Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-08-07
2001-07-24
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S182000, C514S800000, C514S171000, C514S899000
Reexamination Certificate
active
06265393
ABSTRACT:
INTRODUCTION
1. Technical Field
The present invention relates to the coadministration of an estrogen agent and a progestin agent in low doses for the long-term prevention of endometriosis signs or symptoms.
2. Background
Many women, approximately 5-10 percent of those in their reproductive years, are afflicted with endometriosis and suffer progressive, disabling dysmenorrhea and pelvic pain around the time of their menses (Brosens, Endometriosis-A Disease Because it is Characterized by Bleeding,
Am. J. Obstet. Gynecol
. 176:263-7 (1997)). In addition, pelvic pain unassociated with menses may restrict afflicted women to measured participation in athletic and other physical activities, such as dancing and hiking. Through dyspareunia, they suffer not only the pain and often-missed orgasmic fulfillment, but also the doubts of sincerity and the cautious love of their sexual partners, perhaps even marital discord, separation, or infertility. Through relative infertility, they suffer further reductions in self-esteem from the pangs of guilt and failure engendered by struggles to conceive, suffering that adds personal, physical, and economic cost. Often, coital events or pelvic exams produce pelvic aching for hours or even days thereafter.
The peri-menstrual pain experienced by afflicted women may be relieved in part by non-steroidal anti-inflanmmatory drugs (NSAID's). But those not benefitted adequately require ovulation-suppressing treatments, or finally laparoscopy, where the majority are discovered to have the findings typical of endometriosis, i.e., ectopic ‘implants’ of endometrial tissue on the peritoneal surface of the pelvis or extra-genital areas. Others with unexplained infertility have similar findings.
The current concept of this disease is that endometrial glands and stroma are shed through Fallopian tubes during menstruation, after which they implant onto the peritoneum, and initiate growth. Initially, the existence of translocated endometrial cells can only be proven microscopically on the peritoneal lining of the pelvis, or even at extra-pelvic sites such as the diaphragm in the upper abdomen (Murphy et al., Unsuspected Endometriosis Documented by Scanning Electron Microscopy in Visually Normal Peritoneum,
Fert. and Sterility
46: 522-524 (1986)). But the occurrence of regular, menstrual bleeding at those sites over time leads to angiogenesis and growth of visible lesions where none had been visible before, and pain and infertility that develop from the bleeding at, and into those sites (Brosens). Symptoms usually subside during pregnancy and lactation, after castration premenopausally, and as the hypoestrogenemia of the peri-menopause develops. Endometriosis is a life-long, genetically facilitated, pathological condition that may be stimulated at any age by unopposed estrogen therapy to produce recurrent symptoms.
This retrograde menstruation concept as the initiator of the disease of endometriosis is consistent with clinical observations that amenorrhea, the lack of uterine bleeding (and presumed concomitant failure of the ectopic lesions to bleed), is therapeutic for endometriosis. Astute physicians first noted in the 1920's, that castration was therapeutic. In the 1930's, they recognized that pregnancy, with its gestational and lactational amenorrhea, often provided relief from cyclic pelvic pain for months thereafter, but that recurrence was frequent.
In the late 1950's, the continuous coadministration of 19-norsteroids and estrogen emerged as a medical treatment of endometriosis. Regimen of increasing doses for 3-4 months duration, or longer, were found effective for creating a “pseudopregnancy” (Kistner, The use of newer progestins in the treatment of endometriosis,
Am. J. Obstet. and Gynecol
. 75: 265-278 (1958); Andrews et al., Effects of progestin-induced pseudopregnancy on endometriosis: clinical and microscopic studies,
Am. J. Obstet. and Gynecol
. 78: 776-785 (1959)). This treatment also provided a high incidence of amenorrhea, and temporary relief thereafter, but its use was limited by the severe side-effects from the very large doses of the agents necessary to suppress the ovarian cycle and the endometrium.
Application of low-dose oral conceptives in the present invention is different from prior indications in which such agents are administered cyclically and electively to young women for contraception, or in which such agents are administered without interruption to postmenopausal women for hypoestrogenemia. While estrogen agents and progestin agents have been coadministered to reproductive age women before, such agents have been coadministered on a cyclic basis for contraception. Such agents have been coadministered continuously as a postmenopausal hormone replacement therapy, but the women receiving such therapy are past reproductive age. Studies in which a woman's response to oral contraceptives was used to diagnose or treat endometriosis suggested little benefit in the prevention of endometriosis symptoms and long-term hormonal suppression was disfavored (Metzger et al., Hormonal Therapy of Endometriosis,
Endometriosis
16: 105-122 (1989)). Several studies suggested that added pseudopregnancy induced by high dose oral contraceptives was detrimental (Metzger et al.; Wheeler et al., Combined Medical and Surgical Therapy for Endometriosis,
Current Concepts in Endometriosis
p. 281-288, 1990 Alan R. Liss, Inc.). In all of such “pseudopregnancy” studies, oral contraceptives were administered to reproduce the symptoms and signs of endometriosis until amenorrhea was achieved. The common practice was to then discontinue treatment and observe the patient for the recurrence of symptoms. Intolerance to pseudopregnancy regimen, producing side effects such as abdominal swelling, depression, breast tenderness, increased appetite, weight gain and edema, breakthrough bleeding, nausea, breast secretion, and vein varicosity was the most common reason for discontinuation. Thus, physicians have historically been reluctant to treat endometriosis with continuous regimen of oral contraceptives. Prior to this invention, low doses of estrogen agents and progestin agents have never been coadministered continuously and prophylactically following other therapeutic regimen that produce amenorrhea, for preventing the recurrence of symptoms and signs of endometriosis in reproductive age women.
Another therapeutic approach with a synthetic, progestational androgen, danazol, has been used successfully for producing a “pseudomenopause” during a six month treatment schedule (Henzl for the Nafarelin Group, Administration of Nasal Nafarelin as Compared with Oral Danazol for Endometriosis-a Multi-Center, Double-Blind, Comparative Clinical Trial,
N. Eng. J. Med
. 318: 385-9 (1988)). This descriptive term was advanced because the drug reduced circulating estrogen levels and produced amenorrhea in the majority of treated women. The side-effects of masculinization and liver damage restricted the widespread use of danazol.
At about the same time, the oral or parenteral treatment of women with pelvic pain from endometriosis with 6-medroxy-progesterone, a widely used synthetic progestin, was found in high doses to reduce the severity of pelvic pain. Emotional depression, bloating, and weight gain resulting from the large doses necessary to achieve the relief of pain doomed these medical therapeutic approaches to disuse (Hornstein et al., A Randomized, Double-blind Trial of 3 versus 6 Months of Nafarelin Therapy for Endometriosis-associated Pelvic Pain,
Fertility and Sterility
, 63:955-62 (1995)).
The next pharmacological advance for endometriosis therapy was the synthesis and formulation of gonadotropin-releasing hormone agonists (GnRH-agonist) which act at the hypothalamus and hypophysis to suppress the gonadotropin-mediated, ovarian secretion of estrogen (Henzl et al.). The condition so induced was labeled as a “pseudo-ovariectomy”. As a consequence of the resulting hypoestrogenemia, the endometrium becomes atrophic, and amenorrhea occurs promptly for 80-90
Cooley & Godward LLP
Webman Edward J.
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