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.

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.

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.

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.

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.

Progesterone and progesterone receptor modulators in the management of symptomatic uterine fibroids.

The majority of symptomatic uterine fibroids are currently treated by surgical interventions (myomectomy or hysterectomy) or radiological treatments (uterine artery embolisation or focussed ultrasound surgery). None of these treatments is a panacea, and what is conspicuous is the lack of an effective long-term medical therapy for a disorder so common among women of reproductive age. It has been known for some time that progesterone and its receptors enhance proliferative activity in fibroids and this has raised the possibility that anti-progestins and (PRMs) could be useful in the medical management of fibroids. Some of the compounds which have produced promising results in recent clinical trials or research studies include mifepristone, CDB-4124 (telapristone), CP-8947, J-867 (asoprisnil) and CDB-2914 (ulipristal acetate or UA). UA has recently completed Phase III clinical trials with very encouraging results, and has now acquired a licence for clinical use in Europe. While considerable research has yet to be done on the long-term safety and efficacy of UA there is nevertheless good reason for optimism on the emergence of effective medical therapy in the form of UA and possibly other PRMs.

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.

Prevention of pregnancy in cats using aglepristone on days 5 and 6 after mating.

The aim of this study was to test for the efficacy of aglepristone treatment for prevention of early pregnancy in the cat. Eleven cats (Gr. 1) were treated with 10 mg/kg aglepristone on days 5 and 6 after mating, 17 cats (Gr. 2) were used as untreated controls. Blood samples for progesterone (P4) determination were collected from 6 cats of Gr. 1 and 9 cats of Gr. 2, respectively. Ultrasound examination on day 25 revealed no pregnancy in any of the treated cats. In both groups, P4 concentrations increased from day 5 (before treatment) to day 20 (P < 0.01). In Gr. 1, the interval between aglepristone treatment and the subsequent estrus ranged from 5-299 d [18.5 (5.2) d]. Mean interestrus interval was 205 +/- 72 d in Gr. 2. Mean duration of subsequent estrus was not different to duration of estrus before treatment in Gr. 1 and in Gr. 2, respectively. Mean time between treatment and next pregnancy was 56.4 (4.7) d, ranging from 5-325 d. Pregnancy rates after the next estrus following treatment were 64 and 82% after the first and second estrus, respectively. No major treatment-related side effects were observed. In conclusion, treatment was found to be highly effective for prevention of early pregnancy.

Aglepristone (RU534) administration to non-pregnant bitches in the mid-luteal phase induces early luteal regression.

The effect of the antiprogestagen aglepristone (10 mg/kg bw), administered at days 29 and 30 following the estimated day of LH surge (day 0), on corpora lutea (CL) function was examined during the diestrus phase of non-pregnant bitches. Aglepristone shortened (P < 0.01) the luteal phase and complete luteolysis (progesterone <2 ng/mL) was observed at days 40.8 +/- 3.5 and 71.5 +/- 4.6 (means +/- SD; n = 9/group) in treated and control bitches, respectively. Peripheral estradiol-17beta concentrations declined from 91.5 +/- 14.3 pg/mL at day 9 to 50 pg/mL at day 18, remaining at approximately the same levels thereafter in both treated and control bitches. Intraluteal in vitro synthesis of progesterone and estradiol-17beta released by CL explanted at day 38 from control bitches (511.9 +/- 285.6 and 40.7 +/- 17.2 pg/mg protein, respectively) did not differ from that of treated. From day 38, intraovarian hemodynamic variables (arterial blood flow, systolic peak, and end-diastolic velocities), monitored by color-coded and pulsed Doppler, decreased more steeply (P < 0.01) in aglepristone-treated (n = 4) than in control (n = 4) bitches, whereas the resistance index increased (P < 0.01) in treated animals. All the blood flow parameters were undetectable at 60 +/- 3.6 and 68 +/- 2.0 days (medians +/- SD) after LH peak in treated and control bitches, respectively. In conclusion, aglepristone administration to dogs during the mid-luteal phase markedly accelerates the luteolytic process which is accompanied by a parallel decline in ovarian blood flow supply with a shift from approximately 8 to 10 days.

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.

Safety and efficacy of mid-term pregnancy termination using aglepristone in dogs.

OBJECTIVES: To investigate effects and side effects of aglepristone in terminating pregnancy in bitches. METHODS: Twenty-two bitches were treated in mid-pregnancy with subcutaneous injections of aglepristone at a total dose of 20 mg/kg. Short-term follow-up (one to two weeks after treatment) included clinical examination and abdominal ultrasonography in 18 of the dogs. Long-term telephone follow-up was recorded for all 22 dogs. RESULTS: Pregnancy was terminated in 21 bitches (95 per cent). Signs of abortion occurred one to eight days after treatment. Vaginal discharge was evident in 17 (77 per cent) dogs. Obvious signs of parturition were seen in nine (41 per cent) dogs. Eight dogs (36 per cent) developed anorexia, and in two (9 per cent) of the dogs a local reaction at the injection site was evident. Two dogs developed pyometra two and four years after treatment, respectively. CLINICAL SIGNIFICANCE: Aglepristone, when administered in mid-gestation, is effective in terminating pregnancy. Side effects are few and transient.

The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata.

BACKGROUND: Asoprisnil is a selective progesterone receptor modulator with mixed progesterone agonist/antagonist activity which controls uterine bleeding via an endometrial effect. This study examined full-thickness endometrial, leiomyoma and myometrial morphology in hysterectomy specimens from patients with uterine leiomyomata, after treatment with asoprisnil for 3 months. METHODS: In this double-blind, randomized, placebo-controlled study, 33 subjects with uterine leiomyomata were randomized to receive asoprisnil 10, 25 mg or placebo for an average of 95 days prior to hysterectomy. Samples of endometrium, myometrium and leiomyoma tissue were subjected to systematic morphological assessment with quantification of mitotic activity. RESULTS: In patients treated with 10 or 25 mg asoprisnil, a unique pattern called 'non-physiologic secretory effect' was evident in endometrium, recognizable through partially developed secretory glandular appearances and stromal changes. Endometrial thickness was decreased, and there were low levels of mitotic activity in endometrial glands and stroma. Unusual thick-walled muscular arterioles and prominent aggregations of thin-walled vessels were present in endometrial stroma, but not in myometrium or non-endometrial vascular beds. Mitotic activity was decreased in leiomyomata. CONCLUSIONS: Asoprisnil induces unique morphological changes and is associated with low levels of glandular and stromal proliferation in endometrium, and in leiomyomata. These changes are likely to contribute to the amenorrhoea experienced after exposure to the medication.

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.

Treatment of fibroadenomatous hyperplasia in cats with aglépristone.

Fibroadenomatous hyperplasia (FAH) is characterized by a rapid proliferation of mammary stroma and duct epithelium of 1 or more glands and predominantly affects younger female cats. Endogenous progesterone and exogenous progestogens play an important role in the genesis of FAH. The presence of progesterone receptors in fibroadenomatous tissue allows for targeted endocrine therapy with progesterone receptor blockers. We report on 22 young cats with FAH, none of which had responded to the withdrawal of progestogens or ovariectomy. The common signs were tachycardia (11 cats); skin ulceration, painful mammary glands, or both (16 cats); lethargy (8 cats); and anorexia (4 cats). The cats were treated with subcutaneous injections of the progesterone receptor blocker aglépristone on 1 (7 cats, 20 mg/kg) or 2 consecutive days (15 cats, 10 mg/kg/d) once weekly. All but 1 cat responded with a complete and lasting remission of signs after 1-4 weeks of treatment. Two cats had a short-term skin irritation at the site of the aglépristone injection. Two pregnant cats with FAH aborted after treatment with aglépristone and subsequently developed endometritis. In conclusion, the results of this study demonstrate that FAH in cats can be treated successfully with the progesterone receptor blocker aglépristone.

Improving cycle control in progestogen-only contraceptive pill users by intermittent treatment with a new anti-progestogen.

BACKGROUND: The safety and efficacy of the anti-progestogen Org 31710 in improving cycle control in healthy women using the desogestrel progestogen-only pill was investigated in this randomized, double-blind, placebo-controlled study. METHODS: A total of 103 women using the 75 micro g desogestrel progestogen-only pill daily also received either 150 mg Org 31710 or placebo once every 28 days, starting on day 1, for a duration of 4-7 treatment cycles. RESULTS: The percentage of women with bleeding or spotting (B/S) every day in the placebo group was on average 30% during the whole treatment period and no days without reported B/S occurred. In contrast, a cyclic pattern was observed for the Org 31710 group; a peak incidence of B/S was observed on day 3 or 4 of each cycle, followed by a sharp decrease on cycle days 9-15. Compared with controls, less subjects in the Org 31710 group reported irregular, frequent or prolonged bleeding. These differences were clearly observed in the initial cycles, but were somewhat less pronounced during the later cycles of the treatment period. A relatively high incidence of B/S episodes starting in the second section of the cycle was also observed. CONCLUSION: The addition of Org 31710 once a month improved cycle control in women using daily treatment with 75 micro g desogestrel.

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.

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.