Combination of progesterone antagonists and antiestrogens with p

Details Combination of progesterone antagonists and antiestrogens with p Combination of progesterone antagonists and antiestrogens with p

1996-07-05

1998-02-17

Cook, Rebecca

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

514171, 514179, 514324, 514428, 514648, A61K 31565

Patent

active

057191360

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/EP94/03408 Oct. 17, 1994.
This invention relates to the use of at least one compound having a progesterone-antagonistic (PA) action, as well as at least one compound having an antiestrogenic (AO) action with a simultaneous partial agonistic action for the production of pharmaceutical agents for hormone substitution therapy for perimenopausal and postmenopausal women.
Upon entering menopause (climacteric period), so-called climacteric symptoms occur in women owing to altered hormone production. Because of the reduced estrogen production, the risk of osteoporosis (reduction of bone tissue while leaving the bone structure intact, due to increased bone degradation and/or reduced bone accretion) increases at the same time; also, in the case of postmenopausal women, a myocardial infarction rate that is considerably higher than that for premenopausal women, as well as a higher occurrence of other cardiovascular diseases are observed, which is also attributed to reduced estrogen production.
Hormone substitution therapy (hormone replacement therapy=HRT) with estrogens or with an estrogen/gestagen combination has been the standard method to date for treating the symptoms associated with menopause (Ernster VL et al. (1988): Benefits and Risks of Menopausal Estrogen and/or Progestin Hormone Use; Prev. Med. 17:201-223).
Estrogen exerts a protective action on the cardiovascular system, the bones (reduction of the risk of osteoporosis), and the central nervous system (avoidance of so-called "hot flushes"). In contrast, the long-term use of estrogens in hormone replacement therapy leads to an increased risk of developing an endometrial carcinoma (Ernster VL et al. (1988): Benefits and Risks of Menopausal Estrogen and/or Progestin Hormone Use; Prev. Med. 17:201-223).
The stimulating effect of estrogen on the endometrium is suppressed by the simultaneous use of a gestagen for hormone substitution therapy (Gibbson WE, 1986, Biochemical and Histologic Effects of Sequential Estrogen/Progestin Therapy on the Endometrium of Postmenopausal Women; Am. J. Obstet. Gynecol: 154:46-61); however, when combined therapy with an estrogen and gestagen is administered, the protective effects of the estrogenic components with respect to the plasma lipids are at least diminished (Lobo R. (1992): The Role of Progestins in Hormone Replacement Therapy; Am. J. Obstet. Gynecol. 166: 1997-2004).
In addition, because of the hormone dosage, which is reduced in comparison with an oral contraceptive agent, undesirable intracyclic menstrual bleeding occurs with estrogen/gestagen treatment (Hillard TC et al. (1992): Continuous Combined Conjugated Equine Estrogen-Progestagen Therapy: Effects of Medroxyprogesterone Acetate and Norethindrone Acetate on Bleeding Patterns and Endometrial Histologic Diagnosis; A. J. Obstet. Gynecol. 167: 1-7).
Finally, more recent findings show that some gestagens increase the risk of the development of breast cancer disease (Staffa J. A. et al. (1992): Progestins and Breast Cancer: An Epidemiologic Review; 57: 473-491); King R. J. B. (1991): A Discussion of the Roles of Estrogen and Progestin in Human Mammary Carcinogenesis; J. Ster. Biochem. Molec. Bio. 39: 8111-8118).
In summary, the picture arises that the known estrogen monotherapies as well as estrogen/gestagen combination therapies do not provide any satisfactory options for treating the symptoms associated with menopause.
Recently, the use of "true" antiestrogens for the production of pharmaceutical agents for hormone replacement therapy (HRT) has also been proposed (EP-A-0 178 862). "True" antiestrogens, according to EP-A-0 178 862, for example, are defined as tamoxifen, nafoxiden, MER-25, i.e., those antiestrogens that have a receptor-mediated effect and that simultaneously also have a partial estrogenic (agonistic) action.
A drawback to such a pharmaceutical agent that contains a "true" antiestrogen with partial estrogenic action is that because of the long-term estrogenic stimulation of the endometrium, as when estrogens are used, a higher risk

REFERENCES:
RN 96346-61-1 (Onapristone), 1992.

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