
Protein Technologies International
Reamer James H.
Taylor Richard B.
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