Safety and efficacy of the selective progesterone receptor modulator asoprisnil for heavy menstrual bleeding with uterine fibroids: pooled analysis of two 12-month, placebo-controlled, randomized trials.

STUDY QUESTION: Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER: Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY: In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION: In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE: In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66-78% in the asoprisnil 10-mg group and 83-93% in the asoprisnil 25-mg group, significantly higher than with placebo (3-12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to -48% and -28%, respectively) and 25 mg (median changes up to -63% and -39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION: Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS: Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women's Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER: NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT'S ENROLMENT: 12 September 2002; 6 September 2002.

Randomized phase II study of lonaprisan as second-line therapy for progesterone receptor-positive breast cancer.

BACKGROUND: The progesterone-receptor (PR) antagonists onapristone (type I) and mifepristone (type II) showed modest activity in hormone-receptor-positive breast cancer; however, onapristone in particular was associated with hepatotoxicity. Lonaprisan is a novel, type III PR antagonist that was well tolerated in phase I studies. PATIENTS AND METHODS: This randomized, open-label, phase II study evaluated the efficacy and tolerability of lonaprisan as second-line endocrine therapy in postmenopausal women with stage IV, PR-positive, HER2-negative, metastatic breast cancer. RESULTS: Patients received once-daily lonaprisan 25 mg (n = 34) or 100 mg (n = 34). The primary objective was not met (≥ 35% clinical benefit rate: complete/partial responses at any time until month 6 or stable disease [SD] for ≥ 6 months from start of treatment). There were no complete/partial responses. In the 25 mg and 100 mg groups, 6 of 29 patients (21%) and 2 of 29 patients (7%), respectively, had SD ≥ 6 months. Overall, 61 of 68 patients (90%) had ≥ 1 adverse event (AE), the most frequent (≥ 10% overall) being fatigue, hot flush, dyspnoea, nausea, asthenia, headache, constipation, vomiting, and decreased appetite; 33 patients had serious AEs. CONCLUSION: Lonaprisan showed limited efficacy as second-line endocrine therapy in postmenopausal women with PR-positive metastatic breast cancer.

A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer.

BACKGROUND: 2-methoxyestradiol (2ME2) is an estradiol-17ß metabolite with antiproliferative and antiangiogenic activities. ENMD-1198 is an analog of 2ME2 which was developed to decrease the metabolism and increase both the bioavailability and antitumor activities of the parent molecule. This first-in-human phase I study evaluated the tolerability, pharmacokinetics and preliminary evidence of activity of ENMD-1198 in advanced cancer patients. METHODS: Eligible patients received ENMD-1198 orally once daily in Part A (standard 3 + 3 dose escalation design), or in Part B (accelerated dose escalation design). Cycle 1 consisted of 28 days daily dosing followed by a 14-(Part A) or 7-(Part B) day observation period, then continuously in 28 day cycles thereafter. RESULTS: A total of 29 patients were enrolled in 12 dose cohorts (5 to 550 mg/m²)/d). The most common drug-related toxicities were Grade 1/2 fatigue (55%), nausea and vomiting (37%), and constipation (34%). Two DLTs (Grade 4 neutropenia) occurred at 550 mg/m²/day, and 425 mg/m²/d was declared the maximum tolerated dose. ENMD-1198 was absorbed rapidly with a T(max) of 1-2 h. Exposure to ENMD-1198 (C(max) and AUC0₋24 hr increased linearly with dose. The mean terminal half-life was 15 h. A 3-fold accumulation was found after multiple doses. Five patients achieved stabilization of disease for at least 2 cycles, three of whom (with neuroendocrine carcinoma of pancreas, prostate cancer and ovarian cancer) demonstrated prolonged stabilization ranging from 8-24.5 cycles. CONCLUSION: ENMD-1198 is well-tolerated with a pharmacokinetic exposure profile compatible with once daily dosing. The recommended phase II dose of ENMD-1198 is 425 mg/m²/d. Early evidence of prolonged disease stabilization in pre-treated patients suggests ENMD-1198 is worthy of additional investigation.

Effects of the progesterone receptor antagonist aglepristone on implantation administered on days 6 and 7 after mating in rabbits.

There is no safe and accurate method for early termination of pregnancy in the rabbit. So this study was carried out to determine the effect of aglepristone administration in preventing early pregnancy before implantation in this species. Twenty-two animals (10-12 months old, New Zealand White rabbits) were naturally mated and pregnancies were confirmed in all animals by ultrasonographic examinations on day 6 after mating (5-7.5 MHz linear array transducer Dynamic Imaging Sonostar, UK) and the animals were grouped randomly: Group I & Group III: Aglepristone (Alizin, Virbac; 10 mg/kg, subcutaneously) was injected twice, 24 h apart, on days 6 and 7 after mating (n = 5; n = 8). Group II & Group IV: The same volume of 0.9% NaCl solution was subcutaneously injected in the same interval and served as controls (n = 5; n = 3). Ultrasonographical examination of the uterus was performed daily from day 7 to day 11 post-mating to test aglepristone efficiency. Blood samples were collected between days 6 and 30, centrifuged at 3070 g for 10 min and stored at -20 degrees C. The does in aglepristone groups (Group I, III) were not pregnant whereas all animals in control groups were pregnant (Group II, IV). The does in group I & III were examined only clinically and ultrasonographically; however, does in groups III and IV were laparomized on days 6, 7, 9 and 11 post-mating to control countable implantation sites. No implantation sites were present in group III whereas they were seen obviously in group IV. Side effects were not observed. The mean serum progesterone (P4) concentrations were not significantly different between control and treated does (p > 0.05). The results indicate that aglepristone treatment on days 6 and 7 after mating could prevent pregnancy after unwanted matings without any side effects in the rabbit. Aglepristone treatments are possibly not affecting further fertilities before implantation.

Age-related pregnancy results and further examination of bitches after aglepristone treatment of pyometra.

The cystic endometrial hyperplasia and pyometra complex is one of the most common uterine diseases in bitches. The appearance of pharmacological preparations containing anti-progestagens created new possibilities for pyometra treatment. The aim of this study was to evaluate the curative effect of the anti-progestagen aglepristone treatment of pyometra in bitches of different ages. Twenty four bitches of different breeds, aged from 0.8 to 9.5 years (21-48 kg) exhibiting clinical pyometra symptoms (two groups - I < or = 5 years, n = 14 and II >5 years, n = 10) were evaluated. Information about the general reproductive health was collected up to 54 months after anti-progestagen treatment. Remission of clinical symptoms and return of blood chemistry results and total leucocyte count to referential values were achieved in all cases within 14 days of treatment. Bitches were naturally mated at the first, and when unsuccessful, the second oestrus after treatment. In group I, no recurrence of pyometra symptoms was observed during following cycle(s). Eight bitches (57.1%) had a full-term pregnancy and the number of newborn pups ranged from 1 to 12. None of the bitches from the group II became pregnant. In conclusion, the basic indication for conservative pharmacological treatment of pyometra is preserving female fertility and obtaining offspring. The important conditions for successful aglepristone treatment are: the young age (up to 5 years) and the lack of detectible ovarian cysts. It seems necessary to mate bitches in the first or second oestrus after finishing treatment. The efficacy of treatment can be measured by the after-treatment pregnancy rate.

Daily Oral Administration of the Novel Androgen 11ß-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men.

BACKGROUND: 11ß-methyl-19-nortestosterone (11ß-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11ß-MNT dodecylcarbonate (11ß-MNTDC), was well tolerated in healthy men. METHODS: We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18-50 years) were randomized to receive oral placebo or 11ß-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11ß-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires). RESULTS: There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11ß-MNTDC resulted in a dose-related increase in serum 11ß-MNTDC and 11ß-MNT concentrations sustained over 24 hours. Administration of 11ß-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P < 0.01). Adverse effects that may be related to 11ß-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11ß-MNTDC groups. CONCLUSION: Daily oral 11ß-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11ß-MNTDC as a potential male oral contraceptive.

EC313-a tissue selective SPRM reduces the growth and proliferation of uterine fibroids in a human uterine fibroid tissue xenograft model.

Uterine fibroids (UFs) are associated with irregular or excessive uterine bleeding, pelvic pain or pressure, or infertility. Ovarian steroid hormones support the growth and maintenance of UFs. Ulipristal acetate (UPA) a selective progesterone receptor (PR) modulator (SPRM) reduce the size of UFs, inhibit ovulation and lead to amenorrhea. Recent liver toxicity concerns with UPA, diminished enthusiasm for its use and reinstate the critical need for a safe, efficacious SPRM to treat UFs. In the current study, we evaluated the efficacy of new SPRM, EC313, for the treatment for UFs using a NOD-SCID mouse model. EC313 treatment resulted in a dose-dependent reduction in the fibroid xenograft weight (p < 0.01). Estradiol (E2) induced proliferation was blocked significantly in EC313-treated xenograft fibroids (p < 0.0001). Uterine weight was reduced by EC313 treatment compared to UPA treatment. ER and PR were reduced in EC313-treated groups compared to controls (p < 0.001) and UPA treatments (p < 0.01). UF specific desmin and collagen were markedly reduced with EC313 treatment. The partial PR agonism and no signs of unopposed estrogenicity makes EC313 a candidate for the long-term treatment for UFs. Docking studies have provided a structure based explanation for the SPRM activity of EC313.

Evaluation of an alternative treatment protocol by aglepristone to induce parturition in ewes with an experimental model of early pregnancy toxemia.

A new protocol with aglepristone to induce parturition in ewes with pregnancy toxemia has been reported in the present manuscript. Four experimental groups were defined: Group AG5 (n = 10), Group DEX (n = 10), Group NC (n = 5) and Group PT (n = 5) in which ewes were injected twice with 10 mg/kg of aglepristone and 5 ml dexamethasone in first two groups, respectively; whereas negative control and pregnancy toxemia groups received no treatment for parturition induction. Different clinical parameters associated with parturition in ewes and their newborns were investigated. Blood hematology and biochemical measurements were carried out both in ewes and lambs. Blood pH values of lambs were recorded during the study. The injection time-lambing time, injection time-vaginal discharge intervals, placental expulsion periods, placental weight and vaginal delivery interval between lambs, hematological and biochemical results were not statistically different among the groups (p > 0,05). Increased NEFA and ß-HBA concentrations accompanied the disease and all ewes in AG, DEX and PT Groups developed clinical pregnancy toxemia (NEFA; P = 0,009) and ß-HBA; (P = 0,039). The differences in rectal body temperature of lambs were not significant (p > 0,05), whereas birth weight was found statistically significant among groups (p < 0,05). Blood pH, biochemical and hematologic measurements of lambs had also significant differences depending on different time points. Parturition pathology by means of incomplete cervical dilatation was severely observed in DEX Group. The results of this study show that aglepristone application in pregnancy toxemia to induce parturition could precisely control lambing time without any side effects in either mothers or lambs. Apart from these, it could be speculated that dexamethasone seems to induce parturition causing crucial pathologies, which results in important and risky changes in newborns' life. Incomplete cervical dilatation and continued ineffective uterine contractions could be a major factor of newborn losses because of placental separation and cessation of blood supply.

Antiprogestins, a new form of endocrine therapy for human breast cancer.

The antitumor, endocrine, hematological, biochemical, and side effects of chronic second-line treatment with the antiprogestin mifepristone (RU) 486) were investigated in 11 postmenopausal patients with metastatic breast cancer. We observed one objective response, 6 instances of short-term stable disease, and 4 instances of progressive disease. Mean plasma concentrations of adrenocorticotropic hormone (P less than 0.05), cortisol (P less than 0.001), androstenedione (P less than 0.01), and estradiol (P less than 0.002) increased significantly during treatment accompanied by a slight decrease of sex hormone binding globulin levels, while basal and stimulated gonadotropin levels did not change significantly. The increased basal cortisol levels could not be further stimulated by synacthen, nor suppressed by 1 mg of dexamethasone. Plasma estradiol concentrations were significantly correlated with both androstenedione (P less than 0.05) and cortisol levels (P less than 0.01). The percentage of eosinophilic white blood cells (P less than 0.02) and mean plasma creatinine concentration (P less than 0.05) increased significantly. Side effects frequently occurred during long-term treatment and appeared to be caused mainly by the antiglucocorticoid properties of the drug. It is concluded that antiprogestins form a new treatment modality in the endocrine treatment of human breast cancer. New antiprogestins with less antiglucocorticoid side effects might be especially of value as an adjunct to antiestrogenic treatment in view of our finding that combined antiestrogenic and antiprogestational treatment caused additive growth-inhibitory effects in rat mammary tumors.

Changes in ovaries and uterus after aglepristone administration in the third week of luteal phase of non-pregnant bitches.

OBJECTIVE: The mechanism of aglepristone action in the placentation time in the bitch remains unclear. The aim of this study was to describe the mechanism by which aglepristone influences ovaries and uterus and to measure the levels of steroid sex hormones in non-pregnant bitches. MATERIALS AND METHODS: Fourteen bitches assigned to a study (n=9) and control (n=5) group were given aglepristone and saline solution, respectively, on the 19th and 20th day after LH peak. On the 26th day after LH peak an ovariohysterectomy was performed. Blood samples were screened for estradiol and progesterone concentrations. Ovaries and uterine horns and bodies were isolated for histological and morphometrical diagnosis and immunohistochemistry analysis of α-estrogen and progesterone receptor expression. RESULTS: A decrease of progesterone (p<0.01) and no differences in total estrogen level in the study group were observed. There were no significant differences either in the histomorphometry or α-estrogen and progesterone receptors expression in ovaries. Increase in expression of progesterone receptors in endometrium without surface epithelium of horns (p<0.05), endometrial surface epithelium (p<0.05), myometrium of uterine body (p<0.01) and estrogen receptors in endometrium without surface epithelium of horns (p<0.05) was observed. Elevated estrogen receptors probably increased sensitivity of tissues to estrogens in the bloodstream and led to notable inflammation, haemorrhages, and hyperplasia in endometrium with mononuclear immune cell infiltration. The myometrium of horns and endometrium of uterine body of study bitches were significantly thicker than in the control group (p<0.05 and p<0.01). Furthermore myometrium of uterine body was thicker than myometrium of horns (p<0.001) and expression of progesterone receptors was higher in uterine body (p<0.01). No differences were observed between endometrium of horns and body within groups. CONCLUSION: To the knowledge of the authors this is the first study, which describes the inflammatory effect developing in uterus in response to aglepristone administration, and attempts to elucidate its mechanisms.

A case-control study to evaluate the risk of congenital anomalies as a result of allylestrenol therapy during pregnancy.

The 1980-1984 data base of the Hungarian Case Control Surveillance System for Congenital Anomalies was used to evaluate possible teratogenicity of allylestrenol therapy during pregnancy. In an initial global analysis, three of the 24 congenital anomaly groups studied (ie, clubfoot, multiple anomalies, and hypospadias) had a significantly higher incidence of allylestrenol use. A case control analysis, however, excluded a pathogenetic role for allylestrenol in the etiology of clubfoot and multiple congenital anomalies. A greater use of allylestrenol in the first global evaluation was explained by a higher incidence in these groups of impending miscarriage and preterm labor, which are indications for allylestrenol therapy. The case control analysis did indicate a greater use of allylestrenol in the hypospadias group, but this difference was not statistically significant in the critical period for induction of hypospadias (ie, the third and fourth months of gestation). The causal role of subfertility in the etiology of hypospadias was an indirect factor, explaining the greater use of allylestrenol during pregnancy in this group; in Hungary, women with a history of infertility frequently receive hormonal support in the first trimester. The authors conclude that the data analyzed do not indicate any teratogenic effects of the use of allylestrenol during pregnancy.

Early pregnancy termination with antiprogestins: a comparative clinical study of RU 486 given in two dose regimens and Epostane.

Mifepristone, (RU 486, Roussel Uclaf, Romainville, France), a progesterone (P) receptor blocking agent, and Epostane, (WIN 32,729, Sterling-Winthrop, Guildford, United Kingdom), a P synthesis inhibitor, were compared for their ability to terminate early human pregnancy. Seventy-eight healthy women, with a gestational length of less than 49 days from the last menstrual period and who requested termination of pregnancy, were recruited to the study. The patients were randomly allocated to three treatment regimens: (1) Mifepristone 25 mg bid for 7 days; (2) Mifepristone 50 mg bid for 7 days; and (3) Epostane 200 mg qid for 7 days. The results of the study confirmed that both compounds are potent abortifacients in early human pregnancy. No difference in efficacy was seen between the two dose regimens of Mifepristone, which both resulted in 61% complete abortions. Seventy-three percent aborted completely in the Epostane group. Subjective side effects, especially nausea, were more common in the women treated with Epostane, but no serious side effects were seen.

PIP: Two contragestational agents, Mifepristone and Epostane, were compared in 78 pregnancy terminations at 49 days or less gestation. Mifepristone (RU 486, Roussel Uclaf, Romainville, France) is a steroid that antagonizes progesterone receptor binding in the decidua. It was taken twice daily at 25 or 50 mg for 7 days. Epostane (WIN 32,729, Sterling-Winthrop, Guildford, United Kingdom) is a progesterone synthesis inhibitor at 3B-hydroxy steroid dehydrogenase level acting on the endometrium. Women took 200 mg 4 times daily for 7 days. The criteria for complete abortion were bleeding and cervical dilatation with passage of products of gestation by Day 7, return to normal uterine size by Day 14 with hCG less than 10% of initial level. 61% of both Mifepristone groups aborted completely, and 83% of the women who completed the Epostane schedule did so. 3 women abandoned the Epostane regimen because of nausea. Only 2 incomplete abortions occurred in the Mifepristone group; the rest failed to abort and had vacuum aspiration on Day 7. Variations in blood chemistries and analysis of progesterone, hCG, estradiol and cortisol are discussed. The week-long treatment with Epostane is probably necessary, but dose and length of treatment with Mifepristone could be manipulated to get a more rapid response. Although the patients were satisfied with these regimens, they were not as efficient as vacuum aspiration or prostaglandin suppositories. Possibly both antiprogestins and even prostaglandins could be combined for better results.

Antiprogestins and iatrogenic glucocorticoid resistance.

The antiglucocorticoid action of the antiprogestin RU 38486 has interfered with its successful clinical application in long-term treatment. Several new antiprogestins (Org 31710, Org 31806 and ZK 98299) have recently been developed with the aim to eliminate this side-effect. We have used a human lymphocyte proliferation assay to estimate the antiglucocorticoid potency of RU 38486 and the newer antiprogestins. In this assay 100 nmol/L RU 38486 shifted the dexamethasone inhibition curve by at least one order of magnitude. The other antiprogestins showed no effect at 100 nmol/L. RU 38486 (30 nmol/L) was able to antagonize 1000 nmol/L dexamethasone. The other antiprogestins showed only slight effects even at 1000 nmol/L. We conclude that the new antiprogestins have antiglucocorticoid effects that are one to two orders of magnitude lower than that of RU 38486. This may make them more suitable than RU 38486 for application in long-term antiprogestin treatment.

The antiprogestational agent RU 486 as an abortifacient in early human pregnancy: a comparison of three dose regimens.

Three different regimens of RU 486, a progesterone receptor blocking agent, were compared for their ability to terminate early human pregnancy. One-hundred-fifty-three healthy women with a gestational length less than 49 days from the last menstrual period were recruited to the study and randomly allocated to one of three treatment regimens: 1) RU 486 10 mg x 2 for seven days; 2) RU 486 25 mg x 2 for seven days; or 3) RU 486 50 mg x 2 for seven days. No significant difference in efficacy was seen between the three dose regimens. Treatment with 10 mg x 2 x VII resulted in 73 per cent complete abortions, 25 mg x 2 x VII in 66 per cent and 50 mg x 2 x VII in 64 per cent complete abortions. Response to treatment, measured as reported onset of bleeding and passage of products of conception, however, occurred significantly later on the 10 mg x 2 regimen than on the other two dose regimens. In each treatment group, women who subsequently aborted completely had significantly lower pretreatment levels of hCG than women with incomplete abortion or continuing pregnancy. The treatment was well tolerated by the women and except for one woman who experienced a profound bleeding necessitating a blood transfusion, no serious side effects were seen.

Uses of RU 486 for contragestion: an update.

PIP: The effects of a single dose of 600 mg of RU 486 used as a contragestive agent were analyzed in 102 women. The RU 486 was administered the day before the expected menstrual period. 6 pregnancies continued after RU 486 administration, yielding a 17% actural failure rate and a 6% global failure rate. The actual failure rate was comparable to that achieved by high-dose estrogen administration for postcoital contraception. RU 486 has several advantages over high-dose estrogen as a postcoital contraceptive, however. It does not have to be given as an emergency treatment, it is effective after several acts of intercourse, it has no apparent side effects, and it causes no post-treatment menstrual disturbances. At present, ways of improving the efficacy of RU 486 are being investigated, including alternative routes of administration or the combination of RU 486 with oxytocic agents such as prostaglandin. Such combinations should be more effective than RU 486 alone when used later in pregnancy, after 41 days of amenorrhea. At this point, RU 486 can be recommended as a contragestive agent at the end of the luteal phase and at the very beginning of pregnancy, up to 15 days after a missed menstrual period. RU 486 should be prescribed only where there are adequate medical facilities and should not be regarded as a "do-it-yourself" substitute for vacuum aspiration because of the very heavy bleeding that can occur.^ieng

Safety, tolerability, and pharmacokinetics of a novel, selective antiprogestagen (Org 31710) in healthy male volunteers.

The safety and tolerability as well as pharmacokinetics of a new selective antiprogestagen, Org 31710, were studied after oral administration of single doses of 10, 25, 50, or 75 mg to 24 healthy male volunteers. Per dose-group, five subjects received active and one subject received placebo treatment. In subjects receiving 75 mg, the effects of Org 31710 on serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were also studied. No adverse or seriously adverse events were observed. All doses of Org 31710 were well tolerated. Characterization of the Org 31710 plasma pharmacokinetics revealed a statistically significant deviation from linearity: the dose normalized Cmax (nCmax) and dose normalized area under the curve (nAUC) values were significantly lower for the higher dosages (p < 0.05). Furthermore, tmax tended to decrease (from 1.6 to 0.9 h), whereas the elimination half-life (t1/2) tended to increase (from on average 45 to 57 h) with increasing dose. Org 31710 did not have any effect on serum levels of FSH, LH, and testosterone. In conclusion, Org 31710 appears to be a safe and well-tolerated compound in the dosage range studied.

PIP: The pharmacokinetics, safety, and tolerability of a new selective antiprogestagen--Org 31710--were investigated in 24 healthy Dutch men. Single oral doses of 10, 25, 50, or 75 mg were administered. In each dose group, 5 subjects received Org 31710 and 1 was given placebo. All dosages were well tolerated and no clinically relevant adverse events were recorded. Plasma pharmacokinetic characterizations revealed a statistically significant deviation from linearity after single doses of 10-75 mg of Org 31710. The dose-normalized maximum plasma concentrations was significantly higher in the 10 mg group and significantly lower in the 75 mg group compared with the 25 mg and 50 mg groups. Mean values of the normalized area under the plasma concentration time curve at 10 and 25 mg were significantly higher than values at higher dosages. The time to reach maximum plasma concentration decreased from 1.6 to 0.9 hours with increasing Org 31710 dose, while the elimination half-life increased from 45 to 57 hours. Serum levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were not affected by a single dose of 75 mg of Org 31710. These findings demonstrate the safety and tolerability of the novel antiprogestagen Org 31710. The low antiglucocorticoid activity of Org 31710 represents a potential advantage over RU 486.

Pregnancy termination with a high and medium dosage regimen of RU 486.

Sixty healthy pregnant women who wished to terminate their pregnancy and who were no more than 49 days pregnant were treated with one of three different dose regimens of a synthetic progesterone receptor blocker, RU 486. Serum cortisol was measured to determine the antiglucocorticoid effects of this compound. The high dose but shorter treatment regimen (400 mg/day RU 486 X 4 days or 200 mg/day X 4 days) was associated with a high (greater than 80%) rate of side effects, especially nausea, vomiting, weakness and heavy bleeding and a low rate of success (10%). A group of 50 subjects received the medium dose but longer treatment regimen (100 mg/day X 7 days). This group had less side effects (40-60%) and a 72.3% success rate of complete abortion. The AM cortisol values were significantly elevated in all treatment groups but higher in those receiving the high dose. These values returned to normal one week following cessation of treatment. Medium dose but longer duration (100 mg/day X 7 days) of RU 486 treatment is associated with a higher success rate and less side effects than higher dose therapy administered over a shorter period. There were no predictive indices to determine which subjects would respond successfully. The reason for the failure of the drug in 30% of the subjects on the medium dose is not known at this time.

Interruption of early pregnancy by an anti-progestational compound, RU 486.

RU 38-486 (17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)estra-4,9-dien-3-one), an antiprogestational compound, was given to 33 women seeking termination of pregnancy. The patients were divided into two groups, 24 patients in group I with amenorrhoea up to 7 6/7 wk = 55 days, and 9 patients in group II with 8-10 wk amenorrhoea. The patients received 200 mg orally per day for 4 days. The start, duration and amount of bleeding were determined for 14 days. beta-HCG, plasma progesterone, estradiol and cortisol were determined at day 0 and day 7. All patients started to bleed during treatment. The frequency of complete abortion was 79% (19 out of 24 patients) in group I. In group II 33% (3 out of 9 patients) had a complete abortion. Most of the patients experienced only minor side-effects in terms of mild uterine pain and bleeding as in a spontaneous abortion. However, 2 patients in group II with 8 and 9 2/7 wk amenorrhoea suffered from heavy bleeding, requiring blood transfusion and curettage. In the patients with complete abortion, beta-HCG, estradiol and progesterone decreased significantly within 1 week. Cortisol concentrations remained within the normal range at day 0 and day 7. Treatment with RU 486 provides an acceptable method of early abortion, especially in women who refuse operative treatment and prefer a 'spontaneous abortion'. In 22 women RU 486 was administered from day 24 to day 27 of the menstrual cycle as a late 'morning-after pill' in the same dosage. All women except one started to bleed before day 28 and observed a normal menstrual period. One woman stayed amenorrhoeic for 2 months; she was not pregnant but apparently had an anovulatory cycle with a low progesterone level.

Effects of aglépristone, a progesterone receptor antagonist, administered during the early luteal phase in non-pregnant bitches.

Aglépristone, a progesterone receptor antagonist, was administered to six non-pregnant bitches in the early luteal phase in order to determine its effects on the duration of the luteal phase, the interestrous interval, and plasma concentrations of progesterone and prolactin. Aglépristone was administered subcutaneously once daily on two consecutive days in a dose of 10 mg/kg body weight, beginning 12 +/- 1 days after ovulation. Blood samples were collected before, during, and after administration of aglépristone for determination of plasma progesterone and prolactin concentrations. The differences in mean plasma concentration of progesterone and of prolactin before, during, and after treatment were not significant. Also, the duration of the luteal phase in the six treated bitches (72 +/- 6 days) did not differ significantly from that in untreated control dogs (74 +/- 4 days ). However, the intervals during which plasma progesterone concentration exceeded 64 and 32 nmol/l were significantly shorter in the six treated bitches than in untreated control dogs. The interestrous interval was significantly shorter in beagle bitches treated with aglépristone (158 +/- 16 days) than in the same group prior to treatment (200 +/- 5 days ). It is concluded that administration of aglépristone during the early luteal phase in the non-pregnant bitch affects progesterone secretion, but not sufficiently to shorten the luteal phase. The shortening of the interestrous interval suggests that aglépristone administered in the early luteal phase influences the hypothalamic-pituitary-ovarian axis.

The antiprogestin RU486 in advanced breast cancer: preliminary clinical trial.

Twenty-two oophorectomized or postmenopausal women with metastatic breast cancer resistant to several medical therapies (tamoxifen, or other endocrine therapy, and chemotherapy) were treated in a first trial with 200 mg per day of RU486 for 1 to 3 months. The long-term tolerance was good but there was a moderate decrease in plasma potassium. Plasma cortisol was increased 2-fold without clinical hypo- or hypercorticism. Twelve patients had a partial response or a stabilization of secondary deposits for 6 weeks but the response rate at 3 months was 18%. When available, estrogen and progesterone receptor levels were positive in these patients. This preliminary trial shows for the first time that the antiprogestin RU486 is well tolerated for medium term treatment. It suggests that it might be active on advanced breast cancer becoming resistant to tamoxifen.