Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-04-13
2003-11-25
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S179000, C514S324000, C514S651000
Reexamination Certificate
active
06653297
ABSTRACT:
BACKGROUND OF THE INVENTION
The use of estrogens in the course of treatment of a variety of conditions is well known. For example, the most prevalent form of oral contraception is the so-called combined oral contraceptive preparation, a pill that combines both estrogen and a progestin. Apparently, the progestin acts foremostly to block gonadotropin release while the estrogen component primarily provides endometrial control to diminish breakthrough bleeding. Another well-known use is long term estrogen replacement therapy which is common for post-menopausal and other estrogen deficient women. Other estrogen dependent conditions include endometriosis, uterine fibroid tumors (leiomyomata), pre-menstrual syndrome, dysfunctional uterine bleeding, breast tumors (benign and malignant) and the like.
Despite their value, estrogen treatments are also associated with undesirable side effects. For example, estrogen therapy has been associated with an increased incidence of endometrial cancer, especially due to the continual “unopposed” estrogen-induced proliferation of the endometrium. Other side effects include uterine bleeding and cyclotherapeutic withdrawal menstrual bleeding during a time in their lives when many women welcome cessation of menstrual bleeding as a normal occurrence in menopause. Estrogen therapy has also been implicated in the development of a variety of disorders including gallbladder disease, hypertension, abnormal glucose tolerance, hypercoagulable states and breast cancer, although some of these observations are antidotal in nature and have not been confirmed.
There have been numerous efforts to counteract the ill effects of estrogen therapy. For instance, attempts have been made to couple estrogen therapy with short periods of anti-estrogen supplementation. Another approach is to use anti-estrogens in place of the estrogen. Certain compounds are known as “anti-estrogens” because they can bind to the estrogen receptors and competitively block the binding of the more potent estrogens such as estradiol. Among the best known of these anti-estrogens are clomiphene and tamoxifen. However, all such anti-estrogens can be, in fact, active estrogens depending on the tissue, dose/regimen and hormonal milieu of the drug exposure. These are mixed function agonistic/antagonistic activities. The degree to which the anti-estrogen acts as an estrogen also depends on the particular material and the tissue site.
While anti-estrogen therapy has been successful, it is not without its own problems. As is know, there is a hypothalamic-pituitary-gonadal axis involved in endogenous hormone production. As estrogen binds to its receptors, there is a feedback mechanism which regulates the endogenous production of pituitary gonadotropins and, in turn, estrogen so that the hormonal milieu remains within the physiological range. When an anti-estrogen binds to the estrogen receptors, altered estrogen feedback mechanisms are implicated in a pharmacological manner compared to when estrogen binds normally. The anti-estrogens themselves can induce multiple follicular growth which, in turn, causes the production of endogenous ovarian estrogens. A favorable example is the use of clomiphene for ovulation induction. For the first anti-estrogen dose administration and continuing for some period of time, the endogenous estrogen produced as a consequence of the multiple follicular growth may not appear to pose a problem. However, at some point, which is totally unpredictable and which varies from individual to individual, endogenous estrogen can be produced such that the quantity of estrogen present can elevate blood levels well above 300 pg/ml. Indeed, estradiol concentration in plasma may exceed a few thousand in some instances. Therefore, while the use of an anti-estrogen seeks to reduce or modify or eliminate the side effects of estrogen, its use over time may have the reverse effect by inducing an excess concentration of estrogen. Not only may the use of the anti-estrogen exaggerate the estrogen side effects which it seeks to avoid, but the anti-estrogen may also even eliminate the primary benefit of the administration in the first instance. For example, a “run away” endogenous estrogen can induce ovulation in those situations where the administration of the anti-estrogen was designed to provide contraception. This feature of anti-estrogen therapy makes the establishment and maintenance of appropriate dosages of anti-estrogen difficult and in some cases impossible, especially when the therapeutic goal is simultaneous to limit excessive estrogenic impact in one tissue, while itself providing adequate estrogenic stimulation in another tissue.
It is therefore the object of the present invention to keep the hypothalamus and pituitary from becoming deranged and thereby prevent multiple follicular growth and the endogenous estrogen sustained, supraphysiological elevations which result from ovarian hyperstimulation. This and other objects of the invention will become apparent to those of ordinary skill in the art from the following detailed description.
SUMMARY OF THE INVENTION
This invention relates to a method of using a SERM such as clomiphene, for instance, pre- and postmenopausally, e.g., in hormone replacement therapy to prevent osteoporosis, cardiovascular disease and breast cancer, as well as preventing the hypothalamus and pituitary from operating in a deranged manner during any SERM therapy. More particularly, the invention involves superposing upon the use of a selective estrogen receptor modulator, the co-administration of a compound progestationally active to women, either of reproductive age women who are pre-menopausal or who are post-menopausal. The progestationally active compound may also exhibit androgenic activity or an androgenically active compound can be coadmistered.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, an additional hormonal therapy is superposed upon the use of a selective estrogen receptor modulator (also known as a SERM, selective estrogen or anti-estrogen) in the known use of the SERM, for instance, as in treating or controlling an estrogen sensitive condition. Estrogen sensitive conditions include, but are not limited to, contraception, hormone replacement therapy, endometriosis, leiomyoma, dysfunctional uterine bleeding, premenstrual syndrome, hormonal dependent cancers, such as those of the breast, endometrial and ovarian, and the like. Some SERMs have been indicated for the prevention of post-menopausal osteoporosis, modulation of serum lipid profiles and breast cancer prevention.
Any known SERM can be used in the practice of this invention for its known utility in the treatment or modification of a medical condition in mammals. Examples of known SERMs include, but are not limited to, clomiphene; cycladiene; tamoxifen; nafoxidine; nitromifene citrate (N-55,945-27); 13-ethyl-17&agr;-ethynl-17&bgr;-hydroxygona-4-9-11-trien-3-one (R2323); diphenol hydrochrysene; erythro-MEA; allenolic acid; cyclofenyl; chlorotrianisene; ethamoxytriphetol; triparanol; CI-626; CI-680; MER-25; U-11,555A; U-11,100A; ICI-46,669; ICI-46,474; CN-55,945; compounds of the formula:
where R
1
is hydrogen, an aromatic group or alkyl of preferably no more than nine carbon atoms, R is an aromatic or alkyl group of preferably no more than nine carbon atoms and various of their derivatives; the triphenyl compounds described in U.S. Pat. No. 2,914,563 which are of the formula:
wherein one of the R groups is a basic ether of the formula OC
n
H
2n
A in which n is 2, 3 or 4 and A is a C
1-4
dialkylamino group, N-piperidyl or &bgr;-morpholinyl and the other R and R
1
are hydrogen, halogen or methoxy while X is halogen; as well as benzothiophenes such as those described in U.S. Pat. No. 5,624,940 of the formula:
in which R
1
and R
3
are independently hydrogen, C
1−4
alkyl, —CO(C
1-6
alkyl) or —COAr in which Ar is optionally substituted phenyl, R
2
is pyrrolidino, hexamethyleneamino or piperidino, or a salt thereof. Example of the benzothiophenes include ralo
Dickstein Shapiro Morin & Oshinsky LLP.
Medical College of Hampton Roads
Travers Russell
LandOfFree
Control of selective estrogen receptor modulators does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Control of selective estrogen receptor modulators, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Control of selective estrogen receptor modulators will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3184198