Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-29
2001-10-02
Jordan, Kimberly (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252010, C514S254080, C514S267000, C514S299000, C514S334000, C514S874000
Reexamination Certificate
active
06297243
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a pharmaceutical composition, to use of luteinizing hormone (LH) antagonists for preparing a medicament for treatment of hot flushes or hot flashes (i.e., menopausal vaso-motor symptoms), to use of LH antagonists for preparing a medicament for treatment of estrogen deficiencies, to use of LH antagonists for preparing a medicament for decreasing the loss of follicles during the pre- and per-menopausal period, thereby deferring the onset of menopause and consequently the symptoms related to lack of estrogen. Furthermore the invention relates to use of LH antagonists for preparing a contraceptive.
BACKGROUND OF THE INVENTION
The mammalian female is born with a fixed and subsequently decreasing number of meiotically arrested oocytes in the ovaries. Oocytes encompassed by a single layer of flattened epithelial cells form primordial follicles and constitute the fixed resting pool of oocytes in the ovaries from which oocytes are recruited throughout the reproductive life. An unknown signal triggers a cohort of the primordial follicles to develop into primary, secondary and ultimately Graafian follicles.
Approximately one million primordial follicles is present in a human ovary in a newborn. The functional activity of the human ovary depends on the size of the follicle store. It has been speculated that a threshold exist of approximately 1000-2000 oocytes that mediates the onset of menopause or cessation of cyclic activity in the ovary (Gosden, 1996, Serono Symposium, Leeds).
The primordial follicles do not posses receptors for follicle stimulating hormone (FSH) or luteinizing hormone (LH); however, once the growing follicles have reached a certain size, gonadotropins are the major players that controls growth and ovulation. Early in reproductive life the primordial follicles are lost from the ovary at a relative constant rate. Around 35-40 years of age the rate of disappearance apparently accelerates. The reason for this dramatic loss is unknown.
The osteopenia that accompanies the menopause continues to represent a major public health problem. Left unchecked, the cumulative loss of bone can potentially compromise the skeleton's structural integrity, resulting in painful and debilitating fractures of the wrist, spine and femur. Efforts to reduce the risk and incidence of fractures have focused on the development of therapies that conserve skeletal mass by inhibiting bone resorption. Among various treatment modalities, estrogen remains the preferred means to prevent the development of post menopausal osteoporosis (Lindsey R, Hart D M, MacClean A 1978, “The role of estrogen/progestogen in the management of the menopause”, Cooke I D, ed, Proceedings of University of Sheffield symposium on the role of estrogen and progestogen in the management of the menopause, Lancaster, UK: MTP Press Ltd. pp. 9-25; Marshall D H, Horsmann A, Nordin BEC1977, “The prevention and management of post-menopausal osteoporosis.”, Acta Obstet Gynecol Scand (Suppl) 65:49-56; Recker R R, Saville P D, Heaney R P 1977, “Effect of estrogen and calcium carbonate on bone loss in post-menopausal women”, Ann Intern Med. 87:649-655; Nachtigall L E, Nachtigall R H, Nachtigall R D, Beckman E M 1979, “Estrogen replacement therapy”, Obstet Gynecol. 53:277-281) and it is now accepted that estrogens significantly decrease fracture incidence and risk (Krieger N, Kelsey J L, Holford T R, O'Connor T 1982, “An epidemiological study of hip fracture in postmenopausal women”, Am J Epidemiol. 116:141-148; Hutchinson T A, Polansky S M, Feinstein A R 1979, “Post-menopausal estrogens protect against fractures of hip and distal radius: A case-control study”, Lancet 2:705-709; Paginini-Hill A, Ross R K, Gerkins V R, Henderson B E, Arthur M, Mack T M 1981, “Menopausal oestrogen therapy and hip fractures”, Ann Intern Med. 95:28-31; Weiss N S, Ure C L, Ballard J H, Williams A R, Daling J R 1980, “Decreased risk of fractures on the hip and lower forearm with post-menopausal use of estrogen”, N Eng J Med. 303:1195-1198).
While the beneficial actions of estrogen on the skeleton are clearly significant, there is also considerable evidence for a positive effect of estrogen on the cardiovascular system. Previous studies have attributed these actions to estrogen's effects on serum lipids, but recent data has now shown that in addition to the effects on the lipid profile, estrogen can also directly influence vessel wall compliance, reduce peripheral resistance and prevent atherosclerosis (Lobo R A 1990, “Cardiovascular implication of estrogen replacement therapy”, Obstetrics and Gynaecology, 75:18S-24S; Mendelson M E, Karas R H 1994, “Estrogen and the blood vessel wall”, Current Opinion in Cardiology, 1994(9):619-626). Based on available epidemiological data, the overall impact of these physiological and pharmacological actions of estrogen is an age independent reduction in cardiovascular mortality and morbidity in women (Kannel W H, Hjortland M, McNamara P M 1976 “Menopause and risk of cardiovascular disease: The Framingham Study”, Ann Int Med, 85:447-552). Furthermore, a more recent analysis has concluded that post-menopausal estrogen treatment reduces the risk of cardiovascular disease by approximately 50 percent (Stampfer M J, Colditz G A 1991, “Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiological evidence”, Preventive Medicine, 20:47-63.).
In addition to the positive effects of estrogen on bone and cardiovascular system, there is now data which indicate that the central nervous system can benefit from estrogen. Short term studies in human subjects have shown that increased levels of estrogen are associated with higher memory scores in post menopausal women (Kampen D L, Sherwin B B 1994, “Estrogen use and verbal memory in healthy postmenopausal women”, Obstetrics and Gynecology, 83(6):979-983). Furthermore, the administration of exogenous estrogen to surgically post menopausal women specifically enhances short-term memory. Moreover, the effects of estrogen on cognition do not appear confined to short-term effects as epidemiological findings indicate that estrogen treatment significantly decreases the risk of senile dementia-Alzheimers type in women (Paganini-Hill A, Henderson V W, 1994, “Estrogen deficiency and risk of Alzheimer's disease in women”, Am J Epidemiol, 140:256-261; Ohkura T, Isse K, Akazawa K, Hamamoto M, Yoshimasa Y, Hagino N, 1995, “Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer Type: 7 case reports”, Dementia, 6:99-107). While the mechanism whereby estrogens enhance cognitive function is unknown, it is possible to speculate that the direct effects of estrogen on cerebral blood flow (Goldman H, Skelley E b, Sandman C A, Kastin A J, Murphy S, 1976, “Hormones and regional brain blood flow”, Pharmacol Biochem Rev. 5(suppl 1):165-169; Ohkura T, Teshima Y, Isse K, Matsuda H, Inoue T, Sakai Y, Iwasaki N, Yaoi Y, 1995, “Estrogen increases cerebral and cerebellar blood flows in postmenopausal women”, Menopause: J North Am Menopause Soc. 2(1)13-18) and neuronal cell activities (Singh M, Meyer E M, Simpkins J W, 1995, “The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats”, Endocrinology, 136:2320-2324; McMillan P J, Singer C A, Dorsa D M, 1996, “The effects of ovariectomy and estrogen replacement on trkA and choline acetyltransferase mRNA expression in the basal forebrain of the adult female Sprague-Dawley rat”, J Neurosci., 16(5):1860-1865) are potential effectors for these beneficial actions.
The beneficial effect of a prolonged stage of naturally occurring estrogens as a consequence of deferring the menopause are not limited to the chronic conditions described above. Indeed, the more traditional applications of estrogen therapies would include the following: relief of menopausal symptoms (i.e. flushing and urogenital atrophy); oral
Jordan Kimberly
Novo Nordisk A S
Rozek Carol E.
Zelson Steve T.
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